Background

Locally advanced cervical cancer (LACC) is treated with chemoradiation (CRT). However, many patients relapse and die from metastatic disease. A feasibility study demonstrated a good response rate to short course weekly induction chemotherapy (IC) delivered before standard CRT and the INTERLACE trial investigated whether this approach improves both progression free survival (PFS) and overall survival (OS).

Methods

Women with squamous, adeno or adenosquamous carcinoma FIGO (2008) stage IB1 node positive,IB2,II,IIIB, IVA were eligible. Patients were randomised (1:1) to receive either CRT alone (5 cycles weekly cisplatin) or IC (6 weeks carboplatin AUC2 and paclitaxel 80mg/m²) followed by the same CRT in week 7. Mandated minimum total EQD2 dose 78Gy to Point A with 3D brachytherapy recommended. All centres underwent radiation quality assurance. Primary endpoints were PFS (target hazard ratio [HR] 0.65) and OS (target HR 0.65-0.70).

Results

500 patients were recruited from 32 centres in 5 countries (Nov 2012-Nov 2022). Median age 46 (range 24-78) years. Stage distribution was: IB1/2; 9%, II;77%, IIIB;11% and IVA;3%. 57% were node negative and 82% squamous subtype. Arms were balanced. 92% of IC patients had 5/6 cycles carboplatin/paclitaxel. Median interval from IC to CRT was 7 days. 84% (IC/CRT) vs. 89% (CRT alone) had 4/5 cycles cisplatin. In the CRT arm 92% and 89% completed external beam and brachytherapy respectively; corresponding figures in the IC/CRT arm were 97% and 95%. The median overall treatment time for CRT was 45 days in both arms. Grade ≥3 adverse events were seen in 59% (IC/CRT) vs. 48% (CRT alone). Median follow up 64 months. 5 year PFS rate is 73% with IC/CRT and 64% with CRT alone (HR 0.65; 95%CI:0.46-0.91, p=0.013). The corresponding 5-year OS rates are 80% and 72% (HR 0.61:95%CI:0.40-0.91, p=0.04).

Conclusions

Induction chemotherapy followed by CRT significantly improves PFS and OS in LACC and should be considered a new standard of care. INTERLACE recruited patients from diverse health care settings demonstrating that IC followed by CRT is feasible in all countries.

Clinical trial identification

EudraCT: 2011-001300-35.

Legal entity responsible for the study

Trial Sponsor: University College London Trial Sponsor reference: UCL 11/0034.

Funding

Cancer Research UK.

Disclosure

M. McCormack: Other, Personal, Advisory Board: GSK, Eisai, AstraZeneca; Other, Personal and Institutional, Coordinating PI: Roche. L. Farrelly: Financial Interests, Institutional, Other, Research Grant, Institutional, Financial interest, Grant for a UCL-academic sponsored clinical trial: MSD, AstraZeneca, Autolus, Boehringer Ingelheim, GRAIL Inc, Novartis, Pfizer, Roche, Takeda; Financial Interests, Institutional, Other, Takeda: Janssen; Financial Interests, Institutional, Other, Research Grant for commercially sponsored trial through the ENGOT Network: Clovis, Seagen, Immunogen, GSK, Novartis, Aravive. C. Kent: Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen; Financial Interests, Personal, Advisory Board: Clovis; Non-Financial Interests, Personal, Leadership Role, trustee of prostaid Charity: Prostaid Charity. E. Hudson: Financial Interests, Personal, Other, Advisory boards, lecture fees and travel: GSK/Tesaro, Clovis; Financial Interests, Personal, Other, Advisory boards, s and travel: Roche. T. Mathews: Non-Financial Interests, Personal, Leadership Role, NIHR gynae subspeciality lead for gynae research for South/West Yorkshire and Humber side: NIHR. J. Forrest: Non-Financial Interests, Personal, Other, Trsutee FORCE cancer support charity: FORCE cancer support charity; Financial Interests, Institutional, Other, PI EngotCx 11 Trial: Marke Sharpe & Dohme; Financial Interests, Institutional, Other, PI Engot Cx 12 Tria: Seagan. R. Bhana: Financial Interests, Personal, Other, All related to sponsorships for conferences, meetings and courses and market research or teaching sponsorshipAll related to sponsorships for conferences, meetings and courses and market research or teaching sponsorship: Pfizer; Financial Interests, Personal, Other, All related to sponsorships for conferences, meetings and courses and market research or teaching sponsorship: Astellas, Novartis, MSD, Jannsen, Takeda, Eisai, BMS, Clovis, AstraZeneca, GSK, Boston scientific, Palette Life Sciences, Varian, EUSA pharma. H. Stobart: Non-Financial Interests, Personal, Membership or affiliation: Independent Cancer Patients' Voice. A. Mukhopadhyay: Other, Personal, Other, Honoraria for being DSMB member 2023: Canariabio; Financial Interests, Personal, Licencing Fees or royalty for IP, Royalty payment one off in 2019 through Newcastle University: Clovis Oncology; Financial Interests, Institutional, Funding, esearch funding to KolGoTrg for conducting the HPV screening study PRECERCA 2023: Cepheid Global; Non-Financial Interests, Personal, Leadership Role, Project lead- PRECERCA study ( prevention of cervical cancer) - POint of care HPV testing for tea garden workers in Himalayan foothills: N/A; Non-Financial Interests, Personal, Leadership Role, Director: Kolkata Gynecoloy Oncology Trials and Translational Research Group. A.M. Hacker: Financial Interests, Institutional, Other, Research Grant, Institutional, Financial interest, Grant for a UCL-academic sponsored clinical trial: MSD, AstraZeneca, Autolus, Boehringer Ingelheim, GRAIL Inc, Jannsen, Novartis, Pfizer, Roche, Takeda; Financial Interests, Institutional, Other, Research Grant for commercially sponsored trial through the ENGOT Network: Clovis, Seagen, Immunogen, GSK, Novartis, Aravive. A. Hackshaw: Financial Interests, Personal, Advisory Board, AH is an investigator for an academic study (SUMMIT) sponsored by UCL that is funded by GRAIL, Inc.; has received one honorarium for an advisory board meeting for GRAIL, Inc; received a consulting fee from Evidera Inc (for one GRAIL-initiated project).: GRAIL Inc; Financial Interests, Personal, Other, For delivering general education/training in clinical trials.: AbbVie, Boehringer Ingelheim, Clovis, Ipsen, Takeda, AstraZeneca, Daiichi Sankyo, Merck Serono, MSD, UCB, Kyowa Kirin, Servier, Sobi, Pfizer, Roche; Financial Interests, Personal, Stocks/Shares, Shares were sold in 2020: Illumina, Thermo Fisher; Financial Interests, Institutional, Research Grant, Grant for a UCL-academic sponsored clinical trial: Roche, MSD, Autolus, AstraZeneca, Boehringer Ingelheim, GRAIL Inc, Takeda, Pfizer, Novartis, Bristol Myers Squibb, Janssen; Non-Financial Interests, Principal Investigator, Co-lead academic investigator for an observational study sponsored and conducted by Roche. Unpaid/no honoraria for this role.: Roche; Non-Financial Interests, Advisory Role, AH is on the scientific advisory board for Adela Bio and receives no payments/honoraria for this but has share options available.: Adela Bio; Non-Financial Interests, Advisory Role, Unpaid member of advisory board: Navio. J.A. Ledermann: Financial Interests, Personal, Advisory Board, Advisory Board and Speaker Fees: AstraZeneca, Clovis Oncology, GSK; Financial Interests, Personal, Advisory Board: Artios Pharma, Eisai, Merck/MSD, VBL Therapeutics, Bristol Myers Squibb, Nuvation, Ellipses, Immunogen, Miltenyi, Novocure, Immagene; Financial Interests, Personal, Invited Speaker, Speaker Fees: Neopharm; Financial Interests, Personal, Other, Independent Data Monitoring Committee: Mersana; Financial Interests, Personal, Other, IDMC: Sutro Bio, Mersana; Financial Interests, Institutional, Research Grant, Clinical Research University: AstraZeneca, MSD/Merck; Non-Financial Interests, Leadership Role, Vice President ( 2019-2021): European Society of Gynaecological Oncology; Non-Financial Interests, Officer, Chair Gynaecological Clinical Practice Guidelines: ESMO; Other, Associate Editor: Therapeutic Advances in Medical Oncology: Sage Publishing. All other authors have declared no conflicts of interest.

Background

In the phase 3 KEYNOTE-177 (NCT02563002) study, pembrolizumab (pembro) vs chemotherapy (chemo) improved PFS and showed a trend towards improved OS in MSI-H/dMMR mCRC, supporting pembro as first-line therapy. We report efficacy and safety at 5 yrs of follow-up.

Methods

Patients (pts) aged ≥18 y with untreated MSI-H/dMMR mCRC measurable per RECIST v1.1 and an ECOG PS of 0 or 1 were enrolled. Pts were randomly assigned 1:1 to receive pembro 200 mg Q3W or chemo (mFOLFOX6 or FOLFIRI Q2W ± bevacizumab 5 mg/kg Q2W or cetuximab weekly), IV. Pts assigned to chemo could receive ≤35 cycles of pembro after centrally confirmed progressive disease (PD). End points at 5 y were OS, PFS, DOR, and safety.

Results

At data cutoff (July 17, 2023), median follow-up duration was 73.3 mo (6.1 y; range, 64.9-89.2 mo). Of 153 pts assigned to pembro, all pts received treatment and 59 (38.6%) completed 35 cycles of treatment; 143/154 pts assigned to chemo received treatment. A total of 94 (61.4%) pts in the pembro arm and 143 (100%) in the chemo arm discontinued treatment most commonly due to PD (32.7% and 60.8%, respectively). 57 (37.0%) pts in the chemo arm met the crossover criteria and received pembro; 21 (36.8%) completed 35 cycles of pembro. An additional 39 (25.3%) pts who received chemo received a PD-1/L1 inhibitor off-protocol. Median OS (95% CI) was 77.5 mo (6.5 y; 49.2 mo-not reached) with pembro vs 36.7 mo (3.1 y; 27.6-65.3 mo) with chemo (HR 0.73 [95% CI 0.53,0.99]). The 5 y OS rate was 54.8% in the pembro arm and 44.2% in the chemo arm. The 5 y PFS rate was 34.0% and 7.6%, respectively. Median (range) DOR was 75.4 mo (6.3 y; 2.3+ to 80.1+ mo) with pembro vs 10.6 mo (2.8 to 71.5+ mo) with chemo; 85.7% and 33.6% of pts had DOR ≥24 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 79.7% of pts who received pembro and 98.6% who received chemo; grade 3-5 TRAEs occurred in 21.6% and 67.1% of pts, respectively.

Conclusions

After 5 y of follow-up, responses to pembro were more durable than those from chemo, and the trend towards improved OS with pembro persisted despite an effective crossover rate of 62% in pts with MSI-H/dMMR mCRC.

Clinical trial identification

NCT02563002.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Mehak Aggarwal, PharmD and Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

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

Funding

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

Disclosure

K. Shiu: Financial Interests, Personal, Invited Speaker, Educational Webinars on CRC and UGI cancer management with immunotherapy: BMS; Financial Interests, Personal, Advisory Board, Advisory Board on Regorafenib for chemorefractory mCRC in readiness for NICE application: Bayer; Financial Interests, Personal, Invited Speaker, Educational webinars on Pembrolizumab for MSI-High CRC, as well as OG cancers: MSD; Financial Interests, Personal, Advisory Board, For Pembrolizumab in CRC of OG cancers pre or NICE application or post NICE approval: MSD; Financial Interests, Personal, Invited Speaker, Webinars on updates on management of mCRC: Merck Serono; Financial Interests, Personal, Advisory Board, On Mirati GI Global Advisory Board: Mirati Therapeutics; Financial Interests, Personal, Invited Speaker, To update company on indications/updates in landscape of immunotherapy and vaccines in GI cancers: Nouscom; Financial Interests, Personal, Advisory Board, Advisory on Cancer of Unknown Primary, new indications of molecular profiling usingFoundation Medicine 1: Roche; Financial Interests, Personal, Advisory Board, Advisory Board on Lonsurf for chemorefractory mCRC in readiness for NICE application: Servier; Financial Interests, Institutional, Local PI, For MATTERHORN Trial: AstraZeneca; Financial Interests, Institutional, Coordinating PI, UK Chief Investigator on KEYNOTE 177, KEYNOTE 859, KEYNOTE 811, LEAP 17, MK1308A-008 trials: MSD; Financial Interests, Institutional, Research Grant, Chief Investigator of investigator initiated, MSD funded NEOPRISM-CRC trial: MSD; Financial Interests, Institutional, Local PI, UCLH PI for LEAP 15 and MK4280A-007 trials: MSD; Financial Interests, Institutional, Coordinating PI, UK Chief Investigator for NOUS209-001 trial: Nouscom; Financial Interests, Institutional, Coordinating PI, UK Chief Investigator for CUPSICO trial: Roche; Financial Interests, Personal, Steering Committee Member, Steering Committee Member of CUPISCO trial: Roche; Non-Financial Interests, Member: ASCO, Association of Cancer Physicians UK. T. André: Financial Interests, Personal, Advisory Board, Advosiry Board on February 12, 2021: Astellas pharma; Financial Interests, Personal, Advisory Board, Advisory Board on February 2021: Kaleido Biosciences; Financial Interests, Personal, Invited Speaker, and advisory board 2021: Amgen; Financial Interests, Personal, Invited Speaker, Ivited speaker in a symposuim december 2020: AstraZeneca; Financial Interests, Personal, Advisory Board, and consultant fees and consultant contract 2021 and 2022: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory board in Janaury 2020: Clovis; Financial Interests, Personal, Advisory Board, Advisory board in january 2020: Gritstone Oncology; Financial Interests, Personal, Advisory Board, Advisory board 2020: Haliodx; Financial Interests, Personal, Advisory Board, and consultant fees/consultant contract and invited speaker: MSD Oncology; Financial Interests, Personal, Invited Speaker, and other: Pierre Fabre; Financial Interests, Personal, Invited Speaker, in an symposuim in 2020: Roche; Financial Interests, Personal, Invited Speaker, in a meeting in 2019: Ventana; Financial Interests, Personal, Invited Speaker, In a educational meeting in 2019: Sanofi; Financial Interests, Personal, Advisory Board, in a symposuim in 2020: Servier; Financial Interests, Personal, Advisory Board, Consultant with personnal fees and invited speaker: Servier; Financial Interests, Personal, Advisory Board, in 2019: GSK; Financial Interests, Personal, Invited Speaker, in 2020 and 2021: GSK; Financial Interests, Personal, Invited Speaker, Virtual symposuimLecture: 1 MSI-H CRC: Implementation of Immunotherapy in clinical practice (30 minutes) – (this will be pre-recorded)Q&A – Live Q&A – (10 minutes) (on July 2, 2021): MSD Oncology; Financial Interests, Personal, Invited Speaker, June 2022: Sanofi; Financial Interests, Personal, Advisory Board, Contract 2021, 2022, 2023: Merck & Co., Inc; Financial Interests, Personal, Advisory Board, Contrat 2019, 2020, 2021, 2022: BMS; Financial Interests, Personal, Advisory Board, Contract 2021: Gritstone Oncologie; Financial Interests, Personal, Invited Speaker, June 2022 and June 2023 during ESMO GI meeting: Seagen; Financial Interests, Personal, Writing Engagement, Contract of consulting 2021 and 2022 and 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, September 2022: GSK, Seagen; Financial Interests, Personal, Writing Engagement, Contract of consulting 2022 and 2023: GSK; Financial Interests, Personal, Writing Engagement, Contract of consulting 2022: Nordic Pharma; Financial Interests, Personal, Invited Speaker, October 2022: Merk Serono; Financial Interests, Personal, Other, Educationnal in 2022: Roche; Financial Interests, Personal, Other, Contract of consulting 2020, 2021, 2022,2023: Servier; Financial Interests, Personal, Advisory Board, Gilead Sciences Global GI Advisory Board on January 18, 2023: Aptitude Health, Glilead; Financial Interests, Personal, Other, Consultant like member of the SGNTUC-029 Steering Committee (the “Steering Committee”) Services related to the Company’s Study titled “An Open-label Randomized Phase 3 Study of Tucatinib in Combination with Trastuzumab and mFOLFOX6 versus mFOLFOX6 given with or without either Cetuximab or Bevacizumab as First-line Treatment for Subjects with HER2+ Metastatic Colorectal Cancer” (collectively, the “Services”).Including teleconferences and board preparation befor the board (6h)Participation of the Board on September 2022 in Paris, September 10, 2022 MOUNTAINEER-03 Steering Committee Meeting during ESMO: Seagen; Financial Interests, Personal, Other, Consultant like member of the to be a member of the Colorectal Program Scientific Advisory Committee (SAC). In charges for reviewing V940 Pembro on Engagezone (as per your contract in ref).and also an inrtview about Pembrolizumab for MSI/dMMR Metastaic colo-rectal 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, but also formation for the takeda team, and consultant for TakedaContract beetween 1 sept 2023 and 15 october 2024: Takeda; Financial Interests, Personal, Advisory Board, Board Meeting (October 19, 2023): AbbVie; Financial Interests, Institutional, Coordinating PI, PI Garnet study: GSK; Financial Interests, Institutional, Coordinating PI, Keynote 164 and 171 and 811 and C08: MSD; Financial Interests, Institutional, Coordinating PI, BMS CA209-8HW, BMS CA209-142, BMS CA209-577: BMS; Financial Interests, Institutional, Coordinating PI, SPOTLIGHT study: Astellas; Financial Interests, Personal, Steering Committee Member, and international PI (trial chair Solstice study): Servier; Financial Interests, Personal, Steering Committee Member, MOUNTAINEER and MOUNTAINEER-03 study (PI for France) 2022, 2023: Seagen; Financial Interests, Institutional, Local PI, A randomized, open-label, phase 2 study of botensilimab (AGEN1181) AS monotherapy and in combination with balstilimab (AGEN2034) or investigator’s choice standard of care (regorafenib or trifluridine and tipiracil) for the treatment of refractory metastatic colorectal cancer: Agenus; Non-Financial Interests, Member of Board of Directors, Investigator: Gercor group; Non-Financial Interests, Member of Board of Directors, President since october 2022: ARCAD Foundation. T.W. Kim: Financial Interests, Institutional, Research Grant: Genentech. L.H. Jensen: Non-Financial Interests, Institutional, Principal Investigator: 2cureX, BMS, MSD, Roche, Pfizer. C.J.A. Punt: Financial Interests, Institutional, Advisory Board: Nordic Pharma. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board, Invited Speaker: Novartis, Advanz Pharma, Bayer, BMS, Boehringer, Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, PharmaMar, Pierre Fabre, Roche, Servier, Takeda; Financial Interests, Institutional, Research Grant: Pfizer, BMS, MSD. J. Alcaide-Garcia: Financial Interests, Personal, Invited Speaker, Travel/Accommodations/Expenses: Merck, Amgen, Servier; Financial Interests, Personal, Advisory Board, Travel/Accommodations/Expenses: Sanofi, MSD; Financial Interests, Personal, Invited Speaker: Pierre-Fabre. P. Gibbs: Financial Interests, Personal and Institutional, Invited Speaker, Research Grant: MSD, Merck & Co., Inc., Servier; Financial Interests, Institutional, Research Funding: Bayer. C. de la Fouchardiere: Financial Interests, Personal, Advisory Board, Research Grant; Principal Investigator: MSD. F. Rivera: Financial Interests, Personal and Institutional, Advisory Board, Invited Speaker; Research Grant; Funding; Principal Investigator: MSD, Amgen, Roche, BMS, AstraZeneca, Servier, Bayer. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board, Travel/Accommodations/Expenses: Amgen, Bayer, Hoffman La-Roche, Merck Serono, MSD, Pierre Fabre, Sanofi, Servier, Takeda; Financial Interests, Personal, Invited Speaker, Travel/Accommodations/Expenses: Novartis, Organon, Pfizer; Financial Interests, Personal, Training, Travel/Accommodations/Expenses: Seagen; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Array BioPharma, BMS; Financial Interests, Institutional, Funding: Amgen, Array Biopharma Inc., AstraZeneca, Celgene International SARL, BeiGene, Boehringer Ingelheim, BMS, Debiopharm International SA, Genentech Inc., HalioDX SAS, Hoffman-La Roche, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini; Other, Personal, Other, Volunteer member of the ASCO Annual Meeting. Scientific Program Committee: Developmental Therapeutics – Immunotherapy: American Society of Clinical Oncology (ASCO); Other, Personal, Speaker, Consultant, Advisor: European Society for Medical Oncology (ESMO); Other, Personal, Other, Coordinator of the SEOM + MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM). D.T. Le: Financial Interests, Personal and Institutional, Advisory Board, Invited Speaker; Research Grant; Funding; Principal Investigator: Merck; Financial Interests, Personal and Institutional, Advisory Board, Research Grant; Funding; Principal Investigator: BMS, Nouscom; Financial Interests, Personal, Advisory Board: G1 Therapeutics, Merus; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board, Principal Investigator: Regeneron; Non-Financial Interests, Institutional, Research Grant, Principal Investigator: Curegenix; Non-Financial Interests, Institutional, Research Grant, Funding; Principal Investigator: Medivir; Financial Interests, Institutional, Research Grant, Principal Investigator: AbbVie. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd, Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., FALCO Biosystems Ltd.. Y. Zuo: Financial Interests, Personal, Full or part-time Employment: MSD China. D. Fogelman: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Merck & Co., Inc.. D.E. Adelberg: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Merck & Co., Inc.. L.A. Diaz: Financial Interests, Personal and Institutional, Member of Board of Directors: Quest Diagnostics and Epitope; Financial Interests, Personal, Speaker, Consultant, Advisor: PetDx, Innovatus CP, Se’er, Delfi, Blackstone, Kinnate, Neophore; Financial Interests, Personal, Stocks/Shares: Quest Diagnostics, Epitope, PetDx, Se’er, Delfi, Kinnate, Neophore. All other authors have declared no conflicts of interest.

Background

At the protocol-specified first interim analysis of the phase 3 KEYNOTE-671 study of resectable early-stage NSCLC (NCT03425643), neoadjuvant pembrolizumab (pembro) + chemotherapy (chemo) followed by resection and adjuvant pembro significantly improved EFS, mPR, and pCR with an expected safety profile vs neoadjuvant chemo and resection alone. We present results of the protocol-specified second interim analysis of KEYNOTE-671.

Methods

Patients (pts) with resectable stage II, IIIA, or IIIB (N2) NSCLC per AJCC v8 were randomized 1:1 to pembro 200 mg (n = 397) or placebo (n = 400) Q3W. Pts were to receive 4 cycles of neoadjuvant pembro or placebo plus cisplatin-based chemo and ≤13 cycles of adjuvant pembro or placebo. Dual primary endpoints are EFS (time from randomization to local progression precluding planned surgery, unresectable tumor, progression or recurrence per RECIST v1.1 by investigator assessment, or death from any cause) and OS.

Results

Median time from randomization to the 10 July 2023 data cutoff was 36.6 mo (range, 18.8-62.0). With 254 (31.9%) deaths, OS was significantly improved in the pembro arm (HR 0.72 [95% CI 0.56-0.93]; P = 0.00517). Median OS was not reached (NR) (95% CI NR-NR) in the pembro arm vs 52.4 mo (95% CI 45.7-NR) in the placebo arm; 36-mo OS rates were 71.3% vs 64.0%. EFS continued to be improved in the pembro arm (HR 0.59 [95% CI 0.48-0.72]; median [95% CI] 47.2 mo [32.9-NR] vs 18.3 mo [14.8-22.1]; 36-mo rate, 54.3% vs 35.4%). Treatment-related AEs were grade ≥3 in 45.2% of pts in the pembro arm vs 37.8% in the placebo arm, led to discontinuation of all treatment in 20.2% vs 9.3%, and led to death in 1.0% vs 0.8% (no new treatment-related deaths since the first interim analysis).

Conclusions

Neoadjuvant pembro + chemo followed by resection and adjuvant pembro provided a statistically significant and clinically important improvement in OS compared with neoadjuvant chemo and resection alone in pts with resectable stage II, IIIA, or IIIB (N2) NSCLC. The OS gains seen in KEYNOTE-671 with the absence of new safety signals establish the perioperative pembro regimen as a new standard of care for resectable early-stage NSCLC.

Clinical trial identification

NCT03425643, first posted February 7, 2018.

Editorial acknowledgement

Editorial assistance provided by Melanie A. Leiby, PhD, an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

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

Funding

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

Disclosure

J.D. Spicer: Financial Interests, Personal, Advisory Role, honoraria: AstraZeneca, Merck & Co., Inc., Rahway, NJ, USA, Bristol-Myers Squibb, Amgen, Chemocentryx, Regeneron, Protalix Biotherapeutics, Xenetic Biosciences, Novartis; Financial Interests, Institutional, Funding: AstraZeneca, Merck Sharp & Dohme Corp., Bristol-Myers Squibb, CLS Therapeutics, Protalix Biotherapeutics. S. Gao: Financial Interests, Institutional, Funding, To support study conduct: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.. M. Liberman: Financial Interests, Personal, Advisory Board: Johnson & Johnson; Financial Interests, Personal, Stocks/Shares, CMO: Endocision, AssistIQ, Ditch Labs; Financial Interests, Local PI: Merck, AstraZeneca, Pfizer, BMS; Financial Interests, Research Grant: J&J. T. Kato: Financial Interests, Personal, Advisory Board, speaker, consultancy: AstraZeneca, Eli Lilly, Merck Biopharma, MSD; Financial Interests, Personal, Advisory Board, speaker: Pfizer, Amgen, Janssen; Financial Interests, Personal, Other, consultancy: Daiichi Sankyo, Takeda, Taiho; Financial Interests, Personal, Other, consultancy, speaker: Chugai; Financial Interests, Personal, Invited Speaker: Ono, Novartis, Bristol-Meyers Squibb, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Beigene, Glaxo; Financial Interests, Personal, Advisory Board, Steering Committee: Roche; Financial Interests, Personal, Full or part-time Employment, Family member: Eli Lilly; Financial Interests, Institutional, Local PI: Chugai, MSD, Pfizer, Eli Lilly, AbbVie, Regeneron, Novartis, Amgen, Merck Biophama, BeiGene, Haihe Biopharma, Blueprint Medicines, Turning Point, Takeda, Daiichi Sankyo, Gilead, GSK, Janssen, Bayer; Financial Interests, Institutional, Steering Committee Member, Local PI: 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, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical CO.,LTD, Daiichi Sankyo company limited; Financial Interests, Personal, Advisory Board, Advisory boards: Novartis, MiREXS; Financial Interests, Institutional, Research Grant: Beohringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical Co.,Ltd, Bristol-Myers Squibb KK, Novartis, MiRXES; Financial Interests, Personal, Steering Committee Member: MSD, AstraZeneca, Novartis; Financial Interests, Institutional, Steering Committee Member: Eli Lilly Japan. S. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca/MedImmune, Roche, Merck, Pfizer, Lilly, BMS/Ono, Takeda, Janssen, IMBdx; Financial Interests, Personal, Invited Speaker: AstraZeneca/MedImmune, Roche, Merck, Lilly, Amgen; Financial Interests, Institutional, Research Grant: Merck, AstraZeneca, Lunit. K. Chen: Financial Interests, Institutional, Funding, Supports study conduct: MSD. M. Majem: Financial Interests, Personal, Advisory Board: Amgen, Roche, AstraZeneca,Takeda, Janssen, Cassen Recordati, BMS; Financial Interests, Personal, Invited Speaker: Amgen, Roche, AstraZeneca, Pfizer, Takeda, Helsinn; Financial Interests, Institutional, Funding: BMS, AstraZeneca, Roche. E. Eigendorff: Financial Interests, Institutional, Funding, Studying funding to the institution to support study conduct: MSD. G. Martinengo: Financial Interests, Institutional, Funding, Funding to institution to suport study conduct: MSD. O. Bylicki: Financial Interests, Personal, Advisory Board, Expert Board: BMS, Roche, Takeda; Financial Interests, Personal, Advisory Board, Annuel contrat: MSD; Financial Interests, Personal, Advisory Board, expert board: AstraZeneca, janssen. M.C. Garassino: Financial Interests, Personal, Advisory Board: Eli Lilly, SeaGen International GmbH, Eli Lilly, Incyte, GSK, Bayer Healthcare Pharmaceuticals, Blueprint Medicines, AstraZeneca UK, AstraZeneca and Daiichi Sankyo Oncology Teams, Roche, Daiichi Sankyo, Mirati Therapeutics, Inc, Daiichi Sankyo/AstraZeneca, AstraZeneca Poland, Daiichi Sankyo, Inc., MSD, Eli Lilly, Pfizer, AstraZeneca/MedImmune, Sanofi Genzyme corporation, Sanofi / Prex, Regeneron Pharmaceuticals, Eli Lilly, Mirati Therapeutics, Inc.; Financial Interests, Personal, Invited Speaker: WebMD, WebMD Oncology/Takeda, MSD Italia, Srl, GrupoPacifico-Secretaria Técnica ICAPEM/AstraZeneca, S.O.S S.r.l, Medscape, ecancer, Ideology; Financial Interests, Personal, Invited Speaker, Global Experts Meeting: AstraZeneca; Financial Interests, Personal, Other, AstraZeneca Spain: Invitation to a lung cancer investigator meeting: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory Boards: Takeda, Daiichi Sankyo, BeiGene; Financial Interests, Personal, Other, PACIFIC-R Global Scientific Committee: AstraZeneca; Financial Interests, Personal, Other, Steering Committee member and Co-chair at the AstraZeneca Lung Cancer Summit 2019: AstraZeneca; Financial Interests, Personal, Other, MK-3475 KN671 Steering Committee.: MSD; Financial Interests, Personal, Other, Pacific 6 International Coordinating Investigator: AstraZeneca; Financial Interests, Personal, Other, Janssen Scientific Advisory Board and Therapeutic Area Steering Committee Meeting on Lung Cancer: Janssen; Financial Interests, Personal, Other, Pfizer Global Lung Cancer Educational Programme - Steering Committee: Pfizer; Financial Interests, Personal, Other, Seattle Genetics Lung Cancer Platform Study: Seattle Genetics; Financial Interests, Personal, Other, GSK Lung Cancer Global Council: GSK; Financial Interests, Personal, Other, PACIFIC-R Scientific Committee: AstraZeneca UK; Financial Interests, Personal, Other, GSK-Garassino- ZEAL Steering Committee 2020-23: GSK; 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Financial Interests, Institutional, Local PI, Phase II - VISION: Merck KGaA; Financial Interests, Institutional, Local PI, Phase III MK-3475-715: Incyte Corporation; Financial Interests, Institutional, Local PI, Phase 1/2 (TRIDENT-1): Turning Point Therapeutics, Inc.; Financial Interests, Institutional, Local PI, HERTHENA-Lung01: A Phase 2: Daiichi Sankyo Development Ltd.; Financial Interests, Institutional, Local PI, Phase II ATLANTIC: AstraZeneca S.p.A.; Financial Interests, Institutional, Local PI, Clinical trial: Affimed; Financial Interests, Institutional, Local PI, Clinical trial poziotinib: spectrum; Non-Financial Interests, Principal Investigator, STYLE Trial: Pfizer; Non-Financial Interests, Principal Investigator, Studio TYME: Eli Lilly; Non-Financial Interests, Principal Investigator, People: MSD; Non-Financial Interests, Principal Investigator, FAME trial: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, POST-ALK: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, Bando finalizzata Mesotelioma: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, TERAVOLT: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, IND227: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Principal Investigator, Progetto Timoma: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, APOLLO: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, Beverly: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Principal Investigator, RAMES: GOIRC; Non-Financial Interests, Principal Investigator, Studio CHANCE: GOIRC; Non-Financial Interests, Principal Investigator, Creta trial: Sant'Orsola Malpighi - Bologna (Alma Mater Studiorum Università Bologna); Non-Financial Interests, Principal Investigator, MILES 5: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Principal Investigator, LIPI: GUSTAVE-ROUSSY PARIGI LIPI TRIAL- no profit; Non-Financial Interests, Principal Investigator: AO Spedali Civili Brescia; Non-Financial Interests, Principal Investigator, phase III trial: European Thoracic Oncology Platform (ETOP); Non-Financial Interests, Leadership Role, Honorary President and Founder: Women for Oncology Italy; Non-Financial Interests, Other, Member of ASCO Scientific Committee (2018-2021): ASCO; Non-Financial Interests, Leadership Role, Board member: AIOT (Associazione Italiana Oncologia Toracica); Non-Financial Interests, Member: AIOM, AIOT; Non-Financial Interests, Member, WCLC annual congress Lung Cancer Track: WCLC; Non-Financial Interests, Member, Scientific Committee: IPOP (Italian lung cancer charity), TUTOR (Italian thymic malignancies charity); Non-Financial Interests, Member, Member since 2013-2018: EMA Scientific Advisory Group (SAG); Non-Financial Interests, Other, Scientific Programme Committee: AACR; Non-Financial Interests, Leadership Role, previous ESMO National Societies Committee Chair and ESMO Council Member: ESMO; Other, Travel, Accommodations, Expenses: Pfizer; Other, Relationships to Disclose Travel, Accommodations, Expenses: Roche, AstraZeneca; Other, travel and accomodation: Merk. D. Rodriguez Abreu: Financial Interests, Personal, Advisory Board: MSD, Novartis, Roche/Genentech, pfizer, Bristol-Myers Squibb, AstraZeneca, Regeneron, Gilead, Sanofi, Amgen, Takeda, Eli Lilly, Incyte, Merck Serono; Financial Interests, Personal, Invited Speaker: MSD, Novartis, Roche/Genentech, pfizer, Bristol-Myers Squibb, AstraZeneca, Regeneron, Gilead, Sanofi, Amgen, Takeda, Eli Lilly, Merck Serono; Financial Interests, Personal, Other, Travel expenses: MSD, Novartis, Roche/Genentech, pfizer. J. Chaft: Other, Personal, Speaker, Consultant, Advisor: arcus biosciences, AstraZeneca, Bristol Myers Squibb Company, Flame biosciences, Guardant Health, Merck, Regeneron Pharmaceuticals; Financial Interests, Institutional, Funding, Funding to support study conduct: Merck Sharp & Dohme; Financial Interests, Institutional, Funding, Funded by Cancer Center Support Grant P30 CA008748: NIH. S. Novello: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Eli Lilly, Novartis, Beigene, Amgen; Financial Interests, Personal, Advisory Board: BI, BMS, Pfizer, Takeda, Roche, Sanofi, Amgen; Financial Interests, Institutional, Coordinating PI, IIT: MSD, BI; Non-Financial Interests, Leadership Role, president of this european advocacy: WALCE. J. Yang: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.. S.M. Keller: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. A. Samkari: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. H. Wakelee: Financial Interests, Personal, Advisory Board, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Blueprint, Mirati; Financial Interests, Personal, Invited Speaker, Develop and present a series of lectures: Fishawack Facilitate LTD; Financial Interests, Personal, Invited Speaker, Series of CME lectures: Medscape, Research to Practice; Financial Interests, Personal, Other, Discussion of new data at conferences: Curio Science; Financial Interests, Personal, Invited Speaker, Series of lectures/webinars for PER/OncLive: MJH Holdings; Financial Interests, Personal, Writing Engagement: UpToDate; Financial Interests, Personal, Invited Speaker, CME lecture: Axis Medical Education, Nexus Oncology; Financial Interests, Institutional, Local PI, Clinical Trial Conduct: ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, BMS, Clovis Oncology, Novartis, Seagen, Xcovery; Financial Interests, Institutional, Coordinating PI, Clinical Trial Conduct: Celgene; Financial Interests, Institutional, Steering Committee Member, Clinical Trial Conduct: Genentech/Roche, Merck; Non-Financial Interests, Leadership Role, Executive Committee: ECOG-ACRIN; Financial Interests, Institutional, Local PI, clinical trial conduct: Helsinn; Non-Financial Interests, Officer, President: International Association for the Study of Lung Cancer (IASLC). All other authors have declared no conflicts of interest.

Background

KEYNOTE-522 (NCT03036488) showed statistically significant and clinically meaningful improvements in pCR and EFS with the addition of pembrolizumab (pembro) to chemotherapy (chemo) in patients (pts) with early-stage TNBC. Here, we present updated EFS results after ∼5 yr median follow-up.

Methods

Eligible pts with previously untreated, non-metastatic, centrally confirmed TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC) were randomized 2:1 to neoadjuvant pembro 200 mg Q3W or placebo (pbo), both given with 4 cycles of paclitaxel + carboplatin, then with 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After definitive surgery, pts received adjuvant pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity. Dual primary endpoints are pCR (ypT0/Tis ypN0) and EFS (time from randomization to disease progression that precluded definitive surgery, local/distant recurrence, second primary cancer, or death from any cause).

Results

1174 pts were randomized to pembro (n=784) or pbo (n=390). At data cutoff (March 23, 2023), median follow-up was 63.1 mo. 145 pts (18.5%) in the pembro group and 108 pts (27.7%) in the pbo group had an EFS event (HR 0.63 [95% CI, 0.49-0.81]). The 60-mo EFS rate (95% CI) was 81.3% (78.4-83.9) vs 72.3% (67.5-76.5), respectively; the median was not reached in either group. The most common first EFS event was distant recurrence, in 72 pts (9.2%) in the pembro group vs 55 pts (14.1%) in the pbo group. With 210 distant events, rates of distant disease progression- or distant recurrence-free survival at 60 mo were 84.4% with pembro vs 76.8% with pbo (HR 0.64 [95% CI, 0.49-0.84]). The EFS benefit with pembro was consistent across prespecified subgroups, including PD-L1 expression and nodal status. In a prespecified, non-randomized, exploratory analysis, 5-yr EFS rates in the pembro and pbo groups were 92.2% vs 88.2% in pts with a pCR, and 62.6% vs 52.3% in pts without a pCR. Follow-up for OS is ongoing.

Conclusions

Neoadjuvant pembro + chemo followed by adjuvant pembro continues to show a clinically meaningful improvement in EFS compared with neoadjuvant chemo alone in pts with early-stage TNBC, regardless of the pCR outcome.

Clinical trial identification

NCT03036488.

Editorial acknowledgement

Editorial assistance in the writing of the abstract was provided by Christine McCrary Sisk, an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A.

Disclosure

P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Gilead, Eisai, MSD, Seagen, Amgen, Celgene, Lilly; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Leuko, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Jazz Pharmaceuticals, AbbVie, Scorpion Therapeutics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Eisai, Pfizer, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MAJ3 Capital; Financial Interests, Personal, Stocks/Shares, (relative): Leuko; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, Guardant Health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca, Steamline Therapeutics; Other, travel cost and expenses: Merck Sharp&Dhome. R.A. Dent: Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, Merck, Pfizer, Lilly, Novartis, Roche; Financial Interests, Personal, Other, Travel: AstraZeneca, Eisai, Merck, Pfizer, Roche. L. Pusztai: Financial Interests, Personal, Advisory Board, advisory board, trial steering committee membership: AstraZeneca; Financial Interests, Personal, Advisory Board: pfizer, roche genentech, novartis, Exact Sciences, Natera; Financial Interests, Personal, Advisory Board, advisory board, trial steering committee: Merck; Financial Interests, Personal, Advisory Board, advisory board: Biotheranostics; Financial Interests, Personal, Advisory Board, investigator meeting: Biovica; Financial Interests, Institutional, Trial Chair, clinical trial support to institution: pfizer, merck; Financial Interests, Institutional, Local PI, clinical trial support to institution: seagen, AstraZeneca; Financial Interests, Institutional, Research Grant, research grant: bristol myers squibb; Non-Financial Interests, Advisory Role, member of the scientific advisory board: Breast Cancer Research Foundation; Non-Financial Interests, Member of Board of Directors: SWOG Hope Foundation; Non-Financial Interests, Institutional, Product Samples, material transfer agreement: pfizer. H.L. McArthur: Financial Interests, Personal, Advisory Board: Lilly, Pfizer, Immunomedics, Merck, Seattle Genetics, Daiichi Sankyo, Bristol Myers Squibb, AstraZeneca, Puma Biotechnology, Gilead, Crown Bioscience; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MedImmune, AstraZeneca, Merck. S. Kummel: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Stemline, Gilead, MSD; Lilly, Novartis, Pfizer, Seagen, Daiichi Sankyo, Exact Science; Financial Interests, Personal and Institutional, Advisory Board: Roche, AstraZeneca, Stemline, Gilead, MSD; Lilly, Novartis, Pfizer, Seagen, Exact Science, Daiichi Sankyo; Non-Financial Interests, Member of Board of Directors: ESMO, AGO, WSG; Non-Financial Interests, Ownership Interest: WSG; Financial Interests, Personal and Institutional, Principal Investigator, Both financial and non-financial: Roche, AstraZeneca, Stemline, Gilead, MSD; Lilly, Novartis, Pfizer, Seagen, Exact Science, Daiichi Sankyo, GSK; Non-Financial Interests, Advisory Role: ESMO, AGO, WSG; Financial Interests, Personal, Advisory Board: Novartis, MSD, Hologic, Stryker, Lilly. C. Denkert: Financial Interests, Personal, Advisory Board: MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, Roche, Lilly, Diaceutics, VmScope digital pathology software; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche, Myriad, German Breast Group. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Institutional, Other, Research Grant: AstraZeneca, Pfizer, Roche, MSD; Non-Financial Interests, Principal Investigator: AstraZeneca, Lilly, Pfizer, Novartis, MSD, Roche, Daiichi Sankyo; Financial Interests, Institutional, Writing Engagement: Pfizer. R. Hui: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Eisai, Merck, Oncosec, Amgen, Takeda, Zai Lab; Financial Interests, Personal, Invited Speaker: MSD, Novartis, AstraZeneca, Eli Lilly, Janssen; Financial Interests, Institutional, Local PI: AstraZeneca, BMS, Eli Lilly, Janssen, MSD, Novartis, Oncosec, Roche, Seagen, Corvus; Financial Interests, Personal, Steering Committee Member: MSD; Financial Interests, Steering Committee Member: AstraZeneca; Non-Financial Interests, Member: ASCO, IASLC, Medical Oncology Group of Australia (MOGA); Non-Financial Interests, Other, Member of IASLC Education Committee: IASLC. N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Art Tempi, Onkowissen, Medscape, Gilead, Sanofi, Zuelligpharma, Viatris; Financial Interests, Personal, Other, IDMC: Roche; Financial Interests, Personal, Advisory Board: Sandoz-Hexal, Seagen, Aptitude Health, Pfizer, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Funding: AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Palleos, Seagen, TRIO, WSG; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. M. Takahashi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Pfizer, Eisai, Daiichi Sankyo, MSD. T. Foukakis: Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Gilead Sciences; Financial Interests, Personal, Advisory Board: Affibody; Financial Interests, Personal, Royalties, Authorship of two chapters in UpToDate: Wolters Kluwer; Financial Interests, Institutional, Coordinating PI, Clinical trial support (research grant and study drug): Pfizer, AstraZeneca; Financial Interests, Institutional, Coordinating PI, Clinical trial support (research grant and study drug): Novartis. M.A. Mouret Reynier: Financial Interests, Personal and Institutional, Invited Speaker: Novartis, Pfizer, Lilly, AstraZeneca; Financial Interests, Personal and Institutional, Advisory Board: Novartis, Pfizer, Lilly, AstraZeneca, MSD. M.I.R. Ferreira: Financial Interests, Institutional, Local PI: MSD, Taiho Oncology, AstraZeneca; Financial Interests, Institutional, Other, Sub-investigator: Daiichi Sankyo, Roche, AstraZeneca, Novartis, MSD; Non-Financial Interests, Member, Board member (treasurer) of a non-profit association that promotes knowledge in Oncology.: Grupo de Estudos Oncológicos. S. Im: Financial Interests, Personal, Advisory Board, no payment: AstraZeneca, Novartis, Eisai, Roche, Hanmi, Pfizer, Lilly, MSD, GSK, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Bertis; Financial Interests, Personal, Advisory Board: Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Pfizer, Roche, Eisai, Dae Woong; Financial Interests, Institutional, Local PI, Clinical Trial Budget: AstraZeneca, Hanmi, Novartis, Roche, Pfizer, Daiichi Sankyo, MSD, Lilly; Financial Interests, Institutional, Coordinating PI, Clinical Trial Budget: Eisai; Financial Interests, Institutional, Research Grant, Clinical Trial Budget: Boryung Pharm. F. Cardoso: Financial Interests, Personal, Other, Consultancy: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GSK, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, Prime Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva; Financial Interests, Personal, Advisory Board: Gilead, Iqvia, Touchime; Financial Interests, Institutional, Local PI: Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Bayer, Daiichi, Eisai, Fresenius GmbH, Genentech, GSK, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, Medigene, MedImmune, Merck, Millenium, Pfizer, Pierre-Fabre, Roche, Sanofi-Aventis, Sonus, Taiho Oncology, Tesaro, Tigris, Wilex, Wyeth, Gilead; Non-Financial Interests, Leadership Role, President: ABC Global Alliance and ABC Consensus Conference and Guidelines; Non-Financial Interests, Member: ESMO, ESO, EORTC, BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, ASPIC. Y. Ding: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. W. Pan: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. K.E. Tryfonidis: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Ondonate, Pfizer, Puma, Prime Oncology, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Sanofi.

Background

New therapeutic options are needed to delay disease progression for pts with mHSPC. The combination of pembro + enza has shown antitumor activity in pts with metastatic prostate cancer. The phase 3 KEYNOTE-991 study (NCT04191096) investigated pembro or placebo (pbo) + enza + ADT in pts with next-generation hormonal agent (NHA)-naïve mHSPC.

Methods

Eligible pts (aged ≥18 yrs, ECOG PS ≤1) had confirmed mHSPC (≥2 bone lesions and/or visceral disease, verified centrally), no prior NHA, and had completed any prior docetaxel (≤6 cycles) ≤2 mo from randomization. Pts were randomized 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles + enza 160 mg orally daily + continuous ADT (if no history of bilateral orchiectomy). Dual primary endpoints were radiographic progression-free survival (rPFS) per PCWG-modified RECIST 1.1 by blinded independent central review and overall survival (OS). Key secondary endpoints included time to initiation of first subsequent anticancer therapy (TFST) and time to first symptomatic skeletal-related event (TTSSRE). Safety was a secondary endpoint.

Results

Between Mar 2, 2020, and Aug 9, 2021, 626 pts were randomized to pembro + enza and 625 to pbo + enza. As of Oct 31, 2022, the median (range) follow-up time at first prespecified interim analysis was 21.1 mo (14.8−32.0). Baseline characteristics were generally balanced between arms; ∼10% of pts received prior docetaxel in each arm. The primary endpoint of rPFS for pembro + enza vs pbo + enza was not met (median not reached [NR] vs NR, HR 1.20, 95% CI 0.96−1.49, P=0.95). Median OS was NR vs NR (HR 1.16, 95% CI 0.88−1.53). Median TFST was NR in both arms (HR 1.24, 95% CI 1.01−1.54). Median TTSSRE was NR in both arms (HR 0.89, 95% CI 0.61−1.30). Serious AEs occurred in 40.3% vs 23.2% of pts with pembro + enza vs pbo + enza. Any-grade and grade ≥3 treatment-related AEs occurred in 88.0% vs 67.0% and 41.8% vs 13.9% of pts, respectively.

Conclusions

The study was stopped for futility. The addition of pembro to enza plus ADT did not improve rPFS or OS in pts with NHA-naïve mHSPC and was associated with more serious and treatment-related AEs vs enza plus ADT.

Clinical trial identification

NCT04191096.

Editorial acknowledgement

Writing assistance was provided by Ina Nikolaeva of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Astellas provided the enzalutamide for this study.

Legal entity responsible for the study

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

Funding

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

C.J. Gratzke: Financial Interests, Personal, Advisory Board: Astellas Pharma, Bayer, GSK, MSD, AstraZeneca, Janssen, Steba Biotech; Financial Interests, Personal, Invited Speaker: Astellas Pharma, Bayer, MSD, MSD, Bayer, Recordati, Amgen, AstraZeneca, AstraZeneca, Ipsen, Janssen, Janssen, Novartis, Pfizer; Financial Interests, Personal and Institutional, Invited Speaker: MSD, MSD; Financial Interests, Personal and Institutional, Funding: MSD; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Invited Speaker: Bayer, Janssen, Lilly, AstraZeneca; Non-Financial Interests, Principal Investigator: MSD; Non-Financial Interests, Project Lead: Janssen, Bayer; Non-Financial Interests, Advisory Role: STEBA. M. Ozguroglu: Financial Interests, Personal, Advisory Board, prostate cancer: Astellas; Financial Interests, Personal, Invited Speaker, travel and accommodation: Regeneron; Financial Interests, Personal, Advisory Board, lung cancer meeting: Sanofi. A. Peer: Financial Interests, Personal, Advisory Board, and Invited speaker: MSD; Financial Interests, Personal, Advisory Board, And invited speaker: BMS; Financial Interests, Personal, Expert Testimony, and invited speaker: Roche; Financial Interests, Personal, Advisory Board, and invited speaker: Astellas; Financial Interests, Personal, Advisory Board: Janssen, Bayer, Teva, Takeda, Medison pharma; Financial Interests, Personal, Invited Speaker: Exelixis; Financial Interests, Institutional, Research Grant: Sanofi aventis. M.A.N. Sendur: Financial Interests, Personal, Advisory Board: BMS, Pfizer, Takeda, Roche, Astellas; Financial Interests, Personal, Invited Speaker: Astellas, Pfizer, BMS, MSD, Roche. M. Retz: Financial Interests, Personal, Research Grant: BMS. J.C.H. Goh: Financial Interests, Personal, Advisory Board, Prior member of the BMS RCC Advisory Board: BMS; Financial Interests, Personal, Advisory Board, Uterine Cancer Advisory Board: GSK; Financial Interests, Personal, Other, Chairing RCC meeting: Ipsen; Financial Interests, Personal, Invited Speaker, Speaking @ MSD sponsored event on Gynaecological cancerSpeaking at MSD sponsored event on RCC: MSD; Financial Interests, Personal, Advisory Board, Met RCC Advisory Board: MSD/ Eisai; Financial Interests, Personal, Other, 1. Asia-Pacific Advisory Board member for prostate cancer2. Invited Speaker at AZ sponsored molecular/genomic testing meeting: AstraZeneca; Financial Interests, Personal, Stocks/Shares, Private Cancer Centres in Australia: ICON Cancer Centres; Financial Interests, Institutional, Funding, Funding for phase 2 metastatic cervical cancer trial: BeiGene; Non-Financial Interests, Principal Investigator, local PI for CHECKMATE-914, CHECKMATE-9KD trial, CHECKMATE-7DX & CHECKMATE-9ER trials: BMS. G. Jayram: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca; Financial Interests, Personal, Invited Speaker: Photocure, BMS; Financial Interests, Institutional, Invited Speaker: Janssen, Merck. S. Byun: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Clinical trial investigator: Astellas, MSD; Financial Interests, Personal, Other, Clinical trial investigator: Pfizer; Financial Interests, Personal, Invited Speaker, Clinical trial investigator: Janssen; Financial Interests, Personal, Officer, CEO: Inivites Biocore; Financial Interests, Personal, Stocks/Shares: PROCAGEN; Non-Financial Interests, Leadership Role, President: Korean Urological Research Society. M. Kwiatkowski: Financial Interests, Personal, Invited Speaker: Janssen Cilag, Novartis, Roche; Non-Financial Interests, Principal Investigator, Clinical Trials: MSD, BMS; Non-Financial Interests, Principal Investigator, Clinical trials: AstraZeneca, Roche, Hengrui, Janssen Cilag, BeiGene, Shanghai Jinshu, Bayer. R. Manneh Kopp: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, BMS, Janssen, Astellas, Pfizer, Bayer, Eli Lilly, Roche, Tecnofarma, Procaps; Financial Interests, Personal, Advisory Board: MSD, Bayer, Tecnofarma; Financial Interests, Personal and Institutional, Invited Speaker: MSD, Bayer, BMS, Roche, Pfizer, Novartis, AstraZeneca; Non-Financial Interests, Leadership Role: Asociación Colombiana de Hematología y Oncología. J.C. Vazquez Limon: Financial Interests, Institutional, Full or part-time Employment, Attending physician and chief of oncology service: Hospital Civil de Guadalajara; Financial Interests, Personal and Institutional, Local PI: BMS, MSD, Novartis, Janssen, AstraZeneca, Roche, Regeneron, AbbVie, GSK; Non-Financial Interests, Advisory Role: Janssen; Non-Financial Interests, Institutional, Product Samples: GSK. J.F. Escobar Penagos: Financial Interests, Personal, Invited Speaker, Participate like principal investigator in clinical trials: AstraZeneca; Financial Interests, Personal, Invited Speaker, principal investigator in clinical trial: BMS; Financial Interests, Personal, Invited Speaker, principal investigator in clinical trials: MSD. U.F.F. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, Eisai, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, Clovis Oncology, AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca, Sanofi, Roche. K.M.D. Trindade: Financial Interests, Personal, Invited Speaker: Janssen, Merck, Astellas, AstraZeneca, Adium; Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Merck; Financial Interests, Institutional, Invited Speaker: MSD, Janssen, BMS, Roche. C. Niu: Financial Interests, Personal, Full or part-time Employment: MSD China; Financial Interests, Personal, Stocks/Shares: MSD China. Y. Liu, C.H. Poehlein: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. J.M. Piulats Rodriguez: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Roche, BMS, MSD, BeiGene, VCN, AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: BMS, Pfizer, Janssen, BeiGene, Mirati. All other authors have declared no conflicts of interest.

Background

The phase 3 KEYNOTE-585 study (NCT03221426) evaluated neoadjuvant/adjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo) followed by adjuvant pembro vs pbo in locally-advanced, resectable gastric or gastroesophageal junction (G/GEJ) cancer. A separate cohort evaluated pembro + FLOT. We report results of the pre-specified third interim analysis (IA3).

Methods

Patients (pts) with untreated, locally-advanced, resectable G/GEJ cancer were randomized 1:1 to neoadjuvant pembro 200 mg IV Q3W or pbo + chemo (cisplatin + capecitabine or cisplatin + 5-FU) for 3 cycles. After surgery, pts received adjuvant pembro or pbo + chemo Q3W for 3 cycles, then adjuvant pembro or pbo Q3W for 11 cycles (main cohort). In the FLOT cohort, pts were randomized 1:1 to pembro + docetaxel, oxaliplatin, leucovorin, and 5-FU, Q2W. Primary end points were pathCR rate (BICR), EFS (RECIST 1.1, by investigator), OS (main cohort), and safety (FLOT cohort).

Results

804 pts were randomized to the main (402 pembro; 402 pbo) and 1007 to main + FLOT ([502 pembro; 505 pbo) cohorts. Median follow-up was 47.7 mo and 46.3 mo, respectively. In the main cohort, pathCR significantly improved with pembro + chemo (12.9% [95% CI, 9.8-16.6]) vs pbo + chemo (2.0 [95% CI, 0.9-3.9]); Δ (10.9% [95% CI, 7.5-14.8]; P<0.00001). EFS was longer with pembro vs pbo (median 44.4 vs 25.3 mo; HR 0.81; 95% CI, 0.67-0.99; P=0.0198), but was not significant. OS continues to final analysis. Median OS was 60.7 vs 58.0 mo (HR 0.90; 95% CI, 0.73-1.12) at IA3. Grade ≥3 drug-related AE rates were 65% with pembro + chemo and 63% with pbo + chemo. Outcomes in the main + FLOT cohort are in the Table. Table: LBA74

Outcomes in main + FLOT cohort

Conclusions

Neoadjuvant/adjuvant pembro + chemo followed by adjuvant pembro, significantly improved pathCR rate with no significant improvement in EFS vs placebo + chemo in pts with untreated, locally-advanced resectable G/GEJ cancer.

Clinical trial identification

NCT03221426.

Editorial acknowledgement

Medical writing assistance was provided by Luana Atherly-Henderson employed by the sponsor.

Legal entity responsible for the study

Merck & Co., Inc.

Funding

Merck & Co., Inc.

Disclosure

K. Shitara: Financial Interests, Personal, Advisory Board: Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, AbbVie, GSK, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Guardant Health Japan Corp, Astellas Pharma Inc.; Financial Interests, Institutional, Research Grant: Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Eisai, Amgen; Financial Interests, Personal, Invited Speaker: Janssen Pharmaceutical K.K.. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Daiichi Sankyo; Financial Interests, Personal, Steering Committee Member: Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, Durg supply for clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, Drug supply for clincal trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: zy,meworks; Financial Interests, Institutional, Local PI, drug supply for clinical trial: BeiGene; Financial Interests, Coordinating PI, Drug supply for clnical trial: Incyte. L.S. Wyrwicz: Financial Interests, Personal, Advisory Board: BMS, Servier; Financial Interests, Personal and Institutional, Local PI: BMS, MSD, Servier, BeiGene, Roche, AstraZeneca; Financial Interests, Personal, Steering Committee Member: AstraZeneca. T. Oshima: Financial Interests, Personal, Invited Speaker: Taiho, Astellas; Financial Interests, Personal, Writing Engagement: Astellas; Financial Interests, Personal, Other, research grant: Taiho, Kyowa Kirin, Chugai, Nihon kayaku. N. Karaseva: Financial Interests, Institutional, Funding: MSD. M. Osipov: Financial Interests, Institutional, Funding: MSD. H. Yasui: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Terumo, Eli Lilly Japan, Merck Biopharma, Yakult Honsha, Bayer Yakuhin; Financial Interests, Institutional, Local PI: MSD, Daiichi Sankyo, Ono Pharmaceutical, Astellas Pharma, Amgen. H. Yabusaki: Financial Interests, Institutional, Funding: MSD. S. Afanasyev: Financial Interests, Institutional, Research Funding: MSD. Y. Park: Financial Interests, Institutional, Funding: MSD. S. Al-Batran: Financial Interests, Personal, Advisory Board: Lilly, Bristol-Myers Squibb, MacroGenics, Immutep, MSD Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb, Lilly, AIO Studien gGmbH, MCI Deutschland GmbH; Financial Interests, Personal, Other, CEO/founder: Institute of Clinical Cancer Research IKF at Northwest Hospital; Financial Interests, Institutional, Research Grant: Sanofi, Roche, Celgene, Vifor, Medac, Hospira, Lilly, Eurozyto, Immutep, Ipsen, Bristol-Myers Squibb, MSD Sharp & Dohme, AstraZeneca, German Cancer Aid (Krebshilfe), German Research Foundation, Federal Ministry of Education and Research. T. Yoshikawa: Financial Interests, Personal, Other, honoraria: MSD, Ono, BMS, Daiichi Sankyo, Astra-Zeneca, TERUMO, Otsuka, Covidien, Johnson and Johnson, Olympus, Intuitive. P.E. Yanez Weber: Financial Interests, Institutional, Funding: MSD. M. Di Bartolomeo: Financial Interests, Personal, Other, honoraria: MSD, BMS, Novartis, Lilly, Servier; Financial Interests, Personal, Other, Travel: Daiichi; Financial Interests, Personal, Advisory Board: Novartis. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, merck serono, lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol-Myers Squibb, Astellas, GSK, Takeda, Bayer; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GSK, Roche, Servier, Amgen, Bristol-Myers Squibb, Incyte, Lilly, Merck Serono, MSD; Financial Interests, Institutional, Coordinating PI: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol -Myers Squibb; Non-Financial Interests, Member of Board of Directors, Italian No-Profit Oncology Research Foundation supporting academic Clinical trials: GONOFoundation. X. Fang: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.. C. Shih: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. P. Bhagia: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. Y. Bang: Financial Interests, Personal, Advisory Role: Astellas, Amgen, Samyang Biopharm, Hanmi, Daewoong.

Background

In a previous analysis of the phase III KEYNOTE-811 study, pembrolizumab (pembro)/trastuzumab and chemotherapy (chemo) vs placebo (pbo)/trastuzumab and chemo provided an ORR of 74% vs 52% in the first 264 pts. These data led to FDA approval of first-line pembro/trastuzumab and chemo for HER2+ mG/GEJ adenocarcinoma. We present results of a prespecified interim analysis of PFS.

Methods

Eligible patients (pts) aged ≥18 years with treatment-naive unresectable, HER2+ mG/GEJ adenocarcinoma irrespective of PD-L1 status were randomized 1:1 to pembro 200 mg IV Q3W or pbo IV Q3W plus chemo (5-FU and cisplatin [FP] or capecitabine and oxaliplatin [CAPOX] and trastuzumab [SOC]). Randomization was stratified by region, PD-L1 status, and chemo choice. Treatment continued for ≤2 years or until disease progression or intolerable toxicity. Dual primary end points were PFS (RECIST v1.1, BICR) or OS. Data cut-off for this interim analysis was May 25, 2022. Per the DSMC, OS assessment is ongoing.

Results

At data cut-off, 698 pts were randomized (350 to pembro + SOC; 348 to pbo + SOC). Median follow-up was 28.4 mo. In all pts, pembro + SOC vs pbo + SOC significantly improved PFS (median 10.0 vs 8.1 mo; HR 0.72; 95% CI 0.60-0.87; p=0.0002). In pts with PD-L1 CPS ≥1, median PFS was 10.8 vs 7.2 mo (HR 0.70; 95% CI, 0.58-0.85). 24-mo PFS rates were 27% vs 13%. At data cut-off, 75% of required OS events had occurred. OS follow-up is ongoing. ORR was 72.6% vs 59.8% with pembro + SOC vs pbo + SOC (73.2% vs 58.4% [PD-L1 CPS ≥1]); median (range) DOR was 11.2 mo (1.1+ to 40.1+) vs 9.0 mo (1.4+ to 38.3+). Approximately 31% vs 19% of responders had a response duration ≥24 mo. Grade ≥3 drug-related AE rates were 58% vs 51%. Grade 5 drug-related AEs occurred in 4 (1.1%) vs 3 (0.9%) pts, respectively.

Conclusions

First-line pembro plus trastuzumab and chemo provided superior PFS, and improved ORR with durable responses vs pbo plus trastuzumab and chemo in pts with unresectable, HER2+ mG/GEJ adenocarcinoma, notably in pts with PD-L1 CPS ≥1. These efficacy and safety data continue to support use of this regimen in the first-line setting.

Clinical trial identification

NCT03615326.

Editorial acknowledgement

Editorial assistance provided by Luana Atherly-Henderson, an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

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

Funding

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

Disclosure

Y.Y. Janjigian: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Merck; Financial Interests, Personal, Advisory Board: RGENIX, Eli Lilly, Daiichi Sankyo, Pfizer, Bayer, Imugene, Merck, Zymeworks Inc., Seagen, Basilea Pharmaceutica, AstraZeneca; Financial Interests, Personal, Other, Consulting: Michael J. Hennessy Associates, Paradigm Medical Communications, Amerisource Bergen, Arcus Biosciences, Geneos Therapeutics, GSK, Imedex, Lynx Health, Mersana Therapeutics, PeerView Institue, Reasearch to Practice, Silverback Therapeutics; Financial Interests, Personal, Stocks/Shares: RGENIX; Financial Interests, Personal and Institutional, Research Grant: NCI, Department of Defense, Cycle for Survival, Fred's Team, RGENIX, Bayer, Genentech/Roche, Bristol Myers Squibb, Eli Lilly, Merck. A. Kawazoe: Financial Interests, Personal, Advisory Board: Zymeworks; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo, Eli Lilly, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Expert Testimony: Merck & Co. Y. Bai, J. Xu: Financial Interests, Institutional, Research Grant: MSD. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Pierre Fabre, GSK, Roche, Astellas; Financial Interests, Institutional, Invited Speaker: Amgen, Merck, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb. J. Metges: Financial Interests, Personal, Research Grant: MSD, Bristol Myers Squibb, Zymeworks, Daisshi, Astellas, Bayer; Financial Interests, Personal, Speaker’s Bureau, honoraria: MSD, Astellas, Bayer; Financial Interests, Personal, Other, travel fees: MSD, Daiishi, Bristol Myers Squibb. P.E. Yanez Weber: Financial Interests, Institutional, Research Grant: MSD. L.S. Wyrwicz: Financial Interests, Personal, Advisory Board: BMS, Servier; Financial Interests, Personal and Institutional, Local PI: BMS, MSD, Servier, BeiGene, Roche, AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca. L. Shen: Financial Interests, Institutional, Funding: Astellas; Financial Interests, Personal, Writing Engagement: Oxford PharmaGenesis; Financial Interests, Personal, Research Grant: Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), Beihai Kangcheng (Beijing) Medical Technology, Yaojie Ankang (Nanjing) Technology Co., Ltd., Baiji Shenzhou (Beijing) Biotechnology Co., Ltd, Jacobio Pharmaceuticals; Financial Interests, Personal, Speaker, Consultant, Advisor: Mingji Biopharmaceutical, Haichuang Pharmaceutical, Harbour BioMed; Financial Interests, Personal, Speaker’s Bureau: Hutchison Whampoa, Hengrui, ZaiLab, CStone Pharmaceutical; Financial Interests, Personal, Advisory Board: MSD, Merck, Bristol Myers Squibb, BI, Sanofi, Roche, Servier, AstraZeneca. Y.V. Ostapenko: Financial Interests, Institutional, Other, Principal Investigator: Jounce Therapeutics. M. Bilici: Financial Interests, Institutional, Research Grant: MSD. H.C. Chung: Financial Interests, Institutional, Funding: MSD. K. Shitara: Financial Interests, Personal, Advisory Board: Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, MSD, Taiho, Novartis, AbbVie, GSK, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Guardant Health Japan Corp, Astellas Pharma Inc.; Financial Interests, Personal, Invited Speaker: Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Research Grant: Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho, Chugai Pharmaceutical, MSD, Eisai, Amgen. S. Qin: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Personal and Institutional, Principal Investigator: China. E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; Financial Interests, Institutional, Research Grant: Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex/HMP; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer - AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Taiho Pharma USA Inc, Janssen-Cilag International NV, Servier; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Janssen-Cilag International NV, Merus NV, Hutchinson Medipharma, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer-EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. K. Li, C. Shih, P. Bhagia: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Daiichi Sankyo, Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, Drug supply for clinical trial: Merck; Financial Interests, Institutional, Invited Speaker, Drug supply for clinical trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: Zymeworks; Financial Interests, Institutional, Local PI, drug supply for clinical trial: BeiGene; Financial Interests, Invited Speaker, Drug supply for clinical trial: Incyte.