Keytruda (pembrolizumab) and Opdivo (nivolumab) are monoclonal antibodies that disrupt the PD-1 (Opdivo) / PD-L1 (Keytruda) pathway; they are approved by the FDA for the treatment of patients with unresectable melanoma, as well as other cancers including non-small cell lung cancer (NSCLC), head and neck cancer, renal cell carcinoma (Opdivo), and Hodg kin lymphoma (Opdivo). Keytruda is limited to patients with NSCLC with a tumor proportion score (TPS) of greater than 50% for PD-L1 staining.
Does PD-L1 expression matter in lung cancer?
In NSCLC patients that failed following prior chemotherapy, Keytruda has superior overall survival compared to chemotherapy -10.4 months (Keytruda 2 mg/kg every 3 weeks) versus 8.5 months (p < 0.001) and 12.7 months (10 mg/kg every 3 weeks) versus 8.5 months (p < 0.001). The subgroup of patients with a TPS > 50% had a better survival than with chemotherapy – 14.9 months (Keytruda 2 mg/kg every 3 weeks) versus 8.2 months (p < 0.001) and 17.3 months (10 mg/kg every 3 weeks) versus 8.2 months (p < 0.001).
Patients receiving Opdivo had superior overall survival compared to patients treated with chemotherapy – 12.2 months versus 9.4 months (p = 0.0015). PD-L1 expression was not evaluated. The results with Opdivo were in line with the response seen in all patients treated with Keytruda, not just those with a TPS of greater than 50%.
Does PD-L1 expression matter in melanoma?
In the KEYNOYE-001 trial, patients with unresectable melanoma who had higher PD-L1 expression (as assessed using the MEL Score) had better responses to Keytruda than patients whose tumors did not express PD-L1. However, even patients with melanomas that did not express PD-L1 showed some benefit.
Between December 2011 and September 2013, 655 patients with advanced melanoma were enrolled in KEYNOTE-001. Among these 655 patients, biopsy samples from 451 patients that were collected in the 60 days before the first dose of pembrolizumab was administered were evaluable for PD-L1 expression. Of 451 evaluable patients, 344 (76%) had PD-L1–positive tumors and 107 (24%) had PD-L1–negative tumors. The pattern of change in tumor size compared with baseline seemed to vary by MEL score. Among evaluable patients at week 12, 35%, 38%, 57%, 78%, 84%, and 86% showed reductions from baseline tumor measurements for MEL scores 0 to 5, respectively. Of note, patients with MEL scores of 4 or 5, 33% and 22%, respectively, showed a reduction of ≥ 50% at week 12. Qualitatively, patients with MEL scores of 0 or 1 were less likely to have a decrease from baseline tumor size overall, whereas more patients with MEL scores of 2 to 5 had a 100% decrease from baseline.
The authors concluded that:
Given the data described here, PD-L1 expression is correlated with clinical outcome in patients with advanced melanoma. Whereas there is some uncertainty regarding the optimal level of PD-L1 expression, a level that corresponds to MEL scores of 3 to 5 seems to best capture the population that is most highly responsive to PD-1 blockade. Conversely, MEL scores of 0 or 1 represents the least responsive population, and a MEL score of 2, which represents the largest proportion of patients (29%), seems to be intermediate, with many patients experiencing a response to therapy. Furthermore, tumors with the highest levels of PD-L1 staining exhibited deeper responses (33% and 22% of patients showed reductions of ≥ 50% at week 12 with MEL scores of 4 and 5, respectively).
Important questions remain regarding the relationship between PD-L1 expression and the therapeutic effects of anti–PD-1 and anti–PD-L1 antibodies. It is clear that even with a MEL score of 0 in the assay used in this study, durable responses were still observed; response rates were even higher in the other MEL score groups. The high prevalence of PD-L1 positivity observed in this study, along with the durable responses observed in PD-L1–negative tumors, suggest that pembrolizumab treatment should not be limited to patients with PD-L1–positive tumors. Ongoing clinical trials with correlative studies will further delineate the role of PD-L1 expression in melanoma.