LBA56 - MEDI5752 or pembrolizumab (P) plus carboplatin/pemetrexed (CP) in treatment-naïve (1L) non-small cell lung cancer (NSCLC): A phase Ib/II trial

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: 000LBA56

CI, confidence interval; ITT, intent-to-treat; mo, months; NE, not evaluable.

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.

Editorial acknowledgement

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.