Solid tumors with Trk fusion: long-term efficacy evidence for ‘wild card’ therapy
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They have a frightening name because it refers to something difficult to understand: they are tumors with TRK fusion that occur when an NTRK gene fuses with another unrelated gene, producing a chimeric TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed triggering the signaling cascade. TRK fusion cancer occurs, with variable frequency, in various solid tumors in adults and children, including tumors of the lung, thyroid, gastrointestinal tract (colon, cholangiocarcinoma, pancreas and appendix), sarcoma, CNS tumors (glioma and glioblastoma), salivary glands (secretory carcinoma), and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma). This specific form of solid tumors was discussed at Asco where Bayer presented four analyzes on larotrectinib, a drug already defined as a ‘wild card’ in the past because it is capable of selectively targeting certain genetic alterations, regardless of the organ affected by the pathology with a agnostic approach.
Solid tumors with Trk fusion
TRK fusion proteins act as oncogenic drivers that promote cell growth and survival, leading to TRK fusion tumor. TRK fusion cancer is not restricted to certain tissue types and can occur anywhere in the human body. Larotrectinib is approved in over 45 countries, including the United States, Canada, Brazil, Japan and the United Kingdom, European Union (EU) countries, and China. The molecule is approved in all solid tumors for adults and children of all ages who have an NTRK fusion gene.
Tumor with tropomyosin receptor fusion
In an updated subgroup analysis, with longer follow-up in 180 eligible patients out of 194 total adult patients with non-primary central nervous system (CNS) tumors with TRK fusion in 24 solid tumors harboring NTRK gene fusion, it is the safety profile of larotrectinib was demonstrated. Among evaluable patients, the objective response rate (ORR), according to an independent review committee was 57%, including 16% complete responses (including pathologic complete response) and 41% partial responses. In evaluable patients with CNS metastases (n=22), the ORR was 68%. Among all patients, the median time to response was 1.8 months and the median duration of response was 43.3 months at a median follow-up of 32.3 months. Treatment-related adverse events (TRAEs) were primarily Grade 1-2, with Grade 3-4 occurring in 27 patients (14%).
Lung cancer with tropomyosin receptor fusion
In an extensive dataset and extended follow-up, larotrectinib demonstrated long-term efficacy and safety in adult patients with advanced lung cancer with TRK fusion, including those with central nervous system metastases. The findings suggest wider adoption of next-generation sequencing (NGS) assays to identify patients with solid tumors with NTRK gene fusions, including lung cancer. In 27 enrolled independent review committee (IRC) eligible adult patients with TRK fusion lung cancer, the ORR was 74%, with 3 complete responses and 17 partial responses. In the 12 patients with CNS metastases at baseline, the ORR was 67%. The median DoR was 33.9 months; the median follow-up was 22.9 months. Treatment-emergent adverse events were primarily Grade 1-2; Grade 3-4 were reported in 5 patients.
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Thyroid cancer with tropomyosin receptor fusion
Larotrectinib was also evaluated in an updated subgroup analysis of adult and pediatric patients (n=30) with TRK fusion-differentiated thyroid cancer. Among patients eligible for efficacy, 47% had NTRK1 and 53% NTRK2 fusion. Fifty percent of patients (n=15) had received no prior systemic therapies, 20% (n=6) had received ≥ 2, and 77% (n=23) had received radioiodine. The objective response rate was 63%, including 10% complete responses and 53% partial responses. In patients with differentiated thyroid cancer (n=23), the ORR was 78%. In patients with anaplastic thyroid cancer (ATC; n=7), the ORR was 14%. All patients with central nervous system metastases (n=4) at baseline showed a partial response. The median time to response was 1.9 months and the median duration of response was 43.3 months at a median follow-up of 32.3 months. Therapy-related Grade ≥3 adverse events, anemia and decreased lymphocyte counts, were reported in two patients (7%). There were no treatment discontinuations due to adverse events.
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Phase 2 study in children with childhood fibrosarcoma
The drug was also evaluated in pediatric patients newly diagnosed with infantile fibrosarcoma. Eighteen patients with unresectable or metastatic infantile fibrosarcoma and locally identified NTRK gene fusion were eligible for Cohort A. Between October 2019 and May 2022, 17 of 18 patients (94%) had confirmed objective responses, including 1 complete response and 16 partials. The only patient without confirmed response showed a 79% tumor shrinkage after the second cycle. In the first 6 cycles, no patient discontinued therapy due to disease progression or toxicity. Treatment-related Grade ≥3 adverse events occurred in 7 patients, with the most common being neutropenia.
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