Meeting News

Pembrolizumab may Become Standard for Advanced Gastric Cancer

MADRID — Pembrolizumab demonstrated promising activity in patients with pretreated recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma, according to results of the KEYNOTE-059 trial presented at the European Society for Medical Oncology Congress.

“The data shows that the tumors were sufficiently shrunk to warrant a response, particularly in those patients who had PD-L1 expression, and the drug was safe,” Zev A. Wainberg, MD, assistant professor of medicine at UCLA and co-director of the UCLA gastrointestinal oncology program, said in a press release. “The expected response rate in these heavily pretreated patients was close to zero, so the findings are encouraging.”

Most patients with metastatic gastric cancer survive less than 1 year, and treatment advances for this population have been limited over the past decade.

Prior results from the global, phase 2 KEYNOTE-059 study showed pembrolizumab (Keytruda, Merck), an anti-PD-1 antibody, demonstrated promising antitumor activity and a manageable safety profile alone or in combination with chemotherapy for patients with gastric or gastroesophageal junction cancers.

KEYNOTE-059 — one of the biggest to investigate an immunotherapy for patients with metastatic or recurrent gastric cancer — assessed pembrolizumab in three cohorts of patients with pretreated metastatic gastric cancer. Pembrolizumab was administered in 200-mg doses every 3 weeks for up to 2 years.

The first cohort consisted of 259 patients with metastatic disease who previously underwent two or more lines of chemotherapy. These patients received pembrolizumab monotherapy.

The second cohort included 25 patients with newly diagnosed metastatic disease. They received first-line pembrolizumab with chemotherapy, which consisted of cisplatin 80 mg/m2 on day 1 plus 5-FU 800 mg/m2 on days 1 to 5 every 3 weeks. Patients in Japan only received capecitabine 1000 mg/m2 twice daily.

The third cohort included 31 patients with newly diagnosed metastatic disease. They received pembrolizumab monotherapy as firstline treatment.

Safety in all three cohorts, as well as objective response rates in the first and third cohorts, served as primary endpoints. ORR in the second cohort, as well as duration of response, PFS and OS in all cohorts, served as key secondary endpoints.

In the first cohort, after median follow-up of 6 months (range, 1 to 25 months), objective response rate among pretreated patients who received pembrolizumab monotherapy was 12% (95% CI, 8-17). Many responses appeared durable, researchers wrote.

Patients whose tumors expressed PD-L1 appeared more than twice as likely to achieve objective response than those whose tumors did not express PD-L1 (16% vs. 6%).

Eighteen patients experienced grade 3 to grade 5 treatment-related adverse events, and 3% discontinued treatment for this reason.

In the second cohort, after median follow-up of 14 months (range, 2 to 24 months), researchers reported a confirmed ORR of 60% (95% CI, 39-79) overall, 73% (95% CI, 45-92) among those with PD-L1-positive disease, and 38% (95%, 9-76) in those with PD-L1-negative disease.

In the third cohort, researchers reported an ORR of 26% (95% CI, 12-45).

Researchers reported median PFS of 2 months (95% CI, 2-2) in the first cohort, 7 months (95%, 6-11) in the second cohort, and 3 months (95% CI, 2-6) in the third cohort.

Median OS was 6 months (95% CI, 4-7) in the first cohort, 14 months (95% CI, 9 to not estimable) in the second cohort, and not reached (95% CI, 9-21) in the third cohort.

Grade 3 to grade 5 treatment-related adverse events occurred in 46 patients (18%) in the first cohort, 19 patients (76%) in the second cohort, and seven patients (23%) in the third cohort.

Treatment-related adverse events prompted discontinuation among seven patients (3%) in the first cohort and three patients (12%) in the second cohort. They led to two deaths (1%) in the first cohort and one death (3%) in the third cohort.

Because of the efficacy and safety pembrolizumab demonstrated in patients with newly diagnosed metastatic disease who received combination therapy or monotherapy, a larger follow-up study has been established and enrollment is underway.

“We hope these results, in combination with evidence from ongoing randomized trials, will support the regulatory approval of pembrolizumab in metastatic gastric cancer,” Wainberg said.

No standard of care exists for third-line or later treatment of metastatic gastric cancer, Ian Chau, MD, consultant medical oncologist at Royal Marsden Hospital, said in an ESMO-issued press release.

“The KEYNOTE-059 cohort 1 results confirm that the efficacy previously reported for the PD-1 inhibitor nivolumab in patients from East Asia in the ONO-4538 randomized trial can be applied to Western populations,” Chau said. “The likelihood is that pembrolizumab will become a standard treatment option in this setting in the near future.”

However, even though pembrolizumab demonstrated a favorable toxicity profile in KEYNOTE-059, he emphasized that patients may not have been treated long enough to experience adverse effects.

“Unlike with chemotherapy, toxicities from immunotherapy tend to occur later on,” Chau said. “We need to await longer-term results from an ongoing clinical trial in an earlier line of treatment to know the full impact of this drug in metastatic gastric cancer.

“Further research should focus on refining the PD-L1 biomarker and searching for better biomarkers to tell us who benefits from these therapies,” Chau added. “We also need more information about quality of life which should be provided by ongoing studies.” – by Mark Leiser

Reference:

Wainberg L, et al. Abstract LBA28_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

Disclosures: Merck funded this study. Wainberg reports consultant roles with Genentech, Array BioPharma, Sirtex, Novartis and Five Prime Therapeutics. Other researchers report employment and advisory board roles with, honoraria from and travel expenses from Merck. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

MADRID — Pembrolizumab demonstrated promising activity in patients with pretreated recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma, according to results of the KEYNOTE-059 trial presented at the European Society for Medical Oncology Congress.

“The data shows that the tumors were sufficiently shrunk to warrant a response, particularly in those patients who had PD-L1 expression, and the drug was safe,” Zev A. Wainberg, MD, assistant professor of medicine at UCLA and co-director of the UCLA gastrointestinal oncology program, said in a press release. “The expected response rate in these heavily pretreated patients was close to zero, so the findings are encouraging.”

Most patients with metastatic gastric cancer survive less than 1 year, and treatment advances for this population have been limited over the past decade.

Prior results from the global, phase 2 KEYNOTE-059 study showed pembrolizumab (Keytruda, Merck), an anti-PD-1 antibody, demonstrated promising antitumor activity and a manageable safety profile alone or in combination with chemotherapy for patients with gastric or gastroesophageal junction cancers.

KEYNOTE-059 — one of the biggest to investigate an immunotherapy for patients with metastatic or recurrent gastric cancer — assessed pembrolizumab in three cohorts of patients with pretreated metastatic gastric cancer. Pembrolizumab was administered in 200-mg doses every 3 weeks for up to 2 years.

The first cohort consisted of 259 patients with metastatic disease who previously underwent two or more lines of chemotherapy. These patients received pembrolizumab monotherapy.

The second cohort included 25 patients with newly diagnosed metastatic disease. They received first-line pembrolizumab with chemotherapy, which consisted of cisplatin 80 mg/m2 on day 1 plus 5-FU 800 mg/m2 on days 1 to 5 every 3 weeks. Patients in Japan only received capecitabine 1000 mg/m2 twice daily.

The third cohort included 31 patients with newly diagnosed metastatic disease. They received pembrolizumab monotherapy as firstline treatment.

Safety in all three cohorts, as well as objective response rates in the first and third cohorts, served as primary endpoints. ORR in the second cohort, as well as duration of response, PFS and OS in all cohorts, served as key secondary endpoints.

In the first cohort, after median follow-up of 6 months (range, 1 to 25 months), objective response rate among pretreated patients who received pembrolizumab monotherapy was 12% (95% CI, 8-17). Many responses appeared durable, researchers wrote.

Patients whose tumors expressed PD-L1 appeared more than twice as likely to achieve objective response than those whose tumors did not express PD-L1 (16% vs. 6%).

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Eighteen patients experienced grade 3 to grade 5 treatment-related adverse events, and 3% discontinued treatment for this reason.

In the second cohort, after median follow-up of 14 months (range, 2 to 24 months), researchers reported a confirmed ORR of 60% (95% CI, 39-79) overall, 73% (95% CI, 45-92) among those with PD-L1-positive disease, and 38% (95%, 9-76) in those with PD-L1-negative disease.

In the third cohort, researchers reported an ORR of 26% (95% CI, 12-45).

Researchers reported median PFS of 2 months (95% CI, 2-2) in the first cohort, 7 months (95%, 6-11) in the second cohort, and 3 months (95% CI, 2-6) in the third cohort.

Median OS was 6 months (95% CI, 4-7) in the first cohort, 14 months (95% CI, 9 to not estimable) in the second cohort, and not reached (95% CI, 9-21) in the third cohort.

Grade 3 to grade 5 treatment-related adverse events occurred in 46 patients (18%) in the first cohort, 19 patients (76%) in the second cohort, and seven patients (23%) in the third cohort.

Treatment-related adverse events prompted discontinuation among seven patients (3%) in the first cohort and three patients (12%) in the second cohort. They led to two deaths (1%) in the first cohort and one death (3%) in the third cohort.

Because of the efficacy and safety pembrolizumab demonstrated in patients with newly diagnosed metastatic disease who received combination therapy or monotherapy, a larger follow-up study has been established and enrollment is underway.

“We hope these results, in combination with evidence from ongoing randomized trials, will support the regulatory approval of pembrolizumab in metastatic gastric cancer,” Wainberg said.

No standard of care exists for third-line or later treatment of metastatic gastric cancer, Ian Chau, MD, consultant medical oncologist at Royal Marsden Hospital, said in an ESMO-issued press release.

“The KEYNOTE-059 cohort 1 results confirm that the efficacy previously reported for the PD-1 inhibitor nivolumab in patients from East Asia in the ONO-4538 randomized trial can be applied to Western populations,” Chau said. “The likelihood is that pembrolizumab will become a standard treatment option in this setting in the near future.”

However, even though pembrolizumab demonstrated a favorable toxicity profile in KEYNOTE-059, he emphasized that patients may not have been treated long enough to experience adverse effects.

“Unlike with chemotherapy, toxicities from immunotherapy tend to occur later on,” Chau said. “We need to await longer-term results from an ongoing clinical trial in an earlier line of treatment to know the full impact of this drug in metastatic gastric cancer.

PAGE BREAK

“Further research should focus on refining the PD-L1 biomarker and searching for better biomarkers to tell us who benefits from these therapies,” Chau added. “We also need more information about quality of life which should be provided by ongoing studies.” – by Mark Leiser

Reference:

Wainberg L, et al. Abstract LBA28_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

Disclosures: Merck funded this study. Wainberg reports consultant roles with Genentech, Array BioPharma, Sirtex, Novartis and Five Prime Therapeutics. Other researchers report employment and advisory board roles with, honoraria from and travel expenses from Merck. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

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