8MO - Subcutaneous (SC) versus intravenous (IV) pembrolizumab (Pembro) plus chemotherapy (CT) in metastatic non-small cell lung cancer (mNSCLC): Phase III MK-3475A-D77 trial

Background

Pembro for SC dosing (MK-3475A; “pembro SC”) is pembro with berahyaluronidase alfa (MK-5180), a variant of human hyaluronidase developed and manufactured by Alteogen Inc. The phase III open-label MK-3475A-D77 study (NCT05722015) assessed pembro SC vs pembro IV, plus CT, in pts with mNSCLC.

Methods

Eligible pts with newly diagnosed stage IV squamous or nonsquamous NSCLC with no sensitizing EGFR, ALK, or ROS1 alterations were randomized 2:1 to pembro SC 790 mg Q6W or pembro IV 400 mg Q6W (18 cycles), plus platinum doublet CT. Dual primary endpoints were cycle 1 pembro exposure (AUC_0–6wk) and steady-state trough concentration (C_trough). The noninferiority margin with respect to the AUC_0–6wk and C_trough geometric mean ratios (GMR) of pembro SC vs IV was specified as 0.8. Secondary endpoints included ORR, PFS (RECIST v1.1 by BICR), OS, safety, and pembro and MK-5180 ADAs.

Results

377 pts were randomized to CT plus pembro SC (n=251) or pembro IV (n=126). Median time from randomization to data cutoff (12Jul2024) was 9.6 mo. (range 6.2–16.4). The GMR (96% CI) for cycle 1 AUC_0–6wk [1.14 (1.06–1.22)] and GMR (94% CI) for steady-state C_trough [1.67 (1.52–1.84)] were above the noninferiority margin (both p < 0.0001). For SC vs IV arms, ORR was 45.4% vs 42.1% (ORR ratio 1.08, 95% CI 0.85–1.37), median PFS was 8.1 mo vs 7.8 mo (HR 1.05, 95% CI 0.78–1.43), and median OS was not reached in either arm (HR 0.81, 95% CI 0.53–1.22). 47.0% (SC arm) and 47.6% (IV arm) of pts had grade ≥3 drug-related AEs; 8.4% discontinued pembro SC, and 8.7% pembro IV, due to drug-related AEs. 2.4% of pts had injection-site AEs with pembro SC. Pembro ADAs were detected in 1.4% (SC) and 0.9% (IV) of participants. MK-5180 ADAs were detected in 1.5% (SC) of participants.

Conclusions

Pembro SC 790 Q6W resulted in pembro exposure and trough concentrations that were noninferior to those of pembro IV 400 mg Q6W, in combination with CT, in pts with mNSCLC. Efficacy was similar in the SC and IV arms. The safety profile of pembro SC plus CT was manageable and consistent with that of pembro IV plus CT. Results suggest that pembro SC is a viable treatment option in indications where pembro has approval.

Clinical trial identification

NCT05722015.

Editorial acknowledgement

Editorial assistance was provided by Anna Lau, PhD, of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck& Co., Inc., Rahway, NJ, USA.

Funding

Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

E. Felip: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Boehringer Ingelheim, F Hoffmann - La Roche, Gilead, GSK, Iteos Therapeutics, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Regeneron, Turning Point; Financial Interests, Personal, Other, Payment or Honoraria: Eli Lilly, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, F Hoffmann - La Roche, Genentech, Gilead, Janssen, Johnson & Johnson, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, Novartis, PeerVoice, Pfizer, Regeneron; Financial Interests, Personal, Other, Support for travel or meeting attendance: AstraZeneca, Janssen, Roche; Financial Interests, Personal, Member of Board of Directors: Grifols. C.I. Rojas: Financial Interests, Personal, Advisory Board: BMS, Roche, Roche, MSD, Pfizer, Sanofi; Financial Interests, Personal, Invited Speaker: BMS, MSD, AstraZeneca, Knight, Pfizer; Financial Interests, Personal, Member of Board of Directors: Bradford Hill. M. Schenker: Financial Interests, Institutional, Funding, Study conduct: Merck & Co., Inc. D.M. Kowalski: Financial Interests, Personal, Advisory Board: MSD, Amgen, Roche, Pfizer, Takeda, Medison, Pierre Fabre, AstraZeneca. I.A. Casarini: Financial Interests, Personal, Advisory Board, Consulting fee: Amgen; Financial Interests, Personal, Speaker’s Bureau, Honoraria: AstraZeneca. T. Csoszi: Financial Interests, Personal, Other, ESMO for Novartis: Novartis. M.A.N. Sendur: Financial Interests, Personal, Other, Consulting fees and Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, AstraZeneca, Pfizer, Novartis, Astellas, BMS, MSD, Lilly, Gilead, Takeda, Janssen. A. Calles Blanco: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Lilly, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Takeda, Sanofi, Janssen, Regeneron; Financial Interests, Personal, Other, Speaker honoraria: Bayer; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Institutional, Research Grant, Drug-only for Investigator-initiated trial.: Merck Sharp & Dohme. C.C. Wang: Financial Interests, Personal, Other, Patents planned, issued or pending - METHOD FOR DIAGNOSING AND TREATING ASTHMA BY DETECTING OR REGULATING A PANEL OF INTERNAL LIPID SPECIES: N/A. R.A. Ramírez Fallas: Financial Interests, Personal, Invited Speaker: Janssen, Johnson & Johnson. H. Yoshioka: Financial Interests, Personal, Funding, Research funding: Daiichi Sankyo, AstraZeneca, Janssen, MSD, Novartis, Delta Fly Pharma, Boehringer Ingelheim; Financial Interests, Personal, Other, Consulting fee: Delta Fly Pharma; Financial Interests, Personal, Other, Lecture fee: AstraZeneca, Boehringer Ingelheim, Taiho Pharmaceuticals, Ono Pharmaceuticals, Bristol Myers Squibb, Novartis, Kyowa Kirin, Nippon Kayaku, Otsuka Pharmaceuticals, Amgen, Pfizer, Nipro Pharma, Daiichi Sankyo, Merck Biopharma, Eli Lilly, Chugai Pharmaceuticals, MSD. X. Deng: Financial Interests, Institutional, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Institutional, Stocks/Shares: Merck & Co., Inc. M. Lala: Financial Interests, Institutional, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Institutional, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Institutional, Other, Support for attending meetings and/or travel: Merck & Co., Inc. R. Eiras: Financial Interests, Institutional, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Institutional, Stocks/Shares: Merck & Co., Inc. T. Takahashi: Financial Interests, Institutional, Other, Grants or contracts from any entity: AstraZeneca KK, Eli Lilly Japan K.K, Chugai Pharmaceutical CO., LTD, MSD K.K., Pfizer Japan Inc., Amgen inc., Merck Biopharma CO., LTD, Janssen Pharmaceutical K.K., AnHeart Therapeutics Inc., AstraZeneca KK; Financial Interests, Personal, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Chugai Pharmaceutical CO., LTD, Eli Lilly Japan K.K., ONO Pharmaceutical CO., LTD., MSD K.K., Pfizer Japan Inc., Takeda Pharmaceutical CO LTD, BMS Japan, Novartis; Financial Interests, Personal, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen K.K. All other authors have declared no conflicts of interest.