Pembro Noninferior, Less Toxic Than Chemo in Gastric Cancer

Roxanne Nelson, RN, BSN

June 01, 2019

CHICAGO — Pembrolizumab (Keytruda, Merck) could be an alternative treatment option for patients with advanced gastric or gastroesophageal junction G/GEJ) cancer, according to new findings.

As compared with standard chemotherapy, front-line treatment with pembrolizumab was noninferior for overall survival.

There was also a clinically meaningful survival benefit among patients with high PD-L1 expression. In that subset, 2-year overall survival was 39% as compared with 22% of patients who received standard chemotherapy.

Josep Tabernero, MD, PhD

"Patients with advanced gastric or gastroesophageal junction have a very poor prognosis," said lead study author Josep Tabernero, MD, PhD, head of the medical oncology department and the Institute of Oncology at Vall d'Hebron University Hospital, Barcelona, Spain. "There remains a significant unmet need for treatments for these cancers and our results reinforce the importance of continued research in this field."

Tabernero presented the results of the study at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.

The current guidelines for gastric and GEJ recommend treatment with platinum plus fluoropyrimidine in the first-line setting, while second-line recommendations include docetaxel, paclitaxel, irinotecan, and ramucirumab with or without paclitaxel.

However, pembrolizumab may also now have a role in this setting.

"Pembrolizumab has shown antitumor activity and manageable safety in patients with advanced gastric and gastroesophageal junction cancer, with a PD-L1 combined positive score of more than one," Tabernero said.

Pembrolizumab received approval from the US Food and Drug Administration in 2017 for treatment of G/GEJ cancer, becoming the first immunotherapy approved in the United States for gastric cancer.

In findings presented earlier this year and reported by Medscape Medical News at that time, pembrolizumab was also superior to standard chemotherapy in improving overall survival for patients with advanced esophageal cancer who had high levels PD-L1.

High Expression, Better Response

The KEYNOTE-062 is a phase III randomized clinical trial that enrolled 763 patients with advanced gastric cancer who were randomly assigned 1:1:1 to three treatment arms: pembrolizumab 200 mg Q3W for up to 2 years, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2 + 5-FU 800 mg/m2/d on d1-d5 Q3W [or capecitabine 1000 mg/m2 BID on d1-d14 Q3W per local guideline]), or placebo Q3W plus chemotherapy. Randomization was stratified by region, disease status, and fluoropyrimidine treatment.

Patients all had a PD-L1 CPS of one or greater, and 281 (37% of the enrollees) had a score of 10 or more. In addition, all patients were HER2 negative.

The study's primary endpoints were overall survival in patients with CPS ≥ 1 and CPS ≥ 10 for the cohorts using pembrolizumab as compared with chemotherapy alone, and progression free survival for CPS ≥ 1 in the pembrolizumab plus chemotherapy cohort vs chemotherapy alone.

The secondary endpoints were overall response rate (ORR) for CPS ≥ 1 patients in the pembrolizumab plus chemotherapy cohort vs chemotherapy alone, and safety.

Among patients with CPS ≥1, overall survival with pembrolizumab was noninferior to chemotherapy (hazard ratio [HR], 0.91), with a median overall survival of 10.6 months for pembrolizumab vs 11.1 months for the chemotherapy arm.

However, for those with CPS ≥10, survival was superior with pembrolizumab. The median overall survival was 17.4 months for pembrolizumab vs 10.8 months for the chemotherapy group (HR, 0.69).

Combining pembrolizumab with chemotherapy did not improve outcomes as compared with chemotherapy alone. Overall survival and progression-free survival were comparable to that of chemotherapy alone, regardless of CPS score, although there was a favorable trend for the combination. The ORR was higher for pembrolizumab plus chemotherapy vs chemotherapy alone.

Serious adverse events were the lowest among patients who were treated with pembrolizumab alone. "Patients who received pembrolizumab had less adverse events and less grade 3-5 events," said Tabernero. "And fewer patients discontinued therapy due to adverse events."

Grade 3 or higher events occurred in 17% of the pembrolizumab group, 73% of those receiving pembrolizumab and chemotherapy, and 69% treated with chemotherapy alone.

The most common adverse events were nausea and fatigue, and immune-mediated and infusion reactions occurred in 21% of patients receiving pembrolizumab and were primarily grade 1. The safety profile of pembrolizumab was consistent with previous reports.

Practice Changing

"Patients now may have the option of an immunotherapy as a topline agent," commented Nicholas Rohs, MD, assistant professor of medicine, hematology, and medical oncology at Icahn School of Medicine’s The Tisch Cancer Institute at Mount Sinai Health System in New York City. "This is really exciting, to be able to spare patients a lot of toxicity."

"I believe that this is practice changing for patients with a high CPS expression," said Rohs, who was approached by Medscape Medical News for an independent comment.

At his institution, all patients with gastric cancers undergo molecular profiling, which should be standard practice, he explained. "It may not be a standard test in smaller community centers, but these data underscore its importance."

As for which patients should receive pembrolizumab going forward, Rohs emphasized that "it is definitely the right choice for CPS 10 or higher because it improved overall survival, but for lower CPS, 1% or greater, it is not inferior but significantly less toxic."

He noted that there is probably a patient subset who are going to have a very durable, long-lasting response. "But as they were only followed for a year or so, it will be interesting to see the mature data," said Rohs. "The next step is to really identify that subset of patients with specific biomarkers and high CPS, so we can really predict who will have the best response."

Richard L. Schilsky, MD, FACP, FSCT, FASCO, senior vice president and chief medical officer of ASCO, reiterated that G/GEJ cancer is a "tough disease to treat," and until recently the only treatment has been standard cytotoxic chemotherapy, which is difficult for many patients to tolerate.

"This study, demonstrating the potential of immunotherapy to substantially improve outcomes is really important," he said. "It is quite clear that pembrolizumab is superior to chemotherapy in the high biomarker category, and pembrolizumab should replace chemotherapy — in many cases — as first-line therapy in this population."

This study received funding from Merck & Co Inc. Tabernero disclosed consulting or advisory roles with Bayer, Boehringer Ingelheim, Lilly, MSD, Merck Serono, Novartis, Sanofi, Taiho Pharmaceutical, Merrimack, Peptomyc, Rafael Pharmaceuticals, Symphogen, Chugai Pharma, Ipsen, Merus, Pfizer, Seattle Genetics, Array BioPharma, AstraZeneca, BeiGene, Genentech, Genmab, Halozyme, Imugene, Inflection Biosciences, Kura, Menarini, Molecular Partners, Pharmacyclics, ProteoDesign, Roche, Servier, VCN Biosciences, Biocartis, Foundation Medicine, HalioDx and Roche Diagnostics. Several coauthors have also disclosed relationships with industry, as noted in the abstract. Rohs has disclosed no relevant financial relationships.

2019 American Society of Clinical Oncology (ASCO) Annual Meeting: Abstract LBA4007. Presented June 2, 2019.

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