In the phase III JAVELIN Gastric 100 trial, a strategy called “switch maintenance” with the immune checkpoint inhibitor avelumab after 12 weeks of first-line induction chemotherapy did not statistically improve overall survival for treatment-naive patients with HER2-negative advanced gastric or gastroesophageal junction cancer.1 Avelumab targets programmed cell death ligand 1 (PD-L1).
“JAVELIN Gastric 100 did not meet its primary objective of demonstrating superior overall survival with avelumab maintenance vs chemotherapy or best supportive care,” said Markus Moehler, MD, PhD, of Johannes Gutenberg-University Clinic, Mainz, Germany.
“JAVELIN Gastric 100 did not meet its primary objective of demonstrating superior overall survival with avelumab maintenance vs chemotherapy or best supportive care.”— Markus Moehler, MD, PhD
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As Dr. Moehler described at the 2020 Gastrointestinal Cancers Symposium, the JAVELIN Gastric 100 trial enrolled 805 patients with previously untreated, unresectable, locally advanced or metastatic HER2-negative gastric or gastroesophageal junction cancer to receive initial induction chemotherapy with FOLFOX (leucovorin, fluorouracil, oxaliplatin) or XELOX (capecitabine plus oxaliplatin). All 805 patients received 12 weeks of induction chemotherapy, and those without progressive disease were then randomly assigned to receive maintenance therapy with avelumab (n = 249) or to continue first-line chemotherapy vs best supportive care or continuation of chemotherapy, which was received by the vast majority (> 90%) of patients (n = 250). The primary endpoint was overall survival in all patients and in those with expression of PD-L1 (≥ 1% of tumor cells on the 73-10 PharmDx assay).
The median overall survival was 10.4 months for those randomly assigned to avelumab and 10.9 months for the control arm (hazard ratio [HR] = 0.91; P = .178). At 12 months, approximately 45% of patients in each arm were alive; at 24 months, numerically more avelumab-treated patients were alive (22.1% vs 15.5%, respectively). In the 54 patients with PD-L1–positive tumors, the median survival was 16.2 months and 17.7 months, respectively (HR = 1.13; P = .635).
During the maintenance phase, patients who received avelumab had a longer duration of response (not reached vs 5.9 months with chemotherapy). A potential benefit was also seen in the 60 patients without metastatic disease at the end of induction chemotherapy (HR = 0.52, 95% confidence interval [CI] = 0.28–0.98), but no other subgroups appeared to benefit, except for the microsatellite instability–high subgroup, which derived a substantial benefit.
Hint of Benefit in PD-L1–Positive Patients With the Different PD-L1 HC 223 Assay
In an exploratory analysis of 137 PD-L1–positive patients with a Combined Positive Score (CPS) ≥ 1 via the 22C3 pharmDx immunohistochemistry assay, out of the 213 evaluable patients, the median overall survival was 14.9 months in the avelumab arm and 11.6 months in the control arm (HR = 0.72, 95% CI = 0.49–1.05). At the time the study was designed, a CPS scoring approach had not been established. “Nowadays, it’s clear that the CPS score is better, and this might have been a positive trial [had it been used],” he proposed.
The safety profile was better with avelumab in terms of treatment-related adverse events. Although the incidence of all adverse events was similar, regardless of investigator causality assessment (grade ≥ 3 adverse events were observed in 54% of each arm), the incidence of treatment-related adverse events related to the study drug was lower with avelumab as compared to the chemotherapy/best supportive care arm: 61.3% vs 77.3% overall and 13% vs 33%, respectively, for grade ≥ 3. Treatment discontinuations due to treatment-related adverse events were also reported better for avelumab with 10.3% vs 27.3%, respectively.
“Further studies are needed to identify patients who can derive benefit from checkpoint inhibitor therapy across the continuum of care for gastric or gastroesophageal junction cancer,” said
DISCLOSURE: The study was funded by EMD Serono (a subsidiary of Merck KGaA Healthcare Darmstadt, Germany) and Pfizer. Dr. Moehler disclosed other financial relationships with Amgen, AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, Lilly/ImClone, EMD Serono, Merck, Pfizer, Roche/Genentech, Servier, and Taiho Pharmaceutical.
1. Moehler MH, Dvorkin M, Ozguroglu M, et al: Results of the JAVELIN Gastric 100 phase III trial: Avelumab maintenance following first-line chemotherapy vs continuation of chemotherapy for HER2-advanced gastric or gastroesophageal junction cancer. 2020 Gastrointestinal Cancers Symposium. Abstract 278. Presented January 23, 2020.
Daniel V.T. Catenacci, MD, Associate Professor of Medicine and Director of the Gastrointestinal Oncology Program at the University of Chicago, was the JAVELIN Gastric 100 study’s invited discussant. After offering an extensive background on the use of immunotherapy in gastric or gastroesophageal...