Merck to Withdraw Indication for Pembrolizumab in Third Line Gastric Cancer

The accelerated approval indication for pembrolizumab (Keytruda) in patients with gastric cancer in the third-line setting will be voluntarily withdrawn by Merck, the pharmaceutical company responsible for the agent, according to a press release.¹

The accelerated approval was aimed towards patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors expressed PD-L1 as determined by an FDA-approved test and had disease progression on or after 2 or more prior lines of therapy.

“While there remains an unmet need for heavily pre-treated patients with advanced gastric cancer, we recognize that the treatment landscape has evolved and we respect the FDA’s efforts to continually evaluate accelerated approvals,” Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, said in a press release. “Our research with [pembrolizumab] has contributed to recent advances in the treatment of gastric cancer, and we are continuing to advance studies to help more patients with this disease.”

The decision was made following a consultation with an FDA Oncologic Drugs Advisory Committee evaluation of the agent in the third-line setting. The indication’s withdrawal is planned to occur in 6 months, although this will not affect other indications for pembrolizumab.

The first phase 3 trial leading to action was the KEYNOTE-061 trial (NCT02370498) investigating pembrolizumab monotherapy in the second-line setting for patients with advanced gastric or GEJ adenocarcinoma (n = 592). The KEYNOTE-061 trial failed to meet its primary end point of overall survival (OS; HR, 0.82; 95% CI, 0.66-1.03; P = .042).²

Additionally, the phase 3 KEYNOTE-062 trial (NCT02494583) investigated pembrolizumab both as monotherapy and in combination with chemotherapy in the first line in a similar cohort of patients as KEYNOTE-061. While pembrolizumab monotherapy met its primary end point of OS noninferiority in the intent-to-treat population, the combination therapy was not superior for OS.³

The safety profile across both studies of pembrolizumab in patients with advanced gastric or GEJ adenocarcinoma was consistent with previously observed data in gastric cancer.

While Merck is expected to withdraw this approval for pembrolizumab, several other indications remain to treat gastric cancers. Pembrolizumab is approved in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy to treat patients locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma in the first-line setting.

Pembrolizumab monotherapy has been given an accelerated approval to treat adult and pediatric patients with unresectable or metastatic microsatellite instability–high or mismatch repair deficient solid tumors who progressed on prior therapy, as well as for adult and pediatric patients with unresectable or metastatic tumor mutational burden–high solid tumors who progressed on prior therapy.

The PD-1 therapy, pembrolizumab, increases the immune system’s ability to locate and combat tumor cells. Pembrolizumab blocks the interaction between PD-1 and its ligands, which activates T lymphocytes and may impact both healthy and cancerous cells.

Pembrolizumab was previously approved in September 2017 for patients with previously treated, recurrent, locally advanced or metastatic gastric or GEJ cancer with PD-L1–expressing tumors.⁴ Moreover, the single agent was also granted an accelerated approval on the same day for patients with recurrent locally advanced or metastatic gastric and GEJ adenocarcinoma with PD-L1–expressing tumors. The approval was based on the phase 2 KEYNOTE-059 (NCT02335411) trial in which pembrolizumab demonstrated an objective response rate of 13.3%. In total, 58% of patients had a duration of response (DOR) of 6 months or longer and 26% had a DOR of 12 months or longer.⁵

Reference

1. Merck Provides Update on KEYTRUDA (pembrolizumab) Indication in Third-Line Gastric Cancer in the US. News release. Merck. Published July 1, 2021. Accessed July 6, 2021. https://tinyurl.com/7ytmpa77
2. Merck Provides Update on KEYNOTE-061, a Phase 3 Study of KEYTRUDA® (pembrolizumab) in Previously Treated Patients with Gastric or Gastroesophageal Junction Adenocarcinoma. News release. Merck. Published December 14, 2017. Accessed July 6, 2021. https://tinyurl.com/hx5hufrz
3. Merck Provides Update on Phase 3 KEYNOTE-062 Trial Evaluating KEYTRUDA® (pembrolizumab) as Monotherapy and in Combination with Chemotherapy for First-Line Treatment of Patients with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma. News release. Merck. Published April 25, 2019. Accessed July 6, 2021. https://tinyurl.com/49wxueye
4. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for Previously Treated Patients with Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer Whose Tumors Express PD-L1 (CPS Greater Than or Equal to 1). News release. Merck. September 22, 2017. Accessed July 6, 2021. https://bit.ly/3xllps4
5. FDA grants accelerated approval to pembrolizumab for advanced gastric cancer. News release. FDA. September 22, 2017. Accessed July 6, 2021. https://bit.ly/3hgWq3n