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Rozlytrek Studies Show Durable Responses in Patients With Brain Metastases


NEW YORK – Patients with NTRK fusion-positive tumors that have spread to their brain showed durable responses with Genentech's Rozlytrek (entrectinib) in a study with the longest follow-up and largest cohort of patients with brain metastases.

The research combined results from three clinical trials — the Phase I STARTRK-1 trial, Phase I ALKA-372-158-001 trial, and the Phase II basket study STARTRK-2 — in which patients with advanced solid tumors with gene fusions in NTRK received Rozlytrek. The analysis included 121 patients, of which 26 had measurable central nervous system metastases at baseline.

This analysis, published in Clinical Cancer Research earlier this month, includes twice as many patients with CNS metastases than a 2020 analysis of these three trials and provided a better look at the rate of NTRK fusions across tumor types and how well they respond to Rozlytrek, which has tissue-agnostic approval. The study also has an additional year of follow-up compared to the earlier analysis. Across all patients in the study, including those with and without CNS metastases, the response rate on Rozlytrek was 61.2 percent, with 19 patients seeing a complete response.

The study included patients with salivary gland, non-small cell lung, thyroid, colorectal, breast, neuroendocrine, pancreatic, unknown primary, gynecologic, bile duct, head and neck, and upper gastrointestinal cancers, as well as sarcoma and neuroblastoma. Researchers reported responses in all tumor types except in neuroblastoma. The analysis only included one patient with neuroblastoma and that patient died within a week of their first treatment; the researchers noted that the role of Rozlytrek in the death was unclear. The majority of patients who responded did so quickly, with tumors shrinking within the first month of treatment, said Christian Rolfo, associate director for clinical research at the Center for Thoracic Oncology within Mount Sinai's Tisch Cancer Institute, and a senior author of the published paper.

The US Food and Drug Administration granted accelerated approval to Rozlytrek in 2019 for adult and adolescent patients whose cancers have NTRK gene fusions and are out of treatment options and for patients with metastatic non-small cell lung cancer whose tumors are ROS1-positive. In order to convert Rozlytrek's accelerated approval to a full approval, Genentech must provide data from ongoing studies in the postmarket setting to better characterize the drug's efficacy and safety profile.

Based on this updated analysis, the researchers concluded there is more evidence supporting the use of Rozlytrek in patients with CNS metastases. The data showed similar response rates among patients with investigator-assessed baseline CNS metastases and those without, 57.7 percent versus 62.1 percent, respectively. Two patients with CNS metastases even experienced complete responses on Rozlytrek, the researchers found.

Among 11 patients who had blinded independent central review (BICR)-confirmed CNS metastases at baseline, the intracranial response rate on treatment was 63.6 percent. The median intracranial duration of response was 22.1 months, and the median intracranial progression-free survival was 19.9 months.

"The most important thing here is the activity in the brain," Rolfo explained. "The intracranial overall response rate is very high and that confirms the data that we know, even from preclinical studies, that this compound is really made to penetrate the brain."

Rozlytrek's success in crossing the blood-brain barrier may help differentiate it from other pan-tumor TRK inhibitors, including its main market competitor Bayer's Vitrakvi (larotrectinib).

Vitrakvi was the first TRK inhibitor approved in the US in 2018 for patients with refractory solid tumors with NTRK gene fusions, who are out of treatment options. While Vitrakvi has also shown activity in the brain, Rolfo noted that Rozlytrek was specifically designed to cross the blood-brain barrier and remain in the CNS. The researchers noted that Vitrakvi is more easily exported from the brain because of its interaction with P-glycoprotein, a protein that removes foreign substances in cells, but Rozlytrek has a much lower interaction with that protein, which helps it remain in the brain and in the CNS.

In a 2020 analysis of three Vitrakvi clinical trials, the response rate in 14 patients with investigator-assessed CNS metastases was 71 percent. Meanwhile, the response rate among these patients by BICR was 66 percent.

According to Rolfo and colleagues, comparing the CNS efficacy seen with Vitrakvi in those earlier studies and with Rozlytrek in their latest analysis is difficult due to differences in the number of patients with baseline CNS metastases and other reporting methods. For example, the authors noted that the Vitrakvi studies primarily used investigator-assessed response compared to BICR-assessed response in the Rozlytrek trials.

Overall, the latest Rozlytrek data are positive for refractory patients with CNS metastases. "These data are demonstrating a durable systemic and intracranial response, and we believe this [drug] can address the unmet need for CNS-active treatment in this NTRK-positive patient population, specifically in some tumors where we don't have a lot of options in cancer treatment," Rolfo said.

Their positives do come with caveats, however. The researchers pointed out, for example, that patients with NTRK fusion-positive colorectal cancer had a significantly lower response rate than patients with other types of cancer. Only 20 percent of colorectal cancer patients responded to Rozlytrek compared to a response rate of 61 percent across all tumor types.

Rolfo and colleagues attributed this to NTRK fusion-positive colorectal cancer patients having a distinct pathophysiologic profile. Specifically, they found that NTRK fusion-positive colorectal tumors tended to have high tumor mutation burden and high microsatellite instability. They concluded that oncologists should consider TMB and MSI status for colorectal cancer patients with NTRK fusions, since this has implications for TRK inhibitor treatment.

The finding also underscores the need for more widespread testing of colorectal cancer patients, which Rolfo said can improve understanding of the role of NTRK gene fusions.

NTRK fusions are most common in secretory breast carcinoma, mammary analog secretory carcinoma, and certain rare pediatric tumors. However, these fusions occur in less than 1 percent of more common solid tumors like melanoma, lung, breast, colorectal, and pancreatic cancers.

NTRK gene fusions are typically rarer and not well understood in certain tumor types, such as gynecological cancers, cholangiocarcinoma, and gastrointestinal cancers like pancreatic and colorectal cancer. But in order to fully understand the biology of NTRK-positive tumors, Rolfo advocated for increased testing patients with these types of cancer.

"It's important to encourage the community to test these patients because the response rates [on TRK inhibitors] are high," he said. "Also, the inclusion of methodologies like liquid biopsy can help us to identify the mechanisms of resistance and help continue research that is ongoing for new drugs targeting other mutations in the NTRK pathway."