Bayer and Loxo Oncology have won FDA approval for Vitrakvi® (larotrectinib), the first cancer treatment with a tumor-agnostic indication at the time of initial authorization, with approval based on mutation type rather than on where in the body the tumor originated.

The first ever oral tyrosine kinase (TRK) inhibitor, Vitrakvi is indicated for adults and children with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.

NTRK gene fusions are genomic alterations that result in constitutively-activated chimeric TRK fusion proteins that can act as a driver of cancer, promoting cell proliferation and survival in tumor cell lines. Vitrakvi is designed to inhibit these proteins.

“The approval of Vitrakvi is a testament to the relentless prioritization of biology in the drug development process,” stated Loxo CEO Josh Bilenker, M.D. “It is now even more critical to screen patients of all ages with advanced solid tumors for actionable genomic insights that could benefit their care or aid in their referral to clinical trials.”

The FDA is tying continued approval for the indication upon showing clinical benefit in confirmatory trials—after granting Bayer and Loxo accelerated approval based on positive overall response rate (ORR) and duration of response results in three clinical trials.

Larotrectinib demonstrated a 75% ORR across different types of solid tumors, with 22% of patients achieving a complete response and 53% of patients achieving a partial response across various tumor types, including soft tissue sarcoma, salivary gland, infantile fibrosarcoma, thyroid, lung, melanoma, colon, gastrointestinal stromal tumor (GIST), cholangiocarcinoma, appendix, breast, and pancreas.

Six-Month Response Rate

As for the duration of response, 73% of responses lasted at least six months, and 39% lasted a year or more at the time results were analyzed, according to the FDA.

The trials included 55 pediatric and adult patients with solid tumors that had an identified NTRK gene fusion without a resistance mutation and were metastatic or where surgical resection was likely to result in severe morbidity. These patients had no satisfactory alternative treatments or had cancer that progressed following treatment.

Vitrakvi has warnings and precautions of neurotoxicity, hepatotoxicity, and embryo-fetal toxicity. The most common adverse reactions (≥20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).

“Based on [Monday]’s approval, TRK fusion-positive cancers may be the first type of cancer that is more appropriate to define based on a shared genetic mutation than by the organ in which it arises. This distinction marks a new chapter for precision medicine,” David Hyman, M.D., chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSK) and a global principal investigator for one of the clinical trials of Vitrakvi, in a statement released by MSK.

The FDA reviewed Vitrakvi under its Priority Review program, and previously granted its Breakthrough Therapy Designation, Rare Pediatric Disease Designation, and Orphan Drug Designation to Vitrakvi.

“We support innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. This is especially true when it comes to pediatric cancers,” FDA Commissioner Scott Gottlieb, M.D., said in an agency statement. “We’re committed to continuing to advance a more modern framework of clinical trial designs that support more targeted innovations across disease types based on our growing understanding of the underlying biology of diseases like cancer.”

Second Biomarker-Based Approval

Vitrakvi is the second cancer treatment approved by the FDA based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated. The first such approval came in May 2017, when the agency authorized an additional indication for Merck’s anti-programmed cell death protein 1 (anti-PD-1) monoclonal antibody Keytruda® (pembrolizumab) as a treatment pediatric and adult patients with unresectable or metastatic microsatellite instability-high or mismatch repair solid tumors.

Loxo and Bayer co-developed Vitrakvi and another Loxo cancer-fighting TRK inhibitor, LOXO-195, through an exclusive global collaboration launched in November 2017. Loxo has led the ongoing clinical studies as well as the filing in the U.S., with Bayer leading ex-U.S. regulatory activities and worldwide commercial activities.

Bayer is awaiting European Medicines Agency reviews of its Marketing Authorization Application (MAA), submitted by the company in August.

In the U.S., Bayer and Loxo Oncology have agreed to co-promote Vitrakvi and LOXO-195. Vitrakvi will be immediately available as oral capsules as well as a liquid formulation for adults and children, Bayer and Loxo said. Bayer said it plans to maximize access to Vitrakvi for U.S. patients through two programs, the Vitrakvi Commitment ProgramTM and the TRAK AssistTM patient support program.

The Vitrakvi Commitment Program will refund the cost of Vitrakvi to payers, patients, and third-party organizations paying on behalf of patients, in the event eligible patients do not experience clinical benefit within 90 days of treatment initiation. Eligible patients include those who have tested positive for an NTRK gene fusion, have not received clinical benefit within 90 days of treatment initiation, and received Vitrakvi from an in-network specialty pharmacy.

The TRAK Assist patient support program is designed to provide comprehensive reimbursement support and patient assistance services. Bayer said patients seeking more information and eligibility requirements should call 1-844-634-TRAK (8725).

An additional resource for patients in need of financial assistance, Bayer said, is its Bayer U.S. Patient Assistance Foundation, a charitable organization that helps eligible patients get their Bayer prescription medicine at no cost.