Larotrectinib Likely to Get EU Nod for NTRK+ Tumors

Scott Z. Fields, MD, senior vice president and head of Oncology Development at Bayer

Scott Z. Fields, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of larotrectinib (Vitrakvi) for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.¹

The overall response rate (ORR) with the TRK inhibitor larotrectinib was 72% (95% CI, 62-81) in the primary pooled analysis population, comprising a 16% complete response (CR) rate and 55% partial response (PR) rate. When including the primary CNS patients in the analysis, the ORR was 67% (95% CI, 57-76), comprising a 15% CR and 51% PR.

The median duration of response for the pooled primary analysis was not yet reached. Available data showed responses ranging from 1.6+ to 38.7+ months. Seventy-five percent of patients had a ≥12-month duration of response.

The application for larotrectinib will now be reviewed by the European Commission for a final approval decision. If approved, the TRK inhibitor would become the first drug to be granted a tumor-agnostic indication in the EU, according to Bayer, the manufacturer of larotrectinib.

“This positive CHMP recommendation for the first-ever tumor agnostic indication in Europe marks an important step towards delivering a first-of -its -kind precision medicine for children and adults with TRK fusion cancer in Europe,” said Scott Z. Fields, MD, senior vice president and head of Oncology Development at Bayer.

“Larotrectinib was specifically developed to treat patients with TRK fusion cancer, and has the potential to significantly improve treatment outcomes, regardless of tumor type or age. As researchers learn more about tumor genomics, it becomes all the more important to ensure broad access to genomic testing to allow patients that have the potential to benefit from precision medicines to be identified and treated, moving us beyond a one-size-fits-all therapeutic approach.”

Larotrectinib was approved in the United States in November 2018 for this indication, based on pooled results2 from the first 55 evaluable patients in the same 3 clinical trials in the EU application. Larotrectinib induced an ORR of 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) by investigator assessment. Per the independent assessment, there were 7 (13%) complete responses, 34 (62%) partial responses, and 7 (13%) patients with stable disease (SD).

At 1 year, 71% of responses were ongoing. More than half (55%) of patients remained progression-free at 1 year. The median duration of response had not been reached after a median follow-up of 8.3 months. The same was true for median progression-free survival after a median follow-up of 9.9 months.

In the 3 pivotal studies, adult patients received oral larotrectinib at 100 mg orally twice daily and pediatric patients (aged ≤18 years) were treated with larotrectinib at 100 mg/m2 up to a maximum of 100 mg orally twice daily. Treatment was received until disease progression or unacceptable toxicity.

The breakdown by tumor type included salivary gland tumor (n = 12), other soft-tissue sarcoma (n = 11), infantile fibrosarcoma (n = 7), thyroid tumor (n = 5), colon cancer (n = 4), lung cancer (n = 4), melanoma (n = 4), GIST (n = 3), cholangiocarcinoma (n = 2), appendix tumor (n = 1), breast cancer (n = 1), and pancreatic cancer (n = 1).

The median patient age was 45 years (range, 0.3-76.0), with 56% of patients ≥40 years of age. A third of patients (35%) had received ≥3 prior systemic chemotherapies. Twenty-four patients had an ECOG performance status of 0, 27 had a status of 1, and 4 had a status of 2.

The ORR by tumor type was salivary gland tumor (83%), other soft-tissue sarcoma (91%), infantile fibrosarcoma (100%), thyroid tumor (100%), colon cancer (25%), lung cancer (75%), melanoma (50%), GIST (100%), cholangiocarcinoma (best response, SD), appendix tumor (best response, SD), breast cancer (progressive disease), and pancreatic cancer (best response, SD).

The most common all-grade treatment-related adverse events (TRAEs) were increased ALT/AST level (38%), dizziness (25%), fatigue (16%), nausea (16%), constipation (16%), vomiting (11%), increased body weight (11%), anemia (9%), decreased neutrophil count (9%), and diarrhea (5%).

Grade 3 TRAEs included increased ALT/AST level (5%), anemia (2%), decreased neutrophil count (2%), nausea (2%), and dizziness (2%). There were no grade 4/5 TRAEs. Dose reductions were required in 8 of the 55 patients.

TRK gene fusions are genetic alterations that appear across a wide range of tumors—including breast and colorectal cancer, infantile fibrosarcoma, lung cancer, melanoma, and various sarcomas—and lead to uncontrolled TRK signaling and tumor growth. Such fusions are rare, but they are expressed in dozens of adult and pediatric tumor types. To date, researchers have identified more than 50 different partner genes that fuse with 1 of 3 TRK genes (NTRK 1, 2, and 3).

References

1. Bayer receives positive CHMP opinion for precision oncology treatment larotrectinib with first ever tumor-agnostic indication in in Europe. Bayer. Published July 26, 2019. Accessed July 26, 2019. https://bit.ly/2yhxDos.
2. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion—positive cancers in adults and children. N Engl J Med. 2018; 378:731-739. doi: 10.1056/NEJMoa1714448.

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The CHMP based its recommendation on data from patients enrolled across a phase I trial (LOXO-TRK-14001) in adult patients, the phase II NAVIGATE trial in adult and adolescent patients, and the phase I/II SCOUT pediatric trial. The data group included 102 patients, 93 from the pooled primary analysis population and 9 additional patients with primary CNS tumors.