Background

Small cell lung cancer (SCLC) predominantly develops in patients with significant smoking history, but 6-8% of patients in recent SCLC datasets have no tobacco exposure. Prior reports have suggested that SCLC in never smoking patients may have unique genomic traits.

Methods

We retrospectively analyzed records from SCLC patients reporting “never smoking” (NS, n = 54) or “current/former smoking” (C/FS, n = 609) status. Tumors were sequenced with the Tempus xT assay, including a targeted DNA panel (595-648 genes) and whole exome capture RNA-seq. Tumor immune cell infiltration was estimated from RNA expression data. PD-L1 positivity was defined by tumor expression > 1% using 22C3 pharmDx IHC. Statistical significance was assessed with Pearson’s chi-squared test or Fisher’s exact test, using a threshold of p < 0.05 or false discovery rate-adjusted q < 0.05.

Results

Compared with CF/S patients, NS patients were more likely to be female (70% vs 55%, p = 0.031). Tumors of NS patients had a lower prevalence of TP53 mutations (59% vs 85%, q < 0.001) but no significant difference in RB1 mutations (57% vs 63%, q = 0.600). Meanwhile, NS patients had a higher prevalence of EGFR (26% vs 2.6%, q < 0.001) and PIK3CA (15% vs 3.6%, q = 0.022) mutations. We also observed a trend towards higher rates of mutations in FGF4 (7.4% vs 1.6%, q = 0.100) and NF1 (7.4% vs 1.3%, q = 0.092). Gene fusions were infrequently found, with no notable difference across cohorts. With regard to the immune environment, NS patients had lower tumor mutation burden (2.59/Mb vs 4.99/Mb, p < 0.001) and a trend towards higher PD-L1 positivity (20% vs 9%, p = 0.086). NS tumors also had decreased immune cell infiltration (median 2% vs 10%, p = 0.008), and specifically a lower proportion of CD4+ and CD8+ T cells and higher proportion of macrophages.

Conclusions

The mutational landscape of SCLC in NS patients significantly differs from that of C/FS patients. Tumors of NS patients were more likely to harbor mutations in oncogenic drivers – such as EGFR and PIK3CA – and exhibited lower TMB and immune cell infiltration. These findings suggest that the occurrence of SCLC in NS patients may represent a distinct genomic entity and treatment implications should be further explored.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Ashok: Financial Interests, Personal, Full or part-time Employment, I am an employee of Tempus labs: Tempus Labs; Financial Interests, Personal, Stocks/Shares, I do have RSU from Tempus Labs: Tempus Labs. E. Mauer: Financial Interests, Institutional, Full or part-time Employment: Tempus Labs; Financial Interests, Personal, Stocks/Shares: Tempus Labs; Non-Financial Interests, Institutional, Proprietary Information: Tempus Labs. E.B. Garon: Financial Interests, Personal, Advisory Board: Novartis, Merck, BMS, EMD Serono, Regeneron, Sanofi, Natera, Shionogi, ABL Bio, Xilio, GSK, Boehringer Ingelheim, Eisai, Gilead, Eli Lilly, Personalis; Financial Interests, Institutional, Invited Speaker: Novartis, Merck, EMD Serono, Eli Lilly, Genetech, Iovance, Neon, Mirati, AstraZeneca, BMS, ABL Bio; Non-Financial Interests, Advisory Role, Scientific Advisory Board: Lungevity. A.E. Lisberg: Financial Interests, Personal, Research Grant: AstraZeneca, Daiichi Sankyo, Calithera Biosciences, Dracen Pharmaceuticals, WindMIL; Financial Interests, Personal, Advisory Board: Bristol-Meters Squibb, Leica Biosystems, Jazz Pharmaceuticals, Novocure, Pfizer, MorphoSys, Eli-Lilly, Oncocyte, Novartis, Regeneron, AstraZeneca; Financial Interests, Personal, Other, Employment (Immediate Family Member): Boston Scientific; Financial Interests, Personal, Stocks/Shares: Boston Scientific. J.W. Goldman: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Genentech, Eli Lilly, Janssen, AbbVie; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Genentech, Eli Lilly, Janssen, BMS, AbbVie. All other authors have declared no conflicts of interest.

Background

In the PEARLS/KEYNOTE-091 study of completely resected stage IB (T ≥4 cm) to IIIA NSCLC (AJCC v7) following ≤4 cycles of adjuvant chemotherapy as recommended per local guidelines (NCT02504372), pembrolizumab (pembro) significantly prolonged DFS vs placebo in the ITT population at the second interim analysis (IA2) (HR 0.76; P = 0.0014). The DFS benefit in the PD-L1 TPS ≥50% population was not significant (HR 0.82; P = 0.14). We present more detailed results for the PD-L1 subgroups.

Methods

Eligible patients were randomized 1:1 to pembro 200 mg or placebo Q3W for 18 doses. PD-L1 TPS <1% vs 1-49% vs ≥50% was a stratification factor. Dual primary end points were DFS in the ITT and TPS ≥50% populations. Data are from IA2 (median follow-up, 35.6 months).

Results

Of the 1177 randomized patients, PD-L1 TPS was <1% in 39.5%, 1-49% in 32.2%, and ≥50% in 28.3%. Baseline characteristics were generally balanced between the pembro and placebo arms in the ITT and TPS ≥50% populations and were generally similar in the ITT and TPS ≥50% populations. Grade 3-5 AE rates for pembro vs placebo were 34.1% vs 25.8% in the ITT and 37.8% vs 25.0% in the TPS ≥50% population; AEs led to discontinuation in 19.8% vs 5.9% and 23.2% vs 6.7%. Pembro improved DFS in the TPS ≥50%, 1-49%, and <1% subgroups (Table). Table: 930MO

Conclusions

As expected, median and long-term DFS estimates in the pembro arm were numerically improved in the PD-L1 TPS ≥50% subgroup vs the 1-49% and <1% subgroups. The lack of statistically significant benefit for pembro in the TPS ≥50% population at IA2 likely results from placebo overperformance in this population and a smaller population size. DFS in the PD-L1-selected populations will be tested at the next IA. Overall, data support the benefit of pembro for completely resected stage IB-IIIA NSCLC and, if recommended, adjuvant chemotherapy, regardless of PD-L1 expression.

Clinical trial identification

NCT02504372, first posted on July 21, 2015.

Editorial acknowledgement

Medical writing and editorial assistance provided by Melanie Leiby, an employee of the study sponsor, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

EORTC Lung Cancer Group and ETOP.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

S. Peters: Financial Interests, Institutional, Advisory Board: Vaccibody, Takeda, Seattle Genetics, Sanofi, Roche/Genentech, Regeneron, Phosplatin Therapeutics, PharmaMar, Pfizer, Novartis, Mirati, Merck Serono, MSD, Janssen, Incyte, Illumina, IQVIA, GlaxoSmithKline, Gilhead, Genzyme, Foundation Medicine, F-Star, Eli Lilly, Debiopharm, Daiichi Sankyo, Boehringer Ingelheim, Blueprint Medicines, Biocartis, Bio Invent, BeiGene, Bayer, BMS, AstraZeneca, Arcus, Amgen, AbbVie, iTheos, Novocure; Financial Interests, Institutional, Invited Speaker: Takeda, Sanofi, Roche/Genentech, RTP, Pfizer, PRIME, PER, Novartis, Medscape, MSD, Imedex, Illumina, Fishawack, Eli Lilly, Ecancer, Boehringer Ingelheim, AstraZeneca, BMS, OncologyEducation, RMEI, Mirati; Financial Interests, Personal, Other, Associate Editor Annals of Oncology: Elsevier; Financial Interests, Institutional, Invited Speaker, MERMAID-1: AstraZeneca; Financial Interests, Institutional, Invited Speaker, MERMAID-2, Poseidon, MYSTIC: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering committee CheckMate 743, CheckMate 73L, CheckMate 331 and 451: BMS; Financial Interests, Institutional, Invited Speaker, RELATIVITY 095: BMS; Financial Interests, Institutional, Invited Speaker, BGB-A317-A1217-301/AdvanTIG-301: BeiGene; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair ZEAL-1: GSK; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering Committee PEARLS, MK-7684A: MSD; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering Committee SAPPHIRE: Mirati; Financial Interests, Institutional, Invited Speaker, LAGOON: PharmaMar; Financial Interests, Institutional, Invited Speaker, phase 1/2 trials: Phosplatin Therapeutics; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair Skyscraper-01; Chair ALEX; Steering Committee BFAST; Steering Committee BEAT-Meso; Steering Committee ImPower-030, IMforte: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Phase 2 Inupadenant with chemo: iTeos; Non-Financial Interests, Officer, ESMO President 2020-2022: ESMO; Non-Financial Interests, Officer, Council Member & Scientific Committee Chair: ETOP/IBCSG Partners; Non-Financial Interests, Officer, Vice-President Lung Group: SAKK; Non-Financial Interests, Other, Involved in Swiss politics: Swiss Political Activities; Non-Financial Interests, Officer, President and Council Member: Ballet Béjart Lausanne Foundation; Non-Financial Interests, Principal Investigator, Involved in academic trials: ETOP/EORTC/SAKK; Non-Financial Interests, Member: Association of Swiss Physicians FMH (CH), ASCO, AACR, IASLC; Non-Financial Interests, Leadership Role, ESMO President: ESMO; Non-Financial Interests, Member, Vice-President Lung Group: SAKK; Non-Financial Interests, Leadership Role, Vice-President: SAMO; Non-Financial Interests, Member, Association of Swiss interns and residents: ASMAC/VSAO. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Chugai pharmaceutical, Eisai, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. U. Dafni: Financial Interests, Personal, Other, Member of the Tumor Agnostic Evidence Generation working Group: Roche. K. Oselin: Financial Interests, Personal, Advisory Board: MSD, Takeda, AstraZeneca, Janssen, Amgen, Roche; Financial Interests, Institutional, Research Grant: Takeda, Roche, Pfizer. D. Isla: Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Personal, Advisory Role: MSD, AstraZeneca, Roche, Amgen, Pfizer, Sanofi, Bayer, Bristol-Myers Squibb, GSK, Janssen, Takeda, BI; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Roche, MSD, Pfizer, Takeda. A. Martinez-Marti: Financial Interests, Personal, Advisory Board, Speaker's Bureau: Bristol-Myers Squibb, F. Hoffmann La Roche AG, Merck Sharp & Dohme, MSD Oncology, AstraZeneca/MedImmune; Financial Interests, Personal, Other, Speaker's Bureau: Pfizer; Financial Interests, Personal, Invited Speaker, And Local PI: AstraZeneca/MedImmune; Financial Interests, Personal, Invited Speaker: F. Hoffmann La Roche AG, Bristol-Myers Squibb, Merck Sharp & Dohme, MSD Oncology; Non-Financial Interests, Principal Investigator: AstraZeneca/MedImmune, F. Hoffmann La Roche AG, Bristol-Myers Squibb, Merck Sharp & Dohme, MSD Oncology. M. Faehling: Financial Interests, Institutional, Funding: MSD, Roche, AstraZeneca; Financial Interests, Personal, Advisory Board: MSD, Roche, AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Sanofi, Bristol Myers Squibb. M. Tsuboi: Financial Interests, Personal, Invited Speaker, Lecture: Johnson & Johnson Japan; Financial Interests, Personal, Advisory Board, Lectures, Advisory boards: AstraZeneca KK, Chugai Pharmaceutical CO., LTD, MSD; Financial Interests, Personal, Invited Speaker, Lectures: Eli Lilly Japan, Bristol-Myers Squibb KK, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical CO., LTD; Financial Interests, Personal, Advisory Board, Advisory boards: Novartis; Financial Interests, Personal, Invited Speaker: Daiichi-Sankyo Company Limited, MSD, AstraZeneca, Novartis; Financial Interests, Institutional, Research Grant: Beohringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical CO., LTD, Bristol-Myers Squibb KK, Novartis; Financial Interests, Institutional, Invited Speaker: Eli Lilly Japan. K. Nakagawa: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Nippon Kayaku Co., Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., CMIC ShiftZero K.K., Life Technologies Japan Ltd., Neo Communication, Merck Biopharma Co., Ltd., Kyowa Kirin Co., Ltd., Takeda Pharmaceutical Co., Ltd., 3H Clinical Trial Inc., Care Net, Inc., Medical Review Co., Ltd., Medical Mobile Communications co., Ltd, YODOSHA CO., LTD., Nikkei Business Publications, Inc., Japan Clinical Research Operations, CMIC Co., Ltd., Novartis Pharma K.K., Taiyo Pharma Co., Ltd.; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K.; Financial Interests, Institutional, Other, patents sales fee: Daiichi Sankyo Co., Ltd.; Financial Interests, Institutional, Research Grant: Parexel International Corp., PRA Healthsciences, EPS Corporation., Kissei Pharmaceutical Co., Ltd., EPS International Co.,Ltd,., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co.,Ltd., MSD K.K., Ono Pharmaceutical Co.,Ltd., PPD-SNBL K.K, SymBio Pharmaceuticals Limited., IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co.,Ltd., EP-CRSU Co., Ltd., Mebix, Inc., Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K., Eisai Co., Ltd., AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., Covance Japan Inc., Japan Clinical Research Operations, Takeda Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Sanofi K.K., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Sysmex Corporation, Medical Research Support, Eli Lilly Japan K.K., Amgen Inc., Novartis Pharma K.K., Novartis Pharma K.K., SRL, Inc. J. Yang: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp. S.M. Keller: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck Sharp & Dohme Corp. R.A. Stahel: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Blueprint, Boehringer Ingelheim, GSK, MSD, Novartis, Roche, BMS; Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, Seattle Genetics, Takeda, Boehringer Ingelheim, GSK; Financial Interests, Personal, Other, DMC: Takeda; Financial Interests, Personal, Other, Editor in Chief: Lung Cancer; Financial Interests, Personal, Other, Editor: CTR; Financial Interests, Institutional, Research Grant, ETOP study: Roche, AstraZeneca, BMS, MSD, Pfizer, Mirati, Janssen; Financial Interests, Institutional, Research Grant, IBCSG study: Novartis, Ipsen, Piere Fabre, MSD, Pfizer, Roche, AstraZeneka, Celgene; Non-Financial Interests, Invited Speaker, PresidentFoundation Council: IBCSG, ETOP. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme Corp, BMS, Janssen-cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President ASEICA (Spanish Association of Cancer Research): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, Member: Small Lung Cancer Group. M.E.R. O'Brien: Financial Interests, Personal, Advisory Board, virtual ad board: Puma, Sanofi; Financial Interests, Personal, Advisory Board: iTeos, Amgen, MSD, Pierre Fabre; Financial Interests, Institutional, Invited Speaker, we host clinical trials, PI for MSD pearls trial: MSD; Non-Financial Interests, Advisory Role: Eisai; Chair this UK Research Group: NCRI CSG LORD Subgroup. All other authors have declared no conflicts of interest.

Background

For patients with early stage epidermal growth factor receptor mutation positive (EGFR-M+) non-small cell lung cancer (NSCLC), curative surgery followed by adjuvant chemotherapy is considered the standard of care. Recently, based on the ADAURA study, osimertinib was approved in resected stage IB-IIIA EGFR-M+ NSCLC. The circulating tumor DNA (ctDNA) provides a potential biomarker for detection of minimal residual disease (MRD) and recurrence. We investigated the longitudinal monitoring of ctDNA test in early stage EGFR-M+ NSCLC.

Methods

Between August 2015 and October 2017, 278 patients with curative resected, stage IA-IIIA EGFR-M+ NSCLC were enrolled. Radiological follow-up was accompanied with longitudinal monitoring of ctDNA using a droplet digital PCR from baseline and follow-up per protocol until 5 years or recurrence.

Results

Median follow-up duration was 62.0 months (range, 1.5-774). Among 278 patients, stage IA, IB, IIA, IIB, and IIIA comprised 60.1%, 18.3%, 10.1%, 2.2%, and 9.4%, respectively. The EGFR exon 19 del was 60.1% and L858R was 39.9%. The 3-year DFS rate for each stage was 95%, 78%, 58%, 50%, and 32%, respectively. Among 278 patients, baseline ctDNA was detected in 67 (24.1%) patients: 23.4% (stage IA), 17.6% (IB), 17.9% (IIA), 50.0% (IIB), and 42.3% (IIIA) (P=0.06). In 76.1% (51 of 67) of patients with baseline ctDNA, it was cleared up 4 weeks after surgery. Patients were classified into three groups according to the positivity of ctDNA (Group A: baseline ctDNA negative (n=211), Group B: baseline ctDNA positive, but MRD negative (n=51), Group C: baseline ctDNA positive, but MRD positive (n=16)). The 3-year DFS rate was significantly different among the three groups (83.3% for Group A, 78% for Group B, and 50% for Group C, respectively, P=0.02). After adjusting for clinicopathologic variables, ctDNA group (HR 1.27, 95% CI 1.03-1.57, P=0.03) still remains an independent risk factor regardless stage for DFS.

Conclusions

These results suggest that patients with baseline ctDNA positive or MRD positive were associated with poor DFS in curative resected stage IA-IIIA EGFR M+ NSCLC. Further detailed results of longitudinal monitoring of ctDNA and clinical recurrence will be presented.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

In the randomized, phase 3 CheckMate 743 study (NCT02899299), NIVO + IPI significantly prolonged OS vs chemo in pts with uMPM. Identifying pts with uMPM who could benefit from immunotherapy is an unmet need. Here, we report clinical results and exploratory biomarker analyses from CheckMate 743 at 4y minimum follow-up (min f/u).

Methods

Pts with previously untreated uMPM, stratified by histology and sex, were randomized 1:1 to receive NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) for up to 2 y, or chemo (Q3W) for ≤ 6 cycles. Primary endpoint (EP) was OS; secondary EPs included PFS and ORR; exploratory EPs were safety and biomarker analyses. OS was assessed by baseline (BL) soluble mesothelin (sMESO) levels (high, mid, low by ELISA-based assay) and MPM-specific tumor suppressor mutations (TP53, BAP1, SETD2, NF2, LATS2 using whole-exome sequencing).

Results

At 47.5-month min f/u (database lock [DBL] 6 May 2022), NIVO + IPI continued to show OS benefit vs chemo with 4y OS rates of 16.8% vs 10.7%; 4y PFS rates were 9.0% vs 0%, respectively (Table). High (vs low or mid) BL sMESO level was associated with shorter OS in both arms; NIVO + IPI showed a trend of improved OS vs chemo across BL sMESO levels (HRs [95% CI], high: 0.72 [0.53–0.98], mid: 0.77 [0.56–1.06], low: 0.77 [0.56–1.05], respectively). OS favored NIVO + IPI vs chemo for both wild-type (HRs = 0.67–0.72) and MPM-specific tumor suppressor mutation subgroups (HRs = 0.41–0.55), except SETD2 mutation (HR = 1.37). Consistent with the prior DBL, the most common grade 3/4 immune-mediated adverse events with NIVO + IPI were hepatitis (5%), diarrhea/colitis (4%), and rash (3%). Table: LBA71

Efficacy outcomes with NIVO + IPI vs chemo

Conclusions

With 4y min f/u, NIVO + IPI continued to provide long-term, durable OS benefit vs chemo in pts with uMPM. No new safety signals were seen. High BL sMESO levels were prognostic for poor OS. OS benefit with NIVO + IPI vs chemo was generally observed regardless of MPM-specific tumor suppressor mutations.

Clinical trial identification

NCT02899299.

Editorial acknowledgement

All authors contributed to and approved the presentation; writing and editorial assistance were provided by Thai Cao, MS, of Evidence Scientific Solutions, Inc., and funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb (Princeton, NJ) and Ono Pharmaceutical Company Ltd. (Osaka, Japan).

Funding

Bristol Myers Squibb.

Disclosure

G. Zalcman: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Roche, MSD, Pfizer, Boehringer, Inventiva, Paredox Therapeutics, Lilly; Financial Interests, Personal, Other, Travel/Accommodations: AstraZeneca, Bristol Myers Squibb, AbbVie, Roche, MSD, Pfizer, Lilly. Y. Oulkhouir: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb. R. Cornelissen: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Spectrum; Financial Interests, Personal, Speaker’s Bureau: Roche. L. Greillier: Financial Interests, Personal, Advisory Board: AbbVie, AstraZeneca, BMS, MSD, Novartis, Sanofi, Takeda, Roche; Financial Interests, Personal, Invited Speaker: Lilly, Pfizer, Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca, AbbVie, BMS, MSD, Novartis, Sanofi, Takeda, Pfizer, PharmaMar. J.R. Rodriguez Cid: Financial Interests, Personal, Invited Speaker: Roche, MSD, Bristol Myers Squibb, AstraZeneca, Takeda, Amgen, Eli lilly, Pfizer, Bayer, Boehringer Ingelheim, Merck; Financial Interests, Personal, Advisory Role: Roche, MSD, Bristol Myers Squibb, AstraZeneca, Takeda, Amgen, Eli lilly, Pfizer, Bayer, Boehringer Ingelheim, Merck; Financial Interests, Personal, Research Grant: Roche, MSD, Bristol Myers Squibb, AstraZeneca, Takeda, Amgen, Celltrion, Daichi Sankyo, Eli lilly, Pfizer, Bayer . J. Mazieres: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Bristol Myers Squibb, MSD, Daiichi, Novartis, Amgen; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Pierre Fabre, Takeda, Bristol Myers Squibb, MSD, Jiangsu Hengruii, Blueprint, Daiichi, Novartis, Amgen, Lilly, Merck; Financial Interests, Personal, Research Grant: Roche, AstraZeneca, Pierre Fabre, Bristol Myers Squibb; Non-Financial Interests, Personal, Principal Investigator: Roche, AstraZeneca, Pierre Fabre, Takeda, Bristol Myers Squibb, MSD, Jiangsu Hengruii, Blueprint, Daiichi, Novartis, Amgen, Sanofi, Pfizer, Merck. A.K. Nowak: Financial Interests, Institutional, Other, Clinical trial steering committee: Roche Pharmaceuticals; Financial Interests, Personal, Other, Bayer Pharmaceuticals: Bayer Pharmaceuticals; Financial Interests, Personal, Other, Clinical trial steering committee: Boehringer Ingelheim, Merck Sharp Dohme; Financial Interests, Institutional, Other, Clinical trials consulting, payment to institution: Douglas Pharmaceuticals, Atara Biotherapeutics; Financial Interests, Personal, Other, Clinical trials consulting.: Pharmabcine; Financial Interests, Personal, Other, Clinical trials consulting: Trizell Ltd; Financial Interests, Institutional, Funding, Research funding to institution: AstraZeneca, Douglas Pharmaceuticals; Other, Other, Travel funding to attend ASCO 2018: Boehringer Ingelheim; Other, Other, Travel funding to attend ASCO 2019: AstraZeneca. A. Tsao: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Eli Lilly, Genentech, Roche, Novartis, Ariad, EMD Serono, Merck, Seattle Genetics, AstraZeneca, Boehringer-Ingelheim, Sellas Life Science, Takeda, Epizyme, Huron; Financial Interests, Personal, Research Grant: Bristol Myers Squibb, Eli Lilly, Genentech, Ariad, EMD Serono, Merck, Boehringer-Ingelheim, Takeda, Epizyme, Millennuim, Polaris. N. Fujimoto: Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, ONO Pharmaceutical; Financial Interests, Personal, Advisory Board: ONO Pharmaceutical. S. Peters: Financial Interests, Institutional, Advisory Board: Vaccibody, Takeda, Seattle Genetics, Sanofi, Roche/Genentech, Regeneron, Phosplatin Therapeutics, PharmaMar, Pfizer, Novartis, Mirati, Merck Serono, MSD, Janssen, Incyte, Illumina, IQVIA, GlaxoSmithKline, Gilhead, Genzyme, Foundation Medicine, F-Star, Eli Lilly, Debiopharm, Daiichi Sankyo, Boehringer Ingelheim, Blueprint Medicines, Biocartis, Bio Invent, BeiGene, Bayer, BMS, AstraZeneca, Arcus, Amgen, AbbVie, iTheos, Novocure; Financial Interests, Institutional, Invited Speaker: Takeda, Sanofi, Roche/Genentech, RTP, Pfizer, PRIME, PER, Novartis, Medscape, MSD, Imedex, Illumina, Fishawack, Eli Lilly, Ecancer, Boehringer Ingelheim, AstraZeneca, BMS, OncologyEducation, RMEI, Mirati; Financial Interests, Personal, Other, Associate Editor Annals of Oncology: Elsevier; Financial Interests, Institutional, Invited Speaker, MERMAID-1: AstraZeneca; Financial Interests, Institutional, Invited Speaker, MERMAID-2, POSEIDON, MYSTIC: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering committee CheckMate 743, CheckMate 73L, CheckMate 331 and 451: BMS; Financial Interests, Institutional, Invited Speaker, RELATIVITY 095: BMS; Financial Interests, Institutional, Invited Speaker, BGB-A317-A1217-301/AdvanTIG-301: Beigene; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair ZEAL-1: GSK; Financial Interests, Institutional, Invited Speaker, Clinical Trial steering Committee PEARLS, MK-7684A: MSD; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering Committee SAPPHIRE: Mirati; Financial Interests, Institutional, Invited Speaker, LAGOON: Pharma Mar; Financial Interests, Institutional, Invited Speaker, phase 1/2 trials: Phosplatin Therapeutics; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair Skyscraper-01; chair ALEX; steering committee BFAST; steering committee BEAT-Meso; steering committee ImPower-030, IMforte: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Phase 2 Inupadenant with chemo: iTeos; Non-Financial Interests, Officer, ESMO President 2020-2022: ESMO; Non-Financial Interests, Officer, Council Member & Scientific Committee Chair: ETOP/IBCSG Partners; Non-Financial Interests, Officer, Vice-President Lung Group: SAKK; Non-Financial Interests, Other, Involved in Swiss politics: Swiss Political Activities; Non-Financial Interests, Officer, President and Council Member: Ballet Béjart Lausanne Foundation; Non-Financial Interests, Principal Investigator, Involved in academic trials: ETOP / EORTC / SAKK; Non-Financial Interests, Member: Association of Swiss Physicians FMH (CH), ASCO, AACR, IASLC; Non-Financial Interests, Leadership Role, ESMO President: ESMO; Non-Financial Interests, Member, Vice-President Lung Group: SAKK; Non-Financial Interests, Leadership Role, Vice -President: SAMO; Non-Financial Interests, Member, Association of Swiss interns and residents: ASMAC/VSAO. A.S. Mansfield: Financial Interests, Institutional, Funding, Study funding, article processing charges: Bristol Myers Squibb; Financial Interests, Institutional, Funding, Study funding: Novartis, Verily; Financial Interests, Institutional, Other, Grant reviewer: Rising Tide; Financial Interests, Institutional, Advisory Role: TRIPTYCH Health Partners Expert Think Tank; Financial Interests, Institutional, Other, Steering Committee: Janssen, Johnson & Johnson Global Services; Financial Interests, Institutional, Invited Speaker: BeiGene, Chugai Pharmaceutical Co Ltd (Roche), Miami International Mesothelioma Symposium, AXIS Medical Education, Inc.; Financial Interests, Institutional, Invited Speaker, Moderator: Ideology Health LLC (formerly Nexus Health Media); Financial Interests, Personal, Invited Speaker, CME Activity: Antoni van Leeuwenhoek Kanker Instituut; Financial Interests, Institutional, Invited Speaker, CME Activity: Intellisphere LLC (OncLive Summit Series), Answers in CME; Financial Interests, Institutional, Other, Travel/Accomodations: Roche; Financial Interests, Institutional, Advisory Board: AbbVie, AstraZeneca, Bristol Myers Squibb, Genentech/Roche; Non-Financial Interests, Leadership Role, Director: Mesothelioma Applied Research Foundation. S. Popat: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novartis, Amgen, Janssen, Daiichi Sankyo, AstraZeneca, Bayer, BMS, Blueprint, Merck Serono, Guardant Health, Beigene, Takeda, Lilly, Seattle Genetics, Turning Point Therapeutics, Xcovery, GlaxoSmithKline, MSD, Pfizer, Sanofi; Financial Interests, Personal, Expert Testimony: Roche; Financial Interests, Personal, Invited Speaker: Medscape, VJ Oncology, Touch Medical; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Ariad, Roche, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Trizel, GlaxoSmithKline, Takeda, Turning Point Therapeutics, Roche, Janssen, BMS, Lilly; Financial Interests, Personal, Other, Journal Deputy Editor, Lung Cancer: Elsevier; Financial Interests, Institutional, Other, Sub-investigator: Amgen; Financial Interests, Institutional, Other, Sub-Investigator: MSD, Blueprint, Seattle Genetics; Financial Interests, Institutional, Research Grant: Guardant Health; Non-Financial Interests, Leadership Role, Chair of Steering Committee, Unpaid: British Thoracic Oncology Group; Non-Financial Interests, Officer, Thoracic Faculty, Unpaid: European Society of Medical Oncology; Non-Financial Interests, Leadership Role, Foundation Council Member, Unpaid: European Thoracic Oncology Platform; Non-Financial Interests, Advisory Role, Mesothelioma Task-force Member, Unpaid: International Association for the Study of Lung Cancer; Non-Financial Interests, Invited Speaker, Unpaid: Mesothelioma Applied Research Foundation; Non-Financial Interests, Advisory Role, Honorary Clinical Advisor, Unpaid: ALK Positive UK; Non-Financial Interests, Advisory Role, Research Advisory Group Member, Unpaid: Ruth Strauss Foundation; Non-Financial Interests, Advisory Role, Scientific Adivsory Board Member, Unpaid: Lung Cancer Europe. A. Nassar: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. J. Bushong: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. N. Hu: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. T. Spires: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. D. Balli: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. L. Eccles: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. P. Baas: Financial Interests, Institutional, Advisory Board: BMS, MSD, Beigene; Financial Interests, Institutional, Research Grant: MSD, BMS. All other authors have declared no conflicts of interest.

Background

The JIPANG study has demonstrated pemetrexed/cisplatin (Pem/Cis) had a similar efficacy on recurrence-free survival (RFS) to vinorelbine/cisplatin (Vnr/Cis) with a better tolerability as postoperative adjuvant chemotherapy for patients with completely resected non-squamous non-small-cell lung cancer (Ns-NSCLC). Overall survival (OS) is one of secondary endpoints in this trial. The final analysis of OS in the JIPANG study is presented here. An interaction between treatment regimen and EGFR mutation status for OS is also reported.

Methods

Patients with completely resected pathological stage II-IIIA Ns-NSCLC were randomized in a 1:1 ratio to receive either Pem (500 mg/m², day 1)/Cis (75 mg/m², day 1) or Vnr (25 mg/m², days 1 and 8)/Cis (80 mg/m², day 1), and stratified according to sex, age, pathological stage, EGFR mutation status and institution. This analysis was performed by using data at 5 years after last patient enrollment.

Results

Between March 2012 and August 2016, 804 patients were randomized. Of 783 for the efficacy analysis (389 in Pem/Cis and 394 in Vnr/Cis), median age was 65/65 years; stage IIIA 52/52%; and EGFR mutation, 24/25%. An updated median RFS was 43.4 months (mo) in Pem/Cis and 37.5 mo in Vnr/Cis with a hazard ratio (HR) of 0.95 (95% CI, 0.79—1.14; stratified one-sided log-rank test, P=0.249). With a median follow-up of 77.3 mo, OS rate at 3 and 5 years were 87.0% and 75.0% versus 84.1% and 75.6% with a HR of 1.04 (95% CI, 0.81—1.34, P=0.598). In the subgroup analysis of OS, HRs in patients with and without EGFR mutations were 1.98 (95% CI, 1.13—3.28) and 0.86 (95% CI, 0.64—1.14), respectively (Interaction, P=0.011). Among total of 441 recurrences observed, brain metastasis was reported in patients with EGFR mutations (Pem/Cis; 20 (30.3%), Vnr/Cis; 11 (18.6%)) and in those without EGFR mutations (Pem/Cis; 27 (18.6%), Vnr/Cis; 47 (27.5%)).

Conclusions

This final analysis showed that Pem/Cis had a similar efficacy to Vnr/Cis in both RFS and OS for this population. The OS with adjuvant Pem/Cis or Vnr/Cis was one of the longest observed in these population compared with the historical data, regardless of EGFR mutation status.

Clinical trial identification

UMIN000006737, jRCTs041180023.

Legal entity responsible for the study

The authors.

Funding

Japan Agency for Medical Research and Development (Grant No. 16lk0201005h0005). Pemetrexed for this study was provided by Eli Lilly.

Disclosure

K. Yoh: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi sankyo, Janssen, Lilly, Taiho, Novartis, Kyowa kirin, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Lilly, Pfizer, Daiichi sankyo, AbbVie, Taiho, MSD, Takeda. H. Kenmotsu: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co, Ltd., Ono Pharmaceutical Co, Ltd., Boehringer Ingelheim, Eli Lilly K.K, Kyowa Hakko Kirin Co., Ltd., Bristol-Myers Squibb, MSD, Novartis Pharma K.K., Daiichi-Sankyo Co., Ltd., AstraZeneca K.K., Pfizer, Taiho Pharma, Merck, Amgen inc., Bayer, Takeda Pharmaceutical Co., Ltd; Financial Interests, Institutional, Research Grant: AstraZeneca, Chugai Pharmaceutical Co, Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co, Ltd., Loxo Oncology, Eli Lilly K.K; Non-Financial Interests, Principal Investigator: AstraZeneca K.K., Eli Lilly K.K, Boehringer Ingelheim, Takeda Pharmaceutical Co., Ltd. N. Yamamoto: Financial Interests, Personal, Invited Speaker: MSD K.K, AstraZeneca, Ono Pharmaceutical Co., Ltd., Thermo Fisher Scientific, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer-Ingelheim, Novartis, Pfizer Inc., Bristol-Myers Squibb, Nippon Kayaku, GlaxoSmithKline K.K., Sanofi K.K., Hisamitsu Pharmaceutical Co.,Inc., Merck biopharma; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer-Ingelheim, Novartis, Bristol-Myers Squibb, Nippon Kayaku, Life Technologies Japan Ltd., Amgen Inc., Guardant Health Japan, Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Research Grant: MSD K.K; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., Amgen Inc., Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Toppan printing, Terumo. T. Takahashi: Financial Interests, Personal, Invited Speaker: AstraZeneca KK, Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Msd K.K., Pfizer Japan Inc., Boehringer Ingelheim Japan, INC, Takeda Pharmaceutical Co Ltd., Yakult Honsha Co. Ltd; Financial Interests, Institutional, Invited Speaker: AstraZeneca KK, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., MSD K.K., Pfizer Japan Inc., Amgen Inc., Merck Biopharma Co., Ltd. H. Saito: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Chugai Pharmaceutical Co., Ltd., Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd. S. Sugawara: Financial Interests, Personal, Other, Lecture fee: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Lilly, Novartis, Bristol-Myers Squibb, Ono Pharmaceutical, MSD K.K, Yakult Honsha, Kyowa Kirin, Towa Pharmaceutical, Takeda, Nippon Kayaku, Otsuka, Merck, Amgen, Thermo Fisher Scientific, AbbVie. K. Nakagawa: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Nippon Kayaku Co., Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co.,Ltd., Bayer Yakuhin, Ltd., CMIC ShiftZero K.K., Life Technologies Japan Ltd., Neo Communication, Merck Biopharma Co., Ltd., Kyowa Kirin Co., Ltd., Takeda Pharmaceutical Co., Ltd., 3H Clinical Trial Inc., Care Net, Inc., Medical Review Co., Ltd., Medical Mobile Communications co., Ltd, Yodosha Co., Ltd., Nikkei Business Publications, Inc., Japan Clinical Research Operations, CMIC Co., Ltd., Novartis Pharma K.K., Taiyo Pharma Co., Ltd.; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K.; Financial Interests, Institutional, Other, patents sales fee: Daiichi Sankyo Co., Ltd.; Financial Interests, Institutional, Research Grant: PAREXEL International Corp., PRA Healthsciences, EPS Corporation., Kissei Pharmaceutical Co., Ltd., EPS International Co.,Ltd,., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co.,Ltd., MSD K.K., Ono Pharmaceutical Co.,Ltd., PPD-SNBL K.K, SymBio Pharmaceuticals Limited., Iqvia Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co.,Ltd., EP-CRSU Co., Ltd., Mebix, Inc., Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K., Eisai Co., Ltd., AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., Covance Japan Inc., Japan Clinical Research Operations, Takeda Pharmaceutical Co.,Ltd., GlaxoSmithKline K.K., Sanofi K.K., Chugai Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Sysmex Corporation, Medical Reserch Support, Eli Lilly Japan K.K., Amgen Inc., Novartis Pharma K.K., Novartis Pharma K.K., SRL, Inc. K. Sugio: Financial Interests, Institutional, Research Grant: Eli Lilly Japan, Taiho, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi-Sankyo, Covidien Japan. T. Seto: Financial Interests, Personal, Invited Speaker: Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Covidien Japan, Mochida Pharmaceutical, MSD, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Towa Pharmaceutical, Eli Lilly Japan; Financial Interests, Personal, Full or part-time Employment: Precision Medicine Asia; Non-Financial Interests, Invited Speaker: West Japan Oncology Group. S. Toyooka: Financial Interests, Institutional, Research Grant: Eli Lilly, AstraZeneca, Taiho, Chugai; Financial Interests, Personal, Invited Speaker: Eli Lilly, AstraZeneca, Taiho, Chugai, Novartis, Ono Pharmaceutical, Boehringer Ingelheim, Astellas Pharma, Daiichi Sankyo, Bayer, Kyorin, Johnson & Johnson, Medtronic. H. Date: Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical. T. Mitsudomi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Novartis, MSD, Bristol Myers Squibb, Ono, Pfizer, Eli-Lilly, Merck Biopharma; Financial Interests, Personal, Advisory Board: AsreaZeneca, Boehringer-Ingelheim, Chugai, Novartis, MSD, Bristol Myers Squibb, Ono, Pfiezer, Amgen, Janssen, Takeda, Eli-Lilly; Financial Interests, Institutional, Invited Speaker: Boehringer-Ingelheim, AstraZeneca, Chugai, MSD, Taiho, Daiichi-Sankyo, Ono; Non-Financial Interests, Leadership Role: Interanational Association for Study of Lung Cancer. I. Okamoto: Financial Interests, Institutional, Research Grant: Eli Lilly K.K; Financial Interests, Personal, Invited Speaker: Eli Lilly K.K. H. Okamoto: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Taiho, Astellas, Eli Lilly, Merck BioPharma; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Boehringer Ingelheim, Novartis, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd. Y. Takiguchi: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical, AstraZeneca, Chugai Pharma, Boehringer Ingelheim, Daiichi Sankyo, Taiho Pharmaceutical, Bristol-Myers Squibb Japan, Lilly, Pfizer, Novartis, Kyowa Kirin International; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Lilly, Taiho Pharmaceutical, Chugai Pharma, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: MSD Oncology, AstraZeneca. M. Tsuboi: Financial Interests, Personal, Invited Speaker, Lecture: Johnson & Johnson Japan; Financial Interests, Personal, Advisory Board, Lectures, Advisory boards: AstraZeneca KK, Chugai Pharmaceutical Co.,Ltd, MSD; Financial Interests, Personal, Invited Speaker, Lectures: Eli Lilly Japan, Bristol-Myers Squibb KK, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical CO.,LTD; Financial Interests, Personal, Advisory Board, Advisory boards: Novartis; Financial Interests, Personal, Invited Speaker: Daiichi-Sankyo company limited, MSD, AstraZeneca, Novartis; Financial Interests, Institutional, Research Grant: Beohringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical CO.,LTD, Bristol-Myers Squibb KK, Novartis; Financial Interests, Institutional, Invited Speaker: Eli Lilly Japan. All other authors have declared no conflicts of interest.

Background

Neoadjuvant therapy with PD-(L)1 inhibitors, both as monotherapy and in combination, leads to pathological responses in resectable, early-stage NSCLC. NeoCOAST (NCT03794544) is a phase 2 study of the anti-PD-L1 monoclonal antibody (mAb) D alone or combined with the anti-CD73 mAb oleclumab (O), the anti-NKG2A mAb monalizumab (M), or the anti-STAT3 antisense oligonucleotide danvatirsen (Da) as neoadjuvant therapy.

Methods

Pts with untreated, stage I [>2 cm]–IIIA NSCLC were randomized to receive 1 cycle of D alone or in combination. The primary endpoint was investigator-assessed major pathological response (MPR) rate. In a subset of pts, treatment-induced transcriptomic changes were assessed by RNA sequencing from tumor tissue collected pre-treatment and at surgery. Using a tumor-informed method, ctDNA was analyzed pre-treatment, after treatment, and post-surgery. Molecular response (MR) is defined as ≥50% reduction in variant allelic fraction from pre-treatment.

Results

As previously reported, MPR was numerically higher in all combination arms [D+O (n=4/21, 19%), D+M (n=6/20, 30%), and D+Da (n=5/16, 31%)], compared with D monotherapy [n=3/27, 11%]. Among pts with an MPR, 2 had EGFR driver mutations (both D+O arm); KRAS, STK11, RET and ALK alterations were observed in pts without an MPR. Expression of genes associated with NK cells (KLRC1, GNLY) and CD8 T cells (CD8A, GZMK) increased after treatment in all arms; with a greater increase with D+O and D+M (1–5 log₂FC, adj p < 0.1) than D alone (0–1 log₂FC, n.s.). Tertiary lymphoid structure, interferon, and inflammatory signatures were significantly upregulated after treatment in the D+O and D+M arms. Analysis of ctDNA identified pts who had MR (25–60% per arm after treatment, and 75–100% post-surgery), including pts without an MPR. Association of tumor mutational burden and additional biomarkers with clinical outcomes will be reported.

Conclusions

Single cycle of D+O and D+M resulted in greater intra-tumoral immunomodulation than D alone.

Clinical trial identification

NCT03794544.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

J. Spicer: Financial Interests, Personal, Invited Speaker: Merck, BMS, Novartis, AstraZeneca; Financial Interests, Personal, Advisory Board: Merck, BMS, Novartis, AstraZeneca, Roche, Chemocentryx, Protalix Biotherapeutics; Financial Interests, Personal, Research Grant: Merck, AstraZeneca, Roche, Protalix Biotherapeutics, CLS Therapeutics. T. Cascone: Financial Interests, Personal, Invited Speaker: SITC, Bristol-Myers Squibb, Roche, Medscape, Peerview; Financial Interests, Personal, Advisory Board: AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono, Merck, Genentech, Arrowhead Pharmaceuticals; Financial Interests, Institutional, Funding: AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono. G. Kar: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. J. Blando: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. M. Cheng: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. R. Mager: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. O. Hamid: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. Y. Soo-Hoo: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Other, Personal, Proprietary Information: AstraZeneca. W. Weder: Financial Interests, Personal, Advisory Board: AstraZeneca. M.R. Garcia Campelo: Financial Interests, Personal, Advisory Board: MSD, BMS, Roche, BI, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen; Financial Interests, Personal, Invited Speaker: MSD, BMS, Roche, BI, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen. I. Grenga: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. R. Kumar: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Project Lead: AstraZeneca. L. McGrath: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Jounce Therapeutics. All other authors have declared no conflicts of interest.

Background

CheckMate 816 (NCT02998528), a phase 3 study, met its primary endpoints of statistically significant and clinically meaningful improvements in event-free survival and pathological complete response with neoadjuvant NIVO + chemo vs chemo for resectable NSCLC. We present HRQoL results from the neoadjuvant treatment period.

Methods

Adults with stage IB-IIIA resectable NSCLC were randomized 1:1 to neoadjuvant NIVO 360 mg + chemo Q3W or chemo Q3W for 3 cycles. HRQoL (exploratory endpoint) was evaluated using the 3-level version of the EQ-5D (EQ-5D-3L). A mixed-effects model repeated measures analysis evaluated longitudinal changes from baseline in EQ-5D visual analogue scale (VAS; range 0 to 100) and utility index (UI; range −0.594 to 1) scores during the neoadjuvant period (week 4, week 7, and post-neoadjuvant visit 1); higher scores reflect better HRQoL.

Results

EQ-5D-3L completion rates were > 80% in both treatment arms at baseline and during the neoadjuvant period. Baseline EQ-5D-3L VAS and UI scores were consistent with UK population norms. Scores during the neoadjuvant period were generally similar to baseline for both treatment arms; there were no clinically meaningful differences between NIVO + chemo vs chemo (Table). In both treatment arms, most patients reported “no problems” for individual EQ-5D-3L dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) at baseline and during treatment. Analyses from the postsurgical period will be presented. Table: 932MO

EQ-5D-3L in the neoadjuvant period

Conclusions

In CheckMate 816, the addition of NIVO to neoadjuvant chemo for resectable NSCLC had no detrimental impact on HRQoL during the neoadjuvant period. These quality of life findings, along with previously reported efficacy and safety results, support the use of NIVO + chemo as neoadjuvant treatment for resectable NSCLC.

Clinical trial identification

NCT02998528.

Editorial acknowledgement

Editorial assistance in the writing of the abstract was provided by Tracy Wetter, PhD, and Michele Salernitano of Ashfield MedComms.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristrol Meyers Squibb, Eli Lilly, Glaxo Smith Kline, Janssen, Medical Trends, Merck Sharp & Dohme, Pfizer, Puma, Sanofi, Takeda, Merck Serono, Peptomyc, Regeneron, Syneos Health, F. Hoffmann-La Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristrol Meyers Squibb, Eli Lilly, Medscape, Merck Sharp & Dome, Peervoice, Pfizer, Springer, Touch Medical, Amgen, F. Hoffmann-La Roche, Janssen, Medical Trends, Merck Serono; Financial Interests, Personal, Invited Speaker, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme Corp, AstraZeneca AB, Daiichi Sankyo Inc, Exelixis Inc, Merck KGAA, Janssen Cilag International NV, GlaxoSmithKline Research & Development Limited, AbbVie Deutschland GmbH & Co KG, Novartis Farmaceutica SA, Bayer Consumer Care AG, Takeda Pharmaceuticals International, Boehringer Ingelheim International GmbH, Pfizer S.L.U., Amgen Inc, Bristol-Myers Squibb International Corporation (BMS), Mirati Therapeutics Inc; Non-Financial Interests, Leadership Role, President Elect (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of ESMO Nominating Committee and Compliance Committee: ESMO; Non-Financial Interests, Leadership Role, Member of Board of Directors and the Executive Committee (2017-Sept 2021): IASLC (International Association for the Study of Lung Cancer); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform). T. Ciuleanu: Financial Interests, Personal, Other, speaker, consultancy, advisory role: Roche, BMS, MSD, Pfizer, Eli Lilly, AstraZeneca, Sanofi, Sandoz, Novartis, Janssen, Astellas, Amgen. F. Tanaka: Financial Interests, Personal, Speaker’s Bureau: MSD, Bristol Meyers Squibb, Boehringer Ingelheim, Ono Pharmaceutical, Johnson & Johnson, Covidien Japan, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, Chugai Pharmaceutical.; Financial Interests, Personal, Other, Consultant contractor: AstraZeneca, Bristol Meyers Squibb; Financial Interests, Personal, Funding, Research funding: Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Chugai Pharmaceutical. N. Girard: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD, Roche, Pfizer, Mirati, Amgen, Novartis, Sanofi; Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Roche, Pfizer, Janssen, Boehringer, Novartis, Sanofi, AbbVie, Amgen, Lilly, Grunenthal, Takeda, Owkin; Financial Interests, Institutional, Research Grant, Local: Roche, Sivan, Janssen; Financial Interests, Institutional, Funding: BMS; Non-Financial Interests, Officer, International Thymic malignancy interest group, president: ITMIG; Other, Family member is an employee: AstraZeneca. S. Lu: Financial Interests, Institutional, Invited Speaker: Hansoh, AstraZeneca, Roche; Financial Interests, Research Grant: AstraZeneca, Hutchison, BMS, Heng Rui BeiGene, Roche, Hansoh. M. Provencio Pulla: Financial Interests, Personal, Advisory Board: BMS, MSD, Bayer, Lilly, Roche, Takeda, Janssen; Non-Financial Interests, Leadership Role, President of Spanish Lung cancer Group: President; Non-Financial Interests, Leadership Role, Insutituto Investigación Sanitaria Puerta de Hierro: Director. T. Mitsudomi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Novartis, MSD, Bristol Myers Squibb, Ono, Pfizer, Eli-Lilly, Merck Biopharma; Financial Interests, Personal, Advisory Board: AsreaZeneca, Boehringer-Ingelheim, Chugai, Novartis, MSD, Bristol Myers Squibb, Ono, Pfiezer, Amgen, Janssen, Takeda, Eli-Lilly; Financial Interests, Institutional, Invited Speaker: Boehringer-Ingelheim, AstraZeneca, Chugai, MSD, Taiho, Daiichi-Sankyo, Ono; Non-Financial Interests, Leadership Role: Interanational Association for Study of Lung Cancer. M. Awad: Financial Interests, Personal, Other, consultant: Genentech, Bristol Myers Squibb, Merck, AstraZeneca, Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, ArcherDX, Mirati, NextCure, Novartis, EMD Serono; Financial Interests, Institutional, Funding, Research funding to institution: AstraZeneca, Eli Lilly, Genentech, Bristol Myers Squibb. P.M. Forde: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, BMS, Daiichi, F-Star, G1, Genentech, Iteos, Janssen, Merck, Novartis, Sanofi, Surface, LUNGevity; Financial Interests, Institutional, Funding, Research funding to institution: AstraZeneca, BioNTech, BMS, Corvus, Kyowa, Novartis, and Regeneron; Financial Interests, Personal, Other, Trial steering committee membership: AstraZeneca, Biontech, BMS, Corvus; Financial Interests, Personal, Member of the Board of Directors: Mesothelioma Applied Research Foundation. R. Lawrance: Financial Interests, Personal, Full or part-time Employment, provide consultancy services for statistical analysis of Patient Reported Outcome Data to pharmaceutical companies: Adelphi Values. F. Taylor: Financial Interests, Personal, Full or part-time Employment, consulting firm receiving payment from BMS (and other pharmaceutical companies) for analysis of clinical trial HRQL data: Adelphi Values. G. Worthy: Financial Interests, Full or part-time Employment, consultancy services for statistical analysis of Patient Reported Outcome Data to pharmaceutical companies: Adelphi Values. S.I. Blum: Financial Interests, Personal, Full or part-time Employment, Full-time Employee of Bristol Myers Squibb: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares, Stock shareholder of Bristol Myers Squibb: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares, Stock shareholder of GlaxoSmithKline: GlaxoSmithKline. L. Vo: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. J.L. Cai: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. J. Spicer: Financial Interests, Personal, Invited Speaker, speaker, consultancy, advisory role: Merck, BMS, Roche, AstraZeneca, Protalix Biotherapeutics, Chemocentryx; Financial Interests, Personal, Funding, Research funding: Merck, Roche, Protalix Biotherapeutics, CLS Therapeutics; Non-Financial Interests, Personal, Proprietary Information: AstraZeneca, Protalix Biotherapeutics, CLS Therapeutics. All other authors have declared no conflicts of interest.

Background

A post hoc analysis from the phase 3 CheckMate 816 study showed that residual viable tumor (RVT) in the primary tumor (PT) was associated with event-free survival (EFS) with N + C (2y EFS rates: 90%, 60%, 57%, and 39% in patients [pts] with 0–5, > 5–30, > 30–80, and > 80% RVT). Here, we report analyses in pts with or without (w/o) pathologic evidence of lymph node involvement (LN-I).

Methods

Adults with resectable NSCLC were randomized to receive N 360 mg + platinum-doublet C Q3W or C alone Q3W for 3 cycles, followed by resection. Primary endpoints were pathologic complete response (pCR) and EFS (both met). Analyses included efficacy by LN-I and assessment of prespecified histopathologic features (%RVT, regression, and necrosis) in PT and LN. Pts with LN-I could have had either 0% (pathologic evidence of completely regressed tumor) or > 0%RVT in the resected LN. A time-dependent ROC curve analysis assessed the predictive ability of %RVT in PT for 2y EFS.

Results

pCR rates were improved with N + C vs C in both pts with or w/o LN-I (table); similar EFS benefit was seen in pts with or w/o LN-I (HR: 0.69 and 0.74). In the N + C arm, pts with LN-I who had 0% RVT in both PT and LN showed the best EFS outcomes numerically, followed by those with 0% RVT in either PT or LN; those with > 0% RVT in both PT and LN showed shorter EFS (2y EFS rates: 92%, 76%, and 49%). Overall, lower %RVT and higher % regression (appears to be inversely related to RVT) was seen with N + C vs C in PT and LN; % necrosis did not differ between the treatment arms (table). In both pts with or w/o LN-I (N + C), %RVT in PT was predictive of EFS at 2y (AUC: 0.76 and 0.73).

Conclusions

These findings further support neoadjuvant N + C vs C as a novel treatment option for pts with resectable NSCLC, regardless of LN-I. %RVT in PT in pts with or w/o LN-I was associated with EFS with N + C. Further assessment of clinically relevant %RVT cutoffs to predict long-term outcomes with immunotherapy is warranted. Table: LBA50

Clinical trial identification

NCT02998528.

Editorial acknowledgement

Editorial assistance in the writing of the abstract was provided by Wendy Sacks, PhD, and Michele Salernitano of Ashfield MedComms, an Inizio company.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

J.S. Deutsch: Financial Interests, Personal, Other, Application No: 63/313,548: Patent pending. A. Cimino-Mathews: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Institutional, Funding, Research funding to institution: Bristol Myers Squibb. D. Wang: Financial Interests, Personal, Full or part-time Employment: Akoya Biosciences. P. Illei: Financial Interests, Personal, Advisory Board, Pathology advisory board on NSCLC biomarker testing: AstraZeneca, Bristol Myers Squibb, Janssen, Roche; Financial Interests, Personal, Invited Speaker, Unbranded education on NSCLC biomarker testing: Eli Lilly, Genentech; Financial Interests, Personal, Stocks/Shares, 100 SHARES: Bristol Myers Squibb; Non-Financial Interests, Institutional, Other, Co-PI on an institutional grant (central pathology review): Bristol Myers Squibb; Non-Financial Interests, Institutional, Other, Co-PI: Erbe GmBH. J. Spicer: Financial Interests, Personal, Other, speaker, consultancy, advisory role: Merck, BMS, Roche, AstraZeneca, Protalix Biotherapeutics, Chemocentryx; Financial Interests, Personal, Funding, Research funding: Merck, Roche, Protalix Biotherapeutics, CLS Therapeutics; Non-Financial Interests, Personal, Proprietary Information: AstraZeneca, Protalix Biotherapeutics, CLS Therapeutics. M. Provencio Pulla: Financial Interests, Personal, Advisory Board: BMS, MSD, Bayer, Lilly, Roche, Takeda, Janssen; Non-Financial Interests, Leadership Role, President of Spanish Lung cancer Group: President; Non-Financial Interests, Leadership Role, Insutituto Investigación Sanitaria Puerta de Hierro: Director. P.M. Forde: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, BMS, Daiichi, F-Star, G1, Genentech, Iteos, Janssen, Merck, Novartis, Sanofi, Surface; Financial Interests, Institutional, Funding, Research funding to institution: AstraZeneca, BioNTech, BMS, Corvus, Kyowa, Novartis, Regeneron ; Financial Interests, Personal, Other, Trial steering committee membership: AstraZeneca, Biontech, BMS, Corvus; Non-Financial Interests, Personal, Member of the Board of Directors: Mesothelioma Applied Research Foundation; Non-Financial Interests, Personal, Advisory Board: LUNGevity. D. Pandya: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. M.P. Tran: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. J. Fiore: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. V. Devas: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. J.M. Taube: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, AstraZeneca, Genentech, Akoya Biosciences, Lunaphore Technologies, Compugen; Financial Interests, Personal, Stocks/Shares: Akoya Biosciences; Financial Interests, Institutional, Funding, Research funding to institution: Bristol Myers Squibb, Akoya Biosciences; Non-Financial Interests, Personal, Other, Equipment loan and reagent provision: Akoya Biosciences; Other, Personal, Invited Speaker, Patent pending for machine learning for irPRC scoring: Akoya Biosciences. All other authors have declared no conflicts of interest.