Julia A. Beaver

FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer

On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319–0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. Clin Cancer Res; 21(21); 4760–6. ©2015 AACR.

FDA Approval Summary: Rucaparib for the treatment of patients with deleterious BRCA mutation-associated advanced ovarian cancer

On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDxBRCA test (Foundation Medicine, Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparibs approval was based primarily on efficacy data from 106 patients with BRCA mutation–associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% [57/106; 95% confidence interval (CI), 44–64], and median duration of response was 9.2 months (95% CI, 6.6–11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparibs accelerated approval. Clin Cancer Res; 23(23); 7165–70. ©2017 AACR. See related commentary by Kohn et al., p. 7155

FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs

On December 11, 2015, the FDA approved uridine triacetate (VISTOGARD; Wellstat Therapeutics Corporation) for the emergency treatment of adult and pediatric patients following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, and of those who exhibit early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration. Uridine triacetate is not recommended for the nonemergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may diminish the efficacy of these drugs, and the safety and efficacy of uridine triacetate initiated more than 96 hours following the end of administration of these drugs has not been established. The approval is based on data from two single-arm, open-label, expanded-access trials in 135 patients receiving uridine triacetate (10 g or 6.2 g/m2 orally every 6 hours for 20 doses) for fluorouracil or capecitabine overdose, or who exhibited severe or life-threatening toxicities within 96 hours following the end of fluorouracil or capecitabine administration. Ninety-six percent of patients met the major efficacy outcome measure, which was survival at 30 days or survival until the resumption of chemotherapy, if prior to 30 days. The most common adverse reactions were vomiting, nausea, and diarrhea. This article summarizes the FDA review of this New Drug Application, the data supporting approval of uridine triacetate, and the unique regulatory situations encountered by this approval. Clin Cancer Res; 22(18); 4545–49. ©2016 AACR.

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma

On November 23, 2015, the FDA approved nivolumab (OPDIVO; Bristol-Myers Squibb) as a single agent for the first-line treatment of patients with BRAFV600 wild-type, unresectable or metastatic melanoma. An international, double-blind, randomized (1:1) trial conducted outside of the United States allocated 418 patients to receive nivolumab 3 mg/kg intravenously every 2 weeks (n = 210) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 208). Patients with disease progression who met protocol-specified criteria (∼25% of each trial arm) were permitted to continue with the assigned treatment in a blinded fashion until further disease progression is documented. Overall survival was statistically significantly improved in the nivolumab arm compared with the dacarbazine arm [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.30–0.60; P < 0.0001]. Progression-free survival was also statistically significantly improved in the nivolumab arm (HR, 0.43; 95% CI, 0.34–0.56; P < 0.0001). The most common adverse reactions (≥20%) of nivolumab were fatigue, diarrhea, constipation, nausea, musculoskeletal pain, rash, and pruritus. Nivolumab demonstrated a favorable benefit–risk profile compared with dacarbazine, supporting regular approval; however, it remains unclear whether treatment beyond disease progression contributes to the overall clinical benefit of nivolumab. Clin Cancer Res; 23(14); 3479–83. ©2017 AACR.

An FDA Perspective on the Regulatory Implications of Complex Signatures to Predict Response to Targeted Therapies.

As technologies evolve, and diagnostics move from detection of single biomarkers toward complex signatures, an increase in the clinical use and regulatory submission of complex signatures is anticipated. However, to date, no complex signatures have been approved as companion diagnostics. In this article, we will describe the potential benefit of complex signatures and their unique regulatory challenges, including analytic performance validation, complex signature simulation, and clinical performance evaluation. We also will review the potential regulatory pathways for clearance, approval, or acceptance of complex signatures by the FDA. These regulatory pathways include regulations applicable to in vitro diagnostic devices, including companion diagnostic devices, the potential for labeling as a complementary diagnostic, and the biomarker qualification program. Clin Cancer Res; 23(6); 1368–72. ©2016 AACR.

Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis

Background Patients who receive immunotherapeutics may develop an atypical response pattern, which warrants further investigation into the potential benefits and risks for patients who continue immunotherapy beyond RECIST-defined disease progression. Methods A pooled analysis including all submissions to U.S. Food and Drug Administration (FDA) in support of marketing applications for anti-PD-1 antibodies and approved by FDA for treatment of patients with unresectable or metastatic melanoma (MM) was conducted to evaluate the potential benefits and safety of treatment beyond progression (TBP). Trials had to allow for continuation of the antibody beyond RECIST-defined progression (RECISTPD) in the anti-PD-1 arm. Any patient receiving the anti-PD-1 antibody after their RECISTPD date were included in the TBP cohort and analyzed descriptively at baseline and at time of progression with the cohort not receiving treatment beyond progression (noTBP). Patients in the TBP cohort had target lesion (TL) response after progression analyzed relative to PD and baseline TL burden. Findings Of 2624 pooled patients receiving immunotherapy, 52% (1361/2624) had progressive disease (PD); of these, 51% (692/1361) received continued anti-PD-1 antibody beyond RECIST-defined progression. Nineteen percent (95/500) of patients in TBP cohort with evaluable assessments experienced a ≥ 30% decrease in tumor burden, when considering burden at RECISTPD as the reference, representing 14% (95/692) of those TBP and 3·6% (95/2624) of all immunotherapy treated patients. Overall survival (OS) was greater in the TBP cohort compared with the noTBP cohort. One of the pooled trials was a double-blind, randomized, active-controlled trial evaluating an anti-PD-1 antibody vs. chemotherapy in which OS appeared similar in both arms for patients treated beyond progression and longer than the noTBP cohorts. Immune-related adverse events (irAE) up to 90-days from discontinuation were similar between the TBP cohort and the noTBP cohort. Interpretation Continuation of TBP in the product labeling of these immunotherapies has not been recommended as the clinical benefit remains to be proven. TBP with anti-PD-1 antibody therapy may be appropriate for select patients with MM, identified by specific criteria at the time of progression, based on the potential for late responses in the setting of the known toxicity profile. Funding noneBACKGROUND Patients who receive immunotherapeutic drugs might develop an atypical response pattern, wherein they initially meet conventional response criteria for progressive disease but later have decreases in tumour burden. Such responses warrant further investigation into the potential benefits and risks for patients who continue immunotherapy beyond disease progression defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. METHODS For this pooled analysis, we included all submissions of trial reports and data to the US Food and Drug Administration (FDA) in support of marketing applications for anti-programmed death receptor-1 (PD-1) antibodies (alone or in combination) for the treatment of patients with unresectable or metastatic melanoma that allowed for continuation of the antibody beyond RECIST-defined progression in the anti-PD-1 group and were approved by FDA before Jan 1, 2017. To investigate the effect of treatment beyond progression in patients with metastatic melanoma and to better characterise which of these patients would benefit from extended treatment, we pooled individual patient data from patients who received at least one dose of an anti-PD-1 antibody in the included trials. We included any patient receiving the anti-PD-1 antibody after their RECIST-defined progression date in the treatment beyond progression cohort and analysed them descriptively at baseline and at time of progression versus the cohort not receiving treatment beyond progression. We analysed the target lesion response after progression in patients in the treatment beyond progression cohort relative to progressive disease and baseline target lesion burden. We defined a treatment beyond progression response as a decrease in target lesion tumour burden (sum of the reference diameters) of at least 30% from the burden at the time of RECIST-defined progression that did not require confirmation at a subsequent assessment. We also compared individual timepoint responses, overall survival, and adverse events in the treatment beyond progression versus no treatment beyond progression cohorts. FINDINGS Among the eight multicentre clinical trials meeting this studys inclusion criteria, we pooled the data from 2624 patients receiving immunotherapy. 1361 (52%) had progressive disease, of whom 692 (51%) received continued anti-PD-1 antibody treatment beyond RECIST-defined progression and 669 (49%) did not. 95 (19%) of 500 patients in the treatment beyond progresssion cohort with evaluable assessments had a 30% or more decrease in tumour burden, when considering burden at RECIST-defined progression as the reference point, representing 14% of the 692 patients treated beyond progression and 4% of all 2624 patients treated with immunotherapy. Median overall survival in patients with RECIST-defined progressive disease given anti-PD-1 antibody was longer in the treatment beyond progression cohort (24·4 months, 95% CI 21·2-26·3) than in the cohort of patients who did not receive treatment beyond progression (11·2 months, 10·1-12·9). 362 (54%) of 669 patients in the no treatment beyond progression cohort had a serious adverse event up to 90 days after treatment discontinuation compared with 295 (43%) of 692 patients in the treatment beyond progression cohort. Immune-related adverse events that occurred up to 90 days from discontinuation were similar between the treatment beyond progression cohort (78 [11%] of 692 patients) and the no treatment beyond progression cohort (106 [16%] of 669). INTERPRETATION Continuation of treatment beyond progression in the product labelling of these immunotherapies has not been recommended because the clinical benefit remains to be proven. Treatment beyond progression with anti-PD-1 antibody therapy might be appropriate for selected patients with unresectable or metastatic melanoma, identified by specific criteria at the time of progression, based on the potential for late responses in the setting of the known toxicity profile. FUNDING None.

U.S. Food and Drug Administration Approval: Cabozantinib for the Treatment of Advanced Renal Cell Carcinoma.

On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which patients with RCC who had received prior antiangiogenic therapy were treated with either cabozantinib 60 mg orally once daily (n = 330) or everolimus 10 mg orally once daily (n = 328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45–0.74; P < 0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population was also demonstrated, with a median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003). The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar–plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation. Clin Cancer Res; 23(2); 330–5. ©2016 AACR.

FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor–Positive, HER2-Negative Advanced or Metastatic Breast Cancer

On March 13, 2017, the FDA approved ribociclib (KISQALI; Novartis Pharmaceuticals Corp.), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)–positive, HER2-negative advanced or metastatic breast cancer. The approval was based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2). A total of 668 patients were randomized to receive either ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334). An improvement in progression-free survival (PFS) was observed in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole [HR = 0.556; 95% confidence interval (CI), 0.429–0.720]. Overall response rate (ORR) in patients with measurable disease was 52.7% (95% CI, 46.6–58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI, 31.1–43.2) in the placebo plus letrozole arm. Overall survival data were immature. The most common adverse reactions observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. This article summarizes FDA decision-making and data supporting the approval of ribociclib. Clin Cancer Res; 24(13); 2999–3004. ©2018 AACR. See related commentary by Spring and Bardia, p. 2981

FDA ovarian cancer clinical trial endpoints workshop: A Society of Gynecologic Oncology White Paper

a University of Cincinnati Cancer Institute, Dept. of Ob/Gyn, University of Cincinnati, United States b Office of Hematology Oncology Products, OND, CDER, FDA, United States c Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, United States d Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, United States e Division of Biometrics V, OB, OTS, CDER, FDA, United States f Ovarian Cancer Alliance of San Diego, United States g Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States h U.S. Oncology, Phoenix, AZ, United States i Oncology Center of Excellence, OMPT, FDA, United States j Ovarian Cancer Survivor, White Plains, New York

Overview of Oncology and Hematology Drug Approvals at US Food and Drug Administration Between 2008 and 2016

BACKGROUND We previously conducted an overview of oncology products reviewed by the Office of Oncology Drug Products in the Center for Drug Evaluation and Research at the US Food and Drug Administration for marketing approval and the regulatory actions taken during July 2005 to December 2007. There is a need to understand if the changes in the laws, regulations, and the organization that occurred after 2007 had any impact on the regulatory drug approvals. We present a detailed overview of hematology and oncology products reviewed by Office of Oncology Drug Products and Office of Hematology and Oncology Drug Products. METHODS We identified all oncology-hematology applications that were submitted to the US Food and Drug Administration from January 1, 2008 through December 31, 2016, and reviewed the approval actions taken. RESULTS During the study period, the Office of Hematology and Oncology Products approved 239 applications that supported 260 new indications. Of the 239 applications approved, 141 were approved via priority review and 98 were approved via standard review. Fifty-three of these applications were granted accelerated approval, 29 were converted from accelerated approval to regular approval, and 157 received regular approval. Since its promulgation in 2013, breakthrough designation status has been granted to 25.7% of applications. A variety of endpoints were used to support these approvals. CONCLUSION During the study period, despite changes in the regulations and organization, the Office of Hematology and Oncology Products consistently utilized regulatory mechanisms that expedite the development and approval of promising oncology and hematology drug products resulting in the approval of 260 new indications.