Larotrectinib Continues to Show High Efficacy, Low Toxicity in TRK Fusion-Positive Cancers

The tumor-agnostic TRK inhibitor larotrectinib (Vitrakvi) demonstrated marked antitumor efficacy, including objective responses that often persisted for years, and a favorable safety profile.

David M. Hyman, MD

The tumor-agnostic TRK inhibitor larotrectinib (Vitrakvi) demonstrated marked antitumor efficacy, including objective responses that often persisted for years, and a favorable safety profile in adult and pediatric patients with TRK fusion—positive cancers, according to results from an integrated analysis of 3 clinical trials presented at the 2019 ESMO Congress.

Treatment with the drug led to objective responses in 79% of 153 evaluable patients across multiple tumor types (95% CI, 72-85). The overall response rate included complete responses in 24 (16%) patients and partial responses in 97 patients (63%). An additional 12% of patients had stable disease as best response, resulting in a clinical benefit rate of 91%.

In a subset of 108 patients with confirmed responses, the median duration of response was 35.2 months (95% CI, 22.8-NE), David M. Hyman, MD, chief, Early Drug Development Service and medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues reported in a poster session.

“These data confirm the marked tissue-agnostic efficacy and long durability of response in patients with TRK fusion—positive cancer treated with larotrectinib,” the investigators concluded. “Larotrectinib continued to demonstrate a favorable long-term safety profile. Screening patients for NTRK gene fusions should be actively considered.”

Invited discussant Christian Dittrich, MD, professor of medicine, Vienna University School of Medicine, characterized the overall response rate as “sensational.” He noted that the complete responses included 3 pathologic complete responses in patients with infantile fibrosarcoma.

“Altogether, 15 different tumor entities have been responding [to the treatment],” said Dittrich.

The drug is relatively nontoxic, he added, showing very low rates of grade 3/4 adverse events.

The integrated analysis comprised the primary and supplementary cohorts enrolled in an adult phase I trial, the phase I/II SCOUT pediatric trial, and the phase II adult/adolescent NAVIGATE basket trial.

Reflecting the tumor-agnostic nature of the drug’s target, the trials represented 18 different tumor types. The most common tumor types were infantile fibrosarcoma (18%), thyroid cancer (16%), salivary gland cancer (13%), lung cancer (8%), and a variety of other soft-tissue sarcomas (23%).

The median age of the participants was 43, but ages ranged from <1 to 84. The analysis cohort consisted of 52 pediatric patients (33%) and 107 adults (67%), with an almost even distribution between male and female patients. The investigators reported that 35 patients (22%) received larotrectinib as their initial treatment. Additionally, 48 patients (30%) had received 1 prior systemic therapy, 34 (21%) had received 2, while 42 patients (26%) had receive 3 or more prior lines.

The gene fusions associated with the cancers were NTRK1 in 64 cases, NTRK2 in 4 patients, NTRK3 in 88 patients, and unconfirmed in 3 patients.

The 79% overall response rate in the integrated analysis was virtually identical to response rates observed in the primary (80%; 95% CI, 67-90) and supplementary (79%; 95% CI, 69-86) data sets. Among 12 evaluable patients with brain metastases, the overall response rate was 75%.

In addition to the 35.2-month median duration of response, landmark analyses showed that 75% of patients from the primary data set and 83% from the supplementary data set had responses lasting at least 12 months.

The 153 evaluable patients included in the integrated efficacy analysis had a median progression-free survival (PFS) of 28.3 months and a 12-month PFS of 67%. Median overall survival (OS) was 44.4 months, and 12-month OS was 88%.

The median time to objective response was 1.8 months (range of 0.9 to 6.1 months), and the median treatment duration was 8.0 months (range of 0.03 to 47.2 months).

An expanded safety population of 260 patients treated with larotrectinib showed no new safety signals. The most common treatment-emergent adverse events (TEAEs, any grade) were fatigue (33%), increased alanine aminotransferase (ALT; 28%), cough (28%), constipation (27%), anemia (27%), increased aspartate aminotransferase (AST; 27%), dizziness (25%), nausea (25%), vomiting (25%), diarrhea (24%), and pyrexia (20%). The most common grade 3/4 TEAE was anemia (10%, all grade 3). No other grade 3/4 TEAEs occurred in more than 5% of patients.

Treatment-related adverse events (TRAEs) were led by increased ALT (22%), increased AST (20%), dizziness (18%), fatigue (17%), nausea (13%), constipation (11%), and anemia (10%). Grade 3/4 TRAEs were extremely uncommon.

Hyman DM, van Tilburg CM, Albert CM, et al. Durability of response with larotectinib in adult and paediatric patients with TRK fusion cancer. Presented at ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Poster 445PD.

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