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

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.

FDA Approval Summary: Nivolumab in Advanced Renal Cell Carcinoma After Anti-Angiogenic Therapy and Exploratory Predictive Biomarker Analysis.

On November 23, 2015, the U.S. Food and Drug Administration approved nivolumab (OPDIVO, Bristol-Myers Squibb Company) for patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. The approval was based on efficacy and safety data demonstrated in an open-label, randomized study of 821 patients with advanced RCC who progressed after at least one anti-angiogenic therapy. Patients were randomized to nivolumab or everolimus and followed for disease progression. The primary end point was overall survival. Subsequent therapies, including everolimus for patients who developed progressive disease on the nivolumab arm, were allowed, but no cross-over was permitted. The median overall survival was 25.0 months on the nivolumab arm and 19.6 months on everolimus arm (hazard ratio: 0.73; 95% confidence interval: 0.60-0.89). The confirmed response rates were 21.5% versus 3.9%; median durations of response were 23.0 versus 13.7 months, and median times to response were 3.0 versus 3.7 months in the nivolumab and everolimus arms, respectively. A statistically significant improvement in progression-free survival was not observed in this trial. The safety profile of nivolumab in renal cell cancer was similar to that in other disease settings. However, the incidence of immune-mediated nephritis appeared to be higher in patients with RCC. The Oncologist 2017;22:311-317 IMPLICATIONS FOR PRACTICE: The overall benefit/risk profile demonstrated in trial CA209025 supported the approval of nivolumab as an additional treatment option for patients with advanced renal cell carcinoma after anti-angiogenic therapy. The use of nivolumab in patients who had received vascular endothelial growth factor-targeted therapy resulted in a 5.4 month improvement in median overall survival compared with the everolimus arm. This difference is statistically significant and clinically meaningful.

FDA Approval Summary: Atezolizumab for the Treatment of Patients with Progressive Advanced Urothelial Carcinoma after Platinum-Containing Chemotherapy.

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 PRACTICE: This 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.

U.S. Food and Drug Administration Approval Summary: Enzalutamide for the Treatment of Patients With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

The U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm. The overall benefit-risk profile supports the expanded indication for enzalutamide. On September 10, 2014, the U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide was initially approved in 2012 for use in patients with mCRPC who had previously received docetaxel. The current approval was based on the results of a randomized, placebo-controlled, double-blind trial conducted in 1,717 asymptomatic or minimally symptomatic patients with chemotherapy-naïve mCRPC. Patients were assigned to receive either enzalutamide 160 mg or placebo orally once daily. The coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), which was assessed by independent central radiology review. At the prespecified interim analysis, a statistically significant improvement in OS was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.60-0.84). The median OS was 32.4 and 30.2 months in the enzalutamide and placebo arms, respectively. A statistically significant prolongation of rPFS was observed in patients in the enzalutamide arm (HR, 0.17; 95% CI, 0.14-0.21). In addition, the time to initiation of cytotoxic chemotherapy was prolonged in the enzalutamide arm (HR, 0.35; 95% CI, 0.30-0.40), with median times of 28.0 and 10.8 months in the enzalutamide and placebo arms, respectively. The safety profile was similar to that previously reported for enzalutamide. Adverse reactions of interest included seizure, hypertension, and falls. Enzalutamide should be discontinued if a seizure occurs during treatment. The overall benefit-risk profile supports the expanded indication for enzalutamide.

Analysis of the Association Between Adverse Events and Outcome in Patients Receiving a Programmed Death Protein 1 or Programmed Death Ligand 1 Antibody.

PURPOSE: To assess the relationship among tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti-programmed death protein 1 or ligand 1 (anti-PD-1/L1) antibodies. PATIENTS AND METHODS: We examined seven trials in 1,747 patients with metastatic or locally advanced urothelial cancer that led to approval of an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy, and two enrolled patients who were cisplatin ineligible. The data sets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the investigator. ImAEs were defined as AESIs treated with topical or systemic corticosteroids. RESULTS: In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti-PD-1/L1 antibody, whereas a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared with those with no related AESIs (hazard ratio, 0.45; 95% CI, 0.39 to 0.52). Fifty-seven percent of responding patients with a related AESI reported the AESI before documentation of response. CONCLUSION: Patients who responded to treatment with an anti-PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not seem to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.

Immunization with mutant p53- and K-ras-derived peptides in cancer patients: immune response and clinical outcome.

PURPOSE: To determine the ability to induce tumor-specific immunity with individual mutant K-ras-or p53-derived peptides and to monitor clinical outcome. PATIENTS AND METHODS: Patients in varying stages of disease underwent genetic analysis for mutations in K-ras and p53. Thirty-nine patients were enrolled. Seventeen-mer peptides were custom synthesized to the corresponding mutation. Baseline immunity was assessed for cytotoxic T-lymphocyte (CTL) response and interferon gamma (IFN-gamma) release from mutant peptide-primed lymphocytes. Patients' peripheral-blood mononuclear cells were pulsed with the corresponding peptide, irradiated, and applied intravenously. Patients were observed for CTL, IFN-gamma, interleukin (IL) -2, IL-5, and granulocyte-macrophage colony-stimulating factor responses, for treatment-related toxicity, and for tumor response. RESULTS: No toxicity was observed. Ten (26%) of 38 patients had detectable CTL against mutant p53 or K-ras, and two patients were positive for CTL at baseline. Positive IFN-gamma responses occurred in 16 patients (42%) after vaccination, whereas four patients had positive IFN-gamma reaction before vaccination. Of 29 patients with evident disease, five experienced a period of stable disease. Favorable prognostic markers were detectable CTL activity and a positive IFN-gamma reaction but not IL-5 release. Median survival times of 393 v 98 days for a positive versus negative CTL response (P = .04), respectively, and of 470 v 88 days for a positive versus negative IFN-gamma response (P = .02), respectively, were detected. CONCLUSION: Custom-made peptide vaccination is feasible without any toxicity. CTL and cytokine responses specific to a given mutation can be induced or enhanced with peptide vaccines. Cellular immunity to mutant p53 and K-ras oncopeptides is associated with longer survival.

Food and Drug Administration process for development and approval of drugs and radiopharmaceuticals: treatments in urologic oncology.

Regulatory advice and assessment play an important role in the successful development of new drugs and radiopharmaceuticals for the treatment of urologic malignancies. Cooperation between the US Food and Drug Administration (FDA) and the pharmaceutical industry has led to the approval of more than 20 new urologic oncology products in the last 2 decades. Despite these advances, more effective treatments need to be developed and approved for the treatment of urologic malignancies. This review provides general information about the FDA's role in the development of investigational new drugs, with an emphasis on the regulatory process and the requirements for marketing approval. In addition, this review summarizes the products for the treatment of urologic malignancies that were approved by the FDA in the last 30 years and the key issues concerning urologic oncology products that were discussed publicly at Oncologic Drug Advisory Committee meetings in the past 10 years.

Development of Systemic and Topical Drugs to Treat Non-muscle Invasive Bladder Cancer.

There are few approved drugs available for the treatment of patients with non-muscle invasive bladder cancer (NMIBC) and none have been approved in the twenty-first century. Four drugs; thiotepa in 1959, BCG Tice in 1989, BCG Connaught in 1990, and valrubicin in 1998, have been approved for the treatment of NMIBC. In addition to these four agents, mitomycin is commonly used off-label as an intravesical treatment for NMIBC. New drugs are needed for the management of NMIBC. This article outlines important aspects of the design and conduct of clinical trials to develop new therapies for these patients and to obtain marketing approval. It includes a discussion of the patient population, BCG-unresponsive disease, and the appropriate endpoints for drug approval. It is hoped that this article will spur drug development in NMIBC within the Center for Drug Evaluation and Research at the Food and Drug Administration.

Radium Ra 223 dichloride injection: U.S. Food and Drug Administration drug approval summary.

On May 15, 2013, the U.S. Food and Drug Administration (FDA) approved radium Ra 223 dichloride (Ra-223; Xofigo injection; Bayer HealthCare Pharmaceuticals Inc.) for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. The FDA review was based on clinical trial BC1-06, which randomly allocated patients (2:1) to either Ra-223 plus best standard of care (BSoC) or placebo plus BSoC. The primary endpoint was overall survival (OS) with a key secondary endpoint of time to first symptomatic skeletal event (SSE). A statistically significant improvement in OS was demonstrated [HR, 0.70; 95% confidence interval, 0.55-0.88, P = 0.0019]. At the prespecified interim analysis, the median OS durations were 14.0 and 11.2 months in the Ra-223 and placebo arms, respectively. The improvement in OS was supported by a delay in time to first SSE favoring the Ra-223 arm. The most common (>10%) adverse reactions in patients receiving Ra-223 were nausea, diarrhea, vomiting, and peripheral edema. The most common (>10%) hematologic laboratory abnormalities were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. Ra-223 is the first α-emitting radiotherapeutic and the first radiopharmaceutical to demonstrate an OS advantage in metastatic prostate cancer.

Enzalutamide for treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel: U.S. Food and Drug Administration drug approval summary.

This article summarizes the regulatory evaluation that led to the full approval of enzalutamide (XTANDI, Medivation Inc.) by the U.S. Food and Drug Administration (FDA) on August 31, 2012, for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. This approval was based on the results of a randomized, placebo-controlled trial which randomly allocated 1,199 patients with mCRPC who had received prior docetaxel to receive either enzalutamide, 160 mg orally once daily (n = 800), or placebo (n = 399). All patients were required to continue androgen deprivation therapy. The primary endpoint was overall survival. At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for the enzalutamide arm compared with the placebo arm [HR = 0.63; 95% confidence interval: 0.53-0.75; P < 0.0001]. The median overall survival durations were 18.4 months and 13.6 months in the enzalutamide and placebo arms, respectively. The most common adverse reactions (≥10%) included asthenia or fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, and upper respiratory infection. Seizures occurred in 0.9% of patients on enzalutamide compared with no patients on the placebo arm. Overall, the FDA's review and analyses of the submitted data confirmed that enzalutamide had a favorable benefit-risk profile in the study patient population, thus supporting its use for the approved indication. The recommended dose is 160 mg of enzalutamide administered orally once daily. Enzalutamide represents the third product that the FDA has approved in the same disease setting within a period of 2 years. Clin Cancer Res; 19(22); 6067-73. ©2013 AACR.

Abiraterone acetate in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer: U.S. Food and Drug Administration drug approval summary.

On December 10, 2012, the U.S. Food and Drug Administration granted full approval for a modified indication for abiraterone acetate (Zytiga tablets; Janssen Biotech, Inc.) in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). The approval was based on clinical trial COU-AA-302, which randomly allocated asymptomatic or mildly symptomatic patients with chemotherapy-naïve mCRPC and no visceral metastases to either abiraterone acetate plus prednisone (N = 546) or placebo plus prednisone (N = 542). The coprimary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS). The median rPFS was 8.3 months in the placebo arm and had not yet been reached in the abiraterone acetate arm {HR, 0.43 [95% confidence interval (CI) 0.35-0.52]; P < 0.0001}. A prespecified interim analysis demonstrated an improvement in OS favoring the abiraterone acetate arm [HR, 0.79 (95% CI, 0.66-0.96)] but did not cross the O'Brien-Fleming boundary for statistical significance. Safety data confirmed the known adverse reaction profile of abiraterone acetate. Full approval was granted on the basis of a large magnitude of effect on rPFS, a favorable trend in OS, and internal consistency across multiple secondary endpoints and exploratory patient-reported pain data. This is the first drug approval for mCRPC to use rPFS as the primary endpoint. Importantly, this approval was granted in the context of a prior statistically significant OS benefit that formed the basis of the original April 28, 2011, approval of abiraterone acetate for patients with mCRPC who had received prior chemotherapy containing docetaxel.

Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: U.S. Food and Drug Administration drug approval summary.

On April 6, 2011, the U.S. Food and Drug Administration approved vandetanib (Caprelsa tablets; AstraZeneca Pharmaceuticals LP) for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. Vandetanib is the first drug approved for this indication, and this article focuses on the basis of approval. Approval was based on the results of a double-blind trial conducted in patients with medullary thyroid carcinoma. Patients were randomized 2:1 to vandetanib, 300 mg/d orally (n = 231), or to placebo (n = 100). The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared with placebo. Other endpoints included evaluation of overall survival and objective response rate. The PFS analysis showed a marked improvement for patients randomized to vandetanib (hazard ratio = 0.35; 95% confidence interval, 0.24-0.53; P < 0.0001). The objective response rate for the vandetanib arm was 44% compared with 1% for the placebo arm. The most common grade 3 and 4 toxicities (>5%) were diarrhea and/or colitis, hypertension and hypertensive crisis, fatigue, hypocalcemia, rash, and corrected QT interval (QTc) prolongation. This approval was based on a statistically significant and clinically meaningful improvement in PFS. Given the toxicity profile, which includes prolongation of the QT interval and sudden death, only prescribers and pharmacies certified through the vandetanib Risk Evaluation Mitigation Strategy Program are able to prescribe and dispense vandetanib. Treatment-related risks should be taken into account when considering the use of vandetanib in patients with indolent, asymptomatic, or slowly progressing disease.