Silver Spring, Maryland, USA : The U.S. Food and Drug Administration (FDA) has granted accelerated approval to Vitrakvi (larotrectinib), a treatment for adult and pediatric patients whose cancers have a specific genetic feature (biomarker).
This is the second time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated. The approval marks a new paradigm in the development of cancer drugs that are “tissue agnostic.” It follows the policies that the FDA developed in a guidance document released earlier this year.
Vitrakvi is indicated for the treatment of adult and pediatric patients 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.
“Today’s approval marks another step in an important shift toward treating cancers based on their tumor genetics rather than their site of origin in the body,” said FDA Commissioner Scott Gottlieb, M.D. “This new site-agnostic oncology therapy isn’t specific to a cancer arising in a particular body organ, such as breast or colon cancer. Its approval reflects advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine. We now have the ability to make sure that the right patients get the right treatment at the right time. This type of drug development program, which enrolled patients with different tumors but a common gene mutation, wouldn’t have been possible a decade ago because we knew a lot less about such cancer mutations. Using our breakthrough therapy designation and accelerated approval processes, 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. 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.”
Research has shown that the NTRK genes, which encode for TRK proteins, can become fused to other genes abnormally, resulting in growth signals that support the growth of tumors. NTRK fusions are rare but occur in cancers arising in many sites of the body. Prior to today’s approval, there had been no treatment for cancers that frequently express this mutation, like mammary analogue secretory carcinoma, cellular or mixed congenital mesoblastic nephroma and infantile fibrosarcoma.
The efficacy of larotrectinib was studied in three clinical trials that 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.
Larotrectinib demonstrated a 75 percent overall response rate across different types of solid tumors. These responses were durable, with 73 percent of responses lasting at least six months, and 39 percent lasting a year or more at the time results were analyzed. Examples of tumor types with an NTRK fusion that responded to larotrectinib include soft tissue sarcoma, salivary gland cancer, infantile fibrosarcoma, thyroid cancer and lung cancer.
Vitrakvi received an accelerated approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need using clinical trial data that is thought to predict a clinical benefit to patients. Further clinical trials are required to confirm Vitrakvi’s clinical benefit and the sponsor is conducting or plans to conduct these studies.
Common side effects reported by patients receiving Vitrakvi in clinical trials include fatigue, nausea, cough, constipation, diarrhea, dizziness, vomiting, and increased AST and ALT enzyme blood levels in the liver. Health care providers are advised to monitor patient ALT and AST liver tests every two weeks during the first month of treatment, then monthly and as clinically indicated. Women who are pregnant or breastfeeding should not take Vitrakvi because it may cause harm to a developing fetus or newborn baby. Patients should report signs of neurologic reactions such as dizziness.
The FDA granted this application Priority Review and Breakthrough Therapy designation. Vitrakvi also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted the approval of Vitrakvi to Loxo Oncology.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
“Traditionally in cancer therapy, we’ve treated patients based on where their cancer came from, what part of the body. What makes Vitrakvi unique is that it works regardless of where the cancer came from as long as it has the specific mutation,” said Dr. David Hyman, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York.
While several drugs are approved to treat a variety of different cancers based on genetic mutations, Vitrakvi, known generically as larotrectinib, is the first that is approved from the beginning to treat cancers solely based on the mutation.
Keytruda was the first example of a drug approved to treat a genetic mutation. Originally FDA approved in 2014 to treat melanoma that had spread, the makers of Keytruda showed it could treat other tumor types, if they had the same mutation that drives some cases of melanoma. Now it’s used against a range of tumors, including breast cancer.
Vitrakvi treats a different genetic mutation involving genes called NTRK genes. Rarely, they can fuse together and cause the out-of-control growth that results in tumors.
“Prior to today’s approval, there had been no treatment for cancers that frequently express this mutation, like mammary analogue secretory carcinoma, cellular or mixed congenital mesoblastic nephroma and infantile fibrosarcoma,” the FDA said.
Anna Plaza says her daughter, Rihanna, is living proof of how well the drug can work if given to the right patient. When Rihanna was born in Bridgeport, Connecticut last year, she had an enormous mass on her arm.
“They didn’t know what was wrong. They just knew it was a mass and they covered it up with a Pamper and we needed to get transferred to another hospital because nobody knew what to do with us,” Plaza told NBC News.
“I was like, ‘oh my God, what am I going to do? What are we going to do?” she added. “It was horrible.”
Biopsies showed Rihanna had a rare tumor known as infantile fibrosarcoma, a malignant soft tissue tumor typically found in children under one year of age.
Chemotherapy did little to help the tiny baby. The family eventually was referred to the clinical trials being done to test the drug at Memorial Sloan-Kettering.
“It was a syrup. She would take it once in the morning, once at night.” Surprisingly, the baby liked it.
Three days later, the tumor was already shrinking.
“When we went back to Memorial Sloan-Kettering, they were even more shocked,” said Anna Plaza’s husband Enrique. “They were like ‘Whoa, we’ve never seen this process go fast. We’ve seen it in months, but so fast, within a week?’” he added.
“We were happy because they didn’t have to cut her arm off.”
Surgeons could much more easily remove the tumor afterwards. “If we hadn’t shrunk it first, she could had ended up with a forearm and a hand that didn’t work the way they should for the rest of her life,” said Dr. Todd Heaton, a pediatric oncologist who helped treat her.
Rihanna still goes for follow-up treatments and, as with so many targeted cancer therapies, only a small percentage of cancer patients are helped.
“For patients that have this mutation — it is a revolution for these patients,” Hyman said.
“But what we really have recognized about cancer is that it’s not a one-size-fits-all approach, and we need to apply the best therapy for every patient.”
Another roadblock — health insurance companies don’t always pay for the genetic tests needed to guide doctors to the targeted drugs. Hyman hopes having a specific FDA approval can help change that.
And these drugs are not cheap. Bayer, which owns the company that makes Vitrakvi, says it will cost $393,600 a year, while the pediatric syrup formulation will cost $11,000 a month.