Pembrolizumab

[12][23] In 2017, the US Food and Drug Administration approved pembrolizumab for any unresectable or metastatic solid tumor with certain genetic anomalies (mismatch repair deficiency or microsatellite instability).[30] Efficacy was evaluated in KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 participants with metastatic or locally advanced esophageal or gastroesophageal junction carcinoma who were not candidates for surgical resection or definitive chemoradiation.[30] In May 2021, the US FDA approved pembrolizumab in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of people with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.[32] In November 2021, the US FDA approved pembrolizumab for the adjuvant treatment of people twelve years of age and older with stage IIB or IIC melanoma following complete resection.[33] In November 2021, the US FDA approved pembrolizumab for the adjuvant treatment of renal cell carcinoma for people at intermediate-high or high risk of recurrence following nephrectomy.[34] Approval was based on KEYNOTE-564, a multicenter, randomized (1:1), double-blind, placebo-controlled trial in 994 patients with intermediate-high or high risk of recurrence of RCC, or M1 no evidence of disease.[36] In January 2023, the US FDA approved pembrolizumab for adjuvant treatment following resection and platinum-based chemotherapy for stage IB (T2a ≥ 4 cm), II, or IIIA non-small cell lung cancer.[38] In January 2024, the US FDA approved pembrolizumab, in combination with chemoradiotherapy for the treatment of people with FIGO (International Federation of Gynecology and Obstetrics) 2014 Stage III-IVA cervical cancer.[40] In September 2024, the FDA approved pembrolizumab with pemetrexed and platinum chemotherapy as first-line treatment of unresectable advanced or metastatic malignant pleural mesothelioma.[53] Merck at that time had little commitment or expertise in either oncology or immunotherapy, but understood the opportunity and reacted strongly, reactivating the program and filing its IND by the end of 2010.[53] Scientists at the company argued for developing a companion diagnostic and limiting testing of the drug only to patients with biomarkers showing they were likely to respond, and received agreement from management.[62][63][64] In July 2016, the US FDA accepted for priority review an application for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) after a platinum-based chemotherapy.[65] They granted accelerated approval to pembrolizumab as a treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma ("regardless of PD-L1 staining") following progression on a platinum-based chemotherapy, based on objective response rates (ORR) in the phase Ib KEYNOTE-012 study in August of the same year.[66][67] In October 2016, the US FDA approved pembrolizumab for the treatment of people with metastatic non-small cell lung cancer whose tumors express PD-L1 as determined by an FDA-approved test.[74] In August 2018, the US FDA updated the prescribing information for pembrolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.[77] In June 2019, the US FDA granted accelerated approval to pembrolizumab for those with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy,[72] and the FDA approved pembrolizumab for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).[78] The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with head and neck squamous cell carcinoma for treatment with pembrolizumab as a single agent.[78] In July 2019, the US FDA approved pembrolizumab for patients with recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥ 10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.[39] Efficacy was evaluated in KEYNOTE-A18 (NCT04221945), a multicenter, randomized, double-blind, placebo-controlled trial enrolling 1060 participants with cervical cancer who had not previously received definitive surgery, radiation, or systemic therapy.