LUGANO-MADRID – Pembrolizumab has shown a promising response rate in patients with pretreated metastatic gastric cancer, according to late-breaking results from the KEYNOTE-059 trial presented today at the ESMO 2017 Congress in Madrid. (1)
The expected survival of patients with metastatic gastric cancer is less than one year. Very few new drugs have been approved for this disease in the past decade. The phase II KEYNOTE-059 is one of the largest studies to investigate immunotherapy in recurrent or metastatic gastric cancer.
The study included three cohorts: 1) 259 patients with metastatic gastric cancer who received the programmed death 1 (PD-1) inhibitor pembrolizumab alone, after pretreatment with two or more lines of chemotherapy; 2) 25 patients with newly diagnosed metastatic gastric cancer who received a combination of pembrolizumab and chemotherapy; 3) 31 patients with newly diagnosed metastatic gastric cancer who received pembrolizumab alone.
The primary endpoints were safety (all three cohorts) and objective response rate (cohorts one and three).
After a median follow-up of six months, the investigators found an overall objective response rate of 12% with pembrolizumab alone in the pretreated patients (cohort one). Patients who expressed programmed death-ligand 1 (PD-L1) were more likely to respond than those who did not, with objective response rates of 16% and 6%, respectively. Many of the responses were durable. Grade 3 to 5 treatment-related adverse events occurred in 18% of patients in cohort one and 3% had to discontinue treatment as a result.
Lead author Dr Zev Wainberg, co-director of the Gastrointestinal Oncology Programme, UCLA, Los Angeles, US, said: “The data shows that the tumours were sufficiently shrunk to warrant a response, particularly in those patients who had PD-L1 expression, and the drug was safe. The expected response rate in these heavily pretreated patients was close to zero so the findings are encouraging.”
In patients with newly diagnosed metastatic cancer, both the combination therapy (cohort two) and pembrolizumab alone (cohort three) were safe and showed some promising activity. “These results have set the stage for a larger follow-up study which is already enrolling patients,” said Wainberg.
He concluded: “We hope these results, in combination with evidence from ongoing randomised trials, will support the regulatory approval of pembrolizumab in metastatic gastric cancer.”
Commenting on the results for ESMO, Dr Ian Chau, consultant medical oncologist, Royal Marsden Hospital, London and Surrey, UK, said: “There is currently no standard of care for metastatic gastric cancer treated in the third line or beyond. The KEYNOTE-059 cohort 1 results confirm that the efficacy previously reported for the PD-1 inhibitor nivolumab in patients from East Asia in the ONO-4538 randomised trial can be applied to Western populations.”
“The likelihood is that pembrolizumab will become a standard treatment option in this setting in the near future,” he added.
Chau cautioned that while the toxicity profile of pembrolizumab looked quite favourable in KEYNOTE-059, it could be that patients had not been treated long enough to experience side effects. He said: “Unlike with chemotherapy, toxicities from immunotherapy tend to occur later on. We need to await longer-term results from an ongoing clinical trial in an earlier line of treatment to know the full impact of this drug in metastatic gastric cancer.”
He concluded: “Further research should focus on refining the PD-L1 biomarker and searching for better biomarkers to tell us who benefits from these therapies. We also need more information about quality of life which should be provided by ongoing studies.”
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress
1 Abstract LBA28_PR ‘KEYNOTE-059 Update: Efficacy and Safety of Pembrolizumab Alone or in Combination With Chemotherapy in Patients With Advanced Gastric or Gastroesophageal (G/GEJ) cancer’ will be presented by Dr Zev Wainberg during Proffered Paper Session ‘Gastrointestinal tumours, non-colorectal’ on Friday, 8 September 2017, 14:00 to 15:30 (CEST) in the Barcelona Auditorium.
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KEYNOTE-059 Update: Efficacy and Safety of Pembrolizumab Alone or in Combination with Chemotherapy in Patients With Advanced Gastric or Gastroesophageal (G/GEJ) cancer
Z.A. Wainberg1, S. Jalal2, K. Muro3, H.H. Yoon4, M. Garrido5, T. Golan6, T. Doi7, D.V. Catenacci8, R. Geva9, G. Ku10, J. Bleeker11, Y.-J. Bang12, H. Hara13, H.C. Chung14, M. Savage15, J. Wang15, M. Koshiji15, R. Dalal15, C.S. Fuchs16
1Medicine Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, USA, 2Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA, 3Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan, 4Medical Oncology, Mayo Clinic, Rochester, MN, USA, 5Hemato-Oncology, Pontificia Universidad Catolica de Chile, Santiago, Chile, 6Oncology Division, Sheba Medical Center and Sackler School of Medicine, Tel Aviv, Israel, 7Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan, 8Medicine, University of Chicago Medicine, Chicago, IL, USA, 9Oncology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, 10Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 11Medical Oncology, Sanford Health, Sioux Falls, SD, USA, 12Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of, 13Medical Oncology, Saitama Cancer Center, Saitama, Japan, 14Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of, 15Merck Research Laboratory, Merck & Co., Inc., Kenilworth, NJ, USA, 16Cancer Prevention and Control, Yale Cancer Center, New Haven, CT, USA
Background: Prior results from the global, phase 2 KEYNOTE-059 study (NCT02335411) demonstrated manageable safety and promising antitumor activity for pembro alone and pembro + chemo in pts with G/GEJ cancer.
Methods: Pts with recurrent or metastatic G/GEJ adenocarcinoma were enrolled. Pts were enrolled in cohorts 1 and 2 regardless of tumor PD-L1 expression; only pts with PD-L1-positive tumors (combined positive score of ≥1% using the PD-L1 IHC 22C3 pharmDx assay) were enrolled in cohort 3. Cohort 1 pts received pembro alone after ≥2 prior lines of therapy. Cohort 2 pts received pembro + cisplatin (80 mg/m2 day 1) + 5-fluorouracil (800 mg/m2 days 1-5 Q3W) or capecitabine (in Japan only, 1000 mg/m2 twice daily) as first-line. Cohort 3 pts received pembro alone as first-line. In all cohorts, pembro was given at 200 mg Q3W for up to 2 years. Primary end points were safety (all) and ORR by RECIST v1.1 by central review (cohorts 1 and 3); key secondary end points were ORR (cohort 2) and DOR by RECIST v1.1, PFS, and OS.
Results: At data cutoff (Apr 21, 2017), median (range) follow-up was 6 (1-25), 14 (2-24), and 18 (2-21) months for cohorts 1 (259 pts), 2 (25 pts) and 3 (31 pts), respectively. Confirmed ORR (95% CI) was 12% (8-17) overall, 16% (11-23) in PD-L1-positive, and 6% (3-13) in PD-L1-negative tumors in cohort 1. Confirmed ORR was 60% (39-79) overall, 73% (45-92) in PD-L1-positive, and 38% (9-76) in PD-L1-negative tumors in cohort 2. In cohort 3, confirmed ORR (95% CI) was 26% (12-45). Median PFS (95% CI) was 2 (2-2), 7 (6-11), and 3 (2-6) months in cohorts 1, 2, and 3, respectively. Median OS (95% CI) in months was 6 (4-7), 14 (9-not estimable), and not reached (9-21) in cohorts 1, 2, and 3, respectively. In cohorts 1, 2 and 3, grade 3-5 treatment-related adverse event (TRAE) incidence was 46 (18%), 19 (76%), and 7 (23%), respectively. In cohort 1, TRAEs led to discontinuation in 7 pts (3%) and death in 2 pts (1%); in cohort 2, TRAEs led to discontinuation in 3 pts (12%); in cohort 3, TRAEs led to death in 1 pt (3%).
Conclusions: These updated results show manageable safety and promising antitumor activity for pembro alone and pembro + chemo in pts with advanced G/GEJ cancer.
Clinical trial identification: NCT02335411
Legal entity responsible for the study: Merck & Co, Inc., Kenilworth, NJ, USA
Funding: Merck & Co, Inc., Kenilworth, NJ, USA
Disclosure: Z.A. Wainberg: Consultant for Genetech, Array, Sirtex, Novartis, and Five Prime Therapeutics
S. Jalal: Research funding: AstraZeneca
K. Muro: Research funding: Shionogi & Co, MSD K.K., Daiichi Sankyo, Kyowa Hakko Kirin,. Gilead Sciences Honoraria: Chugai Pharmaceutical, Takeda Pharmaceutical, Eli Lilly Japan K.K., Merck Serono, Taiho, Yakult Honsha
T. Doi: Advisory board: Lilly, Chugai Pharma, Kyowa Hakko, Kirin, Novartis, MSD, Daiichi Sankyo, Amgen Research funding: Taiho, Novartis, Merck Serono, Astellas, MSD, Janssen Pharma, Behringer Ingelheim, Takeda, Pfizer, Lilly, Sumitomo Group, Chugai Pharma, Bayer, Kyowa Hakko, Kirin, Daiichi Sankyo, Celegene
D.V. Catenacci: Advisory board: Merck, BMS, Lilly, Genentech Honoraria: Merck, BMS, Lilly, Genentech Travel expenses, including accommodations: Merck, BMS, Lilly, Genentech
R. Geva: Advisory board: Bayer, MSD, Novartis Honoraria: BMS, Lilly, Medison, Roche, Novartis, Janssen Travel expenses: Roche, BMS
G. Ku: Advisory board member: Merck Research funding: Merck (to institution) Travel expenses: Merck
J. Bleeker: Travel expenses: Merck & Co., Inc. Consultant fee: BMS
Y.-J. Bang: Advisory board: AstraZeneca, Novartis, Roche, Genentech, MSD, Pfizer, Bayer, BMS, Eli Lilly, Merck Serano, FivePrime, Merrimack, Taiho, Ono, ADC Therapeutics, GreenCross, Samyang Biopharm Research funding: AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, GSK, BMS, Pfizer, Eli Lilly, Boeringer-Ingelheim, MacroGenics, , Boston Biomedical, FivePrime, CKD, Ono, Otsuka, Taiho, Takeda, BeiGene, Hanmi, Green Cross, Curis
H. Hara: Research funding to institution: AstraZenaca, Chugai Pharma, Merck Serono, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Dainippon Sumitomo Pharma, Daiichi Sankyo, Lilly Honoraria: Chugai Pharma, Taiho Pharmaceuticals, Merck Serono, Yakult Honsha, Lilly
M. Savage, J. Wang, M. Koshiji, R. Dalal: Employment: Merck & Co., Inc.
C.S. Fuchs: Advisory board: Eli Lilly, Entrinsic Health, Genentech, Merck, Gilead, Sanofi, Dicerna, Five Prime Therapeutics, Merrimack, Bayer, Agios, Taiho
All other authors have declared no conflicts of interest.
Keywords: pembrolizumab, gastric cancer, PD-L1, immunotherapy