Larotrectinib Effective in TRK+ Pediatric Cancers and CNS Tumors

Cornelis M. van Tilburg, MD, PhD

The efficacy of larotrectinib (Vitrakvi) is supported in distinct patient populations with TRK fusion cancer—specifically pediatric patients and adult or pediatric patients with brain metastases or primary central nervous system (CNS) tumors, according to analyses presented at the 2019 ASCO Annual Meeting.^1,2

In one analysis, treatment with larotrectinib at either 100 mg or 150 mg twice daily resulted in an overall response rate (ORR) of 94% in pediatric patients with TRK fusion cancers, and responses were durable. In addition, larotrectinib was well tolerated in the pediatric cancer population, said Cornelis M. van Tilburg, MD, PhD.

Larotrectinib is FDA approved for the treatment of patients with solid tumors harboring NTRK fusions, and exhibits high potency against TRKA, TRKB, and TRKC. TRK fusions are oncogenic drivers.

At the data cutoff of July 30, 2018, 12 (35%) experienced a complete response (CR) to larotrectinib, 18 (59%) had a partial response (PR), and 2 (6%) had stable disease. Median time to response was about 1.8 months. Thirty-three patients (87%) remained on treatment or underwent surgery with curative intent.

At a median follow-up of 8.9 months, the median duration of response was not reached. Eighty-four percent of the responders had an estimated duration of response ≥1 year.

At a median follow-up for progression-free survival (PFS) of 10.7 months, the median PFS was not reached. Moreover, the median duration of follow-up of 12.3 months for overall survival (OS), the median OS was not reached.

The study findings expand on those from an earlier dataset of 17 pediatric patients, which showed encouraging antitumor activity with larotrectinib, a first-in-class and selective TRK inhibitor. Based on the recent findings, routing testing for NTRK fusions in pediatric patients is warranted, said van Tilburg, pediatric oncologist, Heidelberg University Hospital and German Cancer Research Center.

“In the event of a fusion, the kinase domain of NTRK is activated, and will activate downstream signaling pathways, like AKT and ERK,” he said.

The data presented at the 2019 ASCO Annual Meeting were from a subset of 38 children and adolescents (<18 years old) with non-CNS TRK fusion cancer who were enrolled in 2 larotrectinib clinical trials (NCT02637687 and NCT02576431).

Larotrectinib was administered until complete surgical resection, disease progression, withdrawal, or unacceptable toxicity. Three patients received the adult equivalence dose of 100 mg twice daily, 6 received 150 mg twice daily, and 29 received 100 mg/m² twice daily (with a maximum dose of 100 mg twice daily).

The 38 patients came primarily from the phase I/II SCOUT study (n = 35), with 3 obtained from the phase II NAVIGATE study.

Twenty females and 18 males were included. The median age of patients overall was 2.3 years, with a range of 0.1 to 14.0 years. Fourteen (37%) were <1 year. Tumor types were infantile fibrosarcoma in 47%, other soft tissue sarcoma in 42%, thyroid in 5%, melanoma in 3%, and congenital mesoblastic nephroma in 3%.

TRK fusions involved NTRK1 (47%), NTRK2 (5%), and NTRK3 (47%). Prior treatments included surgery in 61%, radiotherapy in 11%, and systemic therapy in 68%. Sixteen percent received ≥3 lines of prior systemic therapy. At enrollment, 50% of the patients had locally advanced fusion cancer and 50% had metastatic disease.

The most common grade 3/4 treatment-emergent adverse events were neutropenia (n = 15), increase in weight (n = 9) pyrexia (n = 4), anemia (n = 4), and pain in extremity (n = 4).

Efficacy in CNS tumors

In a separate clinical trial presented here, larotrectinib also proved to be highly active against TRK fusion-positive cancers that involved the CNS. In 24 patients with intracranial disease—18 with primary CNS tumors and 6 with nonprimary CNS tumors and brain metastases—from 3 clinical trials (a phase I study [n = 1], the SCOUT study [pediatric phase I/II [n = 12], and the NAVIGATE phase II basket trial [n = 11]), treatment with larotrectinib at 100 mg or 100 mg/m² induced responses in 3 of 5 (60%) evaluable patients with TRK fusion—positive solid tumor with brain metastases and 5 of 14 (36%) evaluable patients with TRK fusion—positive primary CNS tumors.

The data were reported by Alexander Drilon, MD, research director, Early Drug Development of Memorial Sloan Kettering Cancer Center. Characterizing the CNS activity of larotrectinib in patients with TRK fusion—positive brain metastases and primary brain tumors “is important, as many TRK fusion-positive solid tumors have a propensity for brain metastases,” he said. “Furthermore, TRK fusions are found in primary brain tumors, such as high-grade gliomas and the activity of larotrectinib in these patients has not previously been presented.”

Patients with brain metastases included in this analysis were eligible if they had untreated, asymptomatic, and stable brain metastases. Those with primary CNS tumors had to be neurologically stable and on a stable dose of steroids prior to study initiation.

The frequency of brain metastases in TRK fusion-positive cancers was 5%, yielding the 6 patients in this dataset. Four patients had brain metastases not previously treated with radiation or surgery; in the other 2 patients, local therapy was performed >1 year prior to larotrectinib initiation. The median number of prior systemic therapies was 2. Four of the patients in this group had lung cancer and 2 had thyroid cancer, and fusions that involved NTRK1 (n = 2) and NTRK3 (n = 4).

Results showed that the ORR was 60%. Of the 5 evaluable patients, all 3 responses were PRs. No patient had primary disease progression. Responses occurred early, and 4 of the 6 total patients remained on therapy at the time of data cutoff, which was July 30, 2018. The longest duration of treatment was 18.4 months and was ongoing. In 3 patients with measurable disease in whom an assessment by intracranial response by RECIST was possible, all 3 had intracranial disease regression, including a patient with TRK fusion—positive lung cancer who had complete resolution of target lesions in the brain.

“Importantly, responses were equally impressive in the remaining 3 patients with evaluable but nonmeasurable CNS disease,” said Drilon.

Disease progression after initial benefit was observed in 3 patients “of whom the pattern of disease progression was growth only in extracranial disease in 2 of these 3 patients, and both of these patients were treated past progression for ongoing clinical benefit,” he said. The other patient had disease progression in the brain.

In the 18 patients with primary CNS tumors, the median age was 10 years (range, 1-79). Histology was glioblastoma in 6 (32%), all 6 of which were high grade; glioma in 4 (21%), with 1 being high grade; glioneuronal in 3 (16%), 2 of which were high grade; astrocytoma in 2 (15%), 1 being high grade; and not otherwise specified in 3 (16%). Three-fourths (76%) of cancers harbored the NTRK2 fusion.

In patients with evaluable disease, there were 2 (14%) CRs, 3 (21%) PRs, and 9 (64%) with stable disease. The disease control rate at ≥16 weeks was 79% and at ≥24 weeks, 71%. The 2 CRs were in a patient with astrocytoma and 1 with a glioblastoma. In the 11 evaluable pediatric patients, the response rate was 45%.

“This durability of disease control is further highlighted by the median PFS of 11.0 months,” said Drilon. Responses occurred early, at the first or second follow-up examination. The longest duration of therapy was ongoing at 16.6 months.

References

1. van Tilburg CM, DuBois SG, Albert CM, et al. Larotrectinib efficacy and safety in pediatric TRK fusion cancer patients J Clin Oncol. 2019;37 (suppl; abstr 10010). meetinglibrary.asco.org/record/170953/slide.
2. Drilon AE, DuBois SG, Farago AF, et al. Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors. J Clin Oncol. 2017;37 (suppl; abstr 2006). meetinglibrary.asco.org/record/174568/slide.

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