Larotrectinib Excites in TRK Fusion Cancers for Both Adult and Pediatric Patients

David Hyman, MD

Larotrectinib (LOXO-101), a pan-TRK (tropomyosin receptor kinase) inhibitor co-developed by Bayer and Loxo Oncology, has generated significant excitement for the treatment of both adult and pediatric patients with TRK fusion cancers. Following promising findings for the agent in patients with many TRK fusion-positive solid tumors, many in the field are looking to larotrectinib to becoming the eventual second-ever tumor-agnostic FDA-approved therapy. A new drug application (NDA) was recently submitted to the FDA for the potential approval of larotrectinib for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring an NTRK gene fusion.

When findings of larotrectinib were presented during the 2017 ASCO Annual Meeting, the small molecule was lauded as a future standard of care for patients with advanced solid tumors harboring a TRK fusion.¹

“You would be hard-pressed to find a targeted therapy even within a single disease context that has results like this,” David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center, said when presenting the findings at the ASCO meeting.

FINDING THE FUSIONS

TRK signaling is activated by the binding of neurotrophin ligands, predominantly nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3); they bind, respectively, to the TRK A, B, and C proteins.^2-4These proteins are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. TRK fusions occur when 1 of the TRK genes becomes abnormally connected to another gene. This fusion event causes the TRK gene to be turned on and the cancer to grow. To date, researchers have identified more than 50 different partner genes that fuse with 1 of the NTRK genes.

These fusions are rare, but they occur across a number of diverse histologies in both adult and pediatric cancers.¹It is estimated that up to 5000 patients annually have TRK fusions in the tumors; however, Hyman mentioned during a presentation that “this number may significantly underestimate its prevalence due to inadequate ascertainment by many of the existing profiling technologies.”

Hyman explained that TRK fusions typically follow 2 patterns: In adults, they occur rarely in more common cancers, such as brain, lung, colon, pancreatic, sarcoma, and melanoma; or, they occur more frequently in rare cancers, such as salivary and secretory breast cancer. This pattern also prevails in the pediatric setting, where the mutation is rarely seen in glioma and sarcoma, but more frequently in infantile fibrosarcoma and congenital nephroma, for example. Although relatively rare, he said that it is hard to find a tumor type where TRK fusions have not been reported.

Although the first discovery of TRK fusions dates to the 1980s, the recent uptake of next-generation sequencing (NGS) and the development of newer NGS technologies has aided in the detection of TRK fusions across different cancer types.

Currently, there are 3 modalities for testing for oncogenic mutations or amplifications that have varying potential for use as diagnostics in the TRK space: fluorescence in situ hybridization (FISH), immunohistochemistry, and NGS.

“Gene fusion events in general are best found by looking at a tissue biopsy; it could be a tumor resection specimen, or a biopsy of a tumor or tumor-involved lymph node, but you need the primary tumor tissue,” said Josh Bilenker, MD, CEO of Loxo Oncology, in an interview with Targeted Therapies in Oncology™.

NGS testing, on the other hand, offers a comprehensive approach for identifying any actionable gene amplifications, mutations, or fusions—including TRK fusions—in a definitive readout. NGS will also test for many other genes in the tumor sample at the same time and may identify a different therapeutic option.

Loxo Oncology recommends that oncologists choose a testing instrument from a list of 9 assays that analyze samples for various numbers of genes ranging from 20 to nearly 1400.⁵Samples for multigene panels can either be tested in pathologists’ laboratories or sent out to other companies.

IHC also represents a promising option to test for TRK fusions with a staining method. Loxo Oncology is partnering with Ventana Medical Systems, a member of the Roche Group, to develop a pan-TRK fusion IHC test as a companion diagnostic for larotrectinib. IHC testing has the advantage of being a less expensive test that is mostly reimbursed by insurance companies, and any laboratory has the capability of conducting the test. Additionally, some laboratories feel more comfortable running a series of IHC tests rather than using NGS, as they may want to see the technology and reimbursement process evolve. However, when using IHC testing, laboratories can only run 1 test at a time.

RESULTS WITH LAROTRECTINIB

Updated findings of larotrectinib were published in February 2018 in the New England Journal of Medicine (NEJM),⁶demonstrating an objective response rate of 75% (95% CI, 61%-85%) by independent review and 80% (95% CI, 67%-90%) by investigator assessment.

According to the independent assessment 7 patients (13%) achieved a complete response, 34 (62%) had partial responses, and an additional 5 patients (9%) had stable disease.

At 1 year, 71% of responses were ongoing. More than half of the patients (55%) 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.

The published findings encompassed results from 55 adult and pediatric patients investigated across j3 studies: a phase I adult trial, the phase II NAVIGATE trial, and the phase I/II SCOUT pediatric trial.

The enrolled patients with TRK fusion—positive adult and pediatric advanced solid tumors represented 17 unique cancer types: 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), gastrointestinal stromal tumor (n = 3), cholangiocarcinoma (n = 2), appendix tumor (n = 1), breast cancer (n = 1), and pancreatic cancer (n = 1). TRK fusions involved NTRK1 in 45% of the patients, NTRK2 in 2%, and NTRK3 in 53%. Additionally, there were 14 unique upstream fusion partners.

The median age of patients was 45 years (range, 0.3-76.0), with 56% of patients ≥40 years of age and 11% ≤2 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. Patients were assigned to 100 mg of larotrectinib twice daily.

Investigators did not notice a trend toward better results in 1 tumor type versus another with larotrectinib. Additionally, outcomes appeared similar regardless of the age of patients or the type of NTRK alteration (1, 2, or 3) or fusion partner.

At an AACR Special Conference on Pediatric Cancer in December 2017, the principal investigator of the SCOUT trial, Brian Turpin, DO, said that pediatric patients who were treated with larotrectinib achieved a 93% response rate (95% CI, 68%-100%), including complete responses in 13% and partial responses in 80%.⁷

“Targeted therapy success stories in pediatric oncology are uncommon, and larotrectinib has invigorated the pediatric oncology community,” said Turpin, assistant professor in the Division of Oncology at Cincinnati Children’s Hospital, in a statement. “Larotrectinib’s near universal response rate and compelling durability of response in pediatric patients with TRK fusion cancers is likely to be practice changing.”

The published findings noted that most patients (93%) experienced grade 1 or 2 adverse events (AEs).6 There were no grade 4 AEs related to treatment and the most common treatment-related grade 3 AEs were increased ALT or AST (5%), anemia (2%), decreased neutrophil count (2%), nausea (2%), and dizziness (2%). The most common grade 3 AEs (≥5%) regardless of attribution were anemia (11%), increased ALT or AST (7%), decreased neutrophil count (7%), and increased body weight (7%).

“In this series of studies, larotrectinib had rapid, potent and durable antitumor activity in children and adults who had solid tumors with TRK fusions without regard to patient age, tumor tissue, and fusion status,” David Hong, MD, co-principal investigator on the paper published in NEJM and professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, said in a statement.

In December 2017, Loxo Oncology announced that they had begun to submit the NDA for larotrectinib after the TRK inhibitor received a breakthrough therapy designation from the FDA in July 2016. The submission was completed in March 2018. Bayer is also planning to file a marketing authorization application in the European Union later this year.

References:

1. Hyman DM, Laetsch TW, Kummar S, et al. The efficacy of larotrectinib (LOXO- 101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. J Clin Oncol. 2017;35(suppl; abstr LBA2501). https://meetinglibrary. asco.org/ record/144598/abstract.
2. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023. doi: 10.1136/esmoopen-2015-000023.
3. Khotskaya YB, Holla VR, Farago AF, Mills Shaw KR, Meric-Bernstam F, Hong DS. Targeting TRK family proteins in cancer. Pharmacol Ther. 2017;173:58-66. doi: 10.1016/j.pharmthera.2017.02.006.
4. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34. doi: 10.1158/2159-8290. CD-14-0765.
5. How to test for TRK fusions. Loxo Oncology website. trktesting.com/HowToTest. pdf. Accessed March 27, 2018.
6. 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(8):731-739. doi: 10.1056/NEJMoa1714448.
7. Turpin B, Albert CM, Mascarenhas L, et al. A pediatric phase 1 study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family: an updated analysis. Presented at: American Association for Cancer Research (AACR) Special Conference on Pediatric Cancer Research; December 3-6, 2017; Atlanta, Georgia.