Durability of Responses With Larotrectinib Demonstrated in TRK+ Lung Cancer Population

Alexander Drilon, MD

Larotrectinib (Vitrakvi) induced durable responses in patients with TRK fusion–positive lung cancer, even in patients with central nervous system (CNS) metastases, according to results pooled from 2 trials of the TRK inhibitor and presented in a poster at the European Society of Medical Oncology (ESMO) Virtual Congress 2020.

After more than a year of follow-up, the median progression-free survival (PFS), median overall survival (OS), and the median duration of response (DOR) were all not yet reached in this patient population.

“Larotrectinib demonstrated a high response rate with long durability and extended survival benefit in patients with TRK fusion lung cancer,” the study authors, led by Alexander Drilon, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, wrote in their poster.

The analysis included 14 evaluable patients with lung cancer harboring an NTRK gene fusion from 2 trials of larotrectinib (NCT02576431 and NCT02122913). The studies enrolled patients with locally advanced or metastatic solid tumors who had progressed on or were unresponsive to other available therapies and were unfit for standard therapies. In each trial, larotrectinib was administered at 100 mg twice daily continuously until disease progression, unacceptable toxicity, or withdrawal. Patients could also continue on larotrectinib after progression if benefit continued.

Of the 14 patients, the median age was 52 years (range, 25-76) and 57% were male. The majority (79%) of the patients had gene fusions involving NTRK1 and 21% had an NTRK3 fusion, and half of the patients had CNS metastases at baseline. Ninety-three percent of the patients received prior systemic therapy and the median number of prior therapies was 3 (range, 1-5), with 50% receiving at least 3 regimens. Only 2 patients achieved a response greater than stable disease to prior therapy.

The objective response rate (ORR) was 71% (95% CI, 42%-92%) and among the 7 patients with baseline CNS metastases, the ORR was 57% (95% CI, 18%-90%). One patient achieved a 100% reduction in their CNS lesions by the fourth cycle and 1 patient without CNS metastases had a complete response. Only 1 patient experienced disease progression.

Treatment duration ranged from 2.1 months to 39.6+ months and 9 patients (64%) were continuing to receive treatment at the time of data cutoff on July 15, 2019, which included 3 patients with CNS metastases and 3 who continued treatment beyond progression.

Median follow-up for DOR was 12.9 months and the median DOR was not reached (95% CI, 5.6 to not estimable [NE]). Median follow-up for PFS was 14.6 months and the median PFS was not reached (95% CI, 7.2-NE). At 12+ months, 69% were progression free. Median OS was also not reached (95% CI, 17.2-NE) at a median follow-up of 12.6 months; 91% were still alive at 1 year.

No new or unexpected safety findings were observed in the TRK fusion–positive lung cancer population, the study authors noted. The majority of adverse events (AEs) were grade 1 or 2 but 6 patients experienced a grade 3 event; 2 of these patients experienced treatment-related grade 3 events of hypersensitivity and myalgia. No grade 4 or 5 events were reported.

The most common any-grade AEs with larotrectinib in this group were myalgia (57%), cough (50%), dizziness (50%), arthralgia (43%), aspartate aminotransferase (AST) increase (36%), diarrhea (36%), alanine aminotransferase (ALT) increase (29%), constipation (29%), fatigue (29%), and pyrexia (29%). Frequent treatment-related AEs of any grade included myalgia (36%), dizziness (29%), ALT increase (29%), and AST increase (21%).

Dose reductions as a result of AEs were required in 2 patients due to ALT and AST increase for 1 patient and decreased neutrophil count in the other patient, all of which were considered to be due to treatment. No AEs led to permanent treatment discontinuation.

Larotrectinib received accelerated FDA approved for the treatment of adult and pediatric patients with solid tumors harboring an NTRK gene fusion without a known acquired resistance mutation and that are metastatic or unfit for surgery in November 2018. The tumor-agnostic approval was based on findings pooled from 3 different trial including a total of 159 patients with TRK fusion–positive cancers treated with larotrectinib.

NTRK fusions can be found in more than 80% of certain rare cancer types, but in non–small cell lung cancer, these fusions are found in only 0.1% to 1% of cases. Overall, larotrectinib demonstrated an objective response rate of 79% in the total patient population.

“These findings validate TRK fusions as therapeutic targets and strengthen support for routine testing for NTRK gene fusions in patients with lung cancer,” Drilon et al concluded.

_Reference

_{Drilon A, Moreno V, Patel J, et al. Efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer. Presented at: 2020 ESMO Congress; September 19–21, 2020; Virtual. Abstract 1289P.}