publication date: May. 4, 2018

Drugs and Targets

Novartis’ Kymriah gets second FDA approval—for large B-cell lymphoma

FDA approved Kymriah (tisagenlecleucel) suspension for intravenous infusion for its second indication – the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.

The drug is sponsored by Novartis Pharmaceuticals Corp.

Kymriah is not indicated for patients with primary central nervous system lymphoma. Developed in collaboration with the University of Pennsylvania, Kymriah became the first chimeric antigen receptor T cell therapy to receive regulatory approval in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

The FDA approval is based on the pivotal phase II JULIET clinical trial, the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL.

JULIET was conducted in collaboration with Penn, and is the largest study examining a CAR-T therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the U.S., Canada, Australia, Japan and Europe, including: Austria, France, Germany, Italy, Norway and the Netherlands. In the JULIET trial, patients were infused in the inpatient and outpatient setting.

In this Novartis-sponsored study, Kymriah showed an overall response rate of 50% (95% confidence interval, 38% – 62%), with 32% of patients achieving a complete response and 18% achieving a partial response in 68 patients evaluated for efficacy. The median duration of response was not reached among these patients, indicating sustainability of response.

In all patients infused with Kymriah (n=106), severe or life-threatening (grade III/IV) CRS, defined by the Penn Grading Scale, occurred in 23% of patients. CRS is a known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm.

Eighteen percent of all infused patients experienced grade III/IV neurologic events, which were managed with supportive care. Encephalopathy, a distinctive neurotoxicity associated with CAR-T therapies, was seen as severe or life-threatening in 11% of patients. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema have occurred.

Grade III/IV cytopenias lasting more than 28 days included thrombocytopenia (40%) and neutropenia (25%), and grade 3/4 infections occurred in 25%. The most common (>20%) adverse events in the JULIET study are CRS, infections, pyrexia, diarrhea, nausea, fatigue, hypotension, edema and headache.

Kymriah is now the only CAR-T cell therapy to receive FDA approval for two distinct indications in non-Hodgkin lymphoma and B-cell ALL.

Kymriah is an immunocellular therapy that is a one-time treatment manufactured individually for each patient using the patient’s own T cells. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence.

In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

To ensure all hospitals and their associated clinics are aware of how to manage the risks of cytokine release syndrome and neurological toxicities, Kymriah is available through a Risk Evaluation and Mitigation Strategy program. The REMS program serves to inform and educate healthcare professionals about the risks that may be associated with Kymriah treatment.

To support safe patient access, Novartis has established a network of certified treatment centers throughout the country, which are fully trained on the use of Kymriah and appropriate patient care, and there are currently treatment centers which are certified and fully operational to begin treatment of eligible patients with DLBCL.

In January 2018, the European Medicines Agency granted accelerated assessment to the Marketing Authorization Application for Kymriah for the treatment of children and young adults with r/r B-cell ALL and for adult patients with r/r DLBCL who are ineligible for ASCT.


FDA approves Tafinlar and Mekinist for BRAF V600-mutant melanoma

The FDA granted regular approval to Tafinlar (dabrafenib) and Mekinist (trametinib) in combination for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node, following complete resection.

The drugs are sponsored by Novartis Pharmaceuticals Corp.

Approval was based on COMBI-AD (NCT01682083), an international, multi-center, randomized, double-blind, placebo-controlled trial in 870 patients with stage III melanoma with BRAF V600E or V600K mutations, and pathologic involvement of regional lymph node. Patients were randomly allocated (1:1) to receive dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily or two placebos for up to 1 year.

The major efficacy outcome was relapse-free survival. Patients who received the combination treatment had a statistically significant improvement in RFS compared with those receiving placebo.

Patients in the combination arm experienced fewer recurrences/deaths at the time of data-cutoff: 38% (n=166), compared with 57% (n=248) in the placebo arm (hazard ratio 0.47; 95% confidence interval 0.39, 0.58; p<0.0001). The estimated median RFS was not reached for patients who received the combination therapy, compared with 16.6 months (95% CI: 12.7, 22.1) for those receiving placebo.

The recommended doses for the adjuvant treatment of melanoma are 150 mg of dabrafenib orally twice daily and 2 mg of trametinib orally once daily until disease recurrence or unacceptable toxicity, for up to one year.

FDA granted this application priority review. Dabrafenib in combination with trametinib was granted breakthrough therapy designation and orphan drug designation for this indication.  

Tafinlar + Mekinist is the first oral targeted adjuvant combination therapy to demonstrate significant clinical benefit in patients with a BRAF V600 mutation, following complete surgical resection

In the EU, Tafinlar in combination with Mekinist is approved for patients with a BRAF V600 mutation in metastatic melanoma and non-small cell lung cancer.

In the US, Tafinlar in combination with Mekinist is approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or K mutations, as detected by an FDA-approved test, and for the adjuvant treatment of melanoma with BRAF V600E or K mutations and involvement of lymph node following complete resection. Tafinlar + Mekinist is also approved for BRAF V600E mutation-positive NSCLC.


FDA grants priority review to cemiplimab in advanced cutaneous squamous cell carcinoma

Regeneron Pharmaceuticals Inc. and Sanofi today announced the FDA has accepted for priority review the Biologics License Application for cemiplimab for the treatment of patients with metastatic cutaneous squamous cell carcinoma or patients with locally advanced CSCC who are not candidates for surgery.

Cemiplimab is an investigational human monoclonal antibody targeting the checkpoint inhibitor PD-1 and was granted Breakthrough Therapy designation status by the FDA in September 2017. The target action date for the FDA decision is October 28, 2018.

The BLA submission is based on a phase II pivotal, single-arm, open-label clinical trial of cemiplimab for advanced CSCC (EMPOWER-CSCC 1) in addition to phase I data from two advanced CSCC expansion cohorts.

Both clinical trials enrolled patients with metastatic CSCC and patients with locally advanced CSCC who were not candidates for surgery. Topline results from EMPOWER-CSCC 1 were previously announced in December 2017.

Phase I expansion cohort results were presented at the 2017 American Society of Clinical Oncology Annual Meeting. Updated results from both clinical trials will be presented at the 2018 ASCO Annual Meeting.

In the European Union, the European Medicines Agency accepted for review in April 2018 the Marketing Authorization Application for cemiplimab in patients with metastatic CSCC or patients with locally advanced CSCC who are not candidates for surgery.

Cemiplimab is being jointly developed by Regeneron and Sanofi under a global collaboration agreement and was invented by Regeneron using the company’s proprietary VelocImmune technology that yields optimized fully-human antibodies.


Genocea files IND for neoantigen cancer vaccine candidate GEN-009

Genocea Biosciences Inc., the biopharmaceutical company developing neoantigen cancer vaccines, announced the filing of an Investigational New Drug Application with the FDA to begin a Phase I/IIa clinical program testing the safety, immunogenicity, and clinical efficacy of GEN-009, the company’s lead personalized neoantigen cancer vaccine candidate.

Genocea plans to commence the GEN-009 phase I/IIa clinical program later this year, first studying the safety and immunogenicity of GEN-009 as monotherapy in cancer patients with no evidence of disease, but at high risk of relapse. This part of the program is expected to enroll at least six patients previously treated for melanoma, non-small cell lung cancer, head or neck cancer, or urothelial carcinoma.

Genocea said it expects to announce the first top-line data from this study in the first half of 2019. Following proof of immunogenicity, Genocea expects to study GEN-009 in combination with checkpoint inhibitors in patients with advanced or metastatic solid tumors and as monotherapy in patients who have failed checkpoint inhibitory therapy.

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