Updated Data Continue to Showcase Efficacy of Larotrectinib, Entrectinib in NSCLC

Kelly Davio
Published: Thursday, Apr 11, 2019

Dr Alexander Drilon
Alexander Drilon, MD
Larotrectinib (Vitrakvi) showcased an overall response rate (ORR) of 71% in patients with non–small cell lung cancer (NSCLC) harboring NTRK gene fusions, according to findings presented at the 2019 European Lung Cancer Congress (ELCC).1

The subset data were from the LOXO-TRK-14001 (NCT02122913) and NAVIGATE (NCT02576431) studies, which contributed to the FDA’s accelerated approval of the TRK inhibitor in November 2018. The agent is indicated for the treatment of adult and pediatric patients with solid tumors that have an 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 therapies or that have progressed following treatment.

In the studies, of 7 patients with metastatic lung adenocarcinoma who were evaluable for larotrectinib response, there was 1 complete response (CR), 4 partial responses (PRs), and 2 patients with stable disease. Additionally, the median time to response was 1.8 months, and the median duration of response (DOR) was not reached.

Additionally, an integrated analysis of the ALKA-372-001, STARTRK-1 and STARTRK-2 trials evaluated the activity of entrectinib in patients with locally advanced or metastatic ROS1 fusion–positive NSCLC, which was also presented at the 2019 ELCC. Results showed that the multikinase inhibitor is highly active and well tolerated in this patient population, including those who have CNS metastases.2

Based on these findings, the FDA granted a priority review designation to a new drug application for entrectinib as a treatment for select adult and pediatric patients with NTRK fusion–positive locally advanced or metastatic solid tumors, as well as those with metastatic ROS1-positive NSCLC in February 2019.

“The takeaway message is that entrectinib is an active drug for ROS1 fusion–positive lung cancers. The hope is that at some point in the future, maybe we’ll get the drug approved for this subset of patients. The question then becomes, “When do I use entrectinib versus crizotinib (Xalkori)?,” said Alexander Drilon, MD, clinical director, Early Drug Development Service, associate professor of thoracic oncology service, Memorial Sloan Kettering Cancer Center.

In an interview with OncLive during the 2019 ELCC, Drilon discussed these findings with larotrectinib in NTRK fusion–positive tumors and entrectinib in ROS1 fusion–positive NSCLC.

OncLive: Could you give some background to TRK inhibition and the findings presented at this year’s meeting?

Drilon: First off, TRK fusions are a bona fide driver of both lung cancers and many other different cancers. In fact, larotrectinib was approved late last year, in November 2018, for any TRK fusion–positive cancer, regardless of what the cancer looks like under the microscope. That was really a landmark approval, because it was the first targeted therapeutic that was approved for a genomic signature and really agnostic of tumor type.

At the 2019 ELCC, we specifically pulled out the outcomes of NSCLC patients who harbor TRK fusion in their cancers, and there were 11 patients who were part of the larotrectinib series, and we found that there was a high response rate to therapy. It was a 71% ORR, considering that the denominator isn’t large. We saw a disease reduction in all patients who had therapy, there were deep responses to treatment, and 1 had a CR to larotrectinib.

In terms of durability, the median DOR was actually not reached yet. Most patients who received larotrectinib for their TRK fusion–positive lung cancers remain on therapy. The patient who had been on [treatment] the longest is already pushing 2.5 years.

The last thing we featured was the intracranial activity of larotrectinib—recognizing that there were 3 out of 11 patients who had brain metastases on this trial. This has been a question that’s come up for the TRK field in general, on whether or not these drugs have substantial activity in the CNS. What we saw was that patients had global overall disease control, meaning that patients had disease regression both extracranially and intracranially.

Thus far, we weren’t able to calculate intracranial response rate, but we featured a case of an older woman in her mid-70s who was found to have a TRK fusion in her stage IV lung cancer. She, unfortunately, had multiple asymptomatic brain metastases, and she refused standard-of-care platinum-doublet therapy after hearing the phenomenal results that we’ve achieved with larotrectinib across different cancers. She had a confirmed PR to therapy with a near complete intracranial response. By volumetric analysis, this was almost a 95% reduction in her tumor burden in the CNS.

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