Recently, the U.S. Food and Drug Administration (FDA) granted Priority Reviews for treatments in extensive-stage small cell lung cancer (SCLC), non–muscle invasive bladder cancer, and BRAF V600E–mutant colorectal cancer. The Agency also recently issued multiple Breakthrough Therapy designations and a Fast Track designation.
Priority Review for Durvalumab in Extensive-Stage Small Cell Lung Cancer
The FDA has accepted a supplemental biologics license application (sBLA) and granted Priority Review to durvalumab for the treatment of patients with previously untreated extensive-stage small cell lung cancer (SCLC). A Prescription Drug User Fee Act (PDUFA) date is set for the first quarter of 2020.
Durvalumab is a human monoclonal antibody that binds to programmed cell death ligand 1 (PD-L1) and blocks the interaction of programmed cell death ligand 1 (PD-L1) with programmed cell death protein 1 (PD-1) and CD80, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses.
The sBLA was based on positive results from the phase III CASPIAN trial published by Paz-Ares in The Lancet, which showed that durvalumab in combination with standard-of-care chemotherapy (etoposide with either cisplatin or carboplatin) demonstrated a statistically significant and clinically meaningful improvement in overall survival vs standard-of-care chemotherapy alone. The risk of death was reduced by 27% (hazard ratio = 0.73), with median overall survival of 13.0 months for patients treated with durvalumab plus chemotherapy vs 10.3 months for standard of care. Results showed an estimated 33.9% of patients were alive at 18 months following treatment with durvalumab plus chemotherapy vs 24.7% of patients receiving standard of care.
Priority Review for Pembrolizumab in Certain Patients With High-Risk, Non–Muscle Invasive Bladder Cancer
The FDA has accepted and granted Priority Review to a new sBLA for pembrolizumab. The application seeks approval of pembrolizumab monotherapy for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive, high-risk, non–muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. This application for pembrolizumab was discussed at the December 17 meeting of the FDA’s Oncologic Drugs Advisory Committee (ODAC), and ODAC recommended the treatment. A PDUFA is expected in January 2020, based on Priority Review.
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells.
The filing was based on data from KEYNOTE-057, a phase II, multicenter, open-label, single-arm trial in 102 patients with BCG-unresponsive, high-risk, non–muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who were ineligible for or had elected not to undergo cystectomy (cohort A). In this study, BCG-unresponsive high risk non–muscle invasive bladder cancer is defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG.
Patients received pembrolizumab at 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk non–muscle invasive bladder cancer, or progressive disease. Assessment of tumor status was performed every 12 weeks, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response and duration of response.
Priority Review for Encorafenib/Cetuximab in Metastatic BRAF V600E–Mutant Colorectal Cancer
The FDA has accepted and granted Priority Review to a supplemental new drug application for encorafenib in combination with cetuximab based on results from the phase III BEACON CRC trial, which evaluated the efficacy and safety of encorafenib in combination with cetuximab with or without binimetinib in patients with advanced BRAF V600E–mutant metastatic colorectal cancer following one or two lines of therapy. The PDUFA goal date for a decision by the FDA is April 2020.
As published by Kopetz et al in The New England Journal of Medicine, results from the BEACON CRC trial showed improvements in overall survival and objective response rate for both the encorafenib/cetuximab and encorafenib/binimetinib/cetuximab, compared to cetuximab plus irinotecan-containing regimens. In descriptive analyses comparing the doublet and triplet arms, the results showed comparable efficacy between the doublet and triplet in the overall population. The triplet and doublet regimens showed no unexpected toxicities.
Breakthrough Therapy Designation for Abatacept for the Prevention of Acute Graft-Versus-Host Disease
The FDA granted Breakthrough Therapy designation to abatacept for the prevention of moderate to severe acute graft-vs-host disease in patients receiving hematopoietic stem cell transplants from unrelated donors. There are no approved therapies for the prevention of acute graft-vs-host disease.
Abatacept is a therapy currently approved to treat various arthritic conditions that binds to and inhibits protein targets involved in co-stimulation, thus inhibiting T-cell activation. The Breakthrough Therapy designation is based on findings from an investigator-initiated study. The phase II trial assessed the impact of abatacept on the prevention of severe acute acute graft-vs-host disease, when added to a standard prophylactic regimen administered to patients with hematologic malignancies receiving a stem cell transplant from an unrelated, human leukocyte antigen–matched or mismatched donor.
Breakthrough Therapy Designation for Ivosidenib in Relapsed or Refractory IDH1-Mutated Myelodysplastic Syndrome
The FDA granted Breakthrough Therapy designation to ivosidenib for the treatment of adult patients with relapsed or refractory myelodysplastic syndrome (MDS) with a susceptible IDH1 mutation as detected by an FDA-approved test.
Results from the MDS arm of the ongoing ivosidenib phase I dose-escalation and expansion study in hematologic malignancies were presented at the 7th Society of Hematologic Oncology Annual Meeting. These data demonstrate that ivosidenib administered as a monotherapy was well tolerated and associated with durable remissions, as well as the achievement and maintenance of transfusion independence in patients with relapsed or refractory MDS with an IDH1 mutation.
Among the 12 patients who received 500 mg of oral ivosidenib daily, the median treatment duration was 11.4 months. The median age was 72.5 years, and 42% of patients were aged 75 or older. As of the November 2018 data cutoff, 75% (9 of 12) of patients had a response and 42% (5 of 12) had a complete response. The median duration of complete response had not been reached (95% confidence interval = 2.8 months–not reached). Of the patients who had a complete response, 60% remained relapse-free at 12 months. In addition, nine (75%) patients were transfusion-independent for 56 days or longer during study treatment.
The most common adverse events of any grade were back pain, diarrhea, fatigue, and rash. Grade 2 isocitrate dehydrogenase (IDH) differentiation syndrome was observed in 1 of 12 patients. No adverse events resulted in permanent discontinuation of treatment.
Breakthrough Therapy Designation for Tucatinib in Locally Advanced or Metastatic HER2-Positive Breast Cancer
The FDA granted Breakthrough Therapy designation to tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have been treated with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1). The positive topline results of the HER2CLIMB clinical trial were announced in October 2019. Additional data were presented at the 2019 San Antonio Breast Cancer Symposium and were simultaneously published by Murthy et al in The New England Journal of Medicine. Tucatinib is an oral, small-molecule tyrosine kinase inhibitor that is highly selective for HER2.
This Breakthrough Therapy designation was based on data from the HER2CLIMB clinical trial, which compared tucatinib in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer. Patients had previously received trastuzumab, pertuzumab, and T-DM1. Patients had received a median of four prior lines of therapy overall and three in the metastatic setting. About 47% of the patients enrolled in the trial had brain metastases at the time of enrollment.
Recently published data include the primary endpoint of progression-free survival as assessed by blinded independent central review in the first 480 patients enrolled in the trial. Progression-free survival data showed that the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46% reduction in the risk of disease progression or death (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.42–0.71, P < .00001).
The trial also met the two key secondary endpoints at interim analysis. The tucatinib arm demonstrated an improvement in overall survival, with a 34% reduction in the risk of death (HR = 0.66, 95% CI: = 0.50–0.88, P = .0048), compared to the control arm. For patients with brain metastases at baseline, the tucatinib arm also demonstrated superior progression-free survival, with a 52% reduction in the risk of disease progression or death compared to the control arm (HR = 0.48, 95% CI = 0.34–0.69, P < .00001).
Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated. The most common adverse events occurring in more than 20% of patients in the tucatinib arm vs the control arm included diarrhea, palmar-plantar erythrodysaesthesia syndrome, nausea, fatigue, and vomiting. Discontinuation of tucatinib and placebo due to adverse events occurred in 5.7% of patients in the tucatinib arm and 3.0% of patients in the control arm.
Diarrhea of at least grade 3 was seen in 12.9% of the patients in the tucatinib arm vs 8.6% in the control arm. Antidiarrheal prophylaxis was not required per protocol. Antidiarrheals were used in less than half of all cycles where diarrhea was reported. In both treatment arms, when used, the duration of antidiarrheal treatment was short (median of 3 days per cycle). Aspartate aminotransferase of at least grade 3 was seen in 4.5% of the patients in the tucatinib arm vs 0.5% in the control arm, and alanine aminotransferase elevation was seen in in 5.4% vs 0.5%, respectively. Discontinuations due to liver transaminase elevations were infrequent in both arms.
Fast Track Designation for Tipifarnib in HRAS-Mutant Head and Neck Cancer
The FDA granted Fast Track designation to tipifarnib for the treatment of patients with HRAS-mutant head and neck squamous cell carcinoma after progression on platinum therapy. Tipifarnib is a potent, selective, and orally bioavailable inhibitor of farnesyl transferase.
Enrollment guidance was also provided for AIM-HN, an ongoing registration-directed trial of tipifarnib in patients with recurrent or metastatic HRAS-mutant head and neck squamous cell carcinoma. The global, multicenter trial was initiated in November 2018 and was originally projected to take approximately 2 years to fully enroll. Based on a recent evaluation of current enrollment rates, it is now expected that the trial will complete enrollment in the first quarter of 2021. The slower pace of enrollment is primarily due to delays in site activation and a higher-than-anticipated screen failure rate. The trial is now open in more than 81 clinical sites in the United States, Europe, and Asia.
ODAC Recommendations
The December 17 meeting of the FDA’s Oncologic Drugs Advisory Committee (ODAC) resulted in three votes:
- Unanimous vote (11–0) in favor of tazemetostat for the treatment of patients with epithelioid sarcoma
- 7–5 in favor of olaparib as first-line maintenance treatment of germline BRCA-mutated metastatic pancreatic cancer
- 9–4 in favor of pembrolizumab for the treatment of certain patients with high-risk non–muscle invasive bladder cancer.
