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FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy.

ABSTRACT: The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). The primary endpoint, confirmed objective response rate, was 23.5% (95% confidence interval [CI]: 16.2%-32.2%) in patients receiving atezolizumab and 28.6% (95% CI: 24.1%-33.5%) in patients receiving pembrolizumab. The median duration of response was not reached in either study and responses were seen regardless of PD-L1 status. The safety profiles of both drugs were generally consistent with approved agents targeting PD-1/PD-L1. Two ongoing trials (IMvigor130 and KEYNOTE-361) are verifying benefit of these drugs. Based on concerning preliminary reports from these trials, FDA revised the indications for both agents in cisplatin-ineligible patients. Both drugs are now indicated for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors/infiltrating immune cells express a high level of PD-L1. The indications for atezolizumab and pembrolizumab in patients who have received prior platinum-based therapy have not been changed. This article summarizes the FDA thought process and data supporting the accelerated approval of both agents and the subsequent revision of the indications. IMPLICATIONS FOR PRACTICE: The accelerated approvals of atezolizumab and pembrolizumab for cisplatin-ineligible patients with advanced urothelial carcinoma represent the first approved therapies for this patient population. These approvals were based on single-arm trials demonstrating reasonable objective response rates and favorable durations of response with an acceptable toxicity profile compared with available non-cisplatin-containing chemotherapy regimens. However, based on concerning preliminary reports from two ongoing phase III trials, the FDA revised the indication for both agents in cisplatin-ineligible patients. Both are now indicated either for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors have high expression of PD-L1.

SUBMITTER: Suzman DL

PROVIDER: S-EPMC6459239 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy.

Suzman Daniel L DL Agrawal Sundeep S Ning Yang-Min YM Maher V Ellen VE Fernandes Laura L LL Karuri Stella S Tang Shenghui S Sridhara Rajeshwari R Schroeder Jason J Goldberg Kirsten B KB Ibrahim Amna A McKee Amy E AE Pazdur Richard R Beaver Julia A JA

The oncologist 20181212 4

The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). The primary endpoint, confirmed objective response r ...[more]

PMID: 30541754

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Project description:Until recently in the United States, no products were approved for second-line treatment of advanced urothelial carcinoma. On May 18, 2016, the U.S. Food and Drug Administration approved atezolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody and represents the first approved product directed against PD-L1. This accelerated approval was based on results of a single-arm trial in 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression after prior platinum-containing chemotherapy. Patients received atezolizumab 1,200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. Key efficacy measures were objective response rate (ORR), as assessed by Independent Review per RECIST 1.1, and duration of response (DoR). With a median follow-up of 14.4 months, confirmed ORR was 14.8% (95% CI: 11.1, 19.3) in all treated patients. Median DoR was not reached and response durations ranged from 2.1+ to 13.8+ months. Of the 46 responders, 37 patients had an ongoing response for ≥ 6 months. The most common adverse reactions (≥20%) were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation. Infection and immune-related adverse events also occurred, including pneumonitis, hepatitis, colitis, endocrine disorders, and rashes. Overall, the benefit-risk assessment was favorable to support accelerated approval. The observed clinical benefits need to be verified in confirmatory trial(s).Implications for practiceThis accelerated approval of atezolizumab for second-line use in advanced urothelial carcinoma provides patients with an effective, novel treatment option for the management of their disease. This represents the first immunotherapy approved in this disease setting.

Project description:On August 5, 2016, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA injection, Merck Sharp & Dohme Corp., Kenilworth, NJ) for treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. Approval was based on the objective response rate (ORR) and duration of response (DoR) in a cohort of patients in a nonrandomized multi-cohort trial (KEYNOTE-012) that included 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy. Patients received either intravenous pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks. ORR was determined by independent review according to Response Evaluation Criteria in Solid Tumors 1.1. ORR was 16% (95% confidence interval 11, 22) with a complete response rate of 5%. DoR ranged from 2.4+ months to 27.7+ months. Twenty-three of 28 responding patients (82%) had response durations of ≥6 months. Safety was evaluated in 192 patients with HNSCC receiving at least one dose of pembrolizumab. Frequent (≥2%) serious adverse reactions were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus, skin toxicity, myositis, and thyroid disorders. The benefit-risk profile of pembrolizumab was considered acceptable in this patient population. As a condition of accelerated approval, Merck is required to conduct a confirmatory trial; this trial, KEYNOTE-040, is ongoing. IMPLICATIONS FOR PRACTICE:This accelerated approval expands the U.S. Food and Drug Administration-approved indications for pembrolizumab, providing health care providers with new information regarding pembrolizumab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. Pembrolizumab is the first drug to receive approval for treatment of patients with HNSCC since cetuximab was approved for this indication in 2006.

Project description:On October 24, 2016, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda; Merck & Co., Inc., https://www.merck.com) for treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test, as follows: (a) first-line treatment of patients with mNSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS] ?50%), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, and (b) treatment of patients with mNSCLC whose tumors express PD-L1 (TPS ?1%), with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.Approval was based on two randomized, open-label, active-controlled trials demonstrating statistically significant improvements in progression-free survival (PFS) and overall survival (OS) for patients randomized to pembrolizumab compared with chemotherapy. In KEYNOTE-024, patients with previously untreated mNSCLC who received pembrolizumab (200 mg intravenously [IV] every 3 weeks) had a statistically significant improvement in OS (hazard ratio [HR] 0.60; 95% confidence interval [CI]: 0.41-0.89; p?=?.005), and significant improvement in PFS (HR 0.50; 95% CI: 0.37-0.68; p?<?.001). In KEYNOTE-010, patients with disease progression on or after platinum-containing chemotherapy received pembrolizumab IV 2 mg/kg, 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The HR and p value for OS was 0.71 (95% CI: 0.58-0.88), p?<?.001 comparing pembrolizumab 2 mg/kg with chemotherapy and the HR and p value for OS was 0.61 (95% CI: 0.49-0.75), p?<?.001 comparing pembrolizumab 10 mg/kg with chemotherapy.This is the first U.S. Food and Drug Administration approval of a checkpoint inhibitor for first-line treatment of lung cancer. This approval expands the pembrolizumab indication in second-line treatment of lung cancer to include all patients with programmed death-ligand 1-expressing non-small cell lung cancer.

Project description: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 FDA-approved test. Approval was based on demonstration of durable overall response rate (ORR) in a multicenter, open-label, 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. IMPLICATIONS 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.

Project description:BackgroundIndoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC.MethodsECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1).ResultsA total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%).ConclusionsTreatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted.Trial registrationClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.

Dataset Information

FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy.

Publications

FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy.

Similar Datasets

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