Antibodies targeting the PD-1 pathway have shown durable clinical benefit in multiple cancers. In the KN028 trial, the antitumor activity and safety of pembrolizumab were investigated in 20 solid tumors. Associations between PD-L1 expression and a T-cell inflamed GEP with response to anti-PD-1 therapy were also evaluated.
KN028 is a nonrandomized, phase 1b multicenter trial in patients with PD-L1 positive (≥1%, modified proportion score or interface pattern, QualTek IHC) advanced solid tumors treated with pembrolizumab 10 mg/kg Q2W for ≤2 y or until confirmed progression/unacceptable toxicity, death or withdrawal of consent. Response was assessed every 8 wk for 6 mo then every 12 wk. The primary endpoint was ORR (RECIST v1.1, investigator assessment [INV]) in patients who received ≥1 dose of pembrolizumab and had measurable disease. Secondary endpoints included safety, PFS and OS. ORR by central radiology review (IRC). Exploratory endpoints included relationships between GEP score (FFPE extracted RNA analyzed on NanoString nCounter) and PD-L1 expression levels (combined positive score, Dako IHC) with ORR and PFS. Data cutoff date was Feb 20, 2017.
In the total study population (N = 475), there were 66 responders among 471 evaluable patients. ORR (95% CI) by INV ranged from 4.2% (0.1, 21.1) to 33.3% (15.6, 55.3) in 19/20 tumor types; no responders were observed in pancreatic carcinoma. ORR >10% was observed in 13/20 types (58/66 responders). ORR (95% CI) by IRC ranged from 4.3% (0.1, 21.9) to 26.3% (9.1, 51.2) in 18/20 tumor types. Treatment related AEs occurred in 65.5% of patients (14.1% grade 3-5). PD-L1 expression (p = 0.034) and GEP (p = 0.012) were associated with ORR in meta-analysis across tumors. Data for PFS, OS and relationships between PD-L1, GEP and MSI status with ORR will also be presented.
Pembrolizumab demonstrated favorable responses and manageable toxicity in the majority of the tumor types in KN028. Both PD-L1 and GEP score were predictive of clinical response, suggesting the utility of these biomarkers in selecting patients for immunotherapy and other novel therapies across a wide spectrum of tumor histologies.
Clinical trial identification
NCT02054806, originally posted February 3, 2014, KEYNOTE-028; EudraCT Number 2013-004507-39, originally entered May 30, 2014.
Legal entity responsible for the study
Merck & Co., Inc., Kenilworth, NJ, USA
Merck & Co., Inc., Kenilworth, NJ USA
P.A. Ott: Honoraria from Bristol-Myers Squibb, Merck, Neon Ther, Celldex, Pfizer, CytomX, Novartis, Alexion, Genentech/Roche. Funding from Bristol-Myers Squibb, Merck, Neon Therapeutics, Armo BioSciences, Celldex, MedImmune/AstraZeneca, Pfizer, CytomX. Y-J. Bang: Consultant for MSD. Funding from MSD to the institute. J. Bennouna: Consultant or advisory role, Honoraria from Roche, Boehringer-Ingelheim, AstraZeneca, Shire, MSD, Bristol-Myers Squibb. J-C. Soria: Honoraria from MSD. H.S. Rugo: Consultant for Amgen. Speakers’ bureau for Genomic Health. Travel expenses from Genentech. Funding to the institution from Genentech, Pfizer, Novartis, Lilly, OBI Pharma, Macrogenics, and Merck & Co., Inc. R.B. Cohen: Research funding to the institutiton from Merck & Co., Inc. B.H. O\'Neil: Travel expenses from Amgen. J.M. Mehnert: Advisory board member of Merck & Co., Inc., Genentech, EMD Serono. Consultant for Merck and Amgen. Research funding from Novartis, Merck, Polynoma, AstraZeneca, Immunocore, Macrogenics, Incyte. J. Lopez: Speakers’ Bureau for Roche and travel expenses for Basilea. T. Doi: Consulting/advisory/funding from Lilly Japan, Chugai, Kyowa Hakko Kirin, Nippon Boehringer-Ingelheim, Novartis, MSD, Daiichi Sankyo, Amgen. Funding: Taiho Pharma, Merck Serono, Astellas, Janssen, Takeda, Pfizer, Sumitomo, Bayer, Celgene. D. Levitan, K. Emancipator, A. Joe, M. Ayers, J. Lunceford: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA. Owner of stock or stock options in Merck & Co., Inc. K. Stein: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA and. Owner of stock or stock options in Merck & Co., Inc., Novartis, Sanofi, and Pfizer. G. Zhao: Employee of MSD China. All other authors have declared no conflicts of interest.