Entrectinib Results Emphasize Need for NTRK Detection

Liam Davenport

July 07, 2020

Although fusions in the neurotrophic receptor tyrosine kinase (NTRK) gene are rare in gastrointestinal carcinomas (found in fewer than 5% of cases), they should be looked for, inasmuch as treatment with the TRK inhibitor entrectinib (Rozlytrek, Genentech/Roche) can achieve robust and durable responses, say researchers.

This point was made during several presentations at the virtual World Conference on Gastrointestinal Cancer (WCGC) 2020 on July 1.

Entrectinib and similar agents that act on NTRK fusion genes are described as tumor agnostic, in that they are biomarkers that define the cancer rather than the organ of origin.

The US Food and Drug Administration last year granted accelerated approval of entrectinib for patients with locally advanced or metastatic NTRK-expressing solid tumors that have progressed following prior therapies. The drug can also be used as a first-line treatment when there are no effective therapies.

At the meeting, Manish R. Patel, MD, Department of Medicine, University of Minnesota, in Minneapolis, and colleagues presented combined results from the ALKA-372-001, STARTRK-1, and STARTRK-2 studies of entrectinib.

They identified 12 gastrointestinal carcinoma patients among 74 adults with locally advanced/metastatic NTRK fusion-positive, TRK inhibitor-naive solid tumors who had undergone at least 6 months of follow-up.

Many of these 12 patients had colorectal cancer (58%) or pancreatic cancer (24%).

Treatment with entrectinib elicited an overall response rate of 50%, which consisted entirely of partial responses.

The median duration of response was 12.9 months, which was largely driven by a median duration of response of 15.1 months among colorectal cancer patients, vs 10.0 months among pancreatic cancer patients and 9.3 in the patient with cholangiocarcinoma.

The median progression-free survival was 7.1 months across the whole cohort. It was 8.0 months for pancreatic cancer patients and 12.0 months for the patient with cholangiocarcinoma.

The median overall survival was 16 months.

Patel said that this "demonstrates that entrectinib induces durable and clinically meaningful systemic responses in patients with gastrointestinal carcinomas harboring NTRK fusions."

He noted that entrectinib is "overall very well tolerated, with very few dose interruptions or reductions, and the discontinuation rate was very low." The majority of adverse events were of grade 1/2. The most common event was change in taste, which occurred in 37.3% of patients. There were no treatment-related deaths.

"The main take-away point from this abstract is that, though they are rare, if we identify patients with NTRK fusions during the course of the disease, we can offer them benefit from entrectinib, and I would argue that...we should be screening patients for NTRK fusions much more frequently," Patel added.

In the second study, a Belgian team performed immunohistochemistry (IHC) analysis followed by next-generation sequencing on archived samples of biliopancreatic cancers to determine the prevalence of NTRK fusions.

They found just one fusion among almost 150 biliary tract cancers and none in nearly 300 pancreatic adenocarcinomas.

Lead author Anne Demols, MD, PhD, Department of Gastroenterology and Gastrointestinal Oncology, CUB Hôpital Erasme, Brussels, Belgium, said the results show that, "consistent" with their low frequency in solid tumors, NTRK gene fusions are "also rare" in biliopancreatic cancers.

"Given this low frequency, testing and identification are of high clinical importance, due to possible treatment with pan-TRK inhibitors," she said.

She added that a two-step diagnosis is recommended, in that it is both "time saving" and economical, and that next-generation sequencing is "mandatory" to confirm a positive result on IHC.

For discussant Juan W. Valle, MD, professor of medical oncology at the University of Manchester, United Kingdom, the results of the second study reinforce the take-home message of the first.

He said that "two-step diagnosis can preselect patients suitable for next-generation sequencing assay, and what we saw from the previous [study] is that the therapeutic implications make this an important diagnosis."

Valle noted that there is an "immortal time bias" in the trial analysis, because patients had to be well enough to undergo at least 6 months of follow-up, and that "future work will focus on the best platform to use for known, as well as the identification of new, fusion partners."

He highlighted the "improved response rate and progression-free survival" achieved with entrectinib among patients with gastrointestinal cancers harboring NTRK fusions, which will benefit patient outcomes.

Pashtoon Kasi, MD, a gastrointestinal oncologist at the University of Iowa Holden Comprehensive Cancer Center, Iowa City, commented on Twitter that, for him, the results were more than just about the impressive response rate but how "brisk, robust, and durable these tend to be."

In his experience, even patients with stage IV disease who have responded to entrectinib have been able to undergo "secondary 'curative' resections."

https://twitter.com/pashtoonkasi/status/1278377749162479616?s=21

The ALKA-372-001, STARTRK-1 and STARTRK-2 studies were sponsored by F. Hoffmann-La Roche Ltd. The study by Demols and colleagues was funded by a research grant from Bayer Health. Patel reports relationships with Nektar Therapeutic, MSD, and Fate Therapeutics. Demols reports relationships with Bayer, Ipsen, Vifor, Servier and Roche. Valle reports relationships with numerous companies.

World Conference on Gastrointestinal Cancer (WCGC) 2020: Abstract Oral-3 and Oral-4, presented July 1, 2020.

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