Larotrectinib Maintains Long-Term Efficacy in Advanced GI Cancers Harboring NTRK Fusions

Larotrectinib produced durable responses in patients with NTRK fusion–positive locally advanced or metastatic gastrointestinal cancer, particularly in those with colorectal cancer.

Larotrectinib (Vitrakvi) produced durable responses in patients with NTRK fusion–positive locally advanced or metastatic gastrointestinal (GI) cancer, particularly in those with colorectal cancer (CRC), according to long-term data from the phase 2 NAVIGATE basket trial (NCT02576431) presented at the 2022 ESMO World Congress on Gastrointestinal Cancer.1

Among the total 34 patients treated with larotrectinib, the overall response rate (ORR) was 33% (95% CI, 18%-52%), which included a complete response (CR) rate of 3% and a partial response (PR) rate of 30%. Additionally, 45% of patients had stable disease and 12% experienced disease progression; 9% had a best overall response (BOR) that was not determined. Notably, 9 of 29 patients who had measurable disease at baseline experienced tumor shrinkage.

In the patients with CRC (n = 19), larotrectinib elicited an ORR of 47% (95% CI, 24%-71%), with CR and PR rates of 5% and 42%, respectively. Additionally, 42% of these patients achieved stable disease, 5% experienced progressive disease, and 5% had a BOR that was not determined.

“These results highlight the importance of identifying NTRK gene fusions in patients with GI cancer, particularly in those with microsatellite instability–high [MSI-H] CRC,” lead study Elena Garralda, head of the Early Drug Development Unit at Vall d’Hebron Institute of Oncology in Barcelona, Spain, wrote in a presentation of the data.

Larotrectinib is a first-in-class, highly selective TRK inhibitor that is active in the central nervous system. In November 2018, the FDA granted accelerated approval to larotrectinib 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 treatments or that have progressed following treatment.2

The regulatory decision was based on results from 3 clinical trials, including prior data from NAVIGATE, which showed that larotrectinib generated an ORR of 41% across 17 evaluable patients with GI cancer.

NAVIGATE enrolled patients who were at least 12 years of age and who had locally advanced or metastatic solid tumors harboring an NTRK1, NTRK2, or NTRK3 gene fusion.3 NTRK fusion status was determined by local CLIA-accredited or similar laboratories. Patients were required to have received prior standard therapy for their tumor type or have no satisfactory alternative treatments.

Once enrolled, all patients received 100 mg of larotrectinib twice per day. The primary end point of the trial was investigator-assessed ORR per RECIST v1.1 criteria. Secondary end points consisted of duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The data cutoff for the presentation at the meeting was July 20, 20221. Among all patients, the median age was 63.5 years (range, 32-90). Most patients were female (62%), had an ECOG performance status of 1 (65%), had prior systemic therapy (85%), and had prior surgery (82%). Regarding the number of prior systemic regimens received, 15% of patients had 0 prior lines, 32% had 1 prior line, 35% had 2 prior lines, and 18% had 3 or more prior lines.

Fifty-six percent of patients had CRC. Among those with CRC, 58% had MSI-H disease; in 37% of patients, MSI-H was not detected and 5% had unknown status. Other tumor types included pancreatic (18%), cholangiocarcinoma (12%), appendix (3%), duodenal (3%), gastric (3%), hepatic (3%), and esophageal (3%). Regarding gene fusion status, 71% of patients had NTRK1 fusions, 24% had NTRK3 fusions, and 6% had NTRK2 fusions.

The duration of treatment for all patients with GI cancer ranged from 0.2+ months to 32.2+ months. A total of 4 patients continued to receive larotrectinib for at least 4 weeks after disease progression. The median time to response was 1.9 months (range, 1.7-5.0).

At a median follow-up of 26.4 months, the median DOR with larotrectinib in all patients was 7.3 months (95% CI, 3.5-27.3). The median PFS in all patients was 5.4 months (95% CI, 2.7-9.0) at a median follow-up of 5.4 months. The median OS among all patients was 12.5 months (95% CI, 6.1-33.4) at a median follow-up of 7.7 months.

In those with CRC, the 12-month DOR rate was 67% (95% CI, 29%-100%) at a median follow-up of 17.8 months. At a median follow-up of 5.6 months, the median PFS with larotrectinib was 5.5 months (95% CI, 2.7–not estimable). In patients with CRC, the median OS was 12.5 months (95% CI, 6.1-36.5) at a median follow-up of 7.8 months.

Regarding safety, most treatment-related adverse effects (TRAEs) were grade 1 or 2. Eighteen percent of patients experienced at least 1 grade 3/4 TRAE, which included increase alanine aminotransferase and aspartate aminotransferase, anemia, abnormal hepatic function, hyperesthesia, and nausea.

No patients discontinued treatment with larotrectinib due to TRAEs.


  1. Garralda E, Hong DS, Xu R, et al. Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion gastrointestinal (GI) cancer: an expanded dataset. Ann Oncol. 2022;33(suppl 4):S370. doi:10.1016/j.annonc.2022.04.430
  2. FDA approves larotrectinib for solid tumors with NTRK gene fusions. News release. FDA. November 26, 2018. Accessed August 24, 2022.
  3. A study to test the effect of the drug larotrectinib in adults and children with NTRK-fusion positive solid tumors (NAVIGATE). Updated August 9, 2022. Accessed August 24, 2022.