FDA Grants Pembrolizumab Priority Review for Advanced Gastric Cancer

Roger Dansey, MD, senior vice president and therapeutic area head of oncology late-stage development at Merck Research Laboratories

Roger Dansey, MD

The FDA has granted a priority review to a supplemental Biologics License Application for pembrolizumab (Keytruda) for the treatment of patients who have undergone at least 2 courses of chemotherapy for recurrent or advanced gastric or gastroesophageal junction adenocarcinoma.

The agency is expected to announce a decision by September 22, 2017.

“An estimated 100,000 people are living with gastric cancer in the United States, yet little progress has been made in bringing forward new treatment options to these patients for whom chemotherapy has long been the standard of care,” Roger Dansey, MD, senior vice president and therapeutic area head of oncology late-stage development at Merck Research Laboratories, said in a release. Merck manufactures the PD-1 inhibitor. “We look forward to working with the FDA to bring Keytruda to people with gastric cancer who have progressed after receiving chemotherapy and are in urgent need of another option.”

The application is based on data from cohort 1 of the phase II KEYNOTE-059 trial, a multicohort, international study.¹ Researchers are slated to present the findings, including further safety data, at the 2017 ASCO Annual Meeting in June.

In KEYNOTE-059, adult patients (n = 259) with advanced gastric or gastroesophageal junction cancer who had progressed on at least 2 prior lines of chemotherapy were assigned to 200 mg of pembrolizumab every 3 weeks for up to 2 years, or until progression or unacceptable toxicity. Just over half of patients (51.7%) received treatment as third-line therapy and 48.3% received pembrolizumab in the fourth line.

At a median follow-up was 5.4 months, objective response rate (ORR) was 11.2% (95% CI, 7.6-15.7). More specifically, 1.9% (95% CI, 0.6-4.4) of patients had a complete response, 9.3% (95% CI, 6.0-13.5) had a partial response, 17% (95% CI, 12.6-22.1), had stable disease, and 55.6% (95% CI, 49.3-61.7) experienced disease progression. Median duration of response was 8.1 months.

In PD-L1—positive patients, the ORR was 15.5% (95% CI, 10.1-22.4), 2% of patients had a complete response (95% CI, 0.4-5.8), and 13.5% (95% CI, 8.5-20.1) had a partial response. The ORR was 5.5% (95% CI, 2.0-11.6) in PD-L1–negative patients; 1.8% (95% CI, 0.2-6.5) had a complete response and 3.7% (95% CI, 1.0-9.1) had a partial response.

ORR for patients receiving third-line therapy was 14.9% (95% CI, 9.4-22.1) versus 7.2% (95% CI, 3.3-13.2) in patients receiving treatment in the fourth line. In third-line patients with PD-L1—expressing tumors, ORR was 21.3% (95% CI, 12.7-32.3), with 4.0% (95% CI, 0.8-11.2) achieving a complete response. In third-line patients with PD-L1–negative tumors, ORR was 6.9% (95% CI, 1.9-16.7) with a 3.4% (95% CI, 0.4-11.9) complete response.

Namrata Vijayvergia, MD, assistant chief of gastrointestinal oncology at Fox Chase Cancer Center, reviewed the data for OncLive. She said that, at present, there is little evidence supporting any therapy for patients in third- or fourth-line therapy.

“After [second line], it’s basically dealer’s choice,” she said. “There’s nothing that’s been proven to be very effective so far. The new pembrolizumab monotherapy data, as well as the nivolumab single-agent study that came from Japan, tell us this is an active drug [type] in this disease, and now we have data that third-line therapy improves survival in these patients. I am excited to get this approved as soon as possible so I can use it in my patients.”

She cautioned that there is still more to learn about the drug.

“We only have phase II data, which is a single-arm study that doesn’t have comparators,” Vijayvergia said. “I would like to see a study where it is compared to best supportive care or something like that to confirm what we see, and prove that there is a survival advantage.”

Researchers are also scheduled to present results from KEYNOTE-059 cohort 2 as a poster at ASCO 2017.² Twenty-five patients with treatment-naïve HER2-positive recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma were assigned to 200 mg of pembrolizumab on day 1 of each 21-day cycle, along with 80 mg/m² of cisplatin for 6 cycles and 800 mg/m2 of 5-fluorouracil (or 1000 mg/m² of capecitabine in Japan) every 3 weeks for up to 2 years, or until disease progression or unacceptable toxicity.

Median follow-up was 12.2 months.

At the October 19, 2016, data cutoff, 84% of patients had discontinued treatment, most due to disease progression. Researchers observed grade 3/4 treatment-related adverse events (AEs) in 76% of patients. Treatment-related AEs led to discontinuation in 3 patients: 1 grade 3 stomatitis, 1 grade 2 hypoacusis, and 1 grade 1 creatinine increase. No treatment-related AEs were fatal.

Median progression-free survival was 6.6 months (95% CI, 5.9-10.6) and median overall survival was 13.8 months (95% CI, 7.3-not estimable).

ORR was 60% (95% CI, 38.7-78.9). Overall, 32% (95% CI, 14.9-53.5) of patients had stable disease, 4% (95% CI, 0.1-20.4) had progressive disease, and 4% (95% CI, 0.1-20.4) were not evaluable.

In PD-L1—expressing patients, ORR was 68.8% (95% CI, 41.3-89.0) versus 37.5% (95% CI, 8.5-75.5) in PD-L1–negative patients. Median duration of response was 4.6 months overall, 4.6 months in PD-L1–positive patients, and 5.4 months in PD-L1–negative patients.

Researchers proceeded to KEYNOTE-059 following the phase Ib KEYNOTE-012 study.³ In that international trial, patients (N = 39) with PD-L1—positive recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction received IV pembrolizumab at 10 mg/kg once every 2 weeks for 24 months or until discontinuation.

Eight of 36 patients (22%; 95% CI, 10-39) had measurable responses to treatment, all partial.

All 39 patients were included in the safety analyses. Five patients (13%) had a total of 6 grade 3/4 treatment-related AEs: 2 incidents of grade 3 fatigue; one case each of grade 3 pemphigoid, hypothyroidism, and peripheral sensory neuropathy; and a single incidence of grade 4 pneumonitis.

References

1. Fuchs CS, Doi T, Jang RWJ, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol 35, 2017 (suppl; abstr 4003).
2. Bang YJ, Muro K, Fuchs CS, et a. KEYNOTE-059 cohort 2: Safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer. J Clin Oncol 35, 2017 (suppl; abstr 4012).
3. Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17(6):717-726. doi: 10.1016/S1470-2045(16)00175-3.