Pembrolizumab FDA approvals

Four New Indications Approved for Pembrolizumab in May

In May, the US Food and Drug Administration (FDA) granted four new indications to the programmed death receptor-1 (PD-1) inhibitor pembrolizumab (Keytruda®, Merck). These new indications included first-line treatment of nonsquamous non-small cell lung cancer (NSCLC) in combination with chemotherapy, second-line treatment of advanced urothelial cancer, first-line treatment of urothelial cancer in cisplatin-ineligible patients, and second-line treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. Pembrolizumab has previously been approved for the treatment of metastatic melanoma, advanced NSCLC (first-line for programmed death-ligand 1 [PD-L1] high and second-line for PD-L1 expression ≥1%), recurrent or metastatic squamous cell carcinoma of the head and neck, and refractory classical Hodgkin lymphoma.

  • On 10 May, the FDA granted accelerated approval to pembrolizumab in combination with pemetrexed and carboplatin for first-line treatment of advanced nonsquamous NSCLC. This is the first approval of an immune checkpoint inhibitor in combination with chemotherapy. Approval is based on cohort G of the phase II Keynote-021 trial, where the pembrolizumab combination resulted in improvements in both objective response rate (ORR; 55% vs 29%; P =. 0032) and progression-free survival (PFS; 13.0 months vs 8.9 months; HR 0.53, P = .0205) compared to chemotherapy in patients with previously untreated advanced nonsquamous NSCLC. Improvements in ORR were seen regardless of the level of PD-L1 expression, and pembrolizumab in combination with pemetrexed and carboplatin is approved for use regardless of PD-L1 expression. Combination therapy was associate with higher incidence of severe adverse events (AEs) compared to the chemotherapy arm (41% vs 28%) and pembrolizumab was discontinued due to AEs in 10% of patients.
  • On 18 May, pembrolizumab received full approval for treatment of patients with advanced urothelial cancer who have experienced disease progression during or following platinum-containing chemotherapy. This approval was based on results from the Keynote-045 study, in which treatment with pembrolizumab (regardless of PD-L1 expression) was associated with an almost 3 month improvement in overall survival (OS) compared to chemotherapy (10.3 months vs 7.4 months; HR 0.73, P = .004). Median ORR was 21% with pembrolizumab and 11% with chemotherapy (P = .002). Importantly, patients receiving pembrolizumab have a lower rate of treatment-related adverse events than with chemotherapy. The safety profile of pembrolizumab was consistent with other indications. There are currently four other immunotherapies approved for the second-line treatment of advanced urothelial cancer: avelumab, atezolizumab, durvalumab, and nivolumab; however, pembrolizumab is the only one to demonstrate an OS benefit in this setting.

In addition, pembrolizumab was granted accelerated approval for use as a first-line treatment for patients with advanced urothelial cancer who are ineligible for cisplatin-containing chemotherapy. This indication is based on results from the single-arm Keynote-052 trial in which treatment with pembrolizumab in patients deemed to be ineligible for a front-line cisplatin-based regimen yielded an ORR of 28.6% with durable responses.

  • On 23 May, pembrolizumab received accelerated approval for adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and those patients with MSI-H or dMMR colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This represents the first time that the FDA has granted approval to a cancer treatment based on a biomarker rather than primary tumor site origin. Approval was based on results in 149 patients with MSI-H or dMMR tumors across five trials, including 90 patients with CRC. ORR was 39.6%, including 11 complete responses and 48 partial responses. Responses lasted for 6 months or more. ORR was similar across all examined tumor types. AEs were consistent with other studies. Importantly, pembrolizumab carries a warning stating that safety and efficacy in pediatric patients with MSI-H central nervous system tumors have not been evaluated.



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