Larotrectinib Achieves High Marks in NTRK-Mutant Thyroid Cancer

Maria E. Cabanillas, MD

Larotrectinib (Vitrakvi) has proved to be highly active in patients with thyroid cancer with NTRK gene fusions, exhibiting rapid and durable disease control, according to Maria E. Cabanillas, MD.

Cabanillas, professor of clinical research in the Department of Endocrine Neoplasia and Hormonal Disorders at The University of Texas MD Anderson Cancer Center in Houston, pooled and analyzed larotrectinib therapy outcomes in a subset of patients with thyroid cancer harboring an NTRK gene fusion from a phase 1 trial (NCT02122913) and the phase 2 NAVIGATE trial (NCT02576431) as part of an OncLive^® Rapid Readout program. The video series features experts exploring key findings presented at conferences. The analysis was originally presented at the European Society for Medical Oncology Virtual Congress 2020.

“NTRK gene fusions encode chimeric TRK [tropomyosin receptor kinase] proteins, which are constitutively active and act as oncogenic drivers in a wide variety of adult and pediatric solid tumors,” Cabanillas explained. “Larotrectinib [previously] demonstrated a 79% overall response rate and a 35.2-month duration of response in patients with TRK fusion cancer, regardless of tumor type or age.”

A total of 28 patients were included in the analysis: 4 adult patients from the phase 1 trial and 24 patients older than 12 years from the NAVIGATE trial. Adult patients received 100 mg larotrectinib twice daily, and pediatric patients received 100 mg/m² twice daily. Both groups were treated on a continuous 28-day schedule, with duration of treatment ranging from 0.9 months to 45.4-plus months. The data cutoff date was July 15, 2019, with 68% of patients remaining on the treatment.¹

The primary end point of the analysis was best objective response rate (ORR) per investigator assessment via RECIST v1.1. Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Investigators reported that larotrectinib elicited an ORR of 75% (95% CI, 55%-89%), with 7% of patients experiencing a complete response (TABLE 1¹). The median time to response was 1.9 months (range, 1.6-5.6). Median OS was 27.8 months (95% CI, 16.7not estimable [NE]); both the median PFS (95% CI, 14.8-NE) and median DOR (95% CI, 16.6-NE) were not reached. However, the DOR and PFS rates at 12 months were 95% (95% CI, 85%-100%) and 81% (95% CI, 67%-96%), respectively.

In 7 patients with anaplastic thyroid cancer, the ORR was 29% (95% CI, 4%-71%), which Cabanillas noted was a good result for this highly aggressive cancer type. Twenty one patients with differentiated (papillary or follicular) thyroid cancer experienced a higher ORR than the overall population (90%; 95% CI, 70%-99%). The 18-month PFS for patients with differentiated thyroid cancer was also an impressive 86% (95% CI, 60%-100%).¹

Larotrectinib is a first-in-class, selective, central nervous system (CNS)–active TRK inhibitor that specifically inhibits TRKA, TRKB, and TRKC.² The FDA granted accelerated approval to the agent in November 2018 for adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation that are either metastatic or for which surgical resection is likely to result in severe morbidity and who have no satisfactory alternative treatments or experienced disease progression following treatment.³

NTRK fusions are found at high frequencies (up to or greater than 90%) in rare cancer types such as secretory breast carcinoma, mammary analogue secretory carcinoma, cellular and mixed congenital mesoblastic nephroma, and infantile fibrosarcoma. Fusions can be detected using DNA and RNA sequencing and plasma cell–free DNA profiling, among other methods.⁴

Another TRK inhibitor, entrectinib (Rozlytrek), was approved by the FDA in 2019 for the treatment of adult and pediatric patients 12 years and older with solid tumors that have an NTRK gene fusion with-out a known acquired resistance mutation that are metastatic or for which surgical resection is likely to result in severe morbidity and who have progressed following treatment or have no satisfactory alter-native therapy.⁵

TABLE 1. Larotrectinib Efficacy Results From Pooled Analysis by Thyroid Cancer Subtype

CLINICAL TRIAL DETAILS

The phase 1 trial was a randomized, open-label trial that enrolled 75 adult patients with advanced solid tumors. Larotrectinib was administered orally as a capsule or liquid solution over continuous 28-day cycles in doses ranging from 50 mg to 200 mg, depending on tumor type. Patients with clinically significant cardio-vascular disease or a history of myocardial infarction were excluded from the study, as well as those with an active, uncontrolled infection and those who were pregnant or lactating.⁶

NAVIGATE was an open-label phase 2 study of 203 patients who were 12 years and older with NTRK fusion–positive tumors. Larotrectinib was administered orally as a capsule or liquid solution at a dose of 100 mg twice daily in continuing 28-day cycles. Patients excluded from the trial included those with prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK, those with symptomatic or unstable brain metastases, and those with an active, uncontrolled infection.⁷

Patients with thyroid cancer enrolled in the trial had a median age of 61.5 years (range, 6-80), and 14% had CNS metastases. Nearly half (43%) had received no prior systemic therapies; 25% had received 1, 25% had 2, and 7% had 3 or more. Further, 43% of the population were patients with an NTRK1 gene fusion; the remaining 57% were patients with an NTRK3 fusion.¹

Commonly reported treatment-emergent adverse events in the analysis were mostly grade 1 or 2, with the most frequently observed events being fatigue (36%), consti-pation (32%), and dizziness (32%). No patients experienced adverse events leading to permanent discontinuation of treat-ment (TABLE 2¹).

“Larotrectinib demonstrated a favor-able safety profile and was well tolerated,” Cabanillas said. “Routine testing for NTRK gene fusions should be considered in patients with nonmedullary, advanced thyroid cancer being selected for systemic therapy in the near future.”

TABLE 2. Common Treatment-Emergent Adverse Effects From NCT02122913 and NAVIGATE Trials

References

1. Cabanillas ME, Drilon A, Farago AF, et al. Larotrectinib treatment of advanced TRK fusion thyroid cancer. Ann Oncol. 2020;31(suppl 4):S1026-1033. doi:10.1016/j.annonc.2020.08.1404
2. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Updated December 14, 2018. Accessed April 29, 2021. https://www.fda.gov/drugs/fda-approves-laro-trectinib-solid-tumors-ntrk-gene-fusions
3. Vitrakvi. Prescribing information. Loxo Oncology Inc; 2018. Accessed April 30, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211710s000lbl.pdf
4. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15:731-747. doi:10.1038/s41571-018-0113-0
5. Rozlytrek. Prescribing information. Genetech USA Inc; 2018. Accessed April 30, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf
6. A study to test the safety of the investigational drug laro-trectinib in adults that may treat cancer. ClinicalTrials.gov. Updated April 8, 2021. Accessed April 30, 2021. https://clinicaltrials.gov/ct2/show/NCT02122913
7. A study to test the effect of the drug larotrectinib in adults and children with ntrk-fusion positive solid tumors (NAVIGATE). ClinicalTrials.gov. Updated April 19, 2021. Accessed April 30, 2021. https://clinicaltrials.gov/ct2/show/NCT02576431