Larotrectinib Induces 80% ORR in Advanced NTRK+ Solid Tumors

Larotrectinib induced an objective response rate of 80% in patients with advanced solid tumors who harbored&nbsp;<em>NTRK&nbsp;</em>gene fusions, according to results pooled from 3 small trials of the TRK inhibitor. Results were presented during the 2018 ESMO Congress.

Ulrick Lassen, MD

Larotrectinib induced an objective response rate of 80% in patients with advanced solid tumors who harboredNTRKgene fusions, according to results pooled from 3 small trials of the TRK inhibitor. Results were presented during the 2018 ESMO Congress.

The most recent follow-up data showed complete responses (CRs) in 10 of 55 patients and partial responses (PRs) in 34. Responses occurred in multiple tumor types and across the age range from infants to older adults.

A supplemental dataset comprising an additional 67 patients with TRK fusion cancers showed an overall response rate similar to that observed in the primary group, as reported at the 2018 ESMO Congress.

“Larotrectinib continues to demonstrate robust tumor-agnostic and age-agnostic antitumor activity against TRK fusion cancers, regardless of theNTRKgene or fusion partner involved,” said Ulrik Lassen, MD, of Rigshopitalet in Copenhagen. “The duration of response has improved with additional follow-up. Genomic profiling with assays capable of identifyingNTRKgene fusions should be strongly considered in patients with solid tumors of all histologies when determining systemic treatment options.”

Lassen noted thatNTRKgene fusions are rare, but they have been identified as oncogenic drivers in multiple tumor types. Larotrectinib is a small-molecule inhibitor of TRKA, TRKB, and TRKC. A liquid formulation of the drug allows treatment of infants and children and has pharmacokinetics equivalent to that of capsules.

Data for the analysis came from 3 small single-arm clinical evaluations of larotrectinib in patients with laboratory-confirmed TRK-fusion cancers: a phase I study of 8 adults with advanced solid tumors; a phase I/II trial involved 12 pediatric patients with advanced solid tumors; and a phase II basket trial involving adults and adolescents as young as 12 years with advanced solid tumors (n = 35).

The primary endpoint of the analysis was ORR. Secondary endpoints included duration of response, progression-free survival (PFS), and safety.

Lassen reported that 14 different tumor types were represented in the primary analysis. The study population had a balanced sex distribution. Age groups represented by the patients ranged from <2 years (n = 6) to ≥40 years (n = 31). About a third of the patients had received 3 or more prior treatment regimens.

Initial follow-up through July 17, 2017, showed an ORR of 80% in the 55 patients, including CRs in 16%. An updated analysis that encompassed follow-up through July 30, 2018, continued to show an ORR of 80%, including CRs in 18% of the patients.

After a median follow-up of 17.6 months, the median duration of response has yet to be reached in the primary dataset. Landmark analyses from July 2017 showed 83% of responses persisting at 6 months and 71% at 12 months. The updated analyses from July 2018 showed that 88% of responses were ongoing at 6 months and 75% at 12 months. The median time to onset of response was 1.8 months.

To explore the consistency of data from the 2 analyses of the primary dataset, investigators analyzed data from the supplemental cohort. The supplemental group had baseline characteristics similar to the primary study population.

After excluding 13 patients awaiting their initial response assessment, 54 patients remained for comparison with the primary dataset. The ORR for the supplemental group was 81%, including CRs in 17%. The ORR included 9 unconfirmed PRs pending confirmation and 1 surgical complete response. With a briefer median follow-up of 7.4 months, 93% of responses were ongoing at 6 months and 81% at 12 months.

An integrated analysis of all 109 evaluable patients yielded an ORR of 81%, including CRs in 17% of patients.

“The integrated dataset showed that larotrectinib is efficacious regardless of tumor type and regardless of patient age,” Lassen said.

Further reflecting the durability of larotrectinib’s treatment effect, the integrated analysis showed that 73% of all patients remained on treatment or had curative-intent surgery, including 84% of responding patients.

Safety data for 207 patients treated with larotrectinib suggested the drug is generally well tolerated and associated with low rates of grade 3/4 treatment-emergent adverse events (AEs). The most common AEs (all grades) were fatigue (36%), dizziness (29%), nausea (29%), constipation (27%), anemia (27%), increased ALT (26%), increased AST (26%), diarrhea (23%), and vomiting (23%).

The most common treatment-related adverse events (TRAEs) were dizziness (21%), increased ALT (21%), increased AST (19%), fatigue (18%), and nausea (15%). Grade 3/4 TRAEs were uncommon, with no type of event affecting more than 2% of patients.

Of the 122 patients included in the primary and supplemental datasets, only 1 patient discontinued larotrectinib because of an AE, Lassen reported.

In May 2018, the FDA granted a priority review to a new drug application (NDA) for larotrectinib for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors with anNTRKgene fusion. Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision on the NDA by November 26, 2018.


Lassen U, Albert CM, Kummar S, et al. Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 409O.