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Bayer Continuing Vitrakvi Studies to Improve Understanding of Activity In Specific Tumor Types

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NEW YORK – Encouraged by data showing that previously treated, refractory cancer patients with NTRK fusions are having sustained responses to larotrectinib (Vitrakvi), Bayer is pushing ahead with studies to pin down the drug's efficacy in specific tumor types and exploring its use in earlier cancer settings.

Additionally, given the rarity of NTRK fusions in cancer patients, the drugmaker is also investing in programs to expand test access.

In 2018, larotrectinib became the second drug the US Food and Drug Administration approved with a tissue-agnostic indication for refractory adult and pediatric cancer patients with NTRK fusions. Despite being able to market the drug to cancer patients regardless of their cancer histology, Scott Fields, head of Bayer's global oncology development program, said that the company remains focused on learning about the drug's efficacy in specific tumor types.

NTRK fusions are exceedingly rare, occurring in less than 1 percent of solid tumors. "We have to get more patients with various tumor types to really understand the drug. That's our first priority in children and adults," said Fields.

At the American Society of Clinical Oncology's virtual annual meeting last month, researchers presented data involving 116 adult patients with solid tumors and NTRK fusions and reported that 71 percent saw their tumors shrink. The response didn't favor a particular type of tumor but showed particularly encouraging activity in those with brain metastases. Among 14 patients whose cancer had spread to the brain, 10 had a partial response.

At the time of data cut off on July 15, 2019, 53 percent of patients were still on treatment. Moreover, 21 percent of patients continued treatment after progressing. "It's not just that they respond. These responses last a long time," said Fields. "And then, the people who are taking the drug, they're having a good quality of life."

Fields said that Bayer is continually adding patients to the ongoing larotrectinib trials in order to accrue more efficacy data across a wide range of histologies and tumor types. For example, it is opening enrollment of patients in the NAVIGATE trial and pediatric patients in the SCOUT trial.

Additionally, in the US, Bayer is starting a non-interventional trial to track patients who receive larotrectinib, according to Joe Germino, VP of medical affairs, US Oncology at Bayer. The study includes eight different cohorts, each tracking patients with a specific type of cancer. 

"Data are very limited on any particular tumor type, and there are so many different tumor types that potentially could have this [gene fusion]," said Germino. "We want to get more data on individual tumor types and how the patients of those individual tumor types respond." This includes factors like potential side effects, so that both patients and physicians can get a better idea of what to expect in the real-world setting.

Germino said that Bayer is also having early-stage discussions about running combination studies. As an example, he mentioned that if enough patients have an NTRK fusion and have high microsatellite instability, researchers could study the combination of a checkpoint inhibitor with larotrectinib as an early-stage option.  The aim would be to see if the combination could boost responses and the duration of the responses in patients, he said.

Another possible drug combination that's under consideration is larotrectinib with Bayer's investigational selitrectinib to tackle resistance to first-generation TRK inhibitors.

"Patients, even with these very long responses, will most likely recur at some point in time. These patients generally did not have any treatment available to them at the time they went on this. Now, they're pretty much at the end of the line for treatment," said Fields. "Selitrectinib was developed because when the patient stops responding, what can happen is you will get new mutations in a place that locks [out] larotrectinib from working. But this other drug can still work."

However, this strategy to overcome treatment resistance works only if the resistance mechanism relies on a TRK mutation. "We've seen so far that much of the time it will recur in the TRK fusion. This provides another option for patients who have progressed on a TRK inhibitor but still have a TRK-driven tumor," he said.

Fields further highlighted a study being conducted by the Children's Oncology Group to explore larotrectinib as a first-line treatment for children with solid tumors, or other rare cancers, such as patients with acute leukemias and NTRK fusions.

Testing for a rare mutation

In addition to continuing to study the safety and efficacy of larotrectinib, Bayer is also working to expand access to genetic testing so patients with rare NTRK fusions can be identified.

NTRK fusions are rare and often missed. To that end, in order to assure that all patients who can receive larotrectinib are given the option, Bayer is rolling out a no-cost NTRK gene fusion testing program for patients with RAI-refractory differentiated thyroid cancer and metastatic colorectal cancer with high microsatellite instability called Test4TRK.

Within the program, Bayer will cover the cost of testing for up to 500 patients in the US, but not the costs of extracting a tumor specimen. Enrolled patients will be tested by NeoGenomics on an RNA-based next-generation sequencing test, called NTRK NGS Fusion Profile. If patients have enough tissue, they will also receive the Pan-Tropomyosin Receptor Kinase Immunohistochemistry test.

The testing program is focusing on thyroid cancer patients in particular, since these tumors tend to have NTRK fusions more frequently than other cancers. In smaller, independent pathology studies, fusions have been found in around 10 percent of papillary thyroid cancer patients. Germino added that although thyroid cancer patients don't commonly have their tumors sequenced, research suggests that a relatively high proportion may harbor NTRK fusions, around six percent. "In MSI-high patients, we know that if they progress on an immunotherapy, like a PD-1 inhibitor, they have a high likelihood of having an NTRK fusion," he said.

Still, NTRK fusions are rare enough that the testing program offers an opportunity to identify patients who have them and learn more about these types of cancers, according to Marcia Brose, director of the Center for Rare Cancers and Personalized Therapy at the Abramson Cancer Center of the University of Pennsylvania, and a collaborator in developing the testing platform. "Part of the hope from this program will be that not only will we identify patients who can benefit from [larotrectinib], but we'll also find out a little bit more about what percentage of people do actually have the mutation in that fusion," she said.

When Brose found out that larotrectinib could be a treatment option for her patients, she started testing for NTRK fusions in her patients at the time and found two patients out of 50 who were positive.

"It's not a zero number. It's not a huge number. But it's people that you wouldn't want to miss this option," she said. "If I am treating any solid tumor at this point, I am going to try to get as much genetic information as I can usually before I even start systemic therapy, because almost every therapy I can think of has more side effects than the highly specific TRK inhibitors that are now coming out."

Currently, the standard of care for RAI-refractory thyroid cancer are one of two multi-kinase inhibitors sorafenib (Bayer and Onyx's Nexavar) or lenvantinib (Eisai's Lenvima). "While fairly well tolerated. They do have significant side effects, including significant elevations in blood pressure, weight loss, sometimes diarrhea and fatigue," said Brose. She has not observed these side effects in patients on larotrectinib, barring some patients who have reported muscle cramps.

The free testing program, Brose said, is not so much for big cancer centers like her clinic, but for areas of the country where insurance may not cover the testing.

"A lot of the investigators out there have known about the results of larotrectinib since it was approved, and they have said that one of the limiting factors is getting the testing covered. This is providing a way," she added. "When you're starting to deal with very personalized therapies and rare cancers, and you don't have the large numbers of patients to do large clinical trials, you have to come up with innovative ways to find the patients, get the testing covered, and then be able to provide the drug."

The Bayer and NeoGenomics testing program will ultimately test for more than just NTRK fusions. "We do have a broader panel, and I think in the long run, a broad panel is what would make sense for most cancer patients," said Germino. "Many of these alterations that are driving mutations [for cancers], they're not the most abundant. But if you start adding them all up, you can find patients who will benefit from more targeted therapies, which would be expected to have fewer side effects and possibly better efficacy than what's currently available."