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Immunotherapy for gastric and esophageal cancer got support from three new studies reported during the .

In the largest of these, adding nivolumab (Opdivo) to chemotherapy improved overall survival (OS) by two to three months in untreated advanced/metastatic gastric, gastroesophageal junction (GEJ), or esophageal cancer. The statistically significant improvement occurred in all patients and in analyses of two PD-L1-positive subgroups. Adding nivolumab to chemotherapy led to a two-month improvement in progression-free survival (PFS) but no survival benefit in a smaller study of Asian patients with untreated advanced or recurrent disease.

"Nivolumab is the first PD-1 inhibitor to demonstrate superior overall survival and PFS in combination with chemotherapy in previously untreated patients with advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma," said Markus Moehler, MD, of Johannes-Gutenberg University Clinic in Mainz, Germany and principal investigators in the larger nivolumab study. "We achieved statistical significance for both primary endpoints and for all formally tested secondary endpoints."

"No safety signals were identified for chemo and nivolumab. Therefore, we hope that nivolumab and chemotherapy will present a new potential standard treatment for patients with advanced gastric, gastroesophageal juncture, and esophageal carcinoma."

And, a randomized trial of patients with advanced/metastatic esophageal or GEJ cancer revealed a three-month OS improvement with the addition of pembrolizumab (Keytruda) to chemotherapy.

Nivolumab Trials

Moehler reported primary findings from the randomized trial. Eligible patients had previously untreated HER2-negative disease. They were randomized to one of two standard chemotherapy regimens (XELOX or FOLFOX) alone or in combination with nivolumab. The trial had dual primary endpoints: OS and PFS in the subgroup of patients with a PD-L1 combined positive score (CPS) ≥5%.

Data analysis comprised of 1,571 patients, including 955 with CPS ≥5% and 1,296 with CPS ≥1%. The results showed median OS of 14.4 months with nivolumab and 11.1 months with chemotherapy alone in the CPS ≥5% population. The difference represented a nearly 30% reduction in the mortality hazard (HR 0.71, 98.4% CI 0.59-0.86, P<0.0001). The advantage for nivolumab carried over into the CPS ≥1% population (14.0 vs 11.3 months, HR 0.77, P<0.0001), and all randomized patients (13.8 vs 11.6 months, HR 0.80, P=0.0002). The PFS analysis showed a one-third reduction in the hazard in the CPS ≥5% population (HR 0.68, 98% CI 0.56-0.81, P<0.0001).

Treatment-related adverse events (TRAEs) occurred more often with nivolumab, including all TRAEs (95% vs 88%), grade 3/4 TRAEs (59% vs 44%), and TRAEs leading to discontinuation (38% vs 25%). Moehler said adverse events were consistent with the known safety/toxicity profile of nivolumab and the chemotherapy regimens used in the study.

Narikazu Boku, MD, of the National Cancer Center Hospital in Tokyo, reported initial findings from the randomized trial of 724 patients with previously untreated advanced or recurrent gastric, GEJ, or esophageal cancer. All patients received oxaliplatin with the fluoropyrimidine derivative S-1 or capecitabine and were randomized to nivolumab or placebo. The trial had coprimary endpoints of OS and PFS, but the trial was considered positive if either endpoint was met, said Boku.

The addition of nivolumab was associated with a statistically significant two-month improvement in median PFS (10.45 vs 8.34 months), representing a one-third reduction in the hazard ratio (HR 0.68, 98.5% CI 0.51-0.90, P=0.0007). The 12-month PFS was 45.4% with nivolumab and 30.6% with chemotherapy alone. The OS analysis showed nearly identical median values for the two treatment arms (17.45 vs 17.15 months).

The nivolumab arm had a higher response rate (57.4% vs 47.8%), and responses were more durable (12.91 vs 8.67 months). The disease-control rate was similar between the groups (71.8% vs 68.5%).

"The prespecified objective of the phase III part of ATTRACTION-4 was achieved, showing clinically meaningful efficacy," Boku said in conclusion. "Nivolumab plus chemotherapy could be considered a new first-line treatment option in unresected advanced or recurrent gastric or GEJ cancer."

Pembrolizumab Data

The phase III randomized trial of pembrolizumab involved patients with locally advanced/unresectable or metastatic esophageal cancer (adenocarcinoma, squamous cell, or Siewart type 1 GEJ cancer). Investigators randomized 749 patients to receive chemotherapy alone (cisplatin plus 5FU) or in combination with the PD-1 inhibitor.

The trial had dual primary endpoints of OS and PFS, said Peter Enzinger, MD, of Dana Farber Cancer Institute in Boston. OS was assessed in all patients, in patients with CPS ≥10%, in the squamous-cell subgroup, and in patients with CPS ≥10% in the squamous-cell subgroup. PFS was assessed in all patients, the CPS ≥10% subgroup, and the squamous-cell subgroup.

The OS analysis in all randomized patients produced median OS of 12.4 months with pembrolizumab and 9.8 months with chemotherapy alone. The difference represented a 27% reduction in the survival hazard (HR 0.73, 95% CI 0.62-0.86, P<0.0001). Enzinger said the 12-month OS was 51% with nivolumab and 39% without and 28% versus 16% at 24 months.

The addition of pembrolizumab improved median PFS by less than a month (6.3 vs 5.8 months) but that was still statistically significant (HR 0.65, 95% CI 0.55-0.76, P<0.0001). Landmark PFS analyses strongly favored the pembrolizumab arm at 12 months (25% vs 12%) and 18 months (16% vs 6%).

Frequency of TRAEs (98.4% vs 97.3%) and grade ≥3 TRAEs (71.9% vs 67.6%) was similar between groups. More patients in the pembrolizumab arm discontinued because of adverse events (19.5% vs 11.6%). Immune mediated adverse events and infusion reactions also occurred more often with pembrolizumab (25.7% vs 11.6%).

"Pembrolizumab plus chemotherapy should be a new standard of care as first-line therapy in patients with locally advanced unresectable or metastatic esophageal cancer, including gastroesophageal junction carcinoma, regardless of histology and biomarker status," Enzinger said.