FDA Approval Summary: Pembrolizumab for Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Expressing PD-L1

Abstract

On September 22, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab (Keytruda, Merck & Co., Inc., Whitehouse Station, NJ) for the treatment of patients with recurrent, locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after two or more systemic therapies, including fluoropyrimidine-and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDAapproved test. Approval was based on demonstration of durable overall response rate (ORR) in a multicenter, openlabel, multicohort trial (KEYNOTE-059/Cohort 1) that enrolled 259 patients with locally advanced or metastatic gastric or GEJ adenocarcinoma. Among the 55% (n = 143) of patients whose tumors expressed PD-L1 based on a combined positive score ≥1 and either were microsatellite stable or had undetermined microsatellite instability or mismatch repair status, the confirmed ORR as determined by blinded independent central review was 13.3% (95% CI, 8.2-20.0); 1.4% had complete responses. Response durations ranged from 2.8+ to 19.4+ months; 11 patients (58%) had response durations of 6 months or longer, and 5 patients (26%) had response durations of 12 months or longer. The most common (≥20%) adverse reactions of pembrolizumab observed in KEYNOTE-059/Cohort 1 were fatigue, decreased appetite, nausea, and constipation. The most frequent (≥2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Pembrolizumab was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx test (Dako, Agilent, Santa Clara, CA) for selection of patients with gastric cancer for treatment with pembrolizumab based on PD-L1 tumor expression. The Oncologist 2018;23:1-7Implications for Practice: This report presents key information on the basis for Food and Drug Administration approval of pembrolizumab for the treatment of patients with locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1. The report discusses the basis for limiting the indication to patients with PD-L1-expressing tumors and the basis for recommending that PD-L1 status be assessed using a fresh tumor specimen if PD-L1 expression is not detected in an archival gastric or GEJ cancer specimen.

Tumor immune response and immunotherapy in gastric cancer

“…More recently, immune checkpoint inhibitors have emerged as among the most advanced therapeutic options available for patients with advanced GC [46]. Pembrolizumab is a selective, humanized, high-affinity IgG4 kappa monoclonal antibody that binds to PD-1, blocking its interaction with PD-L1 and 2 [45,47]. The FDA approved pembrolizumab in May 2017 for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that progressed even after prior treatment and who have no other optimal treatment choices [48].…”

“…The duration of response was relatively long, ranging from 2.8 + to 19.4 + months. Based on these results, the FDA granted approval with acceleration for pembrolizumab to treat patients with recurrent, locally advanced or metastatic G/GEJ adenocarcinoma with disease progression on or after two or more standard systemic therapies and if tumors express PD-L1, as determined by an FDA-approved test (PD-L1 IHC 22C3 pharmDx test, Dako, Agilent, Santa Clara, CA, USA) [47]. In the phase 3 KEYNOTE-061 trial, pembrolizumab did not demonstrate significant improvement in overall survival (OS) compared to paclitaxel as second-line therapy for advanced G/GEJ cancer with PD-L1 CPS ≥ 1 [51].…”

Immunotherapy: New Options in Gastrointestinal Cancers?

“…Currently, PD-L1 expression (combined positivity score ≥1) represents a prerequisite for the use of pembrolizumab in pretreated (2 or more lines) gastric and gastroesophageal junction (GEJ) cancer patients according to the approval by the FDA in the US [2]; however, such treatment has not yet been approved in Europe. Moreover, a combined positive score (CPS) of > 10 was successfully applied in the Keynote 181 (press release Merck Nov. 14, 2018) and 180 [3] trials, in patients with both adenocarcinomas and squamous cell carcinomas (SCCs) of the esophagus for second- or third-line pembrolizumab treatment, respectively.…”

Oral immune‐related adverse events associated with PD‐1 inhibitor therapy: A case series

“…The use of such agents has resulted in prolonged disease‐free remission and overall survival in malignancies that were previously fatal (Freeman et al, ; Hanahan & Weinberg, ; Iwai et al, ). To date, PD‐1 inhibitors have been approved for the treatment of advanced and refractory cancers including melanoma, non‐small‐cell lung cancer, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, urothelial cancer, cervical cancer, and gastric cancer; their use is expected to continue to increase with additional approvals (Chen et al, ; Chung et al, ; Fashoyin‐Aje et al, ; Finkelmeier, Waidmann, & Trojan, ; Hauschild & Schadendorf, ; Hodi et al, ; Larkins et al, ; Printz, ; Suzman et al, ).…”

“…To date, PD-1 inhibitors have been approved for the treatment of advanced and refractory cancers including melanoma, non-smallcell lung cancer, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, urothelial cancer, cervical cancer, and gastric cancer; their use is expected to continue to increase with additional approvals Chung et al, 2019;Fashoyin-Aje et al, 2019;Finkelmeier, Waidmann, & Trojan, 2018;Hauschild & Schadendorf, 2016;Hodi et al, 2010;Larkins et al, 2017;Printz, 2017;Suzman et al, 2018).…”