The addition of immune checkpoint inhibitors to perioperative chemotherapy for gastric and gastroesophageal junction cancers boosts pathologic complete response rates, but the ultimate impact on clinical outcomes remains unclear, according to interim analyses from two phase III trials presented at the European Society for Medical Oncology (ESMO) Congress 2023. MATTERHORN1 and KEYNOTE-5852 evaluated PD-1 blockade in the perioperative and adjuvant settings in locally advanced disease. The addition of durvalumab and pembrolizumab, respectively, to chemotherapy increased pathologic complete response rates by approximately 12%, but as yet, no impact on event-free survival has been shown, investigators reported.
Phase III MATTERHORN Trial
The MATTERHORN trial randomly assigned 948 patients newly diagnosed with gastric or gastroesophageal cancer to receive perioperative treatment with the FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) regimen plus durvalumab or placebo. The addition of durvalumab significantly increased the rate of pathologic complete response from 7% to 19%, for a 12% absolute improvement (odds ratio [OR] = 3.08; P < .00001).1 For pathologic and near-pathologic complete responses, the rate was 27% vs 14%, respectively, according to Salah-Eddin Al-Batran, MD, Director of the Institute of Clinical Cancer Research and Director of GI Oncology at Krankenhaus Nordwest–University Cancer Center, Frankfurt, Germany.
Salah-Eddin Al-Batran, MD
Completion of surgery rates were comparable between the arms, 87% with durvalumab plus FLOT and 84% with FLOT alone, as was the achievement of R0 resections, 86% in each arm. Among patients who underwent surgery, downstaging favored the durvalumab arm: the result was pT0 status in 23% of the durvalumab arm vs 11% of the control arm and pN0 in 52% vs 36%, respectively.
The rate of grade 3 or 4 adverse events was similar (approximately 69%), as was the rate of grade 3 or 4 treatment-related adverse events (approximately 57%). The study is ongoing for the primary endpoint of event-free survival.
KEYNOTE-585
The interim analysis of KEYNOTE-585 showed an improvement in pathologic complete response—one of the primary endpoints—in patients randomly assigned to receive pembrolizumab compared with placebo added to neoadjuvant and adjuvant treatments with chemotherapy, according to Kohei Shitara, MD, Chief of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan.2
Kohei Shitara, MD
The study had two cohorts: the first “main” cohort of 804 patients received chemotherapy with either cisplatin and capecitabine or cisplatin and fluorouracil, with or without pembrolizumab. This regimen was followed by surgery, with the treatment delivered again as adjuvant therapy, and then 11 more cycles of pembrolizumab or placebo. For the second “FLOT” cohort of 203 patients, all patients received FLOT as backbone chemotherapy. Table 1 shows the significant boost in pathologic complete response rates with pembrolizumab.
Combination therapy did not, however, significantly prolong the co-primary endpoint of event-free survival in either the main or the main plus FLOT cohorts. In the main cohort, median event-free survival was 44.4 months with pembrolizumab vs 25.3 months with chemotherapy alone (hazard ratio [HR] = 0.81; P = .0198), which did not reach the boundary for significance of P = .0178 at the third interim analysis (final analysis for event-free survival). Median overall survival at this third interim analysis was 60.7 months and 58.0 months, respectively (HR = 0.90; 95% confidence interval [CI] = 0.73–1.12). At 36 months, 54% vs 44%, respectively, were event-free, and 65% and 60%, respectively, were alive.
For the main plus FLOT cohort, median event-free survival was 45.8 months vs 25.7 months (HR = 0.81; 95% CI = 0.68–0.97). The subgroup of patients with microsatellite-unstable tumors appeared to derive particular benefit from pembrolizumab, based, in the main cohort, on the pathologic complete response rate of 37.1%, a hazard ratio of 0.59 for event-free survival, and a hazard ratio of 0.38 for overall survival, Dr. Shitara reported.
Rates of grade ≥ 3 drug-related adverse events were similar with pembrolizumab and placebo in the main cohort (65% vs 63%, respectively).
DISCLOSURE: Dr. Al-Batran reported financial relationships with AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly Germany, Merck Sharp & Dohme, Immutep, Institut fur Klinische Krebsforschung GmbH, AIO GmbH, and MCI Group. Dr. Shitara reported financial relationships with Eli Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Novartis, AbbVie, Daiichi Sankyo, Taiho Pharmaceutical, GlaxoSmithKline, Amgen, Boehringer Ingelheim, MSD, Astellas, Gardant Health Japan, and Janssen.
REFERENCES
1. Shitara K, Rha SY, Wyrwicz L, et al: Pembrolizumab plus chemotherapy vs chemotherapy as neoadjuvant and adjuvant therapy in locally advanced gastric and gastroesophageal junction cancer: The phase III KEYNOTE-585 study. ESMO Congress 2023. Abstract LBA74. Presented October 20, 2023.
2. Janjigian YY, Al-Batran SE, Wainberg ZA, et al: Pathological complete response to durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel in resectable gastric and gastroesophageal junction cancer: Interim results of the global, phase III MATTERHORN study. ESMO Congress 2023. Abstract LBA73. Presented October 20, 2023.
