Promising Responses Observed With Larotrectinib in NTRK Fusion-Positive Cancers

Marcia Brose, MD, PhD

Larotrectinib (Vitrakvi) induced durable tumor-agnostic efficacy as treatment of adult patients with TRKfusion-positive cancer and showed a favorable safety profile, according to an analysis of expanded data pooled from 3 larotrectinib studies, including a phase 1 in adult patients with cancer (NCT02122913), the phase 2 NAVIGATE study (NCT02576431), and a phase 1/2 in pediatric patients (NCT02637687).

These findings underscore the importance of routine NTRK gene fusion testing in patients with any solid tumors, according to the study investigators. The responses seen with larotrectinib in this analysis appeared durable, with a complete response (CR) rate of 10% and a partial response (PR) rate of 60%.

“Larotrectinib is extremely well-tolerated, and when we look at the poster from ASCO, we can actually see there are very few grade 3 toxicities that are attributed to larotrectinib,” study author Marcia Brose, MD, PhD, director of the Center for Rare Cancers and Personalized Therapy, director of the Thyroid Cancer Therapeutics Program, associate professor of Otorhinolaryngology: Head and Neck Surgery at the Hospital of the University of Pennsylvania, and associate professor of Medicine at Penn Medicine, told Targeted Oncology. “With a 10% CR rate and all the patients getting really deep responses, it just blows almost all of the comparative chemotherapies in each of these cancers out of the park.”

The objective response rate (ORR) was 71% (95% CI, 62-79), and these responses were observed regardless of tumor or gene fusion types. CRs were seen in 12 patients (10%) and PRs were observed in 70 patients (60%). Nineteen patients had stable disease (16%), 11 patients had progressive disease (9%), and 4 were not determined (3%).

At baseline, 14 patients (12%) had brain metastases, and the ORR for this population was 71% (95% CI, 42-92). Ten patients had a PR (71%), 2 had stable disease (14%), and 2 had progressive disease (14%).

After a median follow-up of 17.4 months, the median duration of response (DOR) was 35.2 months (95% CI, 21.6-not estimable [NE]), and the median time to response was 1.8 months (range, 0.9-6.0). The 12-month DOR was 76%. The longest ongoing treatment duration on the study was approaching 4 years and 4 months (range, 0.1-51.6+)

The median progression-free survival (PFS) was 25.8 months (95% CI, 15.2-NE) after a median follow-up of 14.6 months, and the PFS rate at 12 months or longer was 61%. Median overall survival (OS) had not yet been reached at a median follow-up of 15.8 months (95% CI, 36.5-NE), but the OS rate at 12 months or longer was 87%.

Treatment-emergent adverse events (TEAEs) were observed in 115 of the 116 patients (99%), of which 98 were considered to be related to larotrectinib by the investigator (84%). Fifty-one patients reported grade 3/4 TEAEs (44%), but only 13 experienced grade 3 or greater TEAEs that were related to the study drug (11%).

TEAEs related to larotrectinib included grade 3 alanine aminotransferase (ALT) increase (3%), grade 4 ALT increase (2%), grade 3 anemia (2%), grade 4 aspartate transaminase (AST) increase, grade 3 dizziness (1%), grade 3 nausea (1%), and grade 3 myalgia (1%). Other frequent TEAEs of any grade included dizziness (29%), ALT increase (25%), AST increase (22%), fatigue (20%), constipation (16%), myalgia (15%), nausea (13%), and weight gain (12%).

The safety profile seen was consistent with prior findings from that of the overall population, which included all patients in the 3 clinical trials who received at least 1 dose of larotrectinib. In this analysis, treatment was discontinued in 8 patients (7%) due to a TEAE, and 1 patient discontinued due to a TEAE related to the study drug. Dose reductions occurred in 12 patients (10%) because of TEAEs.

Eight patients (7%) experienced TEAE-related deaths, but the majority of deaths on this study were due to the progression of underlying oncological disease or related complications. No deaths related to larotrectinib were reported.

Patients had to have locally advanced or metastatic disease and progressed or were unresponsive to available therapies to be included for enrollment, or they had to be unfit for standard chemotherapy or have no standard therapy available. Larotrectinib was given twice daily at 100 mg until disease progression, study withdrawal, or unacceptable toxicity. Patients were allowed to continue treatment beyond progression if benefit continued to be observed.

The primary end point of the study was investigator-assessed ORR, and secondary end points included DOR, PFS, OS, and safety, which included variables such as the frequency of AEs and dose modifications.

Overall, 116 patients with TRK fusion-positive cancers were enrolled. The cancer types seen in this study included thyroid cancer (22%), salivary gland (19%) soft tissue sarcoma (16%), lung (12%), colon (7%), melanoma (5%), breast (5%), gastrointestinal stromal tumor (3%), bone sarcoma (2%), pancreatic (2%), cervix (1%), bone sarcoma (1%), chloangiosarcoma (2%), hepatic (1%), prostate (1%), and unknown (1%) cancers.

The median age of patients was 56 years (range, 19-84), and the majority of patients (53%) were female. Sixty-three patients had an NTRK3 gene fusion (54%), 50 patients had an NTRK1 gene fusion (43%) and 3 patients had an NTRK2 gene fusion (3%). The majority of patients (91%) had received prior surgery, 78% had prior systemic therapy, and 62% had prior radiotherapy. Additionally, 32% had 3 or more prior lines of systemic therapy, 21% had 2 prior lines, 25% had 1 prior line, and 22% had no prior lines of systemic therapy.

TRK proteins play an important role in the development and functioning of the nervous system, and these proteins are encoded by the NTRK genes, which are identified in a number of tumor types. These gene fusions can produce oncoproteins that drive development of the tumor through constitutive kinase domain activity. Larotrectinib is a first-in-class, highly-selective central nervous system-active TRK inhibitor, which has previously received regulatory approval in Brazil, Canada, the United States, Europe, Israel, Hong Kong, Korea, and Saudi Arabia for the treatment of both adult and pediatric patients with cancer who harbor an NTRK gene fusion.

“I think this means we are in a new ballpark for the responses that we can expect or hope for. Ever since I was a fellow, with metastatic disease, the best we could hope for was usually, in most cases, stable disease. There were few exceptions to that, but once patients had metastatic disease, we hoped we could stabilize it, have a little response, and increase OS in that perspective,” said Brose. “Now we have an opportunity to create significant responses, and we start to get back into the realm of significant changes to patient’s quality of life and presumably OS, although that still has to be proven.”

_Reference

_{Drilon AE, Farago AF, Tan DSW, et al. Activity and safety of larotrectinib in adult patients with TRK fusion cancer: An expanded data set. J Clin Oncol 38: 2020 (suppl; abstr 3610). doi:10.1200/JCO.2020.38.15_suppl.3610}