Background

In DESTINY-Lung01, T-DXd 6.4 mg/kg (a HER2-targeting antibody-drug conjugate) showed durable activity in pts with previously treated HER2-mutant (HER2m) NSCLC (Li et al. N Engl J Med 2022). DESTINY-Lung02 assessed the benefit-risk profile of T-DXd doses 5.4 and 6.4 mg/kg in pts with previously treated HER2m metastatic NSCLC (NCT04644237). Here we report interim results for DESTINY-Lung02.

Methods

This was a blinded, randomized, non-comparative, phase 2 trial. Pts were randomized 2:1 to T-DXd 5.4 or 6.4 mg/kg Q3W, respectively. The primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR) by BICR, confirmed disease control rate (cDCR) and safety. The prespecified early cohort (PEC; pts randomized ≥4.5 months [mo] before data cutoff [DCO]) was defined to include pts with postbaseline tumor assessments. The safety analysis set (SAS) was all randomized pts who received ≥1 dose of T-DXd. The study was not powered to statistically compare the doses.

Results

At DCO (03/24/2022), 52 and 28 pts in the PEC were randomized and 101 and 50 pts in the SAS were treated with T-DXd 5.4 or 6.4 mg/kg, respectively. Median follow-up duration was 5.6/5.4 mo and 3.8/3.9 mo. In the PEC, cORR was 53.8% (95% CI, 39.5-67.8%) and 42.9% (95% CI, 24.5-62.8%) in pts receiving T-DXd 5.4 or 6.4 mg/kg, respectively (Table). Treatment-emergent adverse events (TEAEs) were higher with T-DXd 6.4 mg/kg vs 5.4 mg/kg in the PEC and SAS (median treatment duration: 4.7/5.5 mo and 3.3/3.7 mo). In the SAS, any-grade adjudicated drug-related interstitial lung disease occurred in 5.9% and 14.0% of pts receiving T-DXd 5.4 or 6.4 mg/kg, respectively. Table: LBA55

T-DXd in HER2m NSCLC

Conclusions

DESTINY-Lung02 demonstrated clinically meaningful activity with T-DXd 5.4 mg/kg and 6.4 mg/kg in pts with previously treated HER2m NSCLC in the PEC, with a more favorable safety profile with T-DXd 5.4 mg/kg.

Clinical trial identification

NCT04644237.

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Selene Jarrett, PhD, of ApotheCom, and was funded by Daiichi Sankyo.

Legal entity responsible for the study

Daiichi Sankyo and AstraZeneca.

Funding

Daiichi Sankyo and AstraZeneca.

Disclosure

K. Goto: Financial Interests, Personal, Invited Speaker: Amgen Inc., Amgen K.K., Amoy Diagnosties Co.,Ltd., AstraZeneca K.K., Bayer U.S., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Guardant Health Inc., Merck Biopharma Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K.; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K.; Financial Interests, Personal, Expert Testimony: Medpace Japan K.K.; Financial Interests, Personal and Institutional, Funding: Amgen Inc., Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta,Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., Medical ＆ Biological Laboratories Co., LTD., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Turning Point Therapeutics,Inc.; Non-Financial Interests, Member: American Society of Clinical Oncology, The Japan Lung Cancer Society, Japanese Society of Medical Oncology, The Japanese Cancer Association. K. Sang-We: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Novartis, Takeda, Yuhan; Financial Interests, Personal, Speaker’s Bureau, Expert Testimony: Boehringer Ingelheim; Financial Interests, Personal, Research Grant: Yuhan. T. Kubo: Financial Interests, Personal, Other, Honoraria: AstraZeneca. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Thermo Fischer; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, DaiichiSankyo, Eli Lilly, Guardant Health, Preferred Network; Financial Interests, Personal and Institutional, Invited Speaker: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Prefered Network. M. Ahn: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Daichii Sankyo, Yuhan, Amgen, Eli Lilly, TAKEDA, MSD, Merck, Pfizer, Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, Alpha-pharmaceuticals, Eli Lilly, Takeda, Merck, MSD, Amgen, Yuhan, Daichii Sankyo, Roche, Pfizer, Arcus. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen; Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre; Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. D. Kim: Financial Interests, Personal, Other, Travel Expenses: Amgen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Xcovery, Merck, Janssen, Hanmi, GSK, Daiichi Sankyo, Chong Keun Dang, Bridge BioTherapeutics, BMS, Boehringer-Ingelheim, AstraZeneca/Medimmune, Amgen, Alpha Biopharma, Novartis, Mirati Therapeutics, Merus, MSD, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Yuhan. J.C. Yang: Financial Interests, Institutional, Advisory Board: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Amgen, Novartis, Bayer, GSK, Takeda Oncology, Puma Pharmaceuticals, Ono Pharmaceuticals, Merck Serono, MSD, Pfizer, Eli Lilly, Roche/Genentech, Janssen; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Novartis, AstraZeneca, MSD, Ipsen, Takeda Oncology; Financial Interests, Personal, Advisory Board: Yuhan Pharmaceuticals; Financial Interests, Invited Speaker: Dizal Pharmaceutical, Novartis, Numab, Merck, Daiichi Sankyo, Eli Lilly, Bayer, Janssen; Non-Financial Interests, Leadership Role, Board of Director: IASLC; Non-Financial Interests, Member: ASCO. K.M.C. Pereira: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. K. Saxena: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. R. Shiga: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. Y. Cheng: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. M. Aregay: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi-Sankyo, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Trasncenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, Allorion Therapeutics, Accutar Biotech, AbbVie; Financial Interests, Personal, Advisory Board, Consulting fees for advice on diagnostic development: Biocartis; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics; Financial Interests, Personal, Royalties, I receive post-marketing royalties from being an inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Institutional, Research Grant, Sponsored research agreement with my institution: AstraZeneca, Daiichi Sankyo, PUMA, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. All other authors have declared no conflicts of interest.

Background

Prior studies have shown benefit of PD-(L)1/CTLA-4 blockade in NSCLC, especially in PD-L1 negative tumors; however, this benefit is limited by toxicity. MEDI5752 is a PD-1/CTLA-4 bispecific antibody engineered to preferentially bind CTLA-4 in PD-1+ activated T cells, yielding greater T cell proliferation than possible with doses feasible in the clinic (Tran, AACR 2022). Here we present results in 1L non-squamous (Nsq) NSCLC from an ongoing phase 1b/2 study (NCT03530397).

Methods

Patients (pts) were enrolled into randomized (R) and single arm (S) cohorts. In the R cohort, pts received CP x 4, followed by pemetrexed maintenance + either 1500 mg Q3W MEDI5752 (M1500+C) or P (P+C). In the later S cohort, pts received 750 mg Q3W MEDI5752 + CP (M750+C). The primary endpoint was objective response rate (ORR) per RECIST v1.1.

Results

As of 12 July 2022, 105 pts were enrolled. We present the results in 91 pts: 41 pts in the R cohort, and the first 50 pts in the S cohort with at least 8 weeks of follow-up. Baseline characteristics were similar between M1500+C (n=20; 45% PD-L1<1%) and P+C cohorts (n=21; 47.6% PD-L1<1%). DOR, PFS and OS were higher in M1500+C vs P+C in ITT and PD-L1<1% (see table). High Gr3 TRAE (70%) and discontinuation due to TEAE (TEAE-DC; 70%) at M1500+C led to exploring a lower dose of MEDI5752. In M750+C (n=50; 70% PD-L1<1%), at median follow-up of ∼3.9 months, emerging efficacy shows 44% ORR in ITT and 48% in PD-L1<1% and improved safety profile (Gr3 TRAE 32%, TEAE-D/C 20%). M1500+C and M750+C led to greater increase in T cell proliferation (and clonal expansion in M1500+C) than P+C, consistent with pharmacodynamic (PD) effects of CTLA-4 blockade; clonality data on M750+C pending. Table: LBA56

Conclusions

M1500+C improved DOR, PFS and OS compared to P+C in a randomized signal finding trial in 1L Nsq NSCLC. Emerging data with M750+C shows similarly encouraging efficacy, especially in PD-L1<1% subgroup, with improved tolerability.

Clinical trial identification

NCT03530397.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

M. Ahn: Financial Interests, Invited Speaker: AstraZeneca, Lilly, Takeda, Merck, MSD, Amgen, YUHAN; Financial Interests, Advisory Board: AstraZeneca, Lilly, Takeda, Merck, MSD, Amgen, YUHAN, Daiichi-Sankyo, Roche, Pfizer, Arcus, Alpha-Pharmaceuticals. S. Kim: Non-Financial Interests, Personal, Invited Speaker: BI; Financial Interests, Personal, Research Grant: Yuhan; Non-Financial Interests, Personal, Advisory Role: AstraZeneca, BMS, BI, Novartis, Lilly, Takeda, Therapex, Yuhan. J. Oliveira: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: GSK, Janssen, Novartis, Roche, MSD, Bayer, Eisai, AstraZeneca, Pierre Fabre, BMS. M.A. Insa Molla: Financial Interests, Personal, Invited Speaker: Sanofi, BMS, Roche; Financial Interests, Personal, Expert Testimony: AstraZeneca, BMS, MSD, Merck; Financial Interests, Personal, Advisory Board: Sanofi, Pfizer, Roche, Amgen. M. Majem: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche; Financial Interests, Personal, Speaker’s Bureau: Sanofi, Pfizer, Janssen, BMS, MSD, BI, AstraZeneca, Roche, Kyowa Kirin, Pierre Fabre, Takeda, Helsinn, Bayer AG; Financial Interests, Personal, Advisory Board: Sanofi, Pfizer, Janssen, BMS, MSD, BI, AstraZeneca, Roche, Kyowa Kirin, Pierre Fabre, Takeda, Helsinn, Bayer AG; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, BMS. W. Su: Financial Interests, Personal, Advisory Board: Merck, MSD, Bayer, Lilly, Roche. K.H. Lee: Financial Interests, Personal, Advisory Role: BMS, MSD, AstraZeneca, Pfizer, Lilly. D.R. Spigel: Financial Interests, Institutional, Research Grant: Aeglea Biotherapeutics, Agios, Apollomics, Arcus, Arrys Therapeutics, Astellas, AstraZeneca, Bayer, Beigene, BIND Therapeutics, BioNTech RNA Pharmaceuticals, Blueprint Medicine, BI, BMS, Calithera, Celgene, Celldex, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, EMD Serono, Evelo Biosciences, G1 Therapeutics, Roche/Genentech, GSK, GRAIL, Hutchinson MediPharma, ImClone Systems, Incyte, ImmunoGen, Ipsen, Janssen, Kronos Bio, Lilly, Loxo Oncology, Macrogenics, Merck, Molecular Partners, Molecular Template, Nektar, Neon Therapeutics, Novartis, Novocure, Oncologie, Pfizer, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics, Transgene, UT Southwestern, Verastem; Financial Interests, Institutional, Advisory Role: Amgen, AstraZeneca, BMS, Curio Science, EMD Serono, Evidera, Exelixis, GSK, Intellisphere, Ipsen Biopharmaceuticals, Janssen, Jazz Biopharmaceuticals, Lilly, Mirati Therapeutics, Molecular Templates, Novartis, Novocure, Pfizer, Puma Biotechnology, Regeneron Pharmaceuticals, Roche/Genentech, Sanofi-Aventis. M.R. Garcia Campelo: Financial Interests, Personal, Advisory Board: MSD, BMS, Roche, BI, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen; Financial Interests, Personal, Speaker’s Bureau: MSD, BMS, Roche, BI, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen. P. Mitchell: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. I. Achour: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. D. Subramaniam: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. E. Felip: Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, BMS, Lilly, F. Hoffman-La Roche, Janssen, Medscape, MSD, Peervoice, Pfizer, Medical Trends, Merck-Serono, Sanofi, Takeda, TouchOncology; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BMS, Daichii Sankyo, Lilly, F. Hoffman-La Roche, GSK, Ipsen, Janssen, MSD, Merck Serono, Novartis, Peptomyc, Pfizer, Sanofi, Takeda; Financial Interests, Personal, Member of the Board of Directors: Grifols; Financial Interests, Institutional, Research Grant: Merck Healthcare KGAa, Fundacion Merck Salud. All other authors have declared no conflicts of interest.

Background

“Chemo-free” strategy of anti-PD-1 antibody sintilimab combining angiogenesis modulator anlotinib had shown potential clinical benefit in our phase I study in treatment naïve advanced NSCLC. Here we presented the first phase Ⅱ randomized trial comparing sintilimab plus anlotinib with chemo in treatment-naïve metastatic NSCLC.

Methods

This open label, phase II study were conducted at 6 sites. Previously untreated, stage IV, EGFR/ALK/ROS1 negative NSCLC pts were eligible. Pts were randomly assigned (1:1) to Arm A (sintilimab 200mg Day 1, anlotinib 12 mg, QD 1-14) or Arm B (platinum-based chemotherapy, cross-over to sintilimab were allowed after disease progression [PD]), stratified by histology and PD-L1 expression. Treatment was given every 3 weeks until PD, intolerable toxicity, withdrawal, or death. Sintilimab was given up to 24 months or 35 cycles. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression free survival (PFS), disease control rate (DCR), duration of response (DoR), overall survival (OS) and safety.

Results

Between Nov. 2019 to Jul. 2022, 89 pts were randomized (43 to Arm A, 46 to Arm B). As of Jul. 15th 2022, median follow-up was 13.1 months and 84 pts were evaluable (41 vs 43). ORR was 50.0% (95% CI [33.8-66.2]) in Arm A compared with 32.6% (95% CI [19.1-48.5] in Arm B, with a DoR of 16.3 vs 6.2 mo. DCR was 85.0% (95% CI [70.2-94.3]) vs 93.0% (95% CI [80.9-98.5]), and the median PFS was 10.8 vs 5.7 mo (HR 0.4; 95% CI[0.25-0.74]). OS was not matured. Grade 3-4 treatment-related adverse events(TRAE) occurred in 11.6 % vs 43.5% pts in arm A and B, respectively. Hypothyroidism, hyponatremia and AST increased were most frequently observed in Arm A. 2 pts experienced treatment discontinuation and 1 died due to TRAE in Arm B, while none were observed in Arm A.

Conclusions

In this preliminary interim analysis, sintilimab plus anlotinib suggested a trend towards improving response and survival compared with chemotherapy in treatment naïve metastatic NSCLC. Statistical hypothesis testing will be conducted with at least 87 evaluable patients as pre-planned.

Clinical trial identification

NCT04124731.

Legal entity responsible for the study

Baohui, Han.

Funding

Innovent Biologics, Chia Tai Tianqing Pharmaceutical.

Disclosure

All authors have declared no conflicts of interest.

Background

The randomized, double-blind, phase 3 ORIENT-31 study was to evaluate sintilimab (sin, anti-PD-1 antibody) with or without IBI305 (bevacizumab biosimilar) plus chemotherapy (chemo), vs chemo, in patients (pts) with EGFRm nsqNSCLC who progressed on EGFR TKIs therapy. The first interim analysis (IA) showed sin + IBI305 + chemo significantly improved progression-free survival (PFS) vs chemo alone (Lu, et al. Lancet Oncol 2022).

Methods

Eligible pts were randomized (1:1:1 at the first stage and 2:2:1 at the second stage) into Arm A (sin + IBI305 + chemo), Arm B (sin + placebo [pb] 2 + chemo) and Arm C (pb1 + pb2 + chemo). Sin/pb1 (200 mg), IBI305/pb2 (15 mg/kg), pemetrexed (500 mg/m²) and cisplatin (75 mg/m²) were administered IV Q3W for 4 cycles, followed by maintenance treatment of sin/pb1, IBI305/pb2 and pemetrexed. The primary endpoint was PFS assessed by IRRC per RECIST v1.1. Per prespecified statistical analysis plan, the second IA (reported here) aimed to evaluate the PFS between Arm B and Arm C, and the superiority conclusion of Arm A over Arm C has been achieved at the first IA.

Results

By data cutoff (Mar 31, 2022), 476 pts were randomized (Arm A/B/C: 158/158/160). Median age was 57.0 years. 37.0% pts had brain metastasis. Previously, 63.0% pts received 1st or 2nd generation (G) TKI with T790M-, 26.3% pts received 1st or 2nd and then 3rd G TKI with T790M+, and 10.5% pts received first-line 3rd G TKI. With a median follow-up of 13.1 months, median PFS (95% CI) by IRRC was 7.2 months (6.6, 9.3) in Arm A, 5.5 months (4.5, 6.1) in Arm B, and 4.3 months (4.1, 5.3) in Arm C. PFS was significantly improved in Arm B vs Arm C (HR 0.723, 95% CI: 0.552, 0.948; P=0.0181). Confirmed ORR by IRRC was 48.1%, 34.8% and 29.4% in Arm A, B and C respectively; DCR was 86.1%, 81.6% vs 75.6%; median DOR was 8.5 months, 7.4 months vs 5.7 months. Grade ≥3 treatment-emergent adverse events occurred in 59.5%, 46.2%, and 56.9% pts respectively.

Conclusions

Sin combined with or without IBI305 and chemo significantly improved PFS in pts with advanced EGFRm nsqNSCLC who progressed on EGFR-TKI therapy, vs chemo alone.

Clinical trial identification

NCT03802240.

Legal entity responsible for the study

Innovent Biologics, Inc., Suzhou, China.

Funding

Innovent Biologics, Inc., Suzhou, China.

Disclosure

S. Lu: Financial Interests, Personal, Funding: Innovent Biologics (Suzhou) Co., Ltd.; Financial Interests, Institutional, Funding: National Natural Science Foundation of China; Financial Interests, Personal, Research Grant: AstraZeneca, Hutchison, BMS, Hengrui Therapeutics, Beigene, Hansoh, Roche, Lilly Suzhou Pharmaceutical Co. Ltd.; Financial Interests, Personal, Other, consulting fee: AstraZeneca, Ptizer, BoehringerIngelheim, Hutchison, Zailab, GenomiCare, Yuhan Corporation, Menarini, InventisBio Co. Ltd., Roche. L. Wu: Financial Interests, Personal, Funding: Innovent Biologics (Suzhou) Co., Ltd.; Financial Interests, Personal, Research Grant: AstraZeneca, BMS, HengRui. H. Jian: Financial Interests, Personal, Funding: Innovent Biologics (Suzhou) Co., Ltd.. All other authors have declared no conflicts of interest.

Background

In the Phase 3 POSEIDON study, 1L T+D+CT demonstrated statistically significant improvements in PFS and OS (OS HR 0.77; 95% CI 0.65‒0.92; p=0.0030; mFU 34.9 mo in censored pts) vs CT alone in pts with mNSCLC. D+CT showed a statistically significant improvement in PFS and a positive trend for OS improvement vs CT that did not reach significance (OS HR 0.86; 95% CI 0.72‒1.02; p=0.0758). Here we report an updated exploratory analysis of OS, and histology and mutational status subgroups, after a mFU of ∼4 y.

Methods

Pts with EGFR/ALK wild-type mNSCLC were randomised 1:1:1 to 1L D (until progression) ± limited-course T (up to 5 doses) + platinum-based CT (up to 4 cycles); or CT (up to 6 cycles). Alpha-controlled endpoints were PFS and OS for D+CT vs CT and T+D+CT vs CT. Pt tumours were molecularly characterised via sequencing of tissue and/or ctDNA samples.

Results

At an updated data cutoff (DCO) of 11 Mar 2022 (mFU 46.5 mo in censored pts), T+D+CT continued to show OS benefit vs CT (HR 0.75; 95% CI 0.63–0.88) with an estimated 25.0% of pts alive at 3 y vs 13.6% (Table). D+CT continued to numerically improve OS vs CT (HR 0.84; 95% CI 0.71–0.99; 3 y OS 20.7%). Consistent with results at the earlier DCO, OS benefit appeared more pronounced with T+D+CT vs CT in pts with non-squamous (than squamous; data will be presented) histology. A trend for OS benefit with T+D+CT vs CT continued to be observed in non-squamous subgroups with mutations (m) in STK11 (Table), KEAP1 or KRAS (data will be presented). No new safety signals were identified based on collection of serious AEs during long-term FU.

Conclusions

The results of this exploratory analysis from POSEIDON, after mFU of ∼4 y, demonstrate the durable long-term OS benefit of adding a limited course of T to D and 4 cycles of CT. These data support the use of this regimen as a 1L treatment option for pts with mNSCLC, including harder-to-treat mutational subgroups such as STK11m, KEAP1m or KRASm. Table: LBA59

Clinical trial identification

NCT03164616 (release date: 23 May 2017).

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by James Holland, PhD, of Ashfield MedComms (Macclesfield, UK), an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca PLC.

Funding

AstraZeneca.

Disclosure

M.L. Johnson: Financial Interests, Institutional, Funding: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals / Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, Y-mAbs Therapeutics; Financial Interests, Institutional, Advisory Role: AbbVie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech / Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Lilly, Merck, Mirati Therapeutics, Novartis, Oncorus, Regeneron Pharmaceuticals, Revolution Medicines, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics, WindMIL. B.C. Cho: Financial Interests, Personal, Advisory Board: Kanaph Therapeutics Inc., BridgeBio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc.; Financial Interests, Personal, Member of the Board of Directors: Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc., Gencurix Inc., BridgeBio, Kanaph Therapeutics Inc., Cyrus Therapeutics, Interpark Bio Convergence Corp, J Ints Bio, Champions Oncology; Financial Interests, Personal, Research Grant: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, Interpark Bio Convergence Corp; Financial Interests, Personal, Advisory Role: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Medpacto, Blueprint Medicines; Financial Interests, Personal, Other, Founder: DAAN Biotherapeutics. J.A. Alatorre Alexander: Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb, Roche, AstraZeneca, MSD, Boehringer Ingelheim, Takeda, Eli Lilly, Janssen; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb, Roche, AstraZeneca, MSD, Boehringer Ingelheim, Takeda, Eli Lilly, Janssen. S. Lucien Geater: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Advisory Board: AstraZeneca, Roche, Novartis, Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Pfizer. S. Kim: Non-Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Research Grant: Yuhan; Non-Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, Lilly, Takeda, Therapex, Yuhan. M. Hussein: Financial Interests, Personal, Advisory Board: AbbVie, Aptitude Health, AstraZeneca, Biopahrama, Bristol-Myers Squibb, Exelixis, Mirati Therapeutics, Cardinal Health, Coherus Biosciences, Athenex, Karyopharm Therapeutics, IntegraConnect, Oncocyte. C.T. Yang: Non-Financial Interests, Personal, Principal Investigator: AstraZenica, Boehringer Ingelheim, Lilly, MSD, Merck, Amgen, Johnson & Johnson, AbbVie, Hansoh Pharma, Roche, Ono, Bristol-Myers Squibb, Chugai. L.H. Araujo: Financial Interests, Personal, Invited Speaker: MSD, Roche, Pfizer, AstraZeneca, Takeda, Lilly, Janssen, Amgen, Novartis, Bristol-Myers Squibb, Sanofi; Financial Interests, Personal, Advisory Board: Roche, MSD, Takeda, AstraZeneca, Sanofi. H. Saito: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, ONO Pharmaceutical; Financial Interests, Personal, Principal Investigator: AstraZeneca, Chugai Pharmaceutical, ONO Pharmaceutical, Bristol-Myers Squibb. N. Reinmuth: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Hoffmann-La Roche, Janssen, Lilly, MSD, Merck, Pfizer, Takeda; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, Hoffmann-La Roche, Janssen, Lilly, MSD, Merck, Pfizer, Takeda; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bristol-Myers Squibb, Hoffmann-La Roche, Janssen, MSD, Merck, Pfizer, Takeda; Financial Interests, Personal, Other, Data Safety Monitoring Board: Symphogen. Z. Lai: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. H. Mann: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. X. Shi: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. 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. E.B. Garon: Financial Interests, Personal, Advisory Board: ABL Bio, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, Eisai, Eli Lilly, EMD Serono, Gilead, GSK, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, Xilio Therapeutics; Financial Interests, Personal, Research Grant: ABL Bio, AstraZeneca, Bristol-Myers Squibb, Dynavax Technologies, EMD Serono, Genentech, Iovance Biotherapeutics, Eli Lilly, Merck, Mirati Therapeutics, Neon Therapeutics, Novartis. T.S.K. Mok: Financial Interests, Personal, Invited Speaker: ACEA Pharma, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Daz Group, Fishawack Facilitate Ltd., InMed Medical Communication, Janssen Pharmaceutica NV, Jiahui Holdings Co. Ltd., LiangYiHui Healthcare, Lilly, Lucence Health Inc., MD Health Brazil, Medscape LLC, Merck Pharmaceuticals HK Ltd., Merck Sharp & Dohme, MiRXES, Novartis, OrigiMed Co. Ltd., P. Permanyer SL, PeerVoice, Physicians’ Education Resource, Pfizer, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co., Ltd., Taiho Pharmaceutical Co. Ltd, Takeda Oncology, Touch Independent Medical Education Ltd.; Financial Interests, Personal, Advisory Board: AbbVie Inc., ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim Pharmaceuticals Inc., Bristol-Myers Squibb Company, C4 Therapeutics Inc., Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics Inc., Gilead Sciences Inc., Gritstone Oncology Inc., Guardant Health, geneDecode Co. Inc., Hengrui Therapeutics Inc., HutchMed, Ignyta Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lilly, Loxo-Oncology Inc., Lunit Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MiRXES Group, Novartis, OrigiMed, Pfizer, Puma Biotechnology Inc., Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda, Vertex Pharmaceuticals, Virtus Medical Group, Yuhan Corporation; Financial Interests, Personal, Member of the Board of Directors: AstraZeneca, HutchMed; Financial Interests, Personal, Full or part-time Employment: The Chinese University of Hong Kong; Financial Interests, Personal, Stocks/Shares: Aurora Tele-Oncology Ltd., HutchMed, Act Genomics-Sanomics Group, Loxo-oncology, Virtus Medical Group and Lunit USA Inc.; Non-Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ; Non-Financial Interests, Institutional: Takeda. All other authors have declared no conflicts of interest.

Background

Pembro + pem-platinum significantly improved survival vs pbo + pem-platinum in patients (pts) with previously untreated, metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations, regardless of PD-L1 TPS, in the phase III KEYNOTE-189 study (NCT02578680). We report updated results with ∼5 y of follow-up.

Methods

Pts were randomized 2:1 to receive pembro 200 mg or pbo Q3W for up to 35 cycles (2y). All pts also received pem and investigator’s choice of carboplatin/cisplatin for 4 cycles, followed by maintenance pem until PD/unacceptable toxicity. Crossover from the pbo + pem-platinum group to pembro monotherapy was permitted after PD. Primary endpoints were OS and PFS.

Results

Among 616 pts randomized (pembro + pem-platinum, n = 410; pbo + pem-platinum, n = 206), median time from randomization to data cutoff (Mar 8, 2022) was 64.6 (range, 60.1–72.4) mo. 116/202 (57.4%) treated pts crossed over from pbo + pem-platinum to anti–PD-(L)1 therapy during/outside the study. Median (95% CI) OS was 22.0 (19.5‒24.5) mo vs 10.6 (8.7‒13.6) mo with pembro + pem-platinum vs pbo + pem-platinum (HR, 0.60; 95% CI, 0.50‒0.72) and 5-y OS rates were 19.4% vs 11.3%, respectively. Median (95% CI) PFS was 9.0 (8.1‒10.4) mo vs 4.9 (4.7‒5.5) mo (HR, 0.50; 95% CI, 0.42‒0.60). Additional efficacy results are in the table. Among pts with ≥1 dose of assigned treatment, grade 3‒5 AEs occurred in 295/405 (72.8%) vs 136/202 (67.3%) of pts. Among 57 pts who completed 35 cycles of pembro, ORR was 86.0% (CR, n = 8; PR, n = 41); 3-y OS rate after completion of 35 cycles of pembro was 71.9%.

Conclusions

First-line pembro + pem-platinum continued to show OS and PFS benefits with manageable toxicity vs pbo + pem-platinum, irrespective of PD-L1 expression. Pts who completed 35 cycles of pembro experienced durable responses. These data further support pembro + pem-platinum as a standard of care for metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations. Table: 973MO

Clinical trial identification

NCT02578680.

Editorial acknowledgement

Writing support was provided by Christabel Wilson, MSc, of ICON plc (Blue Bell, PA, USA), and 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

M.C. Garassino: Financial Interests, Personal, Research Grant: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, Novartis, Bristol Myers Squibb, Roche, Pfizer, Celgene, Bayer, Tiziana Life Sciences, Clovis, Merck Serono, GlaxoSmithKline, Spectrum Pharmaceuticals, Eli Lilly. S.M. Gadgeel: Financial Interests, Personal, Other, personal fees: Merck, AstraZeneca, Genentech/Roche, Takeda/Ariad, Novocure, Bristol-Myers Squibb, AbbVie, Xcovery, Janssen, Pfizer, Jazz Pharmaceuticals, Blueprint, Lilly. E. Felip: Financial Interests, Personal, Advisory Role: AbbVie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Roche; Financial Interests, Personal, Member of the Board of Directors: Grífols. E. Esteban Gonzalez: Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. M. Domine Gomez: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, MSD Oncology, Pfizer, Roche; Received funding for travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Pfizer, Roche; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. M.J. Hochmair: Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. S.F. Powell: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Genentech, Incyte, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Pfizer, Novartis, Seattle Genetics, Actuate, Vyriad, Sorrento; Financial Interests, Institutional, Advisory Role: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Alkermes. H. Bischoff: Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. N. Peled: Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Roche, NovellusDx, Foundation Medicine, Guardant360; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. F. Grossi: Financial Interests, Personal, Research Grant: AstraZeneca, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi, Takeda. M. Reck: Financial Interests, Personal, Advisory Role: Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Merck Serono, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Roche/Genentech, AbbVie, Amgen, Mirati Therapeutics, Samsung Bioepis, Sanofi/Regen; Financial Interests, Personal, Speaker’s Bureau: Roche/Genentech, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Merck Serono, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati Therapeutics, Sanofi-Aventis. R. Hui: Financial Interests, Personal, Advisory Role: AstraZeneca, BMS, Eli Lilly, Merck, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Oncosec, Pfizer, Roche, Seagen. 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. T. Kurata: Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Ono, Bristol Myers Squibb, AstraZeneca, Chugai, Eli Lilly, Boehringer Ingelheim; Financial Interests, Personal, Research Grant: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, Takeda, Bristol Myers Squibb, Novartis; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. J.E. Gray: Financial Interests, Personal, Research Grant: Array, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Merck; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. P.O. Schwarzenberger: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. E. Jensen: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. D. Rodriguez Abreu: Financial Interests, Personal, Advisory Role: Roche, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Eli Lilly, Pfizer, Novartis; Financial Interests, Personal, Other, Travel expenses: Roche, Bristol Myers Squibb, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Background

Pembrolizumab (pembro) + platinum-based chemotherapy (chemo) significantly prolonged OS and PFS compared with placebo + chemo in patients (pts) with previously untreated, metastatic squamous NSCLC in the phase III KEYNOTE-407 study (NCT02775435). We report the 5-y outcomes in the ITT population and in pts who completed 35 cycles of pembro (∼2 y).

Methods

Eligible pts were randomized 1:1 to receive pembro 200 mg or placebo + carboplatin and paclitaxel/nab-paclitaxel Q3W for 4 cycles, followed by pembro or placebo up to 35 cycles. Eligible pts in the placebo + chemo group were allowed to crossover on-study to up to 35 cycles of open-label pembro monotherapy upon unblinding after verification of PD by BICR. Primary endpoints were OS and PFS per RECIST v1.1 by BICR.

Results

Pts were randomized to pembro + chemo (n = 278) or placebo + chemo (n = 281). As of Feb 23, 2022, median time from randomization to data cutoff was 56.9 (range, 49.9–66.2) mo; 117 pts crossed over from the placebo + chemo group to receive pembro monotherapy, and an additional 26 pts received subsequent anti–PD-(L)1 therapy; the effective crossover rate was 51.1%. Median OS in the ITT population was 17.2 mo for the pembro + chemo group and 11.6 mo for the placebo + chemo group; HR, 0.71 (95% CI, 0.59–0.85). Respective 5-y OS rates were 18.4% and 9.7%. Additional efficacy outcomes are described in the table. Grade 3‒5 AEs occurred in 74.8% and 70.0% of pts in the pembro + chemo and placebo + chemo groups, respectively. Among 55 pts who completed 35 cycles of pembro, ORR was 90.9%, and 3-y OS rate after completion of 35 cycles (⁓5 y after randomization) was 69.5%. Table: 974MO

Conclusions

After 5 y of follow-up, pembro + chemo continued to demonstrate prolonged OS and PFS vs chemo alone without increased toxicity. Most pts who completed 35 cycles had objective responses and were alive at data cutoff. These long-term data support use of pembro + chemo as a standard first-line treatment option for metastatic squamous NSCLC.

Clinical trial identification

NCT02775435.

Editorial acknowledgement

Writing support was provided by Kathleen Estes, PhD, of ICON plc (Blue Bell, PA, USA), and 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

S. Novello: Financial Interests, Personal, Invited Speaker: AZ, MSD, Eli Lilly, Novartis, BeiGene, Amgen; Financial Interests, Personal, Advisory Board: BI, BMS, Pfizer, Takeda, Roche, Sanofi, Amgen; Financial Interests, Institutional, Invited Speaker, IIT: MSD, BI; Non-Financial Interests, Leadership Role, President of this European advocacy: WALCE. D.M. Kowalski: Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb, Boehringer Ingelheim, Merck Serono, Roche/Genentech, AstraZeneca, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Institutional, Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, to support study conduct. D. Vicente Baz: Financial Interests, Personal, Other, received honoraria to self/spouse for scientific advice: AstraZeneca, BMS, Boehringer Ingelheim, MSD, Pfizer, and Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Boehringer Ingelheim, MSD, Pfizer, and Roche. J. Mazieres: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, MSD, Daiichi, Novartis, Amgen; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Jiangsu Hengruii, Blueprint, Daiichi, Novartis, Amgen, Lilly, Merck; Financial Interests, Personal, Research Grant: Roche, AstraZeneca, Pierre Fabre, BMS; Non-Financial Interests, Personal, Principal Investigator: Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Jiangsu Hengruii, Blueprint, Daiichi, Novartis, Amgen, Sanofi, Pfizer, Merck. J.R. Rodriguez Cid: Financial Interests, Institutional, Funding, received funding to the institution during conduct of this trial: MSD; Financial Interests, Institutional, Funding, received funding to the institution to support trial conduct: Bayer, BMS, Celgene, Eli Lilly, MSD, Novartis, and Roche. A. Tafreshi: Financial Interests, Institutional, Funding, support study conduct: Merck. Y. Cheng: Financial Interests, Institutional, Funding, support study conduct: Merck. K.H. Lee: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, Bristol-Myers Squibb, Pfizer, Lilly; Financial Interests, Institutional, Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, to support study conduct. S. Sugawara: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Kyowa Kirin, Lilly, MSD K.K., Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceuticals, Pfizer, Taiho Pharmaceuticals, and Yakult Honsha. A.G. Robinson: Financial Interests, Personal, Funding, received funding for clinical trials: AstraZeneca, Merck, Pfizer, and Roche; Financial Interests, Personal, Advisory Board: Merck. B. Halmos: Financial Interests, Personal, Funding, research funding: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, GSK, Guardant Health, Merck, Mirati, Novartis, Pfizer, and Takeda; Financial Interests, Personal, Other, consultant: AstraZeneca, BMS, Boehringer Ingelheim, Genentech, Guardant Health, Merck, Novartis, Pfizer, and Spectrum. E. Jensen: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. P.O. Schwarzenberger: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. M.C. Pietanza: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. L. Paz-Ares: Financial Interests, Personal, Other, honoraria to self/spouse for scientific advice: Adacap, Amgen, AstraZeneca, Bayer, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Incyte, Ipsen, Lilly, Merck, MSD, Novartis, PharmaMar, Pfizer, Roche, Sanofi, Servier, and Sysmex; Financial Interests, Personal, Invited Speaker: Adacap, Amgen, AstraZeneca, Bayer, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Incyte, Ipsen, Lilly, Merck, MSD, Novartis, PharmaMar, Pfizer, Roche, Sanofi, Servier, and Sysmex; Financial Interests, Personal, Other, board member: Genómica and Altum Sequencing; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, MSD, and Pfizer. All other authors have declared no conflicts of interest.