Relationship between PD-L1 expression and clinical outcomes in patients (Pts) with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012.

Abstract

3 Background: Tumors use the PD-1 pathway to evade immune surveillance. Pembrolizumab, an anti-PD-1 monoclonal antibody, has shown antitumor activity in advanced cancers. We assessed the safety and efficacy of pembrolizumab in patients with advanced gastric cancer in KEYNOTE-012 (Clinicaltrials.gov identifier NCT01848834). Methods: Archival tumor samples from patients from Asia-Pacific (AP) and rest of the world (ROW) with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction were screened for PD-L1 expression using a prototype IHC assay with the 22C3 antibody. Only patients with distinctive stromal or ≥1% tumor nest cell PD-L1 staining were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until complete response, progression, or unacceptable toxicity. Imaging was performed every 8 weeks. Primary efficacy end point is ORR assessed per RECIST v1.1 by independent central review. Secondary end points include duration of response, PFS, and OS. Results: Of the 162 patientts screened, 65 (40%) were PD-L1+. Of these 65 patients, 39 enrolled (19 from AP, 20 from ROW; median age, 63 years [range 33-78]). The number of prior therapies for advanced disease ranged from 0 to 5; 67% received ≥2 prior therapies. Median follow-up duration was 8.8 months (range 6.2-12.6); 13 patients (33%) remain on therapy. Four patients experienced 5 total grade 3-5 drug-related adverse events: peripheral sensory neuropathy, fatigue, decreased appetite, hypoxia, and pneumonitis (n = 1 each). There was 1 drug-related death (hypoxia). ORR was 22% (95% CI 10-39) by central review and 33% (95% CI 19-50) by investigator review. Median time to response was 8 weeks (range 7-16), with a median response duration of 24 weeks (range 8+ to 33+). PD-L1 expression level was associated with ORR (1-sided P = 0.10). The 6-month PFS rate was 24%. The 6-month OS rate was 69%. Conclusions: Pembrolizumab demonstrated manageable toxicity and promising antitumor activity in advanced gastric cancer. These results support the ongoing development of pembrolizumab for gastric cancer. Clinical trial information: NCT01848834.

Mismatch repair deficiency may affect clinical outcome through immune response activation in metastatic gastric cancer patients receiving first-line chemotherapy

“…A possible role for immunotherapy has been shown also in the treatment of gastric cancer patients, not assessed according to a specific clinical or molecular profile [9]. On the other hand, the influence of MMR gene status on treatment outcome during chemotherapy [10][11][12][13] and the potential connection with indirect signs of immune reaction are still lacking in the published literature.…”

Family History of Cancer as Surrogate Predictor for Immunotherapy with Anti-Pd1/Pd-L1 Agents: Preliminary Report of the Fami-L1 Study

“…Common clinical practice and health economics still suffer a lack of validated predictive biomarkers to select patients who would benefit from ICIs. PD-L1 protein expression, evaluated by immunohistochemistry staining, both in tumor and immune cells, has been investigated as a potential predictive biomarker [1], even in prospective trials [2], but its correlation with ICIs efficacy is still debated [3][4][5]. Different companion diagnostics, with different immunohistochemistry techniques and platforms were used in clinical trials, creating difficulties in routine use in clinical practice, despite the efforts of many 'harmonization' studies [6][7][8][9].…”

Novel therapy for advanced gastric cancer

“…PD-L1+ was used as the biomarker with 65 out of 162 (40%) screened patient being positive, and 39 patients enrolled eventually. ORR was 22% by central review and 33% by investigator review [34] . Median time to response was 8 wk with a median response duration of 24 wk.…”