The FDA approved pembrolizumab on June 16, 2020, for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden–high [TMB-H; ≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. FDA granted the approval based on a clinically important overall response rate (29%; 95% confidence interval, 21–39) and duration of response (57% of responses lasting ≥ 12 months) in the subset of patients with TMB-H solid tumors (n = 102) spanning nine different tumor types enrolled in a multicenter single-arm trial (KEYNOTE-158). The efficacy of pembrolizumab was supported by the results of whole-exome sequencing (WES) analyses of TMB in additional patients enrolled across multiple pembrolizumab clinical trials, and a scientific understanding of the effects of PD-1 inhibition. Overall, the adverse event profile of pembrolizumab was similar to the adverse event profile observed in prior trials that supported the approval of pembrolizumab in other indications. This approval of pembrolizumab is the first time that the FDA has approved a cancer treatment for an indication based on TMB, and the fourth based on the presence of a biomarker rather than the primary site of origin.

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.

10009 Background: Older adults are a growing segment of our oncology population, with an expected increase in cancer incidence of 67% from 2010 to 2030 in people age 65 and older. However, older adults have been proportionally underrepresented in clinical trials. We sought to analyze the age-related enrollment of cancer patients onto trials supporting registration of new drugs or new indications approved by the US Food and Drug Administration from 2005 to 2015. Methods: This study involved retrospective analyses of demographic data of cancer patients enrolled onto trials supporting registration from 2005-2015. The data on 224,766 cancer patients supporting 105 drug applications were analyzed according to age distributions of <65, 65-69, 70-74, 75-79, and ≥80 years. The rates of enrollment were compared with the corresponding rates in the US cancer population. The age distributions of the US cancer population were derived from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute for the year 2013 based on the 2010 US Census. Conclusions: Older adults were under-represented in the registration trials of new cancer therapies, especially those over age 75. Various strategies may be needed to evaluate cancer therapies for older adults in prospective clinical trials and to improve cancer care in adults over age 75. These include re-evaluating what may be considered restrictive eligibility criteria so as not to exclude older adults. Incorporating elements from geriatric assessment tools may help identify older adults most likely to benefit from treatment. More detailed labeling information that reflects the clinical experience with older adults could be considered. The FDA encourages drug sponsors as well as clinical trial cooperative groups to devise strategies to recruit patients that are reflective of their intended population. [Table: see text]

On May 29, 2020, the FDA approved atezolizumab for use in combination with bevacizumab, for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) with no prior systemic treatment. The approval was based on data from Study IMbrave150, which randomly allocated (2:1) patients to receive either atezolizumab plus bevacizumab (atezolizumab-bevacizumab) or sorafenib. Overall survival (OS) and independently assessed progression-free survival (PFS) in the intent-to-treat population were the primary endpoints. At the time of the primary analysis, the estimated median OS could not be estimated in the atezolizumab-bevacizumab arm and was 13.2 months in the sorafenib arm [HR, 0.58; 95% confidence interval (CI), 0.42–0.79]. The estimated median PFS was 6.8 months (95% CI, 5.8–8.3) and 4.3 months (95% CI, 4.0–5.6) in the atezolizumab-bevacizumab and sorafenib arms, respectively. Adverse reactions occurring in &gt;20% of patients receiving atezolizumab-bevacizumab were hypertension, fatigue/asthenia, and proteinuria. Adverse reactions occurring in &gt;20% of patients receiving sorafenib were palmar-plantar erythrodysesthesia, diarrhea, hypertension, and decreased appetite. Hemorrhage was reported more frequently in patients receiving atezolizumab-bevacizumab (25%) than in patients receiving sorafenib (17%). An evaluation for the presence of varices is recommended within 6 months of initiation of atezolizumab-bevacizumab in patients with HCC. Approval of atezolizumab-bevacizumab is likely to change the treatment paradigm for HCC, given that treatment with atezolizumab-bevacizumab resulted in improved OS and PFS compared with sorafenib, an accepted standard of care for first-line treatment of patients with unresectable HCC. See related commentary by Castet et al., p. 1827