publication date: Jul. 31, 2020
Drugs & Targets
Tecentriq approved by FDA for BRAF V600 unresectable or metastatic melanoma
Tecentriq (atezolizumab) received FDA approval in combination with cobimetinib and vemurafenib for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.
Tecentriq is sponsored by Genentech Inc.
Efficacy in combination with cobimetinib and vemurafenib was evaluated in a double-blind, randomized (1:1), placebo-controlled, multicenter trial (IMspire150, NCT02908672) in 514 patients. After a 28-day cycle of cobimetinib and vemurafenib, patients received atezolizumab 840 mg intravenous infusion every 2 weeks in combination with cobimetinib 60 mg orally once daily and vemurafenib 720 mg orally twice daily, or placebo in combination with cobimetinib 60 mg orally once daily (21 days on/7 days off) and vemurafenib 960 mg orally twice daily.
The primary efficacy outcome measure was investigator-assessed progression-free survival (PFS) per RECIST 1.1. Median PFS was 15.1 months (95% CI: 11.4, 18.4) in the atezolizumab arm and 10.6 months (95% CI: 9.3, 12.7) in the placebo arm (HR 0.78; 95% CI: 0.63, 0.97; p=0.0249).
This application was granted priority review and atezolizumab was granted orphan product designation. FDA collaborated with Switzerland’s Swissmedic on the review of this application as part of Project Orbis.
FDA approves first cell-based gene therapy for adult patients with relapsed or refractory MCL
Tecartus (brexucabtagene autoleucel), a cell-based gene therapy, received FDA approval for treatment of adult patients diagnosed with mantle cell lymphoma who have not responded to or who have relapsed following other kinds of treatment.
Tecartus is sponsored by Kite Pharma Inc. Tecartus, a CAR T-cell therapy, is the first cell-based gene therapy approved by FDA for the treatment of MCL.
MCL is a rare form of cancerous B-cell non-Hodgkin’s lymphoma that usually occurs in middle-aged or older adults. In patients with MCL, B-cells, a type of white blood cell which helps the body fight infection, change into cancer cells that start to form tumors in the lymph nodes and quickly spread to other areas of the body.
Approval was based on ZUMA-2 (NCT02601313), an open-label, multicenter, single-arm trial of 74 patients with relapsed or refractory MCL who had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton tyrosine kinase inhibitor. Patients received a single infusion of brexucabtagene autoleucel following completion of lymphodepleting chemotherapy. The primary efficacy outcome measure was objective response rate per Lugano  criteria as assessed by an independent review committee.
Of the 60 patients evaluable for efficacy based on a minimum duration of follow-up for response of six months, the ORR was 87% (95% CI: 75, 94), with a complete remission (CR) rate of 62% (95% CI: 48, 74). The estimated median duration of response was not reached (range of 0+ to 29.2+ months) after a median follow-up time for duration of response of 8.6 months. Of all 74 leukapheresed patients, the ORR as assessed by an independent review committee was 80% (95% CI: 69, 88) with a CR rate of 55% (95% CI: 43, 67).
Tecartus is being approved with a risk evaluation and mitigation strategy, which includes elements to assure safe use. The risk mitigation measures for Tecartus are identical to those of the current REMS Program for another CAR-T therapy, Yescarta.
To further evaluate the long-term safety of Tecartus, FDA is also requiring the manufacturer to conduct a post-marketing observational study involving patients treated with Tecartus.
Tecartus was approved under the Accelerated Approval pathway and was granted Priority Review and Breakthrough Therapy designations. Tecartus also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
Keytruda receives two sBLA acceptances from FDA in TNBC in indications
Keytruda has received two sBLA acceptances from FDA for the treatment of triple negative breast cancer:
FDA has accepted and granted priority review for a new sBLA seeking accelerated approval for Keytruda in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10), based on the phase 3 KEYNOTE-355 trial. FDA has set a target action date of Nov. 28, 2020.
FDA also accepted for standard review a new sBLA for Keytruda for the treatment of patients with high-risk early-stage TNBC, in combination with chemotherapy as neoadjuvant treatment, and then as a single agent as adjuvant treatment after surgery, based on the phase 3 KEYNOTE-522 trial. The target action date for this application is March 29, 2021.
Keytruda is sponsored by Merck. These are the first U.S. applications for Keytruda in breast cancer.
The applications are based on data from the KEYNOTE-355 and KEYNOTE-522 trials, respectively. In KEYNOTE-355, Keytruda plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with chemotherapy alone in patients whose tumors expressed PD-L1 at CPS ≥10.
Approximately 38% of patients enrolled in KEYNOTE-355 had tumors expressing PD-L1 at CPS ≥10. As previously announced, the trial will continue without changes to evaluate the other dual primary endpoint of overall survival.
In KEYNOTE-522—the first randomized trial of an anti-PD-1 therapy in the neoadjuvant/adjuvant setting for TNBC—neoadjuvant Keytruda plus chemotherapy resulted in a statistically significant increase in pathologic complete response in patients with early-stage TNBC, regardless of PD-L1 expression.
The Keytruda regimen also demonstrated a favorable trend for the other dual primary endpoint of event-free survival. As previously announced, Keytruda plus chemotherapy was granted Breakthrough Therapy designation by FDA for the neoadjuvant treatment of patients with high-risk early-stage TNBC.
HIF-2α inhibitor MK-6482 receives FDA Breakthrough Designation for Von Hippel-Lindau Disease-associated RCC
The hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor MK-6482, a novel investigational candidate, received Breakthrough Designation from FDA for the treatment of patients with von Hippel-Lindau disease-associated renal cell carcinoma with nonmetastatic RCC tumors less than three centimeters in size, unless immediate surgery is required.
HIF-2α inhibitor MK-6482 is sponsored by Merck.
FDA also granted orphan drug designation to MK-6482 for VHL disease. These designations are based on data from a phase II trial evaluating MK-6482 in patients with VHL-associated clear cell RCC.
Engineered macrophage immunotherapy receives IND clearance from FDA
FDA has cleared an investigational new drug application for CT-0508, an anti-human epidermal growth factor receptor 2-targeted chimeric antigen receptor macrophage.
CT-0508 is sponsored by Carisma Therapeutics Inc.
Under this IND, Carisma intends to initiate its phase I, first-in-human, multi-center study in patients with recurrent or metastatic HER2 overexpressing solid tumors after failure of approved HER2 targeted agents.
“This will be the first time that an engineered macrophage has progressed successfully to the in-patient study phase and represents a new chapter for Carisma: advancing from a preclinical discovery-stage company to a clinical development stage company,” Steven Kelly, president and chief executive officer, said in a statement.
Historically, cell therapies have encountered key challenges treating solid tumors, including limited trafficking to the tumor site, an immunosuppressive tumor microenvironment, and the heterogeneous expression of tumor-associated antigens, but Carisma’s preclinical findings suggest that CAR-M therapy could overcome these challenges.
“Our preclinical findings indicate that CAR-M have the ability to mount a broad immune response against cancers, and the acceptance of the CT-0508 IND brings this technology to patients with incurable solid tumors,” Michael Klichinsky, co-inventor of the CAR-M technology, scientific co-founder, and vice president of discovery at Carisma Therapeutics.
The planned clinical trial will be conducted at two trial sites—University of Pennsylvania in and University of North Carolina—and will enroll patients with different types of recurrent or metastatic cancers with HER2 overexpressing solid tumors.
“HER2 is overexpressed not only in breast and gastroesophageal cancers, but in a wide variety of epithelial origin solid tumors, such as non-small cell lung, colorectal, bladder, and pancreatic cancers,” Debora Barton, chief medical officer at Carisma Therapeutics, said in a statement.
BDTX-189 receives FDA Fast Track Designation for solid tumors harboring HER2 or EGFR mutations
BDTX-189 has received Fast Track Designation from FDA for the treatment of adult patients with solid tumors harboring an allosteric human epidermal growth factor receptor 2 mutation or an epidermal growth factor receptor or HER2 Exon 20 insertion mutation who have progressed following prior treatment and who have no satisfactory treatment options.
BDTX-189, an orally available, irreversible small molecule inhibitor, is sponsored by Black Diamond Therapeutics, Inc. BDTX-189 is Diamond Therapeutics lead product candidate designed to selectively inhibit the activity of a broad range of previously unaddressed oncogenic driver mutations of the ErbB kinases in EGFR and HER2.
“While targeted therapies, such as kinase inhibitors, have transformed the treatment of cancer, only a small percentage of patients with metastatic cancer have tumors with genetic profiles that could make them eligible for an approved precision oncology medicine,” David M. Epstein, president and chief executive officer of Black Diamond Therapeutics, said in a statement.
Tagrisso receives FDA Breakthrough Therapy Designation for adjuvant treatment of stage IB-IIIA EGFR-mutated lung cancer
Tagrisso (osimertinib) has received Breakthrough Therapy Designation from FDA for the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated non-small cell lung cancer after complete tumor resection with curative intent.
Tagrisso is sponsored by AstraZeneca.
“Patients with early-stage EGFRm lung cancer often experience recurrence even after successful surgery and adjuvant chemotherapy, yet there are currently no approved targeted treatments to improve outcomes,” José Baselga, executive vice president of Oncology R&D said in a statement.
FDA granted the Breakthrough Therapy Designation based on data from the phase III ADAURA trial.
In the trial, Tagrisso demonstrated a statistically significant and clinically meaningful improvement in disease-free survival in the adjuvant treatment of Stage IB-IIIA EGFRm NSCLC patients, reducing the risk of disease recurrence or death by 79% (HR 0.21; 95% CI 0.16-0.28; p<0.0001) in a key secondary endpoint. In April 2020, an independent data monitoring Committee recommended the trial to be unblinded two years early based on its determination of overwhelming efficacy.
Tagrisso is approved for the first-line treatment of patients with metastatic EGFRm NSCLC and for the treatment of metastatic EGFR T790M mutation-positive NSCLC in the U.S., Japan, China, and the EU.
Piqray receives approval in Europe for HR+/HER2- advanced breast cancer with a PIK3CA mutation
Piqray (alpelisib) received approval from the European Commission in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine therapy as monotherapy.
Piqray is sponsored by Novartis.
Piqray is the first and only treatment specifically approved for people with advanced breast cancer whose tumors harbor a PIK3CA mutation, which stimulates tumor growth and is associated with poor response to therapy.
This approval follows a positive opinion granted in May by the Committee for Medicinal Products for Human Use of the European Medicines Agency based on the phase III SOLAR-1 trial showing that Piqray nearly doubled median progression-free survival compared to fulvestrant alone.
Overall response rate was more than doubled when Piqray was added to fulvestrant compared to fulvestrant alone.