Approval of Apalutamide for Metastatic Castration-Sensitive Prostate Cancer
The FDA approved apalutamide for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC). The approval follows FDA Priority Review Designation of the supplemental New Drug Application that was submitted in April 2019 and reviewed through the FDA Real-Time Oncology Review program. The new indication for apalutamide will make this androgen receptor inhibitor available for the approximately 40,000 people in the U.S. diagnosed with mCSPC annually.
Approval is based on results from the phase III TITAN study, which achieved statistical significance in the dual primary endpoints of overall survival (OS) and radiographic progression-free survival (rPFS) at the first pre-planned interim analysis. The trial recruited patients regardless of extent of disease, including both high- and low-volume disease, or prior docetaxel treatment history. Results were presented in an oral session at the 2019 ASCO Annual Meeting and simultaneously published in The New England Journal of Medicine (2019; doi: 10.1056/NEJMoa1903307).
"Prostate cancer is more difficult to treat once it spreads, and for patients with castration-sensitive disease, it is clear that androgen deprivation therapy (ADT) alone is often not enough," said Kim Chi, MD, a medical oncologist at BC Cancer - Vancouver and principal investigator of the TITAN study. "Results from the TITAN study showed that, regardless of the extent of disease, patients with metastatic castration-sensitive prostate cancer have the potential to benefit from treatment with apalutamide in addition to ADT."
In the TITAN study, apalutamide plus ADT significantly extended OS compared to placebo plus ADT with a 33 percent reduction in the risk of death (HR=0.67; 95% CI, 0.51-0.89; P=0.0053). Apalutamide plus ADT also significantly improved rPFS compared to placebo plus ADT with a 52 percent lower risk of radiographic progression or death (HR=0.48; 95% CI, 0.39-0.60; P<0.0001). As reported in the published results from the TITAN study, the 2-year OS rates, after a median follow-up of 22.7 months, were 84 percent for apalutamide plus ADT compared to 78 percent for placebo plus ADT.
The most common adverse reactions (>=10%) that occurred more frequently in apalutamide treated patients (>=2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.
FDA Grants Priority Review for Enfortumab Vedotin Biologics License Application in Locally Advanced or Metastatic Urothelial Cancer
The FDA has accepted the Biologics License Application for the investigational agent enfortumab vedotin and granted Priority Review for the treatment of patients with locally advanced or metastatic urothelial cancer who have received a PD-1/L1 inhibitor and who have received a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting. The filing is based on results from the first cohort of patients in the EV-201 pivotal phase II clinical trial presented as a late-breaking oral presentation at the 2019 ASCO Annual Meeting. Under the Prescription Drug User Fee Act, the FDA has set a target action date of March 15, 2020. Enfortumab vedotin is a novel investigational antibody-drug conjugate that targets Nectin-4, a protein that is highly expressed in urothelial cancers.
The FDA granted enfortumab vedotin Breakthrough Therapy Designation in March 2018 for patients with locally advanced or metastatic urothelial cancer whose disease has progressed during or following checkpoint inhibitor therapy.
In cohort 1 of EV-201, 128 patients were enrolled at multiple centers internationally. The primary endpoint is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety, and tolerability. EV-201 continues to enroll patients in cohort 2.
The safety and efficacy of enfortumab vedotin are under investigation and have not been established. There is no guarantee that the agent will receive regulatory approval or become commercially available for the uses being investigated.
Capmatinib Granted Breakthrough Therapy Designation for Patients With MET-Mutated Advanced Non-Small Cell Lung Cancer
The FDA granted Breakthrough Therapy Designation to capmatinib (INC280) as a first-line treatment for patients with metastatic MET exon14 skipping-mutated non-small cell lung cancer (NSCLC).
Recent research concludes that the cMET gene is an oncogenic driver, and the investigational lung cancer therapy capmatinib has been shown to be a highly potent and selective MET inhibitor. The MET mutation is seen in an estimated 3-4 percent of all patients with NSCLC. These patients are generally older and often have a poor prognosis that can limit lung cancer treatment options.
According to FDA guidelines, treatments that receive Breakthrough Therapy Designation must target a serious or life-threatening disease and demonstrate a substantial improvement over existing therapies on one or more significant preliminary research endpoints. The FDA granted Breakthrough Therapy Designation for capmatinib based on positive primary results from the GEOMETRY mono-1 study presented at the 2019 ASCO Annual Meeting.
Capmatinib (INC280) is an investigational, oral, highly potent, and selective MET inhibitor.
FDA Grants Orphan Drug Designation for BXCL701 for the Treatment of Acute Myeloid Leukemia
BXCL701, an investigational, orally available, systemic innate immunity activator with dual mechanisms of action, has been given Orphan Drug Designation for the treatment of acute myeloid leukemia (AML). It is designed to activate innate immune cells, specifically macrophages, by inhibiting the dipeptidyl dipeptidases DPP8 and DPP9, a novel mechanism, and exerts immune stimulatory activity through a pro-inflammatory form of programmed cell death known as pyroptosis.
Researchers are leveraging the pro-inflammatory mechanism of action of BXCL701 for treatment-emergent neuroendocrine prostate cancer and pancreatic cancer. However, recent preclinical work has also pointed to AML as a potential indication for BXCL701, since AML cells are of the same lineage as macrophages (Nat Med 2018; doi: 10.1038/s41591-018-0082-y). Targeting AML represents a novel application of BXCL701's intended mechanism of action of driving programmed cell death. While BXCL701 potentially acts as an activator of the innate immune system in prostate and pancreatic cancer, it may act as a direct cytotoxic agent in AML.
Investigational Therapy Tepotinib for Use in Metastatic NSCLC With METex14 Skipping Alterations
The FDA has granted Breakthrough Therapy Designation for the investigational targeted therapy tepotinib in patients with metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping alterations who progressed following platinum-based cancer therapy. Alterations of the MET signaling pathway are found in various cancer types, including 3-5 percent of NSCLC cases, and correlate with aggressive tumor behavior and poor clinical prognosis.
Tepotinib is an investigational oral MET kinase inhibitor that is designed to be highly potent and selective and to inhibit the oncogenic signaling caused by MET alterations, including both MET exon 14 skipping alterations and MET amplifications, or MET protein overexpression.
In March 2018, tepotinib's potential was recognized by the Japanese Ministry of Health, Labour and Welfare, which granted SAKIGAKE fast-track designation for tepotinib in advanced NSCLC harboring MET exon 14 skipping alterations. SAKIGAKE designation promotes research and development in Japan, aiming at early practical application for innovative pharmaceutical products, medical devices, and regenerative medicines.
Tepotinib is also being investigated in the INSIGHT 2 study (NCT03940703) in combination with the tyrosine kinase inhibitor (TKI) osimertinib in epidermal growth factor receptor (EGFR)-mutated, MET-amplified, locally advanced or metastatic NSCLC having acquired resistance to prior EGFR TKI.
The Breakthrough Therapy Designation is based on data from the ongoing VISION study (NCT02864992), showing preliminary clinical evidence that tepotinib may offer an improvement over available therapy in patients with metastatic NSCLC harboring MET exon 14 skipping alterations detected by liquid biopsy (LBx) or tissue biopsy (TBx) across different lines of treatment.
Results from an interim analysis of the ongoing VISION study in 73 efficacy-evaluable patients with NSCLC with MET exon 14 skipping alterations identified by LBx or TBx testing demonstrate overall objective response rate (ORR) of 50.0 percent for LBx-identified patients as assessed by Independent Review Committee (IRC), and 55.3 percent as assessed by investigators. The ORR for TBx-identified patients was 45.1 percent and 54.9 percent, respectively. The overall median duration of response was 12.4 months and 17.1 months among LBx-identified patients, as assessed by IRC and investigators, respectively, while among TBx-identified patients, 15.7 and 14.3 months were observed, respectively.
Most treatment-related adverse events (TRAEs) were grade 1 and 2. No grade 4 or 5 TRAEs were observed. Any grade TRAEs reported by >=10 percent of 87 patients evaluable for safety were peripheral edema (48.3%), nausea (23.0%) diarrhea (20.7%), and increased blood creatinine (12.6%). Other relevant TRAEs of any grade include increased lipase (4.6%), fatigue (3.4%), and vomiting (3.4%). TRAEs led to permanent discontinuation in four patients (two patients due to peripheral edema, one due to interstitial lung disease, and one due to diarrhea and nausea).
Results from this study were presented in an oral presentation at the 2019 ASCO Annual Meeting. The use of both LBx and TBx to identify patients for the VISION study is intended to support improved patient selection.
FDA Announces Collaboration With Australia & Canada To Provide Framework for Approving Treatment for Patients With Endometrial Carcinoma
The FDA announced Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among its international partners. Under this project, the FDA, the Australian Therapeutic Goods Administration (TGA), and Health Canada collaboratively reviewed applications for two oncology drugs, allowing for simultaneous decisions in all three countries.
"We are pleased to be working alongside our Australian and Canadian colleagues to help make potentially life-changing treatments available to patients as quickly as possible while still ensuring the FDA's high standards of safety and effectiveness," said Acting FDA Commissioner Ned Sharpless, MD. "As Project Orbis expands, we look forward to welcoming additional international partners to collaborate with us in this important initiative as we work to help further serve the global patient community."
Collaboration among international regulators may allow patients with cancer to receive earlier access to products in other countries where there may be significant delays in regulatory submissions, regardless of whether the product has received FDA approval. This is partly due to different standards of care around the world that also have an impact on the increasingly international conduct of cancer clinical trials, potentially slowing the development of anticancer products. With a framework for concurrent submission and review of oncology drugs, Project Orbis facilitates a collaborative review to identify any regulatory divergence across review teams.
As part of Project Orbis, in conjunction with decisions by TGA and Health Canada, the FDA granted accelerated approval to lenvatinib in combination with pembrolizumab for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.
"In addition to the international collaboration with Australia and Canada, this review used the Real-Time Oncology Review (RTOR) pilot program, which can streamline the submission of data prior to the completion and submission of the entire clinical application," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "RTOR, and its accompanying Assessment Aid, facilitated discussions among the regulatory agencies, expediting the approval in the three countries. These applications were approved 3 months prior to the FDA goal date."
Lenvatinib was initially approved by the FDA in 2015 and pembrolizumab was initially approved in 2014. The approval of lenvatinib in combination with pembrolizumab was based on the results of a clinical trial of 94 patients with endometrial carcinoma tumors that were not MSI-H or dMMR. Of the 94 patients, 10 patients (10.6% of responders) had a complete response, or disappearance of all lesions on imaging, and 26 patients (27.7% of responders) had a partial response, or shrinkage of lesions by at least 30 percent, leading to an objective response rate of 38.3 percent. Of these, 25 patients (69% of responders) had a duration of response of greater than 6 months.
Common side effects for patients in the clinical trial included fatigue, high blood pressure, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, and stomatitis. Additional side effects included vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash. Health care professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with lenvatinib in combination with pembrolizumab. Women who are pregnant or breastfeeding should not take this combination because it may cause harm to a developing fetus or newborn baby.
Lenvatinib in combination with pembrolizumab was granted accelerated approval. This approval commits the sponsor to provide additional data to the FDA. The application also received Priority Review and both lenvatinib and pembrolizumab had received Breakthrough Therapy Designation for this indication. This review was conducted under the Oncology Center of Excellence's RTOR pilot program and Assessment Aid.