Anti–PD-1 Agents Gaining Momentum in Gastric Cancer


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In updates of two important studies in metastatic gastric cancer reported at the European Society for Medical Oncology (ESMO) 2017 Congress, nivolumab -(Opdivo) and pembrolizumab (Keytruda) demonstrated activity—but to varying degrees and with some nuances.

“Anti-PD [programmed cell death protein] antibodies will have a role in the management of advanced gastric adenocarcinoma,” said Eric Van Cutsem, MD, PhD, of University Hospitals Leuven, Belgium, the invited discussant. Alluding to some of the differences in the findings, he added that the results “show the need for better understanding of the biology of gastric cancer and for better predictive markers for checkpoint inhibitors in this malignancy.” 

KEYNOTE-059 Trial of Pembrolizumab

The phase II KEYNOTE-059 study evaluated pembrolizumab in three cohorts. Updated findings were presented at the ESMO Congress by Zev Wainberg, MD, of the University of California, Los Angeles.1 Based on the findings from KEYNOTE-059, on September 22, 2017, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab for programmed cell death ligand 1 (PD-L1)–positive patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma progressing after two or more prior lines of systemic therapy.


The expected response rate in these heavily pretreated patients was close to zero, so the findings are encouraging.
— Zev Wainberg, MD

In cohort 1, pembrolizumab alone was assigned to 259 patients with metastatic gastric cancer who had previously received two or more lines of chemotherapy; cohort 2 included 25 patients with newly diagnosed disease who received pembrolizumab in combination with chemotherapy; and cohort 3 included 31 patients who received pembrolizumab alone. Cohorts 1 and 2 could have any degree of PD-L1 expression, whereas only PD-L1–positive patients (combined positive score  ≥ 1%) were enrolled to cohort 3. 

The response rates for the three cohorts and outcomes by PD-L1 expression are shown in Table 1.

Cohort 1 Specifics

Further describing the effect in cohort 1, Dr. Wainberg noted the best response (16%) was in patients who received pembrolizumab as third-line therapy compared to later lines (7%). “The expected response rate in these heavily pretreated patients was close to zero, so the findings are encouraging,” he commented. 

A reduction in target lesion size was observed in 42% of all cohort 1 patients, and in the 31 responders, the median duration of response was 14.2 months. Overall, median progression-free survival was 2.0 months, and median overall survival was 5.5 months. At 6 months, 14.6% were progression-free and 45.7% of patients were alive. Although the statistical comparisons are impossible, there was a trend towards improved progression-free and overall survival rates in PD-L1–positive patients than in PD-L1–negative patients, he reported.

Details by Cohort 

In cohort 2, in which newly diagnosed patients with metastatic disease received pembrolizumab plus chemotherapy, 24 (96%) experienced a reduction in target lesion size, and responders had a median duration of response of 4.6 months. Median progression-free survival was 6.6 months, and median overall survival was 13.8 months. At 6 months, 68% of patients were progression-free, and 76% were alive.


With longer-term follow-up, a significant survival advantage was confirmed for nivolumab vs placebo, regardless of PD-L1 expression, in previously treated patients with advanced gastric cancer.
— Narikazu Boku, MD

In cohort 3, in which newly diagnosed PD-L1–positive patients received pembrolizumab alone, 24 (77%) had a reduction in target lesion size, and responders had a median response duration of 9.6 months. Median progression-free survival was 3.3 months, and median overall survival was 20.7 months. At 6 months, 34.9% were progression-free, and 72.9% were alive. 

In cohorts 1, 2 and 3, grade 3 to 5 treatment-related adverse events were seen in 18%, 76%, and 23%, respectively. These events led to treatment discontinuation in 7 patients (3%) and death in 2 patients (1%) in cohort 1, to discontinuation in 3 patients (12%) in cohort 2, and to the death of 1 patient (3%) in cohort 3. 

Pembrolizumab is being further evaluated in advanced gastric and gastroesophageal cancer in two ongoing phase III KEYNOTE trials. KEYNOTE-061 is comparing pembrolizumab to paclitaxel in patients whose disease progressed after first-line therapy with platinum and a fluoropyrimidine. KEYNOTE-062 is evaluating the agent alone and in combination with chemotherapy, vs chemotherapy alone, as first-line therapy for advanced PD-L1–positive disease. 

ATTRACTION-02 Trial of Nivolumab

In the phase III ATTRACTION-02 trial, which was conducted in Asia, nivolumab became the first immune checkpoint inhibitor to demonstrate a survival benefit in a large randomized study of patients with advanced gastric cancer.2 

“With longer-term follow-up, a significant survival advantage was confirmed for nivolumab vs placebo, regardless of PD-L1 expression, in previously treated patients with advanced gastric cancer,” Narikazu Boku, MD, of Toyo, Japan, reported. “The reduction in the risk of death was 38%, and an improvement in survival was seen across PD-L1–expression levels.” 

The study included 493 patients (randomized 2:1) with advanced or recurrent gastric or gastroesophageal junction cancer who had disease progression after 2 or more chemotherapy regimens. The study met its primary endpoint, showing an improvement in overall survival. Median survival was 5.32 months with nivolumab vs 4.14 months with placebo (hazard ratio [HR] = 0.61; P < .0001). At 12 months, the overall survival rates were 27.6% and 11.6%, respectively. 

ANTI–PD-1 AGENTS IN GASTRIC CANCER

  • Two phase III trials presented at the ESMO 2017 Congress validated the activity of anti–PD-1 agents in advanced gastric and gastroesophageal cancer.
  • In KEYNOTE-059, pembrolizumab showed activity as a single agent, both in PD-L1–positive and PD-L1–negative patients, and in both previously treated and newly diagnosed patients.
  • In ATTRACTION-02, conducted in Asian patients, nivolumab was active, especially in PD-L1–positive patients. 

In an exploratory analysis in 192 patients, nivolumab was shown to be beneficial irrespective of PD-L1 expression. In patients with PD-L1 expression ≥ 1%, median overall survival was 5.2 months with nivolumab vs 3.8 months with placebo (HR = 0.58). In patients with PD-L1–negative (< 1%) tumors, it was 6.1 and 4.2 months, respectively (HR = 0.71). 

“Nivolumab has a manageable safety profile that is consistent with previously reported findings. Most treatment-related adverse events occurred early, within the first 3 months,” Dr. Boku said. ■

DISCLOSURE: Dr. Van Cutsem has been a consultant for and/or ison the advisory board of Bayer, Lilly, Roche, SERVIER; and his institution has recevied research funding from Amgen, Bayer, Boehringer Ingelheim, Lilly, Novartis, Roche, Sanofi, Celgene, Ipsen, Merck, Merck KGaA, and SERVIER. REFERENCES

1. Wainberg Z, Jalal S, Muro K, et al: KEYNOTE-059 update. ESMO 2017 Congress. Abstract LBA28_PR. Presented September 8, 2017. 

2. Kang YK, Boku N, Satoh Y, et al: Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2). Lancet. October 5, 2017 (early release online).


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