NEW YORK – While the TRK inhibitor larotrectinib (Bayer's Vitrakvi) is effective among cancer patients with NTRK gene fusions, it is far less effective among patients harboring other alterations in the NTRK gene, a new analysis has found.
In 2018, the US Food and Drug Administration approved larotrectinib to treat adult and pediatric patients with solid tumors marked by an NTRK gene fusion. This was the second tumor-agnostic precision oncology drug approved by the FDA after the 2017 approval of pembrolizumab in patients with advanced solid tumors with microsatellite instability/mismatch repair deficiency, who are out of options.
NTRK gene fusions are rare events in cancer, but they are found across a range of tumor types. Other genetic alterations in the NTRK gene also occur in different cancers, though it's been unclear whether larotrectinib may be effective as a treatment for patients with those changes.
To guide oncologists choosing treatments for patients with NTRK alterations, the University of Texas MD Anderson Cancer Center's David Hong and his colleagues examined larotrectinib's efficacy among both patients with NTRK gene fusions and among patients with non-fusion alterations. But according to results presented by Hong at the American Association for Cancer Research's Virtual Annual Meeting this week, larotrectinib is not as effective among patients with non-fusion genetic alterations in NTRK.
"These data strongly support the clinical importance of testing for NTRK gene fusions in order to identify patients who would benefit from larotrectinib treatment," Hong said. When the FDA approved larotrectinib, it did not simultaneously approve a companion test that could specifically detect NTRK fusions, but there are a number of next-generation sequencing platforms that can gauge these events.
For their analysis, Hong and his colleagues pooled data from three clinical trials of adult and pediatric cancer patients treated with larotrectinib, the NCT02122913, SCOUT, and NAVIGATE trials. NTRK gene status was determined through local molecular testing and two of the studies at first enrolled patients regardless of their fusion status.
Within these cohorts, 159 patients had NTRK fusions, which most commonly affected the NTRK1 or NTRK3 genes. Seventeen different tumor types were represented in this subset, most commonly soft tissue sarcoma, infantile fibrosarcoma, and thyroid cancer.
But 73 patients did not have NTRK gene fusions. Many instead had NTRK point mutations, amplifications, or rearrangements, as well as other alterations. Twenty-five tumo types were represented in this subset, including lung cancer, soft tissue sarcoma, and colon cancer.
Following treatment with larotrectinib, most of the patients in the NTRK fusion group experienced a decrease in tumor size. The objective response rate to larotrectinib in this group was 79 percent, with 16 percent of patients experiencing a complete response and 63 percent experiencing a partial response to larotrectinib, Hong reported. The median duration of response was 35.2 months.
Patients with other genetic alterations, though, didn't fare as well on larotrectinib, as their tumors continued to increase in size. The objective response rate was 1 percent, with no complete responses. Only one patient had a partial response to larotrectinib therapy and that lasted 3.7 months.
That patient, Hong noted, had an NTRK1 amplification. He added there have been reports in the literature suggesting that patients with NTRK amplifications might benefit from NTRK inhibitor treatment. But none of the other patients with NTRK amplifications in this analysis experienced any tumor shrinkage. This effect would have to be further explored in a clinical trial, he said.
Two patients in the non-fusion group who had stable disease following larotrectinib treatment were found upon closer examination to have NTRK gene fusions.
Survival endpoints varied between the groups, with the fusion group exhibiting a median progression-free survival of 28.3 months and an overall survival of 44.4 months, while the non-fusion group had a median progression-free survival of 1.8 months and a median overall survival of 10.7 months.
This confirms that larotrectinib is effective in treating patients with NTRK fusions. But the data also casts a shadow on the likelihood that the drug has efficacy among patients who have other NTRK gene alterations.
At the meeting, Yale Cancer Center's Patricia Lo Russo said in her discussion that the findings are in line with a recent study published in Cancer. In that study, researchers from the University of California, San Diego, matched patients' genetic alterations to drug treatments to examine progression-free survival. They found a difference in progression-free survival for patients when their drug was matched to their genetic fusion versus other molecular aberrations. That is, it was more important, LoRusso said, to target the gene fusion than other molecular aberrations to influence survival.
She also noted that in this new study some patients with NTRK gene fusions for whom larotrectinib was effective eventually progressed, raising questions about why they do so and whether resistance could be managed through drug combinations or second-generation TRK inhibitors.