Avelumab Clinically Active in Advanced Gastric/GEJ Cancer

Hyun Cheol Chung, MD

The investigational anti—PD-L1 antibody avelumab demonstrated clinical activity as a second-line and maintenance therapy for patients with unresectable gastric or gastroesophageal junction (GEJ) cancer, according to a report at the 2016 Gastrointestinal Cancers Symposium.

Among 55 patients who received avelumab maintenance after first-line chemotherapy in the phase Ib study, one had a complete response and three others had partial responses, for an overall response rate (ORR) of 7.3%. In the second-line setting, avelumab demonstrated an ORR of 15%. Stable disease rates were 35% in the second-line setting and 47.3% in the maintenance cohort.

“Treatment with avelumab in patients with gastric or gastroesophageal junction cancer was associated with an acceptable safety profile and showed clinical activity, including 1 complete response among patients receiving avelumab in the maintenance setting,” Hyun Cheol Chung, MD, a medical oncologist at Yonsei Cancer Center in Shinchon-Dong, South Korea, and colleagues concluded in a poster presentation.

The phase Ib trial focused on patients whose disease progressed after first-line chemotherapy (n = 20) or those who did not have disease progression during first-line therapy (n = 55). In both cohorts, avelumab was administered at 10 mg/kg every 2 weeks.

Safety and tolerability were the trial’s primary objectives. Secondary endpoints included assessment of best overall response, progression-free survival (PFS), and the association between PD-L1 expression (on tumor cells and immune cells) and subsequent clinical activity of avelumab.

Patients in the second-line and maintenance cohorts had similar baseline characteristics. The median ages were 56 and 57 years, 75% to 80% were male, and the histology was unspecified in 60% to 65% of patients in the second-line and maintenance arms, respectively.

Avelumab led to a partial response in 3 patients and stable disease in 7 others in the second-line cohort, resulting in a disease control rate of 50%. In the maintenance cohort, 4 patients had partial responses and 26 had stable disease for a disease control rate of 54.5%.

Nine patients (4 second-line, 5 maintenance) had tumor shrinkage >30%. These responses included 2 patients who had HER2-positive disease and 2 others with stable disease who did not qualify for response because of the appearance of a new lesion on subsequent scans.

At the time of the analysis, median duration of response had not yet been reached. Responses were observed in patients with PD-L1-positive and PD-L1-negative tumors. Responses occurred within 5 to 10 weeks of starting treatment in the second-line cohort and within about 5 weeks in all responding patients in the maintenance cohort. Four of seven responses were ongoing at the last data analysis, Chung reported.

The second-line cohort had a median PFS of 11.6 weeks. At 24 weeks, 19.3% of patients remained progression free and alive. The maintenance cohort had a median PFS of 14.1 weeks and a 24-week PFS rate of 34.0%. A trend toward longer PFS was observed in patients with PD-L1—positive tumors.

PD-L1 expression status was known in 12 of 20 patients in the second-line cohort and 43 of 55 in the maintenance cohort. Using a cutoff of ≥1% expression in tumor cells, five patients (41.7%) in the second-line cohort had PD-L1-positive tumors, as did 15 of those in the maintenance cohort (34.9%).

Raising the cutoff to ≥5% expression produced PD-L1-positive rates of 16.7% and 16.3% and raising the cutoff to 25% resulted in positive rates of 16.7% and 0% for the second-line and maintenance cohorts, respectively. Assessment of PD-L1 expression in tumor-infiltrating lymphocytes showed that 16.7% of patients in the second-line cohort and none of those in the maintenance group had tumors with PD-L1 expression levels ≥10%.

In patients with PD-L1 expression on ≥5% of cells, the ORR in the second-line setting was 50% (1 out of 2). In the maintenance setting (n = 7), there was 1 response, for an ORR of 14.3%. The median PFS was not reached for those in the second-line group and was 18.0 weeks in the maintenance group.

For those with ≥1% tumor expression, the ORR was 20% in the second-line setting. The ORR was 6.7% in the maintenance setting. The median PFS was 36 weeks in the second-line group and 17.6 weeks for those in the maintenance group.

With respect to safety, 47 of the 75 patients (63%) in both cohorts had treatment-emergent adverse events. The most frequently reported adverse events (all grades) were infusion-related reactions (16%), nausea (9.3%), elevated liver enzymes (9.3% each for AST and ALT), fatigue (8%), vomiting (8%), chills (8%), and pruritus (8%). The only grade 3/4 adverse event that occurred in more than one patient was fatigue (two patients, 2.7%).

“Responses were observed in patients with PD-L1-positive and PD-L1-negative tumors, but we observed a trend suggesting that PD-L1 was associated with a higher progression-free survival at 12 weeks in the second-line population,” the investigators wrote. “Additional clinical studies of avelumab, as a single-agent or in combination with other agents, in populations with gastric and gastroesophageal junction cancer are currently underway or planned.”

In contrast with the two currently approved immune checkpoint inhibitors, nivolumab (Opdivo) and pembrolizumab (Keytruda), avelumab targets the PD-L1 ligand, inhibiting PD-1/PD-L1 interaction while leaving the PD-1/PD-L2 pathway intact. The drug’s safety, pharmacokinetic profile, and clinical activity have been confirmed in phase I dose-escalation trials.

The phase III JAVELIN Gastric 300 trial is currently enrolling participants with advanced gastric cancer. The study will compare avelumab plus best supportive care (BSC) with physician's choice of chemotherapy plus BSC. The primary endpoint of the study, which plans to enroll 330 participants, is overall survival. The study was initiated in 2015 with an estimated primary completion date of February 2018 (NCT02625623).

Chung HC, Arkenau H-T, Wyrwicz L, et al. Safety, PD-L1 expression, and clinical activity of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with advanced gastric or gastroesophageal junction cancer. J Clin Oncol. 2016;34 (suppl 4S; abstr 167).

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