File - MedicalSurveys

Report
Developed in association with the
European Thoracic Oncology Platform
2014 ASCO Annual Meeting
30 May – 3 June 2014
Chicago, USA
Supported by Lilly and Company.
Lilly and Company has not influenced the content of this publication
Letter from Prof Rolf Stahel
Dear Colleagues
It is my pleasure to present this ETOP slide set which has been designed to highlight and
summarise key findings in thoracic cancers from the major congresses in 2014. This slide
set specifically focuses on the American Society of Clinical Oncology 50th Annual Meeting
and is available in 4 languages – English, French, Italian and Japanese.
The area of clinical research in oncology is a challenging and ever changing environment.
Within this environment we all value access to scientific data and research which helps to
educate and inspire further advancements in our roles as scientists, clinicians and
educators. I hope you find this review of the latest developments in thoracic cancers of
benefit to you in your practice. If you would like to share your thoughts with us we would
welcome your comments. Please send any correspondence to [email protected]
I would like to thank our ETOP members Drs Enriqueta Felip, Francoise Mornex, Solange
Peters and Martin Reck for their roles as Editors – for prioritising abstracts and reviewing
slide content – also Dr Serena Ricciardi for overseeing translation to Italian. The slide set
you see before you would not be possible without their commitment and hard work.
And finally, we are also very grateful to Lilly Oncology for their financial, administerial and
logistical support in the realisation of this complex yet rewarding activity.
Yours sincerely,
Rolf Stahel
President, ETOP Foundation Council
ETOP Medical Oncology Slide Deck Editors 2014
Focus: biomarkers (all stages)
Dr Enriqueta Felip
Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
Focus: early and locally advanced NSCLC (stage I–III)
Dr Francoise Mornex
Department of Radiation Oncology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France
Focus: advanced NSCLC (not radically treatable stage III & stage IV)
Dr Solange Peters
Multidisciplinary Oncology Center, Lausanne Cancer Center, Lausanne, Switzerland
Focus: other malignancies, SCLC, mesothelioma, rare tumours
Dr Martin Reck
Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany
Contents
• Biomarkers
• Early stage and locally advanced NSCLC – Stages I, II and III
• Advanced NSCLC – Not radically treatable stage III and stage IV
– 1st line
– Maintenance
– Later lines
• Other malignancies
– SCLC and mesothelioma
– Rare tumours
Biomarkers
7550: Serum biomarker analysis of WJOG4107: A randomized phase II trial of
adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA
non-small cell lung cancer (NSCLC) – Mitsudomi T et al
• Study objective
– To identify biomarkers associated with outcome to long-term treatment with S-1
or cisplatin+S-1 after resection of stage II–IIIA NSCLC
• Study design
– Serum biomarker analysis of 16 growth factors and 27 cytokines from 197 of
200 patients from the WJOG4107 study
– Patients treated with S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year)
vs cisplatin (60 mg/m2 d1) + S-1 (80 mg/m2 for 2 weeks) q3w for 4 cycles
• Key results
– HGF, GCSF and leptin showed moderate association with prognosis (HGF,
p=0.0576; GCSF, p=0.0579; leptin, p=0.074)
– Patients with lower serum HGF had a significantly favourable prognosis than
those with higher HGF levels in postoperative long-term S-1 therapy (p=0.0072)
(see next slide)
• Conclusion
– Low serum HGF level may define a patient subset who would benefit from
postoperative long-term S-1 therapy
Mitsudomi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7550)
7550: Serum biomarker analysis of WJOG4107: A randomized phase II trial of
adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA
non-small cell lung cancer (NSCLC) – Mitsudomi T et al
• Key results
Disease-free survival with S-1 + cisplatin
Disease-free survival with S-1 alone
1.0
0.6
0.4
HGF=High
56%
0.2
p=0.0072
0
0
200
400
HGF=Low
56%
0.8
Survival rate
0.8
Survival rate
1.0
HGF=Low
77%
0.6
0.4
HGF=High
61%
0.2
p=0.981
0
600
800
Time (days)
1000 1200 1400
0
200
400
600
800
1000 1200 1400
Time (days)
Mitsudomi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7550)
8057: Molecular profiling of non-small cell lung cancer by histologic subtype
– Peters S et al
• Study objective
– To profile NSCLC by histological subtype
• Study design
– Retrospective analysis of over 6700 NSCLC cases for potential cancer-related genes and
pathways through sequencing, protein expression, gene amplification/rearrangement
(CISH or FISH) and/or RNA fragment analysis
• Key results
– Patients were grouped into cohorts according to histological subtype: adenocarcinoma
(ADC; n=4287), squamous cell carcinoma (SCC; n=1280), adenosquamous carcinoma
(ASQ; n=30), lepidic predominant adenocarcinoma (LPA; n=94) and large cell carcinoma
(LCC; n=153)
– Tumour profiling by histological subtype is shown on the next slide
• ADC tumours had significantly more cMET overexpression (p<0.0001) and
amplification (p=0.0223), more high ER expression (p<0.0001) than SCC tumours
• ADC tumours also had more ALK fusions (p=0.0051) and ROS1 rearrangements
(p=0.0331), higher BRAF (p=0.0218) and EGFR mutations (p<0.0001) prevalence than
SCC tumours
• ADCs (p<0.0001) and LPAs (p=0.0028) had significantly more KRAS mutations than
SCCs
– Similar significant alterations between ADCs compared with SCCs and LCCs (except for
ALK, BRAF and ROS1) were observed
• Conclusion
– These data can help to identify new predictive biomarkers and explore potential innovative
treatment strategies
Peters et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8057)
8057: Molecular profiling of non-small cell lung cancer by histologic subtype
– Peters S et al
Tumour profiling by histological subtype
ADC, adenocarcinoma; SCC, squamous cell carcinoma; ASQ,
adenosquamous carcinoma; LPA. lepidic predominant
adenocarcinoma; LCC, large cell carcinoma
Peters et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8057)
8066: PD-L1 expression and survival in patients with non-small cell lung cancer
(NSCLC) in Korea – Sun J-M et al
• Study objective
– To investigate the prognostic impact of PD-L1 expression among patients with NSCLC
• Study design
– Correlation of expression of PD-L1 by IHC with OS among 1070 patients with NSCLC
• Key results
– Median (range) age 63 (21–86) years; 67% male; 62% adenocarcinoma; 28% SCC; 10%
large cell carcinoma or other; 75% stage I/II; 6.4% strong PD-L1 positivity; 38.3% weak
positivity
– Higher incidence of PD-L1 positivity was observed in males, older patients, smokers, those
with SCC and more advanced stage disease (p<0.001)
– PD-L1 positivity was associated with worse OS, for strong positive vs negative, respectively
• 5-year OS rate overall of 51% (95% CI 39, 63) vs 73% (69, 76) (HRa 1.57; p=0.02)
• 5-year OS in adenocarcinoma 53% (95% CI 36, 69) vs 77% (72, 82) (HRa 1.86; p=0.02)
• Conclusion
– PD-L1 may be a negative prognostic factor among non-SCC NSCLC, particularly
adenocarcinoma
aAdjusted
for age, sex, smoking status, histology, stage, PS with the
PD-L1 negative group as the reference; PD-L1, programmed cell death
ligand-1; SCC, squamous cell carcinoma
Sun et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8066)
8075: Clinicopathologic features of lung cancer patients harboring de novo
EGFR T790M mutation – Lee YJ et al
• Study objective
– To evaluate clinico-pathological features of lung cancer with de novo EGFR
T790M mutations
• Study design
– Genotyping for EGFR T790M mutation of pretreatment tissue from 124
advanced NSCLC patients with EGFR mutations (exon 19 deletion and exon 21
L858R)
• Key results
– 25% (31/124) patients had T790M mutation
– TTP after EGFR TKI was shorter among patients with T790M mutation
compared with patients without (6.3 vs 11.5 months, respectively; p<0.001)
– The T790M mutation frequency at which the risk of progression to EGFR TKI
begins to increase was estimated to be 3.2%
• Conclusion
– Lung cancer patients with 3.2% or more of de novo T790M mutation frequency
showed decreased efficacy to EGFR TKI
Lee et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8075)
8081: EGFR mutation status in cerebrospinal fluid of NSCLC patients who
developed leptomeningeal metastasis after EGFR-TKI treatment – Zhao J et al
• Study objective
– To investigate EGFR mutation status in CSF of NSCLC patients who developed
leptomeningeal metastasis after initial response to EGFR TKI
• Study design
– Droplet digital PCR was used to detect EGFR mutation in CSF samples from
7 patients with NSCLC
• Key results
– EGFR-sensitive mutations were detected in all CSF samples
• Conclusions
– CSF remained positive for EGFR mutations dominant by sensitive mutations
only, even though the plasma was either negative for EGFR mutations or
carried TKI-resistant T790M mutation
– This is supportive of the protection of EGFR mutation-positive tumour cells
within leptomeningeal space from the exposure to current EGFR TKIs
Zhao et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8081)
8082: Clinical significance of TILs subtypes in non-small cell lung cancer –
Schalper KA et al
• Study objective
– To investigate the impact of tumour infiltrating lymphocytes (TILs) on clinico-pathological
characteristics and survival in patients with NSCLC
• Study design
– Quantitative fluorescence was used to measure levels of CD3, CD8 and CD20 in
552 stage I–IV NSCLC in two tissue microarrays (YTMA79, n=202; YTMA140, n=350)
– Multiplexed immunofluorescence was used to simultaneously measure TIL subtypes in
different tumour compartments
• Key results
– CD3, CD8 and CD20 signals showed a positive non-linear relationship (R=0.3–0.7;
p<0.001) in both NSCLC collections
– CD3 levels were not correlated with age, gender, smoking, tumour size, stage and
histology
– High CD3 and CD8 were significantly associated with longer survival in YTMA79 (p=0.009
for CD3 and p=0.004 for CD8) and YTMA140 (p=0.041 for CD3 and p=0.002 for CD8)
• Conclusion
– Increased CD3 and CD8 positive TILs are independent prognostic factors in NSCLC
Schalper et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8082)
Early and locally advanced NSCLC
Stages I, II and III
7514: SELECT: A multicenter phase II trial of adjuvant erlotinib in resected
early-stage EGFR mutation-positive NSCLC – Pennell NA et al
• Study objective
– To investigate the efficacy of adjuvant erlotinib in EGFR-mutant NSCLC
• Study design
– Phase II study of patients treated with erlotinib 150 mg/day for 2 years after completion of
standard adjuvant CT and/or radiotherapy
– Primary endpoint: DFS at 2 years; secondary endpoints: safety/tolerability and OS
• Key results
– 100 patients had a median (range) age of 63 (41–84) years; 77% female; 59% never
smokers; 45% stage I; 27% stage II; 28% stage IIIA; 62% EGFR exon 19 deletion
– 69% of patients completed at least 22 months of treatment although 40% required dose
reduction
– 2-year DFS of 89% (96% for stage I, 78% stage II, 91% stage IIIA) significantly higher
than historical control (p=0.0047); median DFS not yet reached
• Conclusions
– Treatment with 2 years of adjuvant erlotinib for EGFR-mutant NSCLC is feasible
– A randomised trial is planned
Pennell et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7514)
7572: Phase II study of biomarker guided neoadjuvant treatment strategy for
IIIA-N2 non-small cell lung cancer based on EGFR-mutation status
– Zhong W et al
• Study objective
– To evaluate the role of biomarker-guided neoadjuvant treatment strategy in patients with
IIIA-N2 NSCLC stratified by EGFR mutation status
Key patient inclusion criteria
EGFR mutation
Neoadjuvant erlotinib
for 42 days
(n=12)
PD
• Resectable histologically
documented stage IIIA-N2 NSCLC
(n=24)
Primary endpoint
Wild-type EGFR
Neoadjuvant
gemcitabine/carboplatin
for 3 cycles
(n=12)
Secondary endpoints:
• RR
• PFS and OS
PD
Zhong et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7572)
7572: Phase II study of biomarker guided neoadjuvant treatment strategy for
IIIA-N2 non-small cell lung cancer based on EGFR-mutation status
– Zhong W et al
• Key results
– Overall RR was 42%; 58.3% (7/12) for the erlotinib arm with mutant EGFR and 25.0%
(4/12) for the gemcitabine/carboplatin arm with wild-type EGFR (p=0.18)
• Conclusions
– In patients with IIIA-N2 NSCLC, a biomarker-guided neoadjuvant treatment strategy is
feasible
– Erlotinib had a tendency to improve the response, but this did not transfer to a better PFS
or OS in this subgroup
Zhong et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7572)
7557: A randomized phase II trial of concurrent chemoradiation of oral
vinorelbine and two doses of radiotherapy, 60 and 66 Gy, in local-regionally
advanced non-small cell lung cancer (LA-NSCLC) – Hansen O et al
• Study objective
– To investigate two doses of radiotherapy together with vinorelbine in patients with locally
advanced NSCLC
• Study design
– Randomised phase II study of patients treated with navelbine oral 150 mg of vinorelbine
(3 weekly doses for 6–6.5 weeks) with concomitant radiotherapy to 60 Gy (2 Gy x 30,
5 F W) in Arm A or to 66 Gy (2 Gy x 33, 5 F W) in Arm B
– Primary endpoint: Local PFS 9 months after start of radiotherapy; secondary endpoints:
OS and safety
– Comparison with data from historical cohort as control
• Key results
– Local PFS at 9 months was 46% (95% CI 40%, 53%) in Arm A and 56% (95% CI 40%,
63%) compared with 78% (95% CI 68%, 88%) for control
– OS was similar between all three groups
– No haematological grade 4 AEs were observed
• Conclusions:
– Both regimens were well tolerated, but neither met the phase II criteria
– OS was comparable to historical control
Hansen et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7557)
7511^: Phase II study of cetuximab, pemetrexed, cisplatin and concurrent
radiotherapy in patients with locally advanced, unresectable, stage III, nonsquamous, non-small cell lung cancer (NSCLC): Results of the IFCT-0803 trial
– Tredaniel J et al
• Study objective
– To evaluate the benefit of adding cetuximab to radiotherapy+concomitant CT with cisplatin
and pemetrexed in patients with stage III non-squamous NSCLC
• Study design
– Interim analysis of a phase II study in which patients treated with thoracic radiation
(66 Gy) with four cycles of cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) on day 1 q3w
and weekly cetuximab (400 mg/m2 for first week then 250 mg/m2)
– Primary endpoint: disease control rate at week 16
• Key results
– Patients (n=99) had median age of 57 years; 63% male; 60% PS 0; 6% never smokers;
50% stage IIIA; 77% adenocarcinoma
– Disease control rate at 16 weeks was 89.8% (95% CI 83.8, 95.8)
• Conclusion
– This study demonstrated high disease control rate and feasibility of radiation, cisplatin,
pemetrexed and cetuximab combination with a tolerable toxicity profile, especially for
lung parenchyma
^Abstract granted an exception in accordance
with the ASCO Conflict of Interest Policy
Tredaniel et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7511^)
7545: A randomized phase III trial comparing triple weekly usage with weekly
usage of paclitaxel in concurrent chemoradiotherapy for patients with locally
advanced non-small cell lung cancer – Zhu G et al
• Study objective
– To compare triple-weekly usage with weekly usage of paclitaxel in concurrent
chemoradiotherapy for patients with locally advanced NSCLC
• Study design
– Randomised, controlled phase III trial of 60–70 Gy radiotherapy in combination with
paclitaxel (15 mg/m2 triple weekly) or paclitaxel (45 mg/m2 once weekly)
• Key results
– Incidence of radiation-related AEs was generally less with the triple-weekly usage
– Response rate was significantly higher among the patients who received triple-weekly
doses of paclitaxel compared with those who were given once-weekly dosing (87.3% vs
57.7%; p=0.023)
– Similarly, median PFS was higher with triple-weekly dosing (11.0 vs 7.4 months; p=0.039)
• Conclusion
– Triple-weekly usage of paclitaxel is associated with improved tolerability and efficacy over
a once-weekly regimen
Zhu et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7545)
7501: A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus
placebo (P) following complete tumor resection with or without adjuvant
chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) nonsmall cell lung cancer (NSCLC): RADIANT results – Kelly K et al
• Study objective
– To evaluate adjuvant erlotinib vs placebo following complete tumour resection in
patients with stage IB–IIIA NSCLC and EGFR FISH+ or EGFR IHC+
Key patient inclusion
criteria
• Complete resected
NSCLC
• Stage IB–IIIA
• EGFR IHC+/FISH+
• ECOG PS 0–2
(n=973)
Primary endpoint
• Disease-free survival (FAS)
FAS, full analysis set
Erlotinib 150 mg/day
(n=623)
No adjuvant
chemotherapy
≤4 cycles of
platinumbased doublet
R
2:1
Stratification
• Histology, stage, prior adjuvant
CT, EGFR FISH status, smoking
status, country
Placebo
(n=350)
Secondary endpoints
• OS (FAS)
• Disease-free survival and OS (EGFR M+ subset)
Kelly et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7501)
7501: A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus
placebo (P) following complete tumor resection with or without adjuvant
chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) nonsmall cell lung cancer (NSCLC): RADIANT results – Kelly K et al
• Key results
– Adjuvant erlotinib did not prolong disease-free survival
DFS (overall population)
DFS (del19 and L858R)
1.0
1.0
0.8
Placebo
0.6
Placebo (156 events)
Median: 48.2 months
0.4
Erlotinib (254 events)
Median: 50.5 months
0.2
Log-rank test: p=0.3235
HR 0.90 (95% CI 0.74, 1.10)
0.0
0
†Not
6 12 18 24 30 36 42 48 54 60 66
Disease-free survival (months)
significant due to hierarchical testing
Erlotinib
Disease-free survival
(probability)
Disease-free survival
(probability)
Erlotinib
0.8
Placebo
0.6
Placebo (32 events)
Median: 28.5 months
0.4
Erlotinib (39 events)
Median: 46.4 months
0.2
Log-rank test: p=0.0391†
HR 0.61 (95% CI 0.384, 0.981)
0.0
0
6 12 18 24 30 36 42 48 54 60 66
Disease-free survival (months)
Kelly et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7501)
7501: A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus
placebo (P) following complete tumor resection with or without adjuvant
chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) nonsmall cell lung cancer (NSCLC): RADIANT results – Kelly K et al
• Conclusions
– Adjuvant erlotinib did not prolong disease-free survival in patients with early
stage resected EGFR mutation-positive NSCLC
– Survival data immature
– In the subset of patients with exon 19 deletions and L858R mutations, survival
favoured erlotinib
• However, this was not statistically significant due to hierarchical testing
– No DFS survival found at 4 years of follow-up
• Further investigation in EGFR mutation-positive patients is warranted in a
properly conducted randomised dedicated trial in EGFR mutation-positive
NSCLC subpopulation
– The safety profile of erlotinib was consistent with that in advanced disease
Kelly et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7501)
7513: Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC)
patients (pts) with tumors carrying EGFR-sensitizing mutations from the RADIANT trial
– Shepherd FA et al
• Study objective
– To evaluate treatment with erlotinib compared with placebo in patients with
completely resected stage IB–IIIA NSCLC and EGFR IHC+ and/or FISH+
Key patient
inclusion criteria
• Resected stage
IB–IIIA NSCLC
• EGFR IHC+ or
FISH+
(n=973)
Erlotinib 150 mg/day
(n=102)
No adjuvant
chemotherapy
≤4 cycles of
platinumbased doublet
Stratification
• Histology (adenocarcinoma, other)
• Stage (IB, II, IIIA)
• Adjuvant chemotherapy (yes, no)
• Smoking history (never, current/former)
• EGFR FISH (positive, negative/undermined)
• Country
Placebo
(n=59)
Primary endpoint
• DFS
Secondary endpoints
• OS (FAS), disease-free survival and OS
(EGFR M+ subset)
Shepherd et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7513)
7513: Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC)
patients (pts) with tumors carrying EGFR-sensitizing mutations from the RADIANT trial
– Shepherd FA et al
• Key results
– EGFR was mutated in 161 patients (55% exon 19 del, 45% exon 21 L858R)
– There were imbalances in baseline characteristics between the groups
• Erlotinib group had less chemotherapy and lower stage, while placebo group
had smaller tumour size
Median DFS, mo
Erlotinib
Placebo
HR (95% CI)
p-value
46.4
28.5
0.61 (0.38, 0.98)
0.041†
0.60 (0.36, 0.98)
0.041†
1.09 (0.56, 2.16)
0.815‡
Adjusted DFS
Patients relapsed, n (%)
35 (34.3)
31 (52.5)
Brain relapses, %*
40.0
12.9
Bone relapses, %*
14.3
29.0
NR
NR
Median OS, mo
*Percentage calculated using number of patients relapsed as the denominator
†p-values exploratory (Wald test) and not statistically significant
‡log-rank test
Shepherd et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7513)
7513: Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC)
patients (pts) with tumors carrying EGFR-sensitizing mutations from the RADIANT trial
– Shepherd FA et al
• Key results
Erlotinib
Placebo
Any AEs leading to discontinuation, %
30
5.1
Any drug-related AEs leading to discontinuation, %
25
0
AEs leading to dose interruption, %
22
6.8
AE leading to dose reduction, %
22
1.7
Grade ≥3 rash, %
19
0
Grade ≥3 diarrhoea, %
5
0
• Conclusion
– Although not statistically significant, the findings suggest that adjuvant treatment with
erlotinib may prolong DFS in patients with resected NSCLC and EGFR mutations
– Interpretation is limited due to imbalances in stage, use of prior adjuvant chemotherapy
and tumour size
– Small sample size and immature follow-up limit OS interpretation; crossover to EGFR TKI
therapy cannot be determined from the data collected
Shepherd et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7513)
7510: Phase III study of surgery (S) versus definitive concurrent chemoradiotherapy
boost (def ccCRTx-BOx) in patients (pts) with operable (OP+) stage IIIA(N2)/selected IIIb
(sel IIIB) non-small cell lung cancer (NSCLC) following induction (IND) chemotherapy
(CTx) and concurrent CRTx (ESPATUE) – Eberhardt WEE et al
• Study objective
– To determine whether a concurrent chemoradiotherapy boost or surgery in
patients with operable stage III NSCLC following induction chemotherapy
improves survival
Key patient
inclusion criteria
• NSCLC stage
IIIA/B
Induction chemotherapy
Cisplatin/paclitaxel &
concurrent
chemoradiotherapy to
45 Gy (1.5 Gy bid/cc
cisplatin/vinorelbine)
Definitive concurrent
chemoradiotherapy boost
(65/71 Gy)
(n=80)
PD
Surgery
(n=81)
PD
R
• Potentially
resectable
(n=246)
Primary endpoint
• OS
Eberhardt et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7510)
7510: Phase III study of surgery (S) versus definitive concurrent chemoradiotherapy
boost (def ccCRTx-BOx) in patients (pts) with operable (OP+) stage IIIA(N2)/selected IIIb
(sel IIIB) non-small cell lung cancer (NSCLC) following induction (IND) chemotherapy
(CTx) and concurrent CRTx (ESPATUE) – Eberhardt WEE et al
• Key results
– OS did not differ between treatment regimens
OS
Survival probability
1.0
Boost
Surgery
0.8
0.6
0.4
Arm B: 5-year OS=44.2%
Arm A: 5-year OS=40.6%
Log-rank: p=0.31
0.2
0.0
0
• Conclusions
12
24
36
48 60 72
Time (months)
84
96 108 120
– Surgery or definitive concurrent chemoradiotherapy following induction CT are
both valid treatment options, are equally acceptable and their use will depend
on patient preference
Eberhardt et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7510)
7551: The effect of institutional clinical trial enrollment volume on survival of
patients with stage III non-small cell lung cancer treated with chemoradiation: A
report of the Radiation Therapy Oncology Group (RTOG) 0617 – Eaton BR et al
• Study objective
– To examine whether there is an association between institutional clinical trial accrual
volume and outcomes in patients with locally advanced NSCLC receiving
chemoradiation therapy
CRT 60 Gy + concurrent
carboplatin and
paclitaxel +/- cetuximab
Key patient inclusion criteria
• Locally advanced stage IIIA/B
NSCLC
(n=495)
Primary endpoints
R
1:1
PD
Stratification
• Low volume (LVC) vs. high volume (HVC)
centres
CRT 74 Gy + concurrent
carboplatin and
paclitaxel +/- cetuximab
PD
• OS and PFS
• Patients
– Accrual was 1–3 patients in LVC (n=195) and 4–18 patients in HVC (n=300)
Eaton et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7551)
7551: The effect of institutional clinical trial enrollment volume on survival of
patients with stage III non-small cell lung cancer treated with chemoradiation: A
report of the Radiation Therapy Oncology Group (RTOG) 0617 – Eaton BR et al
• Key results
– Both OS and PFS were significantly improved for patients receiving treatment at an HVC
compared with those at LVC (figures)
Median OS
Median PFS
• Conclusion
– Better OS and PFS were observed for patients with locally advanced NSCLC treated at
institutions with higher volume accrual
Eaton et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7551)
7543: Stereotactic body radiotherapy versus lobectomy for operable clinical
stage IA pulmonary adenocarcinoma: Comparison of prospective clinical trials
with propensity score analysis (JCOG1313-A) – Eba J et al
• Study objective
– A combined analysis of two prospective studies to evaluate the effects of
stereotactic body radiotherapy (SBRT) vs lobectomy on survival in patients with
operable early stage NSCLC
JCOG 0403
(n=169)
Key patient inclusion
criteria
SBRT
(n=40)
PD
Lobectomy
(n=219)
PD
• Operable NSCLC
JCOG 0201
(n=811)
• cT1N0M0
• Adenocarcinoma
Primary endpoint
• OS (adjusted with propensity score analysis*)
*Patient factors included age, sex and 2 CT findings – tumour
diameter and consolidation/tumour ratio (CTR)
Eba et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7543)
7543: Stereotactic body radiotherapy versus lobectomy for operable clinical
stage IA pulmonary adenocarcinoma: Comparison of prospective clinical trials
with propensity score analysis (JCOG1313-A) – Eba J et al
• Key results
– Patients in the lobectomy group were younger than in the SBRT group (median age 62 vs
79 years, respectively; p<0.001)
– OS was longer with lobectomy among 21 patients from each group matched for the
propensity score analysis
• Conclusion
– Lobectomy may provide better outcomes than surgery, but no definite conclusions can be
made owing to the small sample size of the SBRT group; further studies are required
Eba et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7543)
7561: Treatment-related deaths after concurrent chemoradiotherapy in locally
advanced non-small cell lung cancer: A meta-analysis of randomized studies
– Zhao J et al
• Study objective
– To compare treatment-related death (TRD) rates between patients treated with concurrent
chemoradiation therapy (cCRT) and non-cCRT among patients with locally advanced
NSCLC
• Study design
– Meta-analysis of randomised controlled trials of any treatment arms of cCRT and
non-cCRT (sequential chemoradiotherapy or radiotherapy alone)
• Key results
– Data from 9 trials (n=1831) included both cCRT and non-cCRT arms
– TRD rates were similar between the two groups; p=0.47
– Neither CRT regimen nor radiation dose fractionation were significantly correlated with
TRDs
• Conclusions
– Compared with sequential chemoradiotherapy or radiotherapy alone, cCRT did not
significantly increase the TRD
– Neither radiation dose nor chemotherapy regimens increased the treatment mortality
Zhao et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7561)
7512: Multidisciplinary treatment for stage IIIA non-small cell lung cancer
(NSCLC): Does institution matter? – Samson P et al
• Study objective
– To investigate the impact of the institution carrying out surgery on survival in
patients with stage IIIA NSCLC
• Study design
– Retrospective analysis of data from the National Cancer Database from patients
who had undergone resection at academic centres or community centres
• Key results
– 11,492 clinical stage IIIA NSCLC patients were treated at community centres
compared with 7743 at academic centres
– Academic centre patients were more likely to receive neoadjuvant CT
(49.6% vs 40.6%; p<0.001)
– 30-day mortality was significantly lower at academic centres
(OR 0.75, 95% CI 0.60, 0.93, 3.3% vs 4.5%; p<0.001)
• Conclusion
– Stage IIIA NSCLC patients treated with pulmonary resection at academic
centres show better survival than those treated in the community
Samson et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7512)
Advanced NSCLC
Not radically treatable stage III and stage IV
1st line
8023: Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in
first-line NSCLC: Interim phase I results – Antonia SJ et al
• Study objective
– To investigate the efficacy and safety of nivolumab in combination with ipilimumab in
patients with advanced NSCLC
• Study design
– Interim results from a phase I study in which CT-naïve patients with squamous or nonsquamous advanced NSCLC received the following first-line regimen q3w for 4 cycles
followed by nivolumab 3 mg/kg q2w: 1) nivolumab 1 mg/kg + ipilimumab 3 mg/kg or
2) nivolumab 3 mg/kg + ipilimumab 1 mg/kg
– Primary endpoint: safety and tolerability; secondary endpoints: objective response rate
and PFS
• Key results
– Grade 3/4 treatment-related AEs occurred in 24 of 49 patients (49%)
– Among patients with squamous NSCLC, objective response rate was better in the higher
nivolumab dose group (33% vs 11% with low-dose nivolumab); this was also higher than
in the non-squamous groups (both 13%)
– Other outcomes were similar between patients with or without PD-L1 expression
• Conclusion
– These interim data suggest that a nivolumab+ipilimumab immunotherapy regimen is
feasible and active in patients with advanced NSCLC, regardless of PD-L1 expression
status
Antonia et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8023)
8024: First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in
advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1
status – Gettinger SN et al
• Study objective
– To investigate PD-L1 as a potential biomarker for nivolumab use in the first-line
treatment of advanced NSCLC
• Study design
– Interim results of phase I study of nivolumab 3 mg/kg q2w in CT-naïve patients
with squamous or non-squamous advanced NSCLC
– Primary endpoint: safety and tolerability; secondary endpoints: objective response
rate and PFS
• Key results
– Five grade 3/4 treatment-related AEs occurred in 4 patients (20%; AST or ALT
elevations, hyperglycaemia, rash and cardiac failure)
– Objective response rate was 30% overall
• Response at first assessment (11 weeks) was observed in 5 of 6 (83%) patients
• Response was 50% in patients with PD-L1 expression; no responses were
observed in patients without PD-L1 expression
• Conclusion
– Nivolumab was associated with early durable responses in patients with advanced
and PD-L1 expression
Gettinger et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8024)
8113: Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with
platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung
cancer (NSCLC) – Antonia SJ et al
• Study objective
– To assess DLT of nivolumab in combination with platinum-based doublet CT in NSCLC
• Study design
– Updated analysis of a phase I study of first-line nivolumab plus PT-DC in CT-naïve patients
– Based on histology patients were assigned to 4 cycles of one of four treatment arms:
1) nivolumab 10 mg/kg q3w + gemcitabine 1250 mg/m2 + cisplatin 75 mg/m2 (sq)
2) nivolumab 10 mg/kg IV q3w + pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 (non-sq)
3) nivolumab 5 mg/kg q3w + paclitaxel 200 mg/m2 + carboplatin AUC6 (sq + non-sq)
4) nivolumab 10 mg/kg q3w + paclitaxel 200 mg/m2 + carboplatin AUC6 (sq + non-sq)
• Key results
– Overall 56 patients were treated across 4 arms with median age of 64 years; 54% female;
96% stage IV
– No DLTs were seen during the first 6 weeks of treatment
– Objective response rate was 33–47% over up to 10 months of follow-up and was similar
between treatment arms
– Median OS was 51–83 weeks; 1-year OS rates were 50–87%
– 45% of patients reported grade 3–4 treatment-related AEs
• Conclusion
– Nivolumab plus PT-DC demonstrated anti-tumour activity with encouraging 1-year OS
DLT, dose-limiting toxicity; non-sq, non-squamous;
PT-DC, platinum-based doublet CT; sq, squamous
Antonia et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8113)
8001: Efficacy and safety of crizotinib in patients with advanced c-METamplified non-small cell lung cancer (NSCLC) – Camidge DR et al
• Study objective
– To assess the efficacy and safety of crizotinib in patients with advanced c-Metamplified (low, intermediate or high amplification*) NSCLC
Key patient inclusion criteria
• c-MET-amplified advanced
NSCLC
• Low, medium or high
• Adequate organ function
• Measurable disease
• Resolution of acute toxic effects
of prior therapies or surgery
Crizotinib 250 mg bid
c-MET amplification:
• Low (n=2)
• Medium (n=6)
• High (n=6)
PD
• No prior MET- or HGF-targeted
therapies
(n=14)
*According to MET/CEP7 ratio: ≥1.8–≤2.2 (low),
>2.2–<5.0 (intermediate) or ≥5.0 (high)
Camidge et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8001)
8001: Efficacy and safety of crizotinib in patients with advanced c-METamplified non-small cell lung cancer (NSCLC) – Camidge DR et al
• Key results
– 1 CR and 4 PRs have been observed with crizotinib among 12 patients to date
100
Low MET
n=2
100
Intermediate MET
n=6
100
80
80
60
60
60
40
40
40
20
20
20
0
0
0
–20
–20
–20
–40
–40
–60
–60
–80
–80
–80
–100
–100
–100
% Change from baseline
80
c
–40
c
High MET
n=6
Disease progression
Stable disease
Partial responseb
Complete responseb
Threshold
for partial
response
–60
• Conclusion
– Crizotinib seemed to have anti-tumour activity and was generally well tolerated which
warrants further study of crizotinib in advanced c-MET-amplified NSCLC
aConfirmed
objective responses
on investigator assessment
cTwo patients in the intermediate MET group had an unconfirmed
PR that was not confirmed in a second assessment
bBased
Camidge et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8001)
8002: First-line crizotinib versus pemetrexed-cisplatin or pemetrexedcarboplatin in patients (pts) with advanced ALK-positive non-squamous
non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014)
– Mok et al
• Study objective
– To evaluate the efficacy and safety of crizotinib compared with pemetrexedplatinum chemotherapy as first-line treatment in patients with advanced
ALK+ NSCLC
Key patient inclusion criteria
• Locally advanced,
recurrent or metastatic
non-squamous NSCLC
• ALK+
Crizotinib 250 mg bid q3w
(n=172)
R
1:1
PD
Stratification
• ECOG PS, ethnicity, presence/absence
of brain metastases
Crizotinib
• No previous treatment
• ECOG PS 0–2
(n=343)
Primary endpoint
• PFS
Pemetrexed-platinum
chemotherapy* IV q3w
(n=171)
PD
Secondary endpoints
• Objective response rate, OS, PROs and safety
*Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5–6
for ≤6 cycles
Mok et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8002)
8002: First-line crizotinib versus pemetrexed-cisplatin or pemetrexedcarboplatin in patients (pts) with advanced ALK-positive non-squamous nonsmall cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014)
– Mok et al
• Key results
– Addition of crizotinib significantly improved PFS but not OS compared with CT alone
PFS
100
Median, months
OS probability (%)
80
Crizotinib
(n=172)
CT
(n=171)
10.9
7.0
HR (95% CI)
0.454 (0.35, 0.60)
p<0.0001
60
Crizotinib
CT
40
20
0
0
No. at risk
Crizotinib
CT
172
171
5
120
105
10
15
20
Time (months)
65
38
19
36
12
2
25
30
7
1
35
1
0
0
0
Mok et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8002)
8002: First-line crizotinib versus pemetrexed-cisplatin or pemetrexedcarboplatin in patients (pts) with advanced ALK-positive non-squamous nonsmall cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014)
– Mok et al
• Conclusions
– First-line treatment with crizotinib compared with standard chemotherapy
demonstrated significant improvements in PFS and objective response rate in
patients with advanced ALK+ non-squamous NSCLC
– The findings suggest that crizotinib should be the standard of care in patients
with previously untreated advanced ALK+ non-squamous NSCLC
Mok et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8002)
8003^: Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged
(ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial
– Kim D-W et al
• Study objectives
– To investigate the efficacy and safety of ceritinib in patients with crizotinib-resistant
advanced ALK-rearranged NSCLC
• Study design
– Expansion phase dose escalation study in which patients were treated with the
established minimum therapeutic dose of ceritinib (750 mg/day)
– Patients were grouped according to: ALK inhibitor-pretreated NSCLC (n=163) or ALK
inhibitor-naïve NSCLC (n=83)
• Key results
– 246 patients had ALK-rearranged NSCLC, with a median follow-up of 7.0 months; of
these, 43% had received at least 3 prior treatment regimens
– Overall response rate: 58.5% all patients; 54.6% ALK inhibitor pretreated; 66.3% ALK
inhibitor naïve
– PFS at 12 months: 39.1% all patients; 28.4% ALK inhibitor pretreated; 61.3% ALK inhibitor
naïve
• Conclusions
– Ceritinib has rapid, durable and high anti-tumour activity in patients with ALK-rearranged
NSCLC, regardless of prior treatment with an ALK inhibitor
Kim et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8003^)
8003^: Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged
(ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial
– Kim D-W et al
• Study objectives
– To investigate the efficacy and safety of ceritinib in patients with crizotinib-resistant
advanced ALK-rearranged NSCLC
• Study design
– Expansion phase dose escalation study in which patients were treated with the
established minimum therapeutic dose of ceritinib (750 mg/day)
– Patients were grouped according to: ALK inhibitor-pretreated NSCLC (n=163) or ALK
inhibitor-naïve NSCLC (n=83)
• Key results
– 246 patients had ALK-rearranged NSCLC, with a median follow-up of 7.0 months; of
these, 43% had received at least 3 prior treatment regimens
– Overall response rate: 58.5% all patients; 54.6% ALK inhibitor pretreated; 66.3% ALK
inhibitor naïve
– PFS at 12 months: 39.1% all patients; 28.4% ALK inhibitor pretreated; 61.3% ALK inhibitor
naïve
• Conclusions
– Ceritinib has rapid, durable and high anti-tumour activity in patients with ALK-rearranged
NSCLC, regardless of prior treatment with an ALK inhibitor
Kim et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8003^)
8004^: Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer
(NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations
(EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3]
and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy – Yang JC-H et al
• Study objective
– Pooled analysis of two Phase III studies (LL3 or LL6) comparing afatinib with
standard CT* in EGFR-mutated patients with advanced NSCLC
Afatinib 40 mg/day
(n=419)
Key patient inclusion criteria
• Treatment-naïve NSCLC
• EGFR mutation (Del19 or
L858R)
• Stage IIIB/IV
• ECOG PS 0–1
(n=631†)
Primary endpoint
• PFS
R
2:1
PD
Stratification
• EGFR mutation (Del19, L858R or other)
• Race (Asian/non-Asian)
Standard CT* (≤6 cycles)
(n=212)
PD
Secondary endpoints
• OS and safety
*Cisplatin/pemetrexed (Study LL3) or gemcitabine/cisplatin (Study LL6);
†709 patients originally randomised to LL3 and LL6
Yang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8004^)
8004^: Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer
(NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations
(EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3]
and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy – Yang JC-H et al
• Key results
Estimated OS probability
– Afatinib significantly prolonged survival in overall EGFR-mutant population
OS 1.0
0.8
Afatinib
(n=419)
CT
(n=212)
27.3
24.3
Median, months
HR (95%CI)
p-value
0.6
0.81 (0.66, 0.99)
0.0374
0.4
0.2
0
0
3
6
9
12
15
18
21 24 27 30
Time (months)
No of patients
Afatinib
419 411 390 371 343 320 284 251 225
CT
212 199 185 173 162 141 124 110 101
33
36
39
42
45
48
51
201 181 141 77
58 33
9
1
0
83 70
52
34
23 10
5
1
0
Yang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8004^)
8004^: Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer
(NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations
(EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3]
and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy – Yang JC-H et al
• Key results
– Afatinib significantly prolonged survival with EGFR Del19, but not L858R mutation
OS (L858R)
OS (Del19)
Median,
months
Estimated OS probability
0.8
HR (95%CI)
p-value
Afatinib
(n=236)
CT
(n=119)
31.7
20.7
0.59 (0.45, 0.77)
0.0001
0.6
0.4
1.0
HR (95%CI)
p-value
CT
(n=93)
22.1
26.9
1.25 (0.92, 1.71)
0.1600
0.4
0.2
0
0
3 6
Afatinib
(n=183)
0.6
0.2
0
Median,
months
0.8
Estimated OS probability
1.0
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
0
Time (months)
3 6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
No of patients
No of patients
Afatinib
236 230 223 217 202 192 173 160 145 131 117 90 50 38 22
6
1
0
Afatinib
183 181 167 154 141 128 111 91 80 70 64 51 27 20 11
3
0
0
CT
119 113 103 95 87 72 63 55 51 43 38 27 14
1
0
0
CT
93 86 82 78 75 69 61 55 50 40 32 25 20 14
4
1
0
9
1
9
Yang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8004^)
8004^: Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer
(NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations
(EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3]
and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy – Yang JC-H et al
• Conclusions
– In both trials, first-line afatinib significantly improved OS in patients with EGFR
Del19 advanced NSCLC compared with CT
– There was no significant difference in OS of patients with L858R mutations,
individually or in exploratory combined analysis
– This is the first analysis to show that genotype-directed therapy for EGFRmutant patients can improve survival
– These results suggest that first-line afatinib might become a standard of care for
EGFR Del19 patients and remains a treatment option for EGFR L858R patients
Yang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8004^)
8005: Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line
treatment for advanced EGFR mutation-positive nonsquamous non-small cell
lung cancer (NSCLC): An open-label randomized trial – Kato T et al
• Study objective
– To compare first-line erlotinib+bevacizumab with erlotinib alone in patients with
EGFR-mutated NSCLC
Erlotinib 150 mg/day +
bevacizumab 15 mg/kg
Key patient inclusion criteria
PD
q3w
• Non-squamous NSCLC
(n=75)
• Stage IIIB/IV or recurrent
Stratification
R
• EGFR mutation (Del19 or L858R)
• EGFR mutation-positive
1:1
• Gender, smoking status, stage
• No previous CT
• ECOG PS 0/1
(n=150)
Primary endpoint
• PFS
Erlotinib 150 mg/day
alone
(n=77)
PD
Secondary endpoints
• OS, tumour response, safety and QoL
Kato et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8005)
8005: Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line
treatment for advanced EGFR mutation-positive nonsquamous non-small cell
lung cancer (NSCLC): An open-label randomized trial – Kato T et al
• Key results
– Median PFS was improved with combination treatment
PFS
Erlotinib +
bevacizumab
Erlotinib
16.0
9.7
Median (months)
PFS probability
100
HR (95% CI)
80
0.54 (0.36, 0.79)
p-value*
0.0015
*log-rank test, two-sided
60
40
20
9.7
16.0
0
0
2
4
6
8
Number at risk
• Conclusion
EB
E
75 72 69 64 60
77 66 57 44 39
10 12 14
16 18 20 22 24 26 28
Time (months)
53 49 38 30 20 13
29 24 21 18 12 10
8
5
4
2
4
1
0
0
– Erlotinib+bevacizumab significantly prolonged PFS compared with erlotinib alone in
patients with EGFR mutation-positive NSCLC
Kato et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8005)
8007: Safety and clinical activity of MK-3475 as initial therapy in patients with
advanced non-small cell lung cancer (NSCLC) – Rizvi NA et al
• Study objective
– To evaluate the safety, tolerability and clinical activity of MK-3475 as an initial
treatment for patients with locally advanced or metastatic NSCLC
Key patient inclusion criteria
• Stage IV NSCLC
MK-3475 10 mg/kg q3w
(n=23)
PD
MK-3475 2 mg/kg q3w
(n=6)
PD
MK-3475 10 mg/kg q2w
(n=16)
PD
• No prior systemic therapy
• PD-L1 expressing tumours
• ECOG PS 0–1
• EGFR/ALK negative
(n=84)
R
Primary endpoint
Secondary endpoint
• Tumour response
• Immune-related response criteria
Rizvi et al. J Clin Oncol 2014; 32 (suppl; abstr 8007)
8007: Safety and clinical activity of MK-3475 as initial therapy in patients with
advanced non-small cell lung cancer (NSCLC) – Rizvi NA et al
• Key results
– MK-3475 showed ORR of 26% by independent central review and 47% by investigator
assessment (table)
ORR (95% CI), %
Interim median PFS (95% CI), weeks
Responses ongoing, n/N (%)
Responders remaining on treatment, n/N (%)
RECIST v1.1 per
independent central
review
Immune-related response
criteria per investigator
assessment
26 (14, 42)
47 (32, 62)
27.0 (13.6, 45.0)
37.0 (27.0, NR)
11/11 (100)
19/21 (90)
7/11 (64)
18/21 (86)
– Treatment-related AEs (any grade) occurring in >5% of patients were: fatigue (22%),
pruritus (13%), hypothyroidism (9%), dermatitis acneiform (7%), diarrhoea (7%),
dyspnoea (7%) and rash (7%)
• Conclusions
– MK-3475 provides robust anti-tumour activity as first-line therapy for patients with NSCLC
and PD-L1 expressing tumours
– MK-3475 has an acceptable and manageable toxicity profile
Rizvi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8007)
8020: Safety and clinical activity of MK-3475 in previously treated patients (pts)
with non-small cell lung cancer (NSCLC) – Garon EB et al
• Study objective
– To evaluate the safety, tolerability and clinical activity of MK-3475 in previously
treated patients with progressive locally advanced or recurrent NSCLC
• Study design
– A phase I study of previously treated patients (n=217) with PD-L1 expressing
tumours were treated with MK-3475 10 mg/kg q2w (n=98) or q3w (n=119), or
patients without PD-L1 expression who had received ≥2 prior lines of therapy
were treated with MK-3475 10 mg/kg q2w
– Primary endpoint: tumour response by RECIST
• Key results
– Incidence of ≥1 drug-related AEs of any grade was 64%; most common AEs
(≥5%) overall were: fatigue (20%), decreased appetite (9%), arthralgia (9%),
pruritus (8%), diarrhoea (7%), nausea (6%), rash (6%), pyrexia (6%) and
hypothyroidism (5%)
– Objective response rate was 20% overall, 23% in patients with PD-L1
expression and 9% in those without PD-L1 expression
• Conclusion
– In previously treated patients with progressive locally advanced or recurrent
NSCLC expressing PD-L1, treatment with MK-3475 was generally well tolerated
and provided robust anti-tumour activity
Garon et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8020)
8008^: A randomized, multicenter, open-label, phase III study of gemcitabinecisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus
GC alone in the first-line treatment of patients (pts) with stage IV squamous
non-small cell lung cancer (sq-NSCLC) – Thatcher N et al
• Study objective
– To compare gemcitabine/cisplatin+necitumumab with gemcitabine/cisplatin
alone as first-line treatment in patients with squamous NSCLC
Key patient inclusion criteria
• Squamous NSCLC
• Stage IV
• ECOG PS 0–2
Gemcitabine/cisplatin* +
necitumumab†
(n=545)
PD
Gemcitabine/cisplatin*
alone
(n=548)
PD
R
1:1
(n=1093)
Primary endpoint
• OS
*Gemcitabine 1250 mg/m² IV days 1 and 8, cisplatin 75 mg/m² IV
day 1; †800 mg IV days 1 and 8
Secondary endpoints
• PFS, objective response rate and safety
Thatcher et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8008^)
8008^: A randomized, multicenter, open-label, phase III study of gemcitabinecisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus
GC alone in the first-line treatment of patients (pts) with stage IV squamous
non-small cell lung cancer (sq-NSCLC) – Thatcher N et al
• Key results
OS
100
HR (95% CI) 0.84 (0.74, 0.96); p=0.012*
Median OS (95% CI), months:
Gemcitabine/cisplatin+necitumumab:
Gemcitabine/cisplatin:
Overall survival (%)
80
*Log-rank test (stratified)
1-year OS
60
11.5 (10.4, 12.6)
9.9 (8.9, 11.1)
47.7%
40
2-year OS
42.8%
19.9%
20
0
Patients/events:
Gemcitabine/cisplatin+necitumuab:
Gemcitabine/cisplatin:
0
4
8
12
16.5%
545 / 418
548 / 442
16
20
24
28
32
36
40
Time since randomisation (months)
Follow-up time (median): Gemcitabine/cisplatin+necitumumab: 25.2 months; gemcitabine/cisplatin: 24.8 months
Thatcher et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8008^)
8008^: A randomized, multicenter, open-label, phase III study of gemcitabinecisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus
GC alone in the first-line treatment of patients (pts) with stage IV squamous
non-small cell lung cancer (sq-NSCLC) – Thatcher N et al
• Key results
Hazard ratio
PFS
HR (95% CI) 0.85 (0.74, 0.98); p=0.020*
Progression-free survival (%)
100
Median PFS (95% CI), months:
Gemcitabine/cisplatin+necitumumab:
Gemcitabine/cisplatin:
80
5.7 (5.6, 6.0)
5.5 (4.8, 5.6)
*Log-rank test (stratified)
0.85
ITT population (N=1093)
0.82
1.07
<70 years (n=888)
≥70 years (n=205)
0.63
0.90
Female (n=185)
Male (n=908)
0.88
0.70
Caucasian (n=913)
0.88
0.85
Ex-light & non-smoker (n=97)
Smoker (n=995)
0.84
0.86
0.79
ECOG PS 0 (n=344)
ECOG PS 1 (n=652)
ECOG PS 2 (n=96)
60
Non-Caucasian (n=180)
40
20
0
I
0
4
8
12
16
20
24
Time since randomisation (months)
28
32
0.5
I
1.0
Favours
GC+necitumumab
I
1.5
Favours
GC
Progression-free survival as assessed by investigators
Thatcher et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8008^)
8008^: A randomized, multicenter, open-label, phase III study of gemcitabinecisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus
GC alone in the first-line treatment of patients (pts) with stage IV squamous
non-small cell lung cancer (sq-NSCLC) – Thatcher N et al
• Conclusions
– SQUIRE is the largest randomised phase III trial of first-line treatment for
metastatic squamous NSCLC
– The study met its primary endpoint by showing a statistically significant
improvement in OS
– Results were consistent across endpoints and pre-specified subgroups,
including patients with ECOG PS 2
– Necitumumab combined with gemcitabine/cisplatin showed an acceptable
safety profile
Thatcher et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8008^)
7558: The impact of EGFR mutation on definitive concurrent chemoradiation
therapy for inoperable stage III lung adenocarcinoma – Tanaka K et al
• Study objective
– To investigate the impact of EGFR mutation on treatment with concurrent chemoradiation
therapy (CRT) in unresectable stage III lung adenocarcinoma
• Study design
– Retrospective analysis of clinical outcomes and recurrence patterns according to mutation
status among patients treated with first-line platinum-doublet in first-line setting
• Key results
– EGFR mutation was detected in 28.8% of patients (21 of 73 patients)
– Survival was significantly shorter in EGFR-mutated patients than wild-type
• Median recurrence-free survival (RFS; 95% CI) was 8.7 (6.7, 10.8) vs 13.5 (11.0, 18.3)
months; p=0.022
• 2-year RFS rate was 5.6% vs 23.8%; p=0.090
• Distant metastases were more frequently identified as the first recurrence site (81.0%
vs 38.5%; p<0.001)
• Conclusion
– Concurrent CRT gave shorter RFS in EGFR-mutated stage III lung adenocarcinoma
patients compared with wild-type patients, mainly due to distant metastasis relapse,
regardless of better local control
Tanaka et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7558)
Advanced NSCLC
Not radically treatable stage III and stage IV
Maintenance
8016: Randomized phase II study of concurrent gefitinib and chemotherapy
versus sequential alternating gefitinib and chemotherapy in previously
untreated non-small cell lung cancer (NSCLC) with sensitive EGFR mutations:
NEJ005/TCOG0902 – Oizumi S et al
• Study objective
– To identify an effective combined regimen of gefitinib + carboplatin/pemetrexed in EGFR
mutation-positive NSCLC for use in a subsequent phase II trial
Key patient inclusion
criteria
• Non-squamous
stage
IIIB/IV/relapse
NSCLC
• Previously
untreated
• EGFR+
• Age 20–75 years
• ECOG PS 0–1
(n=80)
Primary endpoint
Concurrent
Induction
arm
Gefitinib (daily) +
carboplatin+pemetrexed
(4–6 cycles, q3w)
(n=41)
R
1:1
Maintenance
Gefitinib (daily) +
pemetrexed (q3w)
(n=35)
PD
Gefitinib (8 weeks daily) 
pemetrexed
(2 cycles, q3w)
(n=24)
PD
Stratification
• Gender, stage
Gefitinib (8 weeks daily) 
carboplatin+pemetrexed
(2 cycles, q3w)
(n=39)
Sequential
arm
Repeat up to 3 cycles
• PFS
Gefitinib 250 mg/day; carboplatin AUC6; pemetrexed 500 mg/m2
Secondary endpoints
• OS, tumour response and safety
Oizumi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8016)
8016: Randomized phase II study of concurrent gefitinib and chemotherapy
versus sequential alternating gefitinib and chemotherapy in previously
untreated non-small cell lung cancer (NSCLC) with sensitive EGFR mutations:
NEJ005/TCOG0902 – Oizumi S et al
• Key results
– Concurrent administration of CT was associated with better OS than sequential CT but there
was no improvement in PFS
OS
OS
OS probability (%)
100
Median, mo
80
95% CI
60
40
Concurrent
Sequential
20
PFS
Concurrent
Sequential
Concurrent
Sequential
41.9
30.7
18.3
15.3
35.1, NR
23.2, 40.5
9.7, 21.9
11.3, 17.4
HR
0.55
0.80
p-value
0.042
0.20
1-year rate, %
87.8
87.2
61.0
61.2
2-year rate, %
80.5
64.0
29.1
25.2
3-year rate, %
58.9
39.8
20.6
18.9
0
0
12
24
36
Time (months)
48
60
• Conclusion
– Both treatment arms showed promising efficacy with predictable toxicities, although
concurrent regimens might provide better OS
Oizumi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8016)
8019^: Continuation of afatinib beyond progression: Results of a randomized, open-label,
phase III trial of afatinib plus paclitaxel (P) versus investigator’s choice chemotherapy
(CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on
erlotinib/gefitinib (E/G) and afatinib—LUX-Lung 5 (LL5) – Schuler MH et al
• Study objective
– To assess the efficacy of continuation of afatinib beyond progression with the
addition of paclitaxel in patients the NSCLC who have shown prior benefit from
reversible EGFR TKIs and afatinib
Afatinib 40 mg/day +
paclitaxel 80 mg/m2/week
(n=134)
Key patient inclusion criteria
• Stage IIIB/IV NSCLC
• Failed ≥1 line of
chemotherapy and
erlotinib/gefitinib
• ECOG PS 0–2
(n=1302)
Primary endpoint
• PFS
*Those progressing who had received ≥12 weeks
of benefit from afatinib
Afatinib
50 mg/day
(n=1154)
R*
2:1
PD
Stratification
• Gender
• Prior duration of EGFR TKI
Single agent investigator’s
choice chemotherapy
(n=68)
PD
Secondary endpoints
• ORR, OS and safety
Schuler et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8019^)
8019^: Continuation of afatinib beyond progression: Results of a randomized, open-label,
phase III trial of afatinib plus paclitaxel (P) versus investigator’s choice chemotherapy
(CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on
erlotinib/gefitinib (E/G) and afatinib—LUX-Lung 5 (LL5) – Schuler MH et al
• Key results
Afatinib +
paclitaxel
(n=134)
Investigator
choice
(n=68)
PFS event, n (%)
105 (78.4)
54 (79.4)
Median PFS (mo)
5.6
2.8
Progression-free survival
(probability)
1.0
0.8
HR (95% CI)
0.6
0.4
1.0
0.8
0.60 (0.43, 0.85)
p=0.0031
Afatinib
CT
0
• Conclusion
9
12 15 18 21 24 27
Time (months)
46 (67.6)
Median OS (mo)
12.2
12.2
HR (95% CI)
1.00 (0.70, 1.43)
0.4
0
6
100 (74.6)
0.6
0.2
3
OS event, n (%)
p=0.99
0.2
0
Investigator
choice
(n =68)
OS
Overall survival
(probability)
PFS
Afatinib +
paclitaxel
(n=134)
Afatinib
Chemo
0
3 6 9 12 15 18 21 24 27 30 33 36 39
Time (months)
– PFS (and ORR) were significantly improved with continued afatinib combined
with paclitaxel vs CT alone in heavily pretreated patients with acquired
resistance to erlotinib/gefitinib and progression after afatinib monotherapy
Schuler et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8019^)
8040: Sunitinib (S) switch maintenance in advanced non-small cell lung cancer
(NSCLC): An ALLIANCE (CALGB 30607), randomized, placebo-controlled
phase III trial – Socinski MA et al
• Study objective
– To evaluate the effect on survival of sunitinib maintenance vs placebo in patients with
advanced NSCLC who were stable or responding after 4 cycles of first-line platinumbased chemotherapy (with or without bevacizumab)
Key patient inclusion criteria
• Stage IIIB/IV
Sunitinib 37.5 mg qd
(n=106)
PD
Placebo
(n=104)
PD
• ECOG PS 0–1
• Stable or responding disease after
4 cycles of platinum-based therapy
• No symptomatic or untreated brain
metastases or cavitary lesions
(n=210)
Primary endpoint
• PFS after randomisation
R
Secondary endpoints
• OS, safety and QoL
Socinski et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8040)
8040: Sunitinib (S) switch maintenance in advanced non-small cell lung cancer
(NSCLC): An ALLIANCE (CALGB 30607), randomized, placebo-controlled
phase III trial – Socinski MA et al
• Key results
– Patients had a median (range) age 66 (25–89) years , 55.7% male, 61.0% ECOG PS 1,
87.6% stage IV, 91.7% current/past smokers. 45.7% had adenocarcinoma, 33.2%
squamous, 13.5% undifferentiated NSCLC and 4.3% large cell
• Conclusion
– Significant improvement in PFS (but not OS) observed with sunitinib switch maintenance
in patients with advanced NSCLC
Socinski et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8040)
Advanced NSCLC
Not radically treatable stage III and stage IV
Later lines
8009: Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in
patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC)
– Janne PA et al
• Study objective
– To investigate the efficacy of AZD9291 in patients with EGFR-mutant NSCLC
• Study design
– Phase I dose-escalation study of AZD9291 at doses of 20–240 mg qd in patients with
EGFR mutation-positive NSCLC and acquired resistance to EGFR TKIs
• Key results
– To date, 31 and 201 patients have been enrolled to the escalation and expansion studies
(median age 61/60 years; 65%/62% female; 71%/63% Asian), respectively
– Overall response rate (confirmed+unconfirmed) to date are as follows:
• 53% (95% CI 46%, 60%) among all evaluable patients
• 64% (95% CI 55%, 73%) in EGFR T790 mutation-positive patients
• 22% (95% CI 12%, 36%) in EGFR T790 mutation-negative patients
– The overall DCR (CR+PR+SD) in EGFR T790 mutation-positive patients was 94%
– No dose-limiting toxicities were observed
• Conclusions
– AZD9291 has robust efficacy and is well tolerated in patients with EGFR mutation-positive
NSCLC and acquired resistance to EGFR TKIs
Janne et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8009)
8112^: Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with
advanced non-small-cell lung cancer (NSCLC): Survival and clinical activity by
subgroup analysis – Brahmer JR et al
• Study objective
– To investigate the clinical efficacy of the human IgG4 PD1 immune-checkpoint inhibitor
antibody, nivolumab, on patients with previously treated advanced NSCLC
• Study design
– Phase Ib study in which patients received nivolumab (1, 3 or 10 mg/kg) q2w for up to
96 weeks
– PD-L1 tumour cell membrane expression was measured in archival specimens
• Key results
– Overall, 129 subjects were treated with nivolumab across the three doses
– At the 3 mg/kg dose (n=37) median OS was 14.9 months, 1- and 2-year OS rates were
56% and 45%, respectively, objective response rate was 24%
– For patients with PD-L1(+) and (–) tumours, median OS was 7.8 (95% CI 5.6, 21.7) and
10.5 (5.2, 21.2) months, respectively
– The most common grade 3–4 treatment-related AE was fatigue (3%)
• Conclusion
– Nivolumab continues to demonstrate an encouraging survival profile
Brahmer et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8112^)
8010: First-in-human evaluation of CO-1686, an irreversible, highly selective
tyrosine kinase inhibitor of mutations of EGFR (activating and T790M)
– Sequist LV et al
• Study objective
– To investigate the efficacy and safety of CO-1686 in patients with EGFR mutation-positive
advanced or recurrent NSCLC
• Study design
– Dose-finding study of CO-1686 free-base (up to 900 mg bid) and CO-1686 hydrobromide
salt (HBr; 500–1000 mg bid) among patients who had a tumour biopsy in screening for
central EGFR genotyping
• Key results
– 72 patients with median age of 59 years; 75% female; 14% Asian
– PK of the CO-1686 HBr formulation was consistently linear with a half-life suitable for bid
dosing
– Objective response rate to date of 58% among T790 mutation-positive patients (n=40)
– Median PFS has not yet been reached, but current estimate exceeds 12 months
– Treatment-related AEs occurring in >10% were: nausea, hyperglycaemia/IGT, diarrhoea,
vomiting, decreased appetite, myalgia and QTc prolonged
• Conclusions
– CO-1686 shows promising efficacy in patients with T790 EGFR-mutant NSCLC
– CO-1686 HBr delivered higher exposures than free-base and was equally well tolerated
Sequist et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8010)
8011: Clinical activity and safety of HM61713, an EGFR-mutant selective
inhibitor, in advanced non-small cell lung cancer (NSCLC) patients (pts) with
EGFR mutations who had received EGFR tyrosine kinase inhibitors (TKIs)
– Kim D-W et al
• Study objective
– To evaluate safety, pharmacokinetics and preliminary efficacy of HM61713 in
patients with EGFR mutation-positive advanced NSCLC
• Study design
– Phase I dose-escalation study of HM61713 at 300 mg qd (up to 500 mg/day so
far) assigned to treatment arm according to time since EGFR TKI (Arm A:
<4 weeks; Arm B: ≥4 weeks)
• Key results
– 83 patients enrolled to date
– Treatment-related AEs were mostly grade 1/2; those occurring in ≥10% were:
nausea, skin exfoliation, headache, rash, decreased appetite, diarrhoea,
pruritus, constipation, dry skin, vomiting, productive cough, upper abdominal
pain, cough, dyspepsia and dyspnoea
– Disease control rate was 61.9% and 73.2% in Arm A and B, respectively
• Conclusions
– HM61713 showed good safety profile and promising anti-tumour activity in
patients with EGFR-mutated NSCLC who failed to respond to EGFR TKIs,
especially in patients with T790M mutation
Kim et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8011
8021^: Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in
patients with NSCLC – Brahmer JR et al
• Study objective
– To evaluate the safety and efficacy of MEDI4736 in patients with NSCLC and other solid
tumours
• Study design
– Ongoing phase I study of patients with NSCLC who are receiving MEDI4736 IV q2w or
q3w using 3+3 dose-escalation followed by expansion cohorts stratified by histology and
line of therapy
– Primary endpoint: maximum tolerated dose and safety
• Key results
– As of May 2014, 155 patients with NSCLC have been treated with MEDI4736 in the doseescalation and expansion cohorts, 143 patients were dosed at 10 mg/kg q2w
– Most patients have remained on treatment with median duration of 6 weeks
– Grade 3/4 treatment-related AEs were seen in 3% of all patients; the most common grade
≥3 AE was arthralgia (1%)
– Efficacy of MEDI4736 10 mg/kg q2w was higher in patients with PD-L1 expression
• Response (CR + PR) 13% overall; 39% with PD-L1 expression; 5% without
• Disease control rate 30% overall; 54% with PD-L1 expression; 32% without
• Conclusions
– The findings support the continuing clinical development of MEDI4736
– Response rates were higher in patients with PD-L1 expression
Brahmer et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8021^)
8047: Updated efficacy and safety of the ALK inhibitor AP26113 in patients (pts)
with advanced malignancies, including ALK+ non-small cell lung cancer
(NSCLC) – Gettinger SN et al
• Study objective
– To investigate the efficacy and safety of AP26113 in patients with advanced
NSCLC (including ALK+)
• Study design
– Ongoing phase II portion of a phase I/II single arm study
• Key results
– 125 patients enrolled in phase II to date with median age 57 years; 58% female
– Most common treatment-emergent AEs (≥20%) were generally grade 1/2 in
severity: nausea (40%), diarrhoea (34%), fatigue (34%), cough (26%),
headache (25%) and vomiting (21%)
– Among 51 evaluable ALK+ NSCLC patients with prior crizotinib, 35 (69%)
responded (23 confirmed response, 7 awaiting confirmation and 5 not
confirmed); duration of response was 1.6–14.7 months (ongoing)
– Among 49 patients with follow-up scans, median PFS is 10.9 months
• Conclusion
– AP26113 has promising anti-tumour activity in patients with crizotinib-resistant
ALK+ NSCLC, including patients with brain metastases
Gettinger et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8047)
8014: Phase II trial of XL184 (cabozantinib) plus erlotinib in patients (pts) with advanced
EGFR-mutant non-small cell lung cancer (NSCLC) with progressive disease (PD) on
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy: A
California Cancer Consortium phase II trial (NCI 9303) – Reckamp KL et al
• Study objective
– To investigate the efficacy and safety of the dual MET-VEGF inhibitor, cabozantinib, plus
erlotinib in pretreated EGFR mutation-positive NSCLC
• Study design
– Single-arm study of cabozantinib 40 mg/day + erlotinib 150 mg/day on a 28-day cycle in
patients with progressive disease on an EGFR TKI immediately prior to enrolment
– Primary endpoint: response rate (proportion of patients with ≥30% increase in tumour
doubling time); secondary endpoints: PFS, OS and safety
• Key results
– 37 patients have been treated, median age 64.6 years; 62% female; 51% ECOG PS 0
– Tumour growth rate reduction of ≥30% was achieved in 85% of patients
– Diarrhoea (11/37, 30%) was the most common grade 3 AE; 4 patients had grade 4 AEs:
1 increased serum amylase, 2 patients increased lipase and 1 patient nausea/vomiting
•
Conclusion
– Combination of erlotinib and cabozantinib demonstrates anti-tumour activity in patients
with EGFR mutation-positive NSCLC and progressive disease on EGFR TKI
Reckamp et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8014)
8015: Phase II study of the AKT inhibitor MK-2206 plus erlotinib (E) in patients
(pts) with advanced non-small cell lung cancer (NSCLC) who progressed on
prior erlotinib: A California Cancer Consortium Phase II trial (NCI 8698)
– Lara P et al
• Study objective
– To investigate the efficacy and safety of the highly selective inhibitor of AKT, MK2206, in
combination with erlotinib in patients with advanced NSCLC
• Study design
– Single-arm study of erlotinib 150 mg/day + MK-2206 45 mg/day on a 28-day cycle in
patients who had responded previously to erlotinib (response or stable disease
>12 weeks)
– Accrual into two strata: presence of EGFR-activating mutation; EGFR wild-type
– Primary endpoints: response rate >30% and disease control rate >20% at 12 weeks
• Key results
– 80 patients have been treated, median (range) age 64 (40–86) years; 58% EGFR
mutation-positive; 64% female; 66% PS 90–100%
– Disease control rate was higher among patients with EGFR wild-type NSCLC treated with
a combination of erlotinib+MK2206 compared with those with EGFR-mutant disease (47%
vs 39%); median PFS was similar between groups (4.6 and 4.4 months, respectively)
• Conclusion
– Combination of erlotinib and MK2206 demonstrates anti-tumour activity in patients with
EGFR wild-type NSCLC
Lara et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8015)
8043: E7080 (lenvatinib) in addition to best supportive care (BSC) versus BSC
alone in third-line or greater nonsquamous, non-small cell lung cancer (NSCLC)
– Havel L et al
• Study objective
– To investigate the efficacy of lenvatinib as a third-line or greater treatment of NSCLC
• Study design
– Randomised, controlled phase II study of lenvatinib 24 mg/day + BSC vs placebo+BSC in
patients who had failed ≥2 systemic treatments
– Primary endpoint: OS; secondary endpoints: PFS, ORR and DCR
• Key results
– Patients in the lenvatinib/placebo groups (n=89/n=46) had median age of 63/64 years;
% male 51/59; % white 70/67; % former smokers 55/63; % ECOG PS1 71/63;
% adenocarcinoma 93/98
– There were clinically meaningful improvements (>3 months) in OS and PFS with
lenvatinib+BSC vs placebo+BSC:
• OS 38.4 vs 24.1 weeks (HR 0.7 [95% CI 0.45, 1.03]; p=0.065)
• PFS 20.9 vs 7.9 weeks (HR 0.4 [95% CI 7.43, 8.14]; p<0.001)
– A post-hoc analysis showed similar treatment effect in subjects with wild-type EGFR
• Conclusion
– Lenvatinib showed clinical meaningful improvement in survival in heavily pretreated
patients with NSCLC, including those with prior EGFR inhibitors
Havel et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8043)
8045: Phase 2 HERALD study of patritumab (P) with erlotinib (E) in advanced
NSCLC subjects (SBJs) – Von Pawel J et al
• Study objective
–
To assess safety and efficacy patritumab+erlotinib vs placebo+erlotinib in erlotinib-naïve
patients with advanced NSCLC (second-line or later)
• Study design
–
Phase II study in which patients were randomised to erlotinib 150 mg/day and either high-dose
patritumab (18 mg/kg q3w) or low-dose patritumab (18 mg/kg loading dose followed by 9 mg/kg
q3w) or to erlotinib 150 mg/day plus placebo
–
Heregulin mRNA was measured using a quantitative polymerase chain reaction assay
–
Primary endpoints: PFS; secondary endpoints: OS and safety
• Results
–
Among 212 subjects in the ITT population, PFS was similar among the treatment groups (1.4,
2.5 and 1.6 months in the high, low and placebo arms, respectively)
–
PFS was significantly improved in the heregulin high subgroup (3.4, 3.0 and 1.4 months in the
high, low and placebo arms, respectively)
–
Safety was similar with the exception of rash and gastrointestinal effects
• Conclusions
–
Patritumab improved PFS in the heregulin high subgroup, but not the ITT population
–
Heregulin appears to be a predictive biomarker for patritumab
Von Pawel et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8045)
8026: Clinical activity of LY2835219, a novel cell cycle inhibitor selective for
CDK4 and CDK6, in patients with non-small cell lung cancer – Goldman JW et al
• Study objective
– To investigate the efficacy and safety of the cell cycle inhibitor, LY2835219 (abemaciclib),
in patients with advanced NSCLC and other solid tumours
Key patient inclusion criteria
• Advanced NSCLC
• PD or relapse after
standard treatments
LY2835219
150 mg or 200 mg q12h,
days 1–28
PD
(n=57)
Primary endpoint
• Safety
Secondary endpoints
• Anti-tumour activity, pharmacodynamics
and predictive biomarkers
Goldman et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8026)
8026: Clinical activity of LY2835219, a novel cell cycle inhibitor selective for
CDK4 and CDK6, in patients with non-small cell lung cancer – Goldman JW et al
• Key results
Percentage change from baseline
80
Disease control rate (CR + PR + SD)
All NSCLC (n=57) 49.1%
KRAS mutant (n=29) 55.2%
KRAS wild-type (n=24) 37.5%
60
40
20
0
†
SQ
SQ
SQ
–20
–40
–60
–80
–100
KRAS status:
Mutant
Best overall
response
All NSCLC KRAS mutant
N=57, n (%) N=29, n (%)
KRAS wild-type
N=24, n (%)
CR
0 (0.0)
0 (0.0)
0 (0.0)
PR
2 (3.5)
1 (3.4)
1 (4.2)
SD
26 (45.6)
15 (51.7)
8 (33.3)
PD
14 (24.6)
7 (24.1)
7 (29.2)
Not evaluable
15 (26.3)
6 (20.7)
8 (33.3)
SQ
Wild-type
Unknown
Each bar represents
one evaluable patient
†Value truncated
• Conclusions
– LY2835219 demonstrated anti-tumour activity in advanced NSCLC, particularly in KRAS
mutation-positive disease
– LY2835219 had an acceptable safety profile
Goldman et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8026)
8000: Onartuzumab plus erlotinib versus erlotinib in previously treated stage
IIIb or IV NSCLC: Results from the pivotal phase III randomized, multicenter,
placebo-controlled METLung (OAM4971g) global trial – Spigel DR et al
• Study objective
– To evaluate the efficacy and safety of onartuzumab in combination with erlotinib
vs erlotinib alone in patients with stage IIIB/IV NSCLC
Erlotinib 150 mg/day +
onartuzumab 15 mg/kg IV q3w
(n=250)
Key patient inclusion criteria
•
Stage IIIB/IV NSCLC
•
MET-positive (2+ or 3+)
•
1 prior platinum-based
treatment
•
ECOG PS 0–1
(n=490)
Primary endpoint
• OS
R
1:1
PD
Stratification
• EGFR mutant vs wild-type, MET 2+ vs 3+,
number of prior treatments, histology
Erlotinib 150 mg/day +
placebo
(n=249)
PD
Secondary endpoints
• PFS, ORR, QoL, safety and PK
Spigel et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8000)
8000: Onartuzumab plus erlotinib versus erlotinib in previously treated stage
IIIb or IV NSCLC: Results from the pivotal phase III randomized, multicenter,
placebo-controlled METLung (OAM4971g) global trial – Spigel DR et al
• Key results
– An independent committee recommended to stop the trial for futility
OS
PFS
1.0
Median 9.1 months
(95% CI 7.1, 10.2)
0.8
HR 1.27
(95% CI 0.98, 1.65)
p=0.07
0.6
0.4
Median 6.8 months
(95% CI 6.1, 7.5)
0.2
0.0
Probability of PFS
Probability of OS
1.0
Median 2.6 months
(95% CI 1.5, 2.8)
0.8
HR 0.99
(95% CI 0.81, 1.2)
p=0.92
0.6
0.4
0.2 Median 2.7 months
(95% CI 2.4, 2.9)
0.0
0
3
6
9
12
15
18
Time (months)
Placebo+erlotinib (n=249)
Onartuzumab+erlotinib (n=250)
21
0
3
6
9
12
15
Time (months)
Censored
Placebo+erlotinib (n=249)
Censored
Onartuzumab+erlotinib (n=250)
ORR 8.8% placebo+erlotinib vs. 6.4% onartzumab+erlotinib
• Conclusions
– Addition of onartuzumab did not confer any benefit on survival in patients with
MET-positive 2/3L NSCLC regardless of MET FISH or EGFR mutation status
Spigel et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8000)
8041: Randomized phase III study comparing gefitinib (G) with erlotinib (E) in
patients (pts) with previously treated advanced lung adenocarcinoma (LA):
WJOG 5108L – Katakami N et al
• Study objective
– Phase III study to demonstrate non-inferiority of gefitinib to erlotinib as second-line therapy
in patients with advanced lung adenocarcinoma
Key patient inclusion criteria
Erlotinib 150 mg/day
(n=280)
• Lung adenocarcinoma
• Stage III/IV or recurrence
• ECOG PS 0–2
• ≥1 previous CT regimen
R
PD
Stratification
• Gender, PS, stage, smoking history,
EGFR status, institution, prior regimen
• Evaluable disease
• Age ≥20 years
(n=561)
Primary endpoint
• PFS
• Patients
Gefitinib 250 mg/day
(n=279)
PD
Secondary endpoints
• OS, RR, DCR, safety and time to treatment
failure (TTF)
– Median age of 67/68 years; % female 54.3/54.5; % PS0 50.0/40.1; % PS1 42.5/53.8;
% stage IV 69.3/69.2; % 2nd-line 68.9/71.3; % smokers 49.6/49.5; for erlotinib and gefitinib
Katakami et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8041)
8041: Randomized phase III study comparing gefitinib (G) with erlotinib (E) in
patients (pts) with previously treated advanced lung adenocarcinoma (LA):
WJOG 5108L – Katakami N et al
• Key results
– TTF: 5.3 vs 5.6 months (HR 1.032, 95% CI 0.866, 1.231) for erlotinib vs gefitinib
– OS: 24.5 vs 22.8 months (HR 1.038, 95% CI 0.833, 1.394) for erlotinib vs gefitinib
– Median PFS and OS in patients with activating mutation for erlotinib vs gefitinib
were 10.1 vs 8.9 months (p=0.532) and 32.0 vs 26.6 months (p=0.111),
respectively
• Conclusion
– Non-inferiority in PFS was not demonstrated between erlotinib and gefitinib, and there were
no significant differences in PFS or OS
Katakami et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8041)
8046: Efficacy and safety results from CurrentS, a double-blind, randomized,
phase III study of second-line erlotinib (150 mg versus 300 mg) in current
smokers with advanced non-small cell lung cancer (NSCLC) – Smit EF et al
• Study objective
– To investigate the use of a higher than usual dose of erlotinib in smokers with stage IIIB/IV
NSCLC
Erlotinib 150 mg/day
(n=154)
Key patient inclusion criteria
• Stage IIIB/IV
• Failed first-line platinum-based
CT
R
PD
Stratification
• Disease stage, ECOG PS,
geographic region
• Current smokers
(n=213)
Primary endpoint
• PFS
Erlotinib 300 mg/day
(n=159)
PD
Secondary endpoints
• OS, DCR and safety
• Patients
– % female 22/22; % Asian 30/31; median pack-years 31/30; % adenocarcinoma 65/60;
% squamous cell carcinoma 27/30; % large cell carcinoma 4/4; for standard- and highdose erlotinib, respectively
Smit et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8046)
8046: Efficacy and safety results from CurrentS, a double-blind, randomized,
phase III study of second-line erlotinib (150 mg versus 300 mg) in current
smokers with advanced non-small cell lung cancer (NSCLC) – Smit EF et al
• Key results:
– No significant increase observed in PFS when erlotinib given at 300 mg vs 150 mg
• Conclusions
– Increased dose of erlotinib did not improve survival of smokers with NSCLC and was
associated with decreased tolerability
Smit et al. J Clin Oncol 2014; 32 (suppl; abstr 8046)
8103: Antitumor activity of alectinib (CH5424802/RO5424802) for ALKrearranged NSCLC with or without prior crizotinib treatment in bioequivalence
study – Nakagawa K et al
• Study objective
– To investigate bioequivalence and food effect of a high-dose formulation of the
highly selective ALK inhibitor, alectinib, in ALK-rearranged NSCLC
• Study design
– Crossover study of alectinib 300 mg bid with 20/40 mg capsules for 10 days
followed by 150 mg capsules for 10 days, followed by 150 mg after meals for
last 10 days
• Key results
– Among 35 patients with ALK-rearranged NSCLC exposure was similar between
20/40 mg and 150 mg capsules
– Food effect with 150 mg capsules at steady state was negligibly small
• Conclusions
– Exposure was similar between capsule strengths, with no food effects
– Alectinib 150 mg capsules were efficacious for ALK-rearranged NSCLC patients
regardless of crizotinib treatment history, with quick and high efficacy and a
good safety profile
Nakagawa et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8103)
8018: Randomized, double-blinded study of dacomitinib, an irreversible panhuman epidermal growth factor receptor (HER) inhibitor, versus erlotinib for
second-line/third-line therapy of locally advanced/metastatic non-small cell
lung cancer (ARCHER 1009) – Ramalingam SS et al
• Study objective
– To compare the efficacy and safety of the irreversible pan-HER kinase inhibitor,
dacomitinib, with erlotinib as second-/third-line therapy for locally advanced
metastatic NSCLC
• Study design
– Interim analysis of a randomised, placebo-controlled phase III study of
dacomitinib 45 mg/day or erlotinib 150 mg/day in patients with advanced NSCLC
– Primary endpoint: PFS; secondary endpoints: OS and best overall response
• Key results
– 878 patients were enrolled, median age 63 years; 64% male; 76% Caucasian;
90% ECOG PS 0/1; 69% adenocarcinoma; 18% never smokers
– Median PFS was 2.6 months in both the dacomitinib and erlotinib groups, with
HR 0.941 (95% CI 0.802, 1.104; p=0.229) across all patient population and HR
1.022 (95% CI 0.834, 1.253; p=0.587) in KRAS wild-type patients
• Conclusion
– Dacomitinib was not superior to erlotinib in pretreated patients with advanced
NSCLC
– Data from the EGFR mutation-positive subset will be reported when mature
Ramalingam et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8018)
8022: Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538)
plus erlotinib in patients (pts) with epidermal growth factor receptor mutant
(EGFR MT) advanced NSCLC – Rizvi NA et al
• Study objective
– To evaluate the safety and efficacy of nivolumab added to erlotinib in patients
with advanced NSCLC and EGFR mutations
Key patient inclusion criteria
• Stage IIIB/IV NSCLC
• Non-squamous
• EGFR+
Nivolumab 3 mg/kg q2w
+ erlotinib 150 mg/day
PD
• CT naïve
(n=21)
Primary endpoint
• Safety and tolerability
Secondary endpoints
• Objective response rate and PFS at
24 weeks
Rizvi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8022)
8022: Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538)
plus erlotinib in patients (pts) with epidermal growth factor receptor mutant
(EGFR MT) advanced NSCLC – Rizvi NA et al
• Key results
– Grade 3 treatment-related AEs occurred in 24% of patients (no grade 4 reported)
– Objective response rate was 19% (PR in 3 of 20 patients treated previously with erlotinib
and 1 of 1 patient with no prior erlotinib)
– Survival outcomes among all patients are shown in the table
Nivolumab+erlotinib (n=21)
PFS
PFS rate (95% CI) at 24 weeks, %
Median (range) PFS, weeks
51 (28, 70)
29.4 (4.6, 81.7+)
OS
1-year OS rate (95% CI), %
73 (46, 88)
Median (range) OS, weeks
NR (10.7+, 86.9+)
• Conclusion
– Nivolumab in combination with erlotinib may provide durable clinical benefit in EGFR
mutation-positive advanced NSCLC, with evidence of activity at TKI resistance
Rizvi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8022)
7500: A multinational phase III randomized trial with or without consolidation
chemotherapy using docetaxel and cisplatin after concurrent chemoradiation
in inoperable stage III non-small cell lung cancer (CCheIN) – Park K et al
• Study objective
– To assess the efficacy of consolidation CT with docetaxel and cisplatin after CCRT with
the same agents in patients with inoperable stage III NSCLC
CCRT* + D (20 mg/m2)
+ P (20 mg/m2)
(n=211)
Key patient inclusion criteria
• Inoperable stage III NSCLC
• Locally advanced
• ECOG PS 0–1
R
1:1
PD
Stratification
• Centre
• Performance
• Age >18 years
(n=437)
Primary endpoint
• PFS
CCRT*† alone
(n=209)
PD
Secondary endpoints
• OS, RR, pattern of failure and safety
*DP (20 mg/m2 each per week for 6 weeks, total dose of 66 Gy of thoracic
RT as 33 fractions); †Additional DP (35 mg/m2 each on days 1 + 8, q3w);
CCRT, concurrent chemoradiotherapy; D, docetaxel; C, cisplatin
Park et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7500)
7500: A multinational phase III randomized trial with or without consolidation
chemotherapy using docetaxel and cisplatin after concurrent chemoradiation
in inoperable stage III non-small cell lung cancer (CCheIN) – Park K et al
• Key results
– Survival was similar between treatment arms during a median follow-up of 50.7 months
PFS
Progression-free survival
1.0
CCRT alone
CCRT + consolidation
0.8
0.6
HR 0.906
(95% CI 0.734, 1.119)
p=0.410
0.4
0.2
0.0
0
12
24
36 48
60
Time (months)
72
84
Patients
Events
mPFS (95% CI)
CCRT alone
209
180
8.05 (7.56, 8.90)
CCRT + consolidation
211
169
9.10 (7.92, 10.94)
Park et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7500)
7500: A multinational phase III randomized trial with or without consolidation
chemotherapy using docetaxel and cisplatin after concurrent chemoradiation
in inoperable stage III non-small cell lung cancer (CCheIN) – Park K et al
• Conclusions
– The primary endpoint of increased PFS with the addition of weekly docetaxelcisplatin consolidation therapy was not met in this study
– Concurrent chemoradiotherapy alone should remain as the standard of care for
inoperable stage III NSCLC
Park et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7500)
LBA8006^: REVEL: A randomized, double-blind, phase III study of docetaxel
(DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the
second-line treatment of stage IV non-small cell lung cancer (NSCLC) following
disease progression after one prior platinum-based therapy – Pérol M et al
• Study objective
– To compare the efficacy and safety of ramucirumab+docetaxel with
placebo+docetaxel in pretreated patients with stage IV non-squamous and
squamous NSCLC
Ramucirumab 10 mg/kg +
docetaxel 75 mg/m2 q3w
(n=628)
Key patient inclusion criteria
• Stage IV NSCLC
• Non-squamous or squamous
• Previous platinum-based CT
• ECOG PS 0/1
(n=1253)
Primary endpoint
• OS
R
1:1
PD
Stratification
• Gender, region (East Asia vs ROW),
ECOG PS (0 vs 1), prior
maintenance therapy
Placebo +
docetaxel 75 mg/m2 q3w
(n=625)
PD
Secondary endpoints
• PFS, objective response rate, safety and PROs
Pérol et al. J Clin Oncol 2014; 32 (suppl 5; abstr LBA8006^)
LBA8006^: REVEL: A randomized, double-blind, phase III study of docetaxel
(DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the
second-line treatment of stage IV non-small cell lung cancer (NSCLC) following
disease progression after one prior platinum-based therapy – Perol M et al
• Key results
– Ramucirumab+docetaxel significantly improved survival over placebo+docetaxel
PFS
OS
Overall survival (%)
100
31.8%
27.0%
Progression-free survival (%)
RAM+DOC
PL+DOC
80
Censoring rate
Median (95% CI)
10.5 (9.5, 11.2)
9.1 (8.4, 10.0)
100
RAM+DOC vs PL+DOC:
Stratified HR (95% CI) 0.857 (0.751, 0.979)
Stratified log-rank p=0.0235
60
40
20
RAM+DOC
PL+DOC
Censored
0
3
6
9
12
18
21
24
27
30
33
36
527
501
415
386
60
RAM+DOC vs PL+DOC:
Stratified HR (95% CI) 0.762 (0.677, 0.859)
Stratified log-rank p<0.0001
40
20
RAM+DOC
PL+DOC
Censored
329
306
231
197
156
129
103
86
70
56
RAM, ramucirumab; DOC, docetaxel
0
3
6
9
12
15
18
21
24
27
30
33
36
7
4
3
3
3
2
0
0
0
0
0
0
Survival time (months)
Survival time (months)
Number at risk
RAM+DOC 628
PL+DOC 625
15
11.1%
6.7%
80
0
0
Censoring Rate
Median (95% CI)
4.5 (4.2, 5.4)
3.0 (2.8, 3.9)
RAM+DOC
PL+DOC
45
36
23
23
11
9
2
0
0
0
Number at risk
RAM+DOC 628
PL+DOC
625
383
301
204
172
120
95
59
37
38
17
11
9
Pérol et al. J Clin Oncol 2014; 32 (suppl 5; abstr LBA8006^)
LBA8006^: REVEL: A randomized, double-blind, phase III study of docetaxel
(DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the
second-line treatment of stage IV non-small cell lung cancer (NSCLC) following
disease progression after one prior platinum-based therapy – Perol M et al
• Conclusions
– REVEL met its primary endpoint of OS improvement
– Ramucirumab+docetaxel showed statistically significant improvement in PFS
and ORR compared with placebo+docetaxel
– Benefits were similar in non-squamous and squamous patients
– No unexpected AEs were identified
– REVEL is the first study showing that the addition of a novel agent to standard
chemotherapy improves survival in stage IV NSCLC patients with progression
after platinum-based chemotherapy
Pérol et al. J Clin Oncol 2014; 32 (suppl 5; abstr LBA8006^)
7508: A randomized trial of prophylactic cranial irradiation versus observation
in patients with fully resected stage IIIA N2 non-small cell lung cancer and high
risk of cerebral metastases after adjuvant chemotherapy – Wang S-Y et al
• Study objective
– To evaluate survival benefit of prophylactic cranial irradiation (PCI) in patients
with resected stage IIIA-N2 NSCLC and a high risk of cerebral metastases
following adjuvant chemotherapy
Key patient inclusion criteria
• Resected stage IIIA-N2 NSCLC
• High risk for cerebral metastases
• No recurrence following postoperative adjuvant CT (≥2 cycles)
• ECOG PS 0–2
(n=156)
Primary endpoint
• DFS
Study was terminated due to slow accrual
Prophylactic cranial
irradiation
(30 Gy in 10 fractions)
(n=81)
PD
Observation
(n=75)
PD
R
Secondary endpoints
• Incidence of brain metastases, OS, toxicity
and QoL
Wang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7508)
7508: A randomized trial of prophylactic cranial irradiation versus observation
in patients with fully resected stage IIIA N2 non-small cell lung cancer and high
risk of cerebral metastases after adjuvant chemotherapy – Wang S-Y et al
• Key results
– Prophylactic cranial irradiation increased disease-free survival compared with control
OS
1.0
1.0
0.8
0.8
Overall survival
(probability)
Disease-free survival
(probability)
Disease-free survival
0.6
Median
(months)
PCI
28.5
Control 21.2
HR 0.67 (95% CI 0.46, 0.98), p=0.037
0.4
0.2
0
0
6
12
18
24
30
36
42
48
Time from randomisation (months)
0.6
Median
(months)
PCI
31.2
Control 27.4
HR 0.81 (95% CI 0.56, 1.16), p=0.310
0.4
0.2
0
54
60
0
6
12
18
24
30
36
42
48
54
60
Time from randomisation (months)
• Conclusion
– Prophylactic cranial irradiation prolonged disease-free survival and reduced the incidence
of brain metastases in patients with fully resected stage IIIA NSCLC who were at high risk
of cerebral metastases following adjuvant CT
Wang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7508)
8036^: NCIC CTG BR.26: A phase III randomized, double blind, placebo
controlled trial of dacomitinib versus placebo in patients with
advanced/metastatic non-small cell lung cancer (NSCLC) who received prior
chemotherapy and an EGFR TKI – Ellis PM et al
• Study objective
– To investigate the efficacy and safety of the irreversible pan-HER inhibitor, dacomitinib, in
pretreated patients with advanced NSCLC
• Study design
– Randomised phase III study of dacomitinib 45 mg/day (n=480) vs placebo (n=240) in
patients with advanced or metastatic NSCLC after 1–3 lines of CT and an EGFR TKI
• Key results
– Median OS was similar between dacomitinib and placebo (6.8 vs 6.3 months, respectively,
HR 1.002 [95% CI 0.828, 1.212]; p=0.9873)
• OS in KRAS wild-type HR 0.792 (95% CI 0.606, 1.034; p=0.0858) and KRAS mutant
HR 2.104 (95% CI 1.05, 4.216; p=0.0330)
• OS in EGFR wild-type HR 0.925 (95% CI 0.7008, 1.208; p=0.5656) and EGFR mutant
HR 0.981 (95% CI 0.669, 1.438; p=0.9218)
– PFS was significantly improved with dacomitinib (2.7 vs 1.4 months with placebo; HR 0.661
[95% CI 0.551, 0.793]; p<0.0001)
– Dacomitinib was associated with longer time to deterioration of cough (p=0.0001),
dyspnoea (p=0.049) and pain (p=0.049)
• Conclusion
– Dacomitinib showed no activity in patients with pretreated NSCLC, although there was a
trend to improved survival in patients with KRAS wild-type
Ellis et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8036^)
8037: Randomized phase III trial of stereotactic radiosurgery (SRS) versus
observation for patients with asymptomatic cerebral oligo-metastases in nonsmall cell lung cancer (NSCLC) – Lim SH et al
• Study objective
– To determine if early treatment with stereotactic radiosurgery (SRS) can
improve OS in NSCLC patients with asymptomatic oligo-brain metastases
Key patient inclusion criteria
SRS then systemic CT
(n=53)
PD
Systemic CT alone
(n=52)
PD
• NSCLC
• Synchronous asymptomatic
brain metastases (<3 cm)
R
1:1
• >18 years
(n=105)
Primary endpoint
• OS
Secondary endpoints
• CNS disease progression and
salvage brain treatment
Lim et al. J Clin Oncol 2014; 32 (suppl; abstr 8037)
8037: Randomized phase III trial of stereotactic radiosurgery (SRS) versus
observation for patients with asymptomatic cerebral oligo-metastases in nonsmall cell lung cancer (NSCLC) – Lim SH et al
• Key results
– Median OS (95% CI): 15.8 (8.1, 23.5) months with SRS+CT vs 17.6 (12.4, 22.8)
months with CT alone (p=0.346)
– CNS disease progression: 9.4 vs 8.7 months for SRS+CT vs CT (p=0.579)
– Salvage treatment for progression of CNS disease was more frequent with CT
alone (52.8% vs 47.2% with SRS+CT), but was not significant (p=0.201)
– Independent risk factors associated with poor OS were:
• Higher extra-cranial disease activity, number of brain metastases (≥2), age
older than 65 years and non-adenocarcinoma histology
• Conclusion
– SRS followed by systemic CT did not improve OS in asymptomatic oligo-brain
metastases NSCLC patients compared with upfront CT alone
Lim et al. J Clin Oncol 2014; 32 (suppl; abstr 8037)
7509: Postoperative radiotherapy (PORT) for pathologic N2 non-small cell lung
cancer (NSCLC) treated with adjuvant chemotherapy: A review of the National
Cancer Database – Robinson CG et al
• Study objectives
– To investigate the impact on survival of modern postoperative radiotherapy
(PORT) on OS in N2 NSCLC after surgery and adjuvant CT
• Study design
– Retrospective analysis of data from the National Cancer Database from 4483
patients who had undergone complete resection (R0) and adjuvant CT between
2006 and 2010, of whom 1850 (41.3%) received PORT
– Stratified by use of PORT (≥45 Gy)
Robinson et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7509)
7509: Postoperative radiotherapy (PORT) for pathologic N2 non-small cell lung
cancer (NSCLC) treated with adjuvant chemotherapy: A review of the National
Cancer Database – Robinson CG et al
• Key results
– Use of PORT was associated with a
significant increase in median OS
(figure)
• Conclusion
1.00
Survival (probability)
– In multivariate analysis, younger
age, treatment at an academic
facility, higher income, lower
Charlson score, smaller tumour,
≥ lobectomy, and use of PORT (HR
for PORT 0.89 [95% CI 0.80, 0.99];
p=0.029) were predictive of
improved OS for the entire group
OS
Standard treatment
PORT
0.75
0.50
0.25
Median OS: 45.0 vs 40.9 months
p=0.029
0.00
0
12
24
36
48
Time (months)
60
72
– Modern PORT may confer an additional 5% survival advantage in
NSCLC patients after complete resection beyond that achieved with
adjuvant CT alone
Robinson et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7509)
Other malignancies
SCLC and mesothelioma
8034: Targeting FGFR1-amplified lung squamous cell carcinoma with the
selective pan-FGFR inhibitor BGJ398 – Nogova L et al
• Study objective
– To investigate the potent, selective pan-FGFR inhibitor, BGJ398, in patients with FGFR1amplified lung squamous cell carcinoma
• Study design
– Subgroup analysis of phase I dose-escalation study of patients with FGFR1-amplified
advanced or metastatic lung squamous cell carcinoma treated with BGJ398 5–150 mg/day
in 28-day cycles who had progressed following at least one line of therapy
• Key results
– 26 patients were treated at the maximum tolerated dose of 150 mg/day (n=3), 125 mg/day
(n=21) or 100 mg/day (n=2)
– Of the 26 patients receiving ≥100 mg/day, 4 patients achieved PR; 9 patients had SD,
6 patients had PD and status was unknown in 7 patients
– AEs were manageable and reversible
• Conclusion
– This molecular targeted therapy shows evidence of activity supporting further development
of BGJ398 in FGFR1-amplified lung squamous cell carcinoma
FGFR, fibroblast growth factor receptors
Nogova et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8034)
8035: A phase 1b open-label multicenter study of AZD4547 in patients with
advanced squamous cell lung cancers: Preliminary antitumor activity and
pharmacodynamic data – Paik PK et al
• Study objective
– To investigate the safety and efficacy of the FGFR1-3 inhibitor, AZD4547, in squamous
cell lung cancer
• Study design
– Phase I expansion study of AZD4547 80 mg bid q3w in patients with previously treated
stage IV FGFR1-amplified squamous cell lung cancer stratified by high and low levels
– Primary endpoint: safety; secondary endpoint: preliminary anti-tumour activity
• Key results
– 15 patients were treated with a median (range) age of 66 (48–72) years; 40% female;
67% WHO PS restricted activity
– Grade ≥3 treatment-related AEs occurred in 20% with 3 patients discontinuing due to AEs
(asthenia, retinal oedema and deterioration)
– 14 patients had evaluable tumour response (1 PR, 4 SD, 9 PD)
• Conclusions
– AZD4547 was well tolerated in patients with FGFR1-amplified squamous cell lung cancer
– Prespecified primary efficacy endpoint was not met
FGFR, fibroblast growth factor receptors
Paik et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8035)
7506: A randomized double-blind phase II trial of platinum (P) plus etoposide
(E) with or without concurrent ZD6474 (Z) in patients (pts) with previously
untreated extensive stage (ES) small cell lung cancer (SCLC): Hoosier
Oncology Group LUN06-113 – Sanborn RE et al
• Study objective
– To evaluate the efficacy and tolerability of concurrent ZD6474 added to
standard platinum+etoposide treatment in patients with extensive-stage SCLC
Key patient inclusion criteria
• Untreated extensive-stage
SCLC or high grade poorly
differentiated
neuroendocrine tumours
R
1:1
• ECOG PS 0–1
(n=74)
Primary endpoint
• Time to disease progression
*Cisplatin 60 mg/m2 day 1/etoposide 120 mg/m2 days 1–3 OR
Carboplatin AUC5 day 1/etoposide 100 mg/m2 days 1–3 q3w
for 4 cycles
ZD6474 (100 mg qd) +
CT*
(cisplatin/carboplatin,
etoposide) (n=41)
PD
Placebo + CT*
(cisplatin/carboplatin,
etoposide)
(n=33)
PD
Secondary endpoints
• Safety, RR, DCR and OS
Sanborn et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7506)
7506: A randomized double-blind phase II trial of platinum (P) plus etoposide
(E) with or without concurrent ZD6474 (Z) in patients (pts) with previously
untreated extensive stage (ES) small cell lung cancer (SCLC): Hoosier
Oncology Group LUN06-113 – Sanborn RE et al
• Key results
– Higher incidence of grade 3/4 toxicities observed with ZD6474 vs placebo (69% vs 37%)
– Survival was not improved by ZD6474
Time to progression
Censored
Log-rank p=0.9518
Probability of survival
1.0
0.6
5.6 vs 5.5 months with ZD6474 vs placebo
(HR 1.13; p=0.66)
0.4
0.2
0.0
• Conclusions
Placebo
ZD6474
0.8
31
31
16
16
1
2
1
1
1
0
1
0
0
5
10
15
20
25
30
Time to disease progression (months)
– ZD6474 in combination with CT did not improve outcomes for patients with newlydiagnosed extensive stage SCLC
– Toxicity was increased with the combination compared with CT alone
– Therefore, ZD6474 is not recommended for unselected patients with extensive SCLC
*PE, platinum+etoposide
Sanborn et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7506)
7505: Randomized phase II-III study of bevacizumab in combination with
chemotherapy in previously untreated extensive small-cell lung cancer: Results
from the IFCT-0802 trial – Pujol J-L et al
• Study objective
– Phase II study to assess the efficacy and safety of adding bevacizumab to first-line
standard CT in extensive disease SCLC
Key patient
inclusion criteria
• Extensive
disease SCLC
• ECOG PS 0–2
• Age ≤75 years
• Weight loss
<10%
2 x induction
cycles of CT
(cisplatin+
etoposide) or
(cisplatin+
cyclophosphamide
+epidoxorubicin+
etoposide)
(n=147)
4 x cycles of CT
(n=37)
R
1:1
PD
Stratification
• ECOG PS, liver metastases, gender,
induction CT, centre
4 x cycles of CT +
bevacizumab 7.5 mg/kg
q3w
(n=37)
Primary endpoint
Secondary endpoints
• Response rate 2 cycles after randomisation
• PFS, OS, biomarkers, safety and QoL
PD
• Patients
–
Median number of CT cycles was 6 in both treatment arms
Pujol et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7505)
7505: Randomized phase II-III study of bevacizumab in combination with
chemotherapy in previously untreated extensive small-cell lung cancer: Results
from the IFCT-0802 trial – Pujol J-L et al
• Key results
– Survival was unchanged by the addition of bevacizumab
OS
CT alone (n=37)
mOS = 13.3
(95% CI 9.8, 16.6)
Probability of survival
1.0
0.8
0.4
CT plus bevacizumab (n=37)
mOS = 11.1
(95% CI 8.7, 14.0)
0.2
HR for CT alone = 0.80
(95% CI 0.50, 1.28)
0.6
0.0
0
6
12
18
24
30
Months after randomisation
• Conclusions
– The addition of bevacizumab to CT did not improve survival in patients with extensivestage SCLC
– Phase III study has been cancelled
Pujol et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7505)
7519: Randomized phase III trial in extensive-disease small cell lung cancer
comparing first-line etoposide to topotecan in combination with platinum
– Mau-Soerensen M et al
• Study objective
– To compare first-line treatment with etoposide to topotecan in combination with platinum in
patients with extensive disease SCLC
• Study design
– Interim analysis of a randomised phase III study of 6 cycles of topotecan 2.0 mg/m 2
days 1–3 + cisplatin 50 mg/m2 day 3, or etoposide 120 mg/m2 days 1–3 + carboplatin
AUC5 day 1, q3w in previously untreated patients with extensive disease SCLC
– Primary endpoint: OS; secondary endpoints: response, PFS and safety
• Key results
– Trial stopped prematurely due to poor accrual (281 patients recruited out of 380 planned)
– Survival was similar between arms (OS: 10.9 vs 9.8 months with topotecan and etoposide
[HR 0.87, 95% CI 0.67, 1.17, p=0.26; PFS: 6.9 vs 6.6 months [HR 0.93, 95% CI 0.72,
1.19], p=0.55)
• Conclusions
– No differences in survival observed between first-line treatment with etoposide and
topotecan in patients with extensive disease SCLC
– Significantly more haemtological toxicity was observed in the etoposide group
Mau-Soerensen et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7519)
7502: Randomized trial on thoracic radiotherapy (TRT) in extensive-stage small
cell lung cancer – Slotman BJ et al
• Study objective
– To assess the role of thoracic radiotherapy (TRT) in extensive-stage SCLC
patients receiving prophylactic cranial irradiation (PCI) following 4–6 cycles of
standard CT
TRT (30 Gy/10 fractions)
+ PCI (n=247)
Key patient inclusion criteria
PD
• Extensive-stage SCLC
• WHO PS 0–2
• Any response to 4–6 cycles
of platinum-based CT
(n=495)
Primary endpoint
• OS
R
1:1
Stratification
• Institute
• Presence of intrathoracic disease
PCI
(n=248)
PD
Secondary endpoints
• Local control, failure pattern and toxicity
Slotman et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7502)
7502: Randomized trial on thoracic radiotherapy (TRT) in extensive-stage small
cell lung cancer – Slotman BJ et al
• Key results
– Addition of TRT to PCI improved 2-year survival
OS
PFS
1.0
0.8
24 months (95% CI), %
Thoracic RT :
13 (8.8, 18.7)
No thoracic RT : 3 (1.5, 7.6)
0.6
Survival difference at:
18 months: p=0.03
24 months: p=0.004
0.4
No
thoracic RT
0.2
Thoracic RT
247
147
67
26
0.0 248
0
160
61
17
6
• Conclusion
12
Time (months)
18
HR (95% CI) 0.73 (0.61, 0.87)
p=0.001
0.8
PFS Probability
OS Probability
1.0
Thoracic RT
0.6
0.4
0.2
14 Thoracic RT
5 No thoracic RT
24
No
thoracic RT
247
163
59
31
15
10
9
0.0 248
0
126
48
15
8
3
3
3
6
9
12
15
18
Time (months)
9
3
21
7 Thoracic RT
3 No thoracic RT
24
– Although TRT did not influence the median OS (primary endpoint) or the risk of death after
1 year (data not shown), it significantly increased 2-year survival and is an option in
extensive-stage SCLC patients with a response to initial CT
Slotman et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7502)
7503: Prophylactic cranial irradiation (PCI) has a detrimental effect on the
overall survival (OS) of patients (pts) with extensive disease small cell lung
cancer (ED-SCLC): Results of a Japanese randomized phase III trial
– Seto T et al
• Study objective
– To investigate impact of prophylactic cranial irradiation on survival of patients with
extensive-disease SCLC
Arm A
Prophylactic cranial
Key patient inclusion criteria
irradiation
(n=84)
• Extensive-disease SCLC
• Any response to first-line
platinum doublet CT
• No BM by MRI assessment
PD
Stratification
• Age, ECOG PS, response, institution
R
• ECOG PS 0–2
(n=163)
Arm B
Primary endpoint
• OS
Observation alone
(n=79)
PD
Secondary endpoints
• Time to BM, PFS, safety, MMSE
• Patients
– Patients in Arms A/B had median age 69/68 years; % male 81/89; % ECOG PS 0–1 95/97;
% PR+MR response to CT 88/85
BM, brain metastases; MMSE, Mini-Mental State Examination
Seto et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7503)
7503: Prophylactic cranial irradiation (PCI) has a detrimental effect on the
overall survival (OS) of patients (pts) with extensive disease small cell lung
cancer (ED-SCLC): Results of a Japanese randomized phase III trial
– Seto T et al
• Key results
– Study was terminated because of futility
– Prophylactic cranial irradiation had no positive impact on OS (figure) but reduced the risk
of brain metastases (32.4% vs 58.0% at 12 months; Gray’s test, p<0.001)
100
Arm A: PCI
n=84
Arm B: no PCI
n=79
61
50
No. of OS events
80
Hazard ratio (95% CI)
1.38 (0.95, 2.02)
Median OS (95% CI), mo
10.1 (8.5, 13.2)
15.1 (10.2, 18.7)
60
Arm A: PCI
40
Arm B: No PCI
20
Stratified log-rank test: p=0.091 (2-sided)
0
0
• Conclusion
3
6
9
12
15
18
21
24
27
30
33
36
39
months
– Prophylactic cranial irradiation had no positive impact on OS in patients with extensivedisease SCLC with a confirmed absence of brain metastases
Seto et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7503)
7504: A randomized phase III study of cisplatin (CDDP), etoposide (ETOP) and
irinotecan versus topotecan as second-line chemotherapy in patients with
sensitive relapsed small-cell lung cancer (SCLC): Japan Clinical Oncology
Group study JCOG0605 – Goto K et al
• Study objective
– To confirm the superiority of cisplatin+etoposide+irinotecan over topotecan as second-line
treatment in patients with sensitive relapsed SCLC
Key patient inclusion criteria
Arm A
• SCLC
• Responded to first-line
treatment
• Relapse/PD ≥90 days after
treatment
Primary endpoint
• OS
PD
Stratification
• PS, localised/extensive disease, institution
R
• ECOG PS 0–2
(n=180)
5 cycles of
cisplatin (25 mg/m2 d1/8) +
etoposide (60 mg/m2 d1–3) +
irinotecan (90 mg/m2 d8)
(n=90)
Arm B
4 cycles of topotecan
(1.0 mg/m2 d1–5, q3w)
(n=90)
PD
Secondary endpoints
• PFS, response rate and safety
• Patients
– 180 patients with a median (range) age of 64 (44–75) years; 86% male; 75% extensive
disease; 97% ECOG PS 0–1
Goto et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7504)
7504: A randomized phase III study of cisplatin (CDDP), etoposide (ETOP) and
irinotecan versus topotecan as second-line chemotherapy in patients with
sensitive relapsed small-cell lung cancer (SCLC): Japan Clinical Oncology
Group study JCOG0605 – Goto K et al
• Key results
– OS was significantly longer with cisplatin+etoposide+irinotecan vs topotecan
Proportion of OS
1.0
OS
0.8
Topotecan
(n=90)
PEI
(n=90)
82
72
12.5 months
(10.8, 14.9)
18.2 months
(15.7, 20.6)
Events
PEI
0.6
MST (95% CI)
0.4
Topotecan
0.2
One-sided p
0.0079
HR (90% CI)
0.67 (0.51, 0.88)
0.0
0
6
12
18
24
30
36
42
48
Months after randomisation
54
60
66
– Cisplatin+etoposide+irinotecan had a higher incidence of grade 3/4 AEs than topotecan for
the following: leukopenia (80.0% vs 51.1%), anaemia (84.4% vs 27.8%), thrombocytopenia
(41.1% vs 27.8%), hyponatremia (16.7% vs 11.1%), diarrhoea (7.8% vs 0%) and febrile
neutropenia (31.1% vs 6.7%)
• Conclusion
– Combination CT with cisplatin, etoposide and irinotecan is a good option for second-line
CT for sensitive relapsed SCLC
PEI, cisplatin+etoposide+irinotecan
Goto et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7504)
7596: Comparison of cisplatin- versus carboplatin-based concurrent
chemoradiation for limited-stage small cell lung cancer using SEER-Medicare
data – Kim E et al
• Study objective
– To compare impact on survival of cisplatin vs carboplatin as concurrent chemoradiation
therapy (cCRT) in patients with limited-stage SCLC
• Study design
– Retrospective study of 1603 cases from the population-based SEER-Medicare lung cancer
database who had been treated with radiation within 60 days of starting cCRT
– Endpoints: OS and cause-specific survival (CSS)
• Key results
– Median age 72 years; 50% male; 85% stage III; 37% received cisplatin and this group was
younger (p=0.0039)
– Survival was not different between the cisplatin and carboplatin groups, respectively
• Median survival (months) was OS: 13.3 and 13.8 (p=0.59), CSS: 15.0 and 16.0 (p=0.86)
• 5-year survival was OS: 10.1% and 10.5% (p=0.16) and CSS: 25.2% and 22.3% (p=0.68)
• Conclusions
– Cisplatin and carboplatin had comparable survival even though the cisplatin group was
younger
– Therefore, carboplatin is preferable for patients with limited-stage SCLC providing that it
can be tolerated
Kim et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7596)
7532: Antimesothelin vaccine CRS-207 plus chemotherapy as front-line
treatment for malignant pleural mesothelioma (MPM) – Hassan R et al
• Study objective
– To investigate the impact of adding the anti-mesothelin vaccine, CRS-207, to
CT in patients with malignant pleural mesothelioma
• Study design
– Phase Ib study in which CT-naïve patients with unresectable malignant pleural
mesothelioma received two prime vaccinations with CRS-207 (1 x 109 CFU;
250 mL IV over 2 hours) 2 weeks apart, followed by up to 6 cycles of
pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) 3 weeks apart, and two
CRS-207 boost vaccinations 3 weeks apart
• Key results
– 16 patients with median age 68 years; 88% male; 50% ECOG PS 0
– Of 16 subjects evaluable for response, 69% (11/16) had confirmed PR post
CRS-207 and CT and 25% (4/16) had stable disease
• Conclusions
– CRS-207 combined with CT shows encouraging anti-tumour activity better than
those expected with CT alone
Hassan et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7532)
7507: Randomized trial of arginine deprivation with pegylated arginine
deiminase in patients with malignant pleural mesothelioma – Sziosarek PW et al
• Study objective
– To examine the efficacy and safety of the arginine-lowering agent ADI-PEG20
Key patient inclusion criteria
Arm A
• Inoperable mesothelioma
• Measurable disease by CT
• CT naïve or prior platinumdoublet
Best supportive care +
ADI-PEG20 320 IU/m2 IM
injection/week (36.8 mg/m2)
(n=44)
PD
Best supportive care
(n=24)
PD
R
• ASS1-deficient
• ECOG PS 0–1
(n=68)
Primary endpoint
• PFS
Arm B
Secondary endpoints
• Response rate, OS and toxicity
FDG-PET was used to measure plasma arginine, citrulline, ADI-PEG20 antibody, ASS1 methylation status
and metabolic response
ADI-PEG20, pegylated arginine deiminase; ASS1, argininosuccinate
synthetase 1; FDG-PET [18F]Fluorodeoxyglucose Positron
Sziosarek et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7507)
Emission Tomography
7507: Randomized trial of arginine deprivation with pegylated arginine
deiminase in patients with malignant pleural mesothelioma – Sziosarek PW et al
• Key results
– Survival was improved by ADI-PEG20
% alive and progression-free
PFS
100
BSC
BSC + ADI-PEG20
80
HR (95% CI) 0.51 (0.30, 0.86), p=0.012
60
Median PFS (67 events*)
BSC
1.9 months
BSC + ADI-PEG20
3.2 months
40
20
0
0
50 100 150 200 250 300 350 400 450
Time since randomisation (days)
*One patient remains progression-free and alive: 12 months (BSC + ADI+PEG20)
• Conclusion
– Arginine deprivation using ADI-PEG20 in patients with ASS1-deficient malignant
pleural mesothelioma almost halved the risk of progression
ADI-PEG20, pegylated arginine deiminase; ASS1,
argininosuccinate synthetase 1; BSC, best supportive care; FDGPET, [18F]Fluorodeoxyglucose Positron Emission Tomography
Sziosarek et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7507)
7589: T-cell inflamed phenotype and PDL1 expression in malignant
mesothelioma – Kindler HL et al
• Study objective
– To investigate markers of an anti-tumour immune response in malignant mesothelioma
• Study design
– Data from a 44 malignant mesothelioma gene expression dataset that were retrospectively
analysed using a melanoma-derived signature of T-cell inflammation and evaluated for
other immune response-related genes; results were validated by IHC (CD68 staining, CD8,
PD-L1)
• Key results
– 32% (14/44) of malignant mesothelioma had high CD8 gene expression
– 11% had a T-cell inflamed phenotype similar to melanoma
– Two patterns of PD-L1 expression were observed
• Conclusions
– Malignant mesothelioma is an inflammatory tumour with prominent infiltration with CD68+
cells (macrophages)
– A fraction of malignant mesothelioma showed CD8+ tumour infiltrating lymphocytes and
T-cell inflamed expression pattern similar to other tumours that benefit from immune
checkpoint blockade
– PD-L1 may be an appropriate target for future research in this cancer
IHC, immunohistochemistry
Kindler et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7589)
Other malignancies
Rare tumours
7525: Phase II trial of sunitinib in patients with thymic epithelial tumors (TET)
– Thomas A et al
• Study objective
– To evaluate the efficacy of sunitinib in patients with thymic epithelial tumours
who have failed prior platinum-based chemotherapy
• Study design
– Non-randomised, phase II study of sunitinib 50 mg qd in 6-week cycles for
4 weeks followed by 2 weeks off until PD
– Primary endpoint: objective response rate in two parallel cohorts (thymoma and
thymic carcinoma)
• Key results
– 24 patients with thymic carcinoma (median age 58 years, 63% male) and
16 patients with thymoma (median age 54 years, 44% male)
– Objective response and disease control rates were 26% (95% CI 10.2, 48.4)
and 91% (72.0, 98.9) for thymic carcinoma and 6% (0.2, 30.2) and 81% (54.4,
96.0) for thymoma, respectively
• Conclusions
– Sunitinib demonstrated anti-tumour activity unprecedented for a targeted agent
in previously treated patients with thymic carcinoma
– Activity was modest in thymoma
Thomas et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7525)
7526: A phase II study of milciclib (PHA-848125AC) in patients (pts) with thymic
carcinoma (TC) – Besse B et al
• Study objective
– To investigate the efficacy and safety of milciclib in patients with advanced thymic
carcinoma or B3 thymoma
• Study design
– Single arm phase II study of milciclib 150 mg qd 7 days on/7 days off in 2-week cycles in
patients with thymic carcinoma or B3 thymoma who have received only one prior systemic
therapy
– Primary endpoint: PFS rate at 3 months
• Key results
– 49 patients have been treated to date with median (range) age of 55 (21–80) years; 55%
female
– Successful treatment achieved with 14 of 28 evaluable patients with an overall 3-month
PFS rate of 50.0% (95% CI 30.6, 69.3)
– Toxicity was generally moderate with asthenia (10.3%) and nausea (7.7%) the most
common grade 3/4 AEs
• Conclusion
– The study has already met its predefined endpoint and supports the full investigation of
milciclib as a new therapeutic agent to treat thymic carcinoma and B3 thymoma
Besse et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7526)
7528: Capecitabine plus gemcitabine in thymic epithelial tumors: Final analysis
of a phase II trial – Buonerba C et al
• Study objective
– To investigate the efficacy and safety of capecitabine+gemcitabine in patients with thymic
epithelial tumours
• Study design
– Phase II study of capecitabine (650 mg/mq bid, days 1–14) + gemcitabine (1000 mg/mq,
days 1 and 8) q3w in patients with thymic epithelial tumours who have PD after at least
one prior systemic therapy
– Primary endpoint: radiographic response rate
• Key results
– 30 patients with median (range) age 57 (48–61) years; 60% male; 73% thymoma;
63% disease progression within 2 months from last dose of previous systemic CT
– Overall, there was a response rate of 40% (3 CR, 8 PR)
– PFS for patients with thymoma and thymic carcinoma was 11 (95% CI 6, 17) months and
6 (95% CI 3, 11) months, respectively
• Conclusion
– Capecitabine and gemcitabine is an active combination therapy in thymic epithelial
tumours and might deserve further prospective evaluation
Buonerba et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7528)
Developed in association with the
European Thoracic Oncology Platform
2014 ASCO Annual Meeting
30 May – 3 June 2014
Chicago, USA
Supported by Lilly and Company.
Lilly and Company has not influenced the content of this publication

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