Larotrectinib Efficacy Confirmed in TRK+ GI Cancer

Jordan D. Berlin, MD

The efficacy of larotrectinib (Vitrakvi) has been confirmed in patients with heavily pretreated TRK fusion—positive gastrointestinal (GI) cancers. In a subset of patients with GI cancer who had participated in 1 of 3 clinical trials of the selective TRK inhibitor in pretreated locally advanced or metastatic solid tumors, the overall response rate (ORR) was 43% (95% CI, 18%-71%) and was 50% in patients with colon cancer,¹ reported Jordan D. Berlin, MD, at the 2020 Gastrointestinal Cancers Symposium.

Among responders, the median time to response was 1.8 months (range, 1.7-2.1). The duration of response ranged from 3.5 to more than 14.7 months, and the time on treatment ranged from 0.9 to more than 19.0 months.

At a median follow-up of 19.0 months, the median overall survival was 33.4 months (95% CI, 2.8-36.5) in this subset of patients with TRK fusion—positive GI cancers.

“We showed that patients with GI cancer are no different than the other cohorts [of patients] with TRK fusion cancers in the way they respond to larotrectinib. Responses are durable. One patient with colon cancer has an ongoing response at 20 months, which is remarkable,” said Berlin, associate director for Clinical Research and director of the phase I clinical trials program at Vanderbilt University in Nashville, Tennessee.

TRK fusions are generally rare, occurring in <1% of all solid tumors. “It’s a rare cohort, but it’s nice if you have something for that cohort,” he added.

Larotrectinib is a first-in-class, selective inhibitor of TRK approved for the treatment of adult and pediatric patients with TRK fusion—positive cancers.² TRK fusions are oncogenic drivers of various adult and pediatric tumors and arise from rearrangements between neurotrophic tyrosine receptor kinase (NTRK) 1, 2, or 3 genes and an unrelated gene.¹

In a primary analysis of 55 patients with tumors harboring TRK fusions, larotrectinib exhibited tumor agnostic activity in 17 distinct tumor types with an investigator-assessed ORR of 80%.³ That rate was confirmed in the expanded dataset, said Berlin.

Fourteen patients with TRK fusion—positive GI cancers from a total of 159 enrolled patients treated on either the NCT02122913, SCOUT (NCT02637687), or NAVIGATE (NCT02576431) trials formed the population for this analysis.1 All were treated with oral larotrectinib at 100 mg twice daily, until disease progression, withdrawal, or unacceptable toxicity.

The median patient age for the GI cancer subset was 68.0 years (range, 32.0-84.0). Nine of the patients had ≥2 prior lines of therapy. The best response to the most recent therapy was 1 instance of a partial response (PR); 4 others had stable disease (SD). Of the 14 with GI cancer, 8 had colon cancer, 2 had cancer of the bile duct, 2 had pancreatic cancer, 1 had cancer of the appendix, and 1 had liver cancer. Twelve patients had NTRK1 gene¬ fusions and 2 had NTRK3 gene fusions. Eight patients had stage IV cancer at initial diagnosis. Thirteen patients received prior systemic therapy (7 of whom had 2 prior lines and 2 who had ≥3 prior lines), 12 had surgery, and 1 underwent radiotherapy.

By tumor type, of the 8 patients with colon cancer, 4 had a PR and 4 had SD as their best response; of the 2 patients with pancreatic cancer, 1 had a PR and 1 had SD; of the 2 patients with bile duct cancer, 1 had a PR; and the 1 patient with cancer of the appendix had SD. Response could not be determined in the 1 patient with liver cancer. Overall, 6 patients had a PR and 6 had SD.

At data cutoff, 4 patients with colon cancer and 1 with pancreatic cancer were alive and without disease progression. Median progression-free survival (PFS) was 5.3 months (95% CI, 2.2-9.0) for the patients with colon cancer (range, 1.5-16.7+).

The 6-month rate of PFS from the start of treatment in all patients with TRK fusion GI cancers was 22%, and the 12-month rate was 11%. The 12-month OS rate was 69%.

Seven of the 8 patients with colon cancer were microsatellite instability (MSI)-high, which is consistent with the literature showing that, “patients with TRK fusion cancer are predominantly identified in the MSI-high subset of patients with colorectal cancer,” said Berlin.

Nine patients experienced grade-3 or -4 treatment-emergent adverse events (TEAEs), with 2 occurrences each of grade 3/4 anemia, bile duct obstruction, hyperbilirubinemia, and sepsis. Two patients had grade-5 TEAEs: 1 with intestinal perforation and 1 with small intestinal obstruction. Seven patients required dose modification (missed, skipped, or delayed dose) due to AEs, but none needed dose reduction.

“Across cancers, I believe that if patients have good performance status and have the potential to be treated, it’s worthwhile to do next-generation sequencing [NGS]. I think TRK fusions are among the things you should be testing for,” Berlin said. “It’s a rare cohort but because the drug can work, it’s hard to say that you should miss that.”

References

1. Berlin J, Hong DS, Deeken JF, et al. Efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal cancer. J Clin Oncol. 2020;38(suppl 4;abstr 824). bit.ly/2TV7s3g.
2. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA website. bit.ly/36mQkWv. Published November 26, 2018. Accessed January 24, 2020.
3. Drilon A, Laetsch TW, Kummar S, et al: Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi: 10.1056/NEJMoa1714448.

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