Larotrectinib Highly Active in TRK Fusion+ Advanced Solid Tumors

Article

Data from 3 phase I/II clinical trials confirm that larotrectinib is a highly active agent for the treatment of TRK fusion-positive advanced solid tumors and is feasible for long-term use, according to a pooled analysis recently published in The Lancet Oncology.

David S. Hong, MD

David S. Hong, MD

David S. Hong, MD

Data from 3 phase I/II clinical trials confirm that larotrectinib is a highly active agent for the treatment of TRK fusion-positive advanced solid tumors and is feasible for long-term use, according to a pooled analysis recently published inThe Lancet Oncology.

In 159 patients who were evaluated between May 1, 2014, and February 19, 2019, objective responses were achieved in 121 patients (79%; 95% CI, 72-85). Complete responses (CRs) and partial response (PRs) were observed in 21 patients (16%) and 97 patients (63%), respectively. A total of 19 patients had stable disease (12%), and 9 had progressive disease (6%). In 4 patients, responses were not determined due to withdrawal for clinical deterioration before an initial response assessment. Responses were seen regardless of theNTRKfusion gene and occurred in 92% of evaluable patients. The median time to response was 1.8 months (range, 0.9-6.1).

A proportion of patients presented with brain metastases at baseline (8%). Of these patients, 75% of these patients had a response to treatment in the study. The best intracranial responses observed in these patients included 1 CR, and 1 PR, which resulted in a 46% reduction in tumor size per RECIST v1.1. There was 1 patient with stable disease who had a 14% reduction in tumor size. There was also 1 patient who presented with non-target intracranial disease at baseline who progresses in the brain after 2 months of treatment.

At a median follow-up of 12.9 months, the overall study population had 25 progressive events, which occurred in 23% of patients who had confirmed responses. The median duration of response (DOR) was 35.2 months (95% CI, 22.8-not estimable [NE]). At 12 months, roughly 80% (95% CI, 71-89) responses were ongoing. The longest duration of response observed was with a patient with TRK fusion-positive sarcoma treated with larotrectinib. The DOR in these patients was 44.2 months and was ongoing at the time of data cutoff.

In total, 47 progressive events in 159 patients in the study, resulted in a median progression-free survival (PFS) of 28.3 months (95% CI, 22.1-NE) with a median follow-up of 11.1 months. At 12 months, the estimated proportion of patients who were progression-free was 67% (95% CI, 58%-76%). Disease progression (n = 17), bleeding from stoma (n = 1), bowel perforation secondary to colon cancer progression (n = 1), and an unreported reason led to death in 14% of 159 patients ( n = 23), at a median follow-up of 13.9 months. The median overall survival (OS) was 44.4 months (95% CI, 36.5-NE), with approximately 88% (95% CI, 83%-94%) of patients surviving at 12 months.

In 44 patients of the 55 patients from the primary analysis set had a median duration of follow-up of 25.9 months. Progression events occurred in 39% of patients in this group (n = 17). The median DOR among these patients was found to be similar to the overall population evaluated for efficacy at 35.2 months (95% CI, 21.2-NE). The median PFS observed was 25.8 months (95% CI, 9.9-NE), also showing similarity to the overall population. The median OS followed the pattern of similarity at 44.4 months (95% CI, 36.5-NE), at a median follow-up of 28.5 months.

Across all subgroups, the safety profile observed with larotrectinib appeared to be consistent with previous findings. Most adverse events (AEs) were grade 1 and 2 in severity and patterns were similar among adult and pediatric patients. Out of 260 patients total, the proportion of patients who experienced grade 3 treatment-emergent adverse events TEAEs was 39%, and 7% of patients experienced grade 4 TEAEs. The most common ≥ grade 3 TEAEs were anemia (10%) and decreased neutrophil count (5%). The most common serious TEAEs were pneumonia, (2%), pyrexia (2%), abdominal pain (2%), and diarrhea (2%).

Larotrectinib-related AEs did occur during the study but were infrequent. In total, 33 patients (13%) experienced a grade 3 larotrectinib-related AE and 2 patients (1%) experienced a grade 4 AE related to larotrectinib. The most common AE related to larotrectinib were increased alanine aminotransferase (1%), increased aspartate aminotransferase (1%), and nausea (1%). TEAEs led to death in 5% of the patients (n = 14) in the overall population. Additionally, death occurred in 4% of patients in the TRK fusion-positive cancer efficacy population. Most deaths occurred secondary to disease progression and none were related to larotrectinib treatment.

In 22 patients (8%) in the overall population, treatment doses were reduced because of the emergence of AEs. In 8% of patients in the TRK fusion-positive can population, dose reductions were also observed. Overall, 6 patients discontinued treatment because of TEAEs, which included increased alanine aminotransferase, increased amylase, increased aspartate aminotransferase, prolonged electrocardiogram QT, enterocutaneous fistula, increased lipase, muscular weakness, and nausea. Two of the patients who discontinued treatment because of an AE had TRK fusion-positive cancer.

The pooled analysis included data from a phase I study of larotrectinib in adults with solid tumors (NCT02122913), a phase I/II SCOUT study of larotrectinib in pediatric patients with advanced solid tumors (NCT02576431), and the phase II basket study (NAVIGATE) of larotrectinib in subject with NTRK fusion-positive tumors (NCT02576431).

Patients received oral larotrectinib continuously for 28 days. In adults, the dosage was 100 mg twice daily and in pediatric patients, the dose was 100 mg/m2 twice daily.

The primary end point of the analysis was objective response per local investigator assessment in the intent-to-treat population. The secondary end points included DOR, PFS, time to response, and OS.

“This expanded analysis confirms that TRK fusions define a unique molecular subgroup of advanced solid tumors in children and adults for which larotrectinib is highly active and amenable to long-term administration. Testing for TRK fusions in the clinic remains crucial to identify patients likely to benefit from treatment with this agent,” wrote Hong et al.

Reference:

Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020. DOI: https://doi.org/10.1016/S1470-2045(19)30856-3.

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