Marc R. Theoret

FDA Approval Summary: Vemurafenib for Treatment of Unresectable or Metastatic Melanoma with the BRAFV600E Mutation

On August 17, 2011, the U.S. Food and Drug Administration (FDA) approved vemurafenib tablets (Zelboraf, Hoffmann-LaRoche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation as detected by an FDA-approved test. The cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.) was approved concurrently. An international, multicenter, randomized, open-label trial in 675 previously untreated patients with BRAFV600E mutation–positive unresectable or metastatic melanoma allocated 337 patients to receive vemurafenib, 960 mg orally twice daily, and 338 patients to receive dacarbazine, 1,000 mg/m2 intravenously every 3 weeks. Overall survival was significantly improved in patients receiving vemurafenib [HR, 0.44; 95% confidence interval (CI), 0.33–0.59; P < 0.0001]. Progression-free survival was also significantly improved in patients receiving vemurafenib (HR, 0.26; 95% CI, 0.20–0.33; P < 0.0001). Overall response rates were 48.4% and 5.5% in the vemurafenib and dacarbazine arms, respectively. The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas or keratoacanthomas were detected in approximately 24% of patients treated with vemurafenib. Other adverse reactions included hypersensitivity, Stevens–Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities. Clin Cancer Res; 20(19); 4994–5000. ©2014 AACR.

U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab

On December 22, 2014, the FDA granted accelerated approval to nivolumab (OPDIVO; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on a clinically meaningful, durable objective response rate (ORR) in a non-comparative analysis of 120 patients who received 3 mg/kg of nivolumab intravenously every 2 weeks with at least 6-month follow-up in an ongoing, randomized, open-label, active-controlled clinical trial. The ORR as assessed by a blinded independent review committee per RECIST v1.1 was 31.7% (95% confidence interval, 23.5–40.8). Ongoing responses were observed in 87% of responding patients, ranging from 2.6+ to 10+ months. In 13 patients, the response duration was 6 months or longer. The risks of nivolumab, including clinically significant immune-mediated adverse reactions (imARs), were assessed in 268 patients who received at least one dose of nivolumab. The FDA review considered whether the ORR and durations of responses were reasonably likely to predict clinical benefit, the adequacy of the safety database, and systematic approaches to the identification, description, and patient management for imARs in product labeling. Clin Cancer Res; 23(14); 3484–8. ©2017 AACR.

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma

On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15–34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666–70. ©2017 AACR.

Regulation of immunotherapeutic products for cancer and FDA's role in product development and clinical evaluation

Immunotherapeutics include drugs and biologics that render therapeutic benefit by harnessing the power of the immune system. The promise of immune-mediated therapies is target specificity with a consequent reduction in off-target side effects. Recent scientific advances have led to clinical trials of both active and passive immunotherapeutic products that have the potential to convert life-ending diseases into chronic but manageable conditions. Clinical trials investigating immunotherapeutics are ongoing with some trials at advanced stages of development. However, as with many products involving novel mechanisms of action, major regulatory and scientific issues arising with clinical use of immunotherapeutic products remain to be addressed. In this review, we address issues related to different immunotherapeutics and provide recommendations for the characterization and evaluation of these products during various stages of product and clinical development.

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.

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.

FDA Approval Summary: Eribulin for Patients with Unresectable or Metastatic Liposarcoma who have Received a Prior Anthracycline-Containing Regimen

On January 28, 2016, the FDA approved eribulin (Halaven; Eisai Inc.) for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen. The approval was based on results from a single, randomized, open-label, active-controlled trial (Trial E7389-G000-309) enrolling 452 patients with advanced, locally recurrent or metastatic liposarcoma or leiomyosarcoma. Patients were randomized to eribulin 1.4 mg/m2 intravenously (i.v.) on days 1 and 8 or dacarbazine 850, 1,000, or 1,200 mg/m2 i.v. on day 1 of a 21-day cycle. There was a significant improvement in overall survival [OS; HR, 0.75; 95% confidence interval (CI), 0.61–0.94; P = 0.0119, stratified log-rank] for the overall population. Estimated median OS was 13.5 months (95% CI, 11.1–16.5) in the eribulin arm and 11.3 months (95% CI, 9.5–12.6) in the dacarbazine arm (HR, 0.75; 95% CI, 0.61–0.94; P = 0.011).There were no differences in PFS for the overall population. The effects of eribulin were limited to patients with liposarcoma (n = 143) based on preplanned, exploratory subgroup analyses of OS (HR, 0.51; 95% CI, 0.35–0.75) and progression-free survival (PFS; 0.52; 95% CI, 0.35–0.78). Response rates in both treatment arms were less than 5% in the overall population and in the liposarcoma subgroup. The safety profile was similar to that previously reported for eribulin. The FDA determined that, based on the data reviewed, the benefit–risk assessment for eribulin is positive for patients with advanced, pretreated liposarcoma. Clin Cancer Res; 23(21); 6384–9. ©2017 AACR.

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma.

On December 18, 2015, the FDA granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma based on results of two randomized, open-label, active-controlled clinical trials. In trial PN006, 834 patients with ipilimumab-naïve metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 or 3 weeks until disease progression or ipilimumab 3 mg/kg every 3 weeks for up to four doses. In trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg i.v. every 3 weeks or to investigators choice of chemotherapy. In trial PN006, patients randomized to pembrolizumab demonstrated a statistically significant improvement in overall survival compared with ipilimumab [every-2-week arm: hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.47–0.83; P < 0.001; every-3-week arm: HR = 0.69; 95% CI, 0.52–0.90; P = 0.004]. In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (≥2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response–based endpoints using RECIST or immune-related RECIST. Clin Cancer Res; 23(19); 5661–5. ©2017 AACR.

FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen

On October 23, 2015, the FDA approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks with dacarbazine 1,000 mg/m2 i.v. once every 3 weeks. Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS), with a PFS of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively (HR, 0.55; 95% confidence interval, 0.44–0.70; unstratified log-rank test, P < 0.001). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis. A postmarketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival. A key regulatory consideration during review of this application was the use of PFS as an endpoint to support regular approval of trabectedin. Clin Cancer Res; 23(24); 7448–53. ©2017 AACR.