Larotrectinib Elicits Durable Responses, Extends Survival in TRK+ Sarcomas

Shivaani Kummar, MD, FACP

Larotrectinib (Vitrakvi) was found to induce a high response rate with long durability and improve survival in patients with TRK-positive sarcomas, according to results from an analysis of 3 clinical trials (NCT02122913, NCR02576431, NCT02637687) that were presented during the 2020 Connective Tissue Oncology Society (CTOS) Virtual Meeting.¹

Among 25 adult patients with sarcomas, the agent elicited an objective response rate (ORR) of 72% (95% CI, 51-88). Additionally, in 19 patients with soft tissue sarcoma (STS), the ORR was 68% (95% CI, 43-87); this included 3 complete responses (CRs) and 10 partial responses (PRs). The ORR in 4 patients with gastrointestinal stromal tumor (GIST) was 100%; 1 patient achieved a CR and 3 had PRs. In 2 patients with bone sarcoma, the ORR was 50%. One patient with bone sarcoma not otherwise specified experienced a PR, while 1 patient with chondrosarcoma achieved stable disease.

“Larotrectinib demonstrated a high response rate with long durability and extended survival benefit in patients with TRK fusion sarcomas, including STS of various histologies, GIST, and bone sarcoma,” Shivaani Kummar, MD, FACP, director of the Phase I Clinical Research Program in the Division of Oncology; professor of medicine and associate division chief of Faculty Affairs in the Division of Medical Oncology of the Department of Medicine of the Stanford School of Medicine; and co-director of the Translational Oncology Program at Stanford, Stanford Cancer Institute, said in a presentation during the meeting.

The first-in-class, highly selective, central nervous system–active TRK inhibitor larotrectinib has received regulatory approval in more than 40 countries for use in adult and pediatric patients with TRK-positive cancer. In November 2018, the FDA granted an accelerated approval to larotrectinib for adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no acceptable alternative treatments or have progressed after treatment.

In a previous pooled analysis of 175 patients with TRK-positive cancer who were treated in 3 clinical trials with larotrectinib, an ORR of 78% was reported, along with a median progression-free survival (PFS) of 36.8 months.²

The analysis presented during the 2020 CTOS Virtual Meeting included 25 adult patients with TRK-positive sarcomas who were 18 years of age or older who had sarcomas harboring NTRK gene fusions and who were treated with larotrectinib in 3 clinical trials. In these trials, patients received oral larotrectinib at a twice-daily dose of 100 mg, with 1 patient having received the agent at a twice-daily dose of 150 mg.

The primary end point of the analysis was ORR, per investigator assessment in accordance with RECIST v1.1 criteria.

The median age of participants was 45 years and the majority, or 52%, were female. Of the 25 patients included, 76% had soft tissue sarcoma; 4 patients had malignant peripheral nerve sheath tumor, 3 had epithelioid spindle sarcoma, 2 had carcinoma not otherwise specified, 2 had stromal tumor, and 8 had tumors defined as other. Moreover, 16% had GIST and 8% had bone sarcoma; of the latter group, 1 patient had chondrosarcoma and 1 had carcinoma not otherwise specified.

Regarding prior treatment, 96% of patients had undergone surgery, 52% had received radiotherapy, and 68% had prior systemic therapy. Thirty-two percent of patients received 0 prior systemic therapies, 20% had 1 prior line, 24% had 2 prior lines, and 24% had 3 or more prior lines.

The median time to response to larotrectinib was 1.8 months (range, 0.9 months-3.5 months). The duration of treatment ranged from 0.1 months to 51.6+ months. At the time of data cutoff, which was July 15, 2019, 40% of patients were still receiving treatment and 28% continued to receive treatment following progression.

Additional results showed that at a median follow-up of 22.9 months, the median duration of response (DOR) with larotrectinib was not estimable (95% CI, 7.2–not estimable [NE]). At 24 months, the DOR rate was 68% (95% CI, 42-94). Among patients with GIST, the DOR ranged from 7.6 months-31+ months. In the patient with bone sarcoma who responded to treatment, the median DOR was 7.7 months.

At a median follow-up of 22.1 months, the median PFS was 28.3 months (95% CI, 6.8-NE). Moreover, the 24-month PFS rate with larotrectinib was 52% (95% CI, 28-77). At a median follow-up of 21.4 months, the median overall survival (OS) was 44.4 months (95% CI, 44.4-NE); at 24 months, the OS was 91% (95% CI, 80-100). Among patients with soft tissue sarcoma, the median OS was NE (95% CI, NE-NE) at a median follow-up of 14.5 months; at 24 months, the OS rate was 89% (95% CI, 74-100).

With regard to safety, the toxicities reported with larotrectinib were mainly grade 1 or 2 in severity. No unexpected safety signals were reported in the analysis. Forty-four percent of patients experienced grade 3 or 4 treatment-emergent adverse effects (TEAEs), although none of these toxicities were determined to be associated with larotrectinib.

Twelve percent of patients discontinued treatment because of TEAEs. One of these patients had gait disturbance, which was grade 3; another patient had spinal cord compression, which was grade 3; and 1 patient had viral infections, which was grade 3, as well as malignant neoplasm progression, which was grade 5.

References

1. Kummar S, Hong DS, McDermott R, et al. Larotrectinib efficacy and safety in adult patients with TRK fusion sarcomas. Presented at: 2020 CTOS Virtual Meeting; November 18-21, 2020; Virtual. https://bit.ly/2L4pE8B.

2. McDermott R, van Tillburg CM, Farago AF, et al. 1955P survival benefits of larotrectinib in an integrated dataset of patients with TRK fusion cancer. Ann Oncol. 2020;31(suppl 4):S1101-S1102. doi:10.1016/j.annonc.2020.08.1347