Clinical Testing of Pan-TRK Inhibitor Progresses Across Multiple Tumor Types

Alexander Drilon, MD

The pan-TRK inhibitor entrectinib (RXDX101) is being tested simultaneously in multiple locally advanced or metastatic solid tumor types as a treatment for patients harboring fusions involving the NTRK1/2/3, ROS1, or ALK genes.

The phase II, multicenter, STARTRK-2 basket trial (NCT02568267) stratifies patients based on their tumor type and genetic fusion. In 2 prior phase I trials, investigators tested entrectinib for safety and efficacy and demonstrated robust activity in multiple tumor types. The trials showed that the drug was well tolerated, with generally reversible and manageable low-grade adverse events (AEs).¹

In all, STARTRK-2 consists of 9 arms in which patients will receive single-agent entrectinib therapy. There are 3 arms for non—small cell lung cancer (NSCLC): 1 each based on whether the patient has an NTRK1/2/3 or ROS1 rearrangement, or either ALK— or ROS1—rearranged disease with central nervous system (CNS)-only progression. There are 3 arms for metastatic colorectal cancer (CRC) and 3 for other solid tumors, with patients assigned to arms within each tumor type based on whether they have NTRK1/2/3, ROS1, or ALK rearrangements (FIGURE).

Figure. Entrectinib in Solid Tumors With NTRK1/2/3, ROS1, or ALK Gene Fusions

Additionally, investigators are allowing patients with CNS involvement, including leptomeningeal carcinomatosis, that is either asymptomatic or previously treated and controlled. This is because entrectinib has demonstrated active coverage of the CNS, according to Alexander Drilon, MD, a medical oncologist and principal investigator for STARTRK-2 at Memorial Sloan Kettering Cancer Center in New York, New York. One patient with SQSTM1-NTRK1-rearranged lung cancer achieved a complete CNS response, and entrectinib was identified as a CNS-penetrant drug.¹

Another TRK inhibitor, larotrectinib (LOXO-101), has also shown penetration of the CNS. In a phase I trial of adult patients, 1 patient with TRK fusion—positive NSCLC had regression of a nontarget lesion in the brain.² Additionally, in a pediatric phase I study, 1 patient with TRK fusion—positive glioblastoma multiforme who had failed multiple treatments demonstrated a radiographic and clinical response with larotrectinib.³

Entrectinib is an ATP-competitive tyrosine kinase inhibitor (TKI) that has demonstrated low to subnanomolar efficacy against 5 kinases: TRK A, B, and C; ROS1; and ALK. Rearrangements of NTRK1/2/3, the genes that encode the TRK proteins, as well as ROS1, and ALK rearrangements occur in multiple types of cancer, especially some less common malignancies, such as glioblastoma, Spitz melanoma, cholangiocarcinomas, and papilloma thyroid cancer. The drug also is active at low nanomolar concentrations, allowing for once-daily administration to patients with the relevant gene fusions.¹

Notably, STARTRK-2 will include patients with pancreatic and neuroendocrine tumors, which are notoriously difficult disease types to diagnose and treat effectively, especially in the metastatic setting. In an earlier study, entrectinib demonstrated prolonged stable disease in a patient with ROS1-rearranged pancreatic cancer.⁴

In October, promising results for entrectinib were presented for patients with ROS1-positive NSCLC at the World Conference on Lung Cancer.⁵ In this trial, the objective response rate (ORR) with entrectinib was 68.8% by blinded independent central review (BICR), which included 2 complete responses (6.3%). Entrectinib also demonstrated an intracranial ORR by BICR of 83.3% for those with measurable CNS lesions at baseline (95% CI, 35.9%-99.6%).

In combined results from 2 phase I trials, entrectinib demonstrated similar efficacy.¹ Of the 119 patients in the trial, the most common tumor types were NSCLC (60%) and gastrointestinal cancers (15%). Patients in this analysis were not all specifically selected based on mutation status, with 60 having a gene rearrangement in NTRK1/2/3, ROS1, or ALK, with 30 meeting the criteria for the phase II study and 25 evaluable for efficacy.¹

Of those with NTRK alterations (n = 3), the ORR was 100% (95% CI, 44%-100%). In patients with ROS1 rearrangements, the ORR was 86% (95% CI, 60%-96%), which included 2 complete responses. In the ALK-rearranged cohort, the ORR was 57% (95% CI, 25%-84%).

The median progression-free survival (PFS) for those with NTRK alterations was not yet reached. In the ROS1 group, the median PFS was 19.0 months (95% CI, 6.5-not reached), and for those with ALK rearrangements the median PFS was 8.3 months (95% CI, 4.6-12). Median overall survival was not reached across mutations, with 89.4% of patients alive at 12 months.

The majority of treatment-related AEs seen in the 2 trials were grade 1 or 2 in severity, and all were reversible with dose interruption or modification. The most common AEs of any grade were fatigue (46%), dysgeusia (42%), paresthesia (29%), nausea (28%), and myalgia (23%).¹

“On-target TRK inhibitor toxicities that have been seen in patients include paresthesias, dysgeusias, weight gain, and dizziness. These make the profile of this drug different from other TKIs previously developed, at least for ALK and ROS1,” Drilon said.

In May 2017, the FDA granted a breakthrough therapy designation to entrectinib for use as a treatment for adult and pediatric patients with NTRK fusion—positive, locally advanced or metastatic solid tumors who have either progressed after prior therapies or have no acceptable standard therapies.

Entrectinib is being developed by Ignyta, a biotech company based in San Diego, California. In December, Ignyta entered into a merger agreement with Roche that is expected to become finalized in first quarter of 2018.

This article was updated on February 13, 2018, to reflect corrected information on the ability of TRK inhibitors to penetrate the brain.

References

1. Drilon A, Siena S, Ou SI, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400-409. doi: 10.1158/2159-8290.CD-16-1237.
2. Hong DS, Farago AF, Brose MS, et al. Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions. Presented at: 2016 AACR Annual Meeting; April 16-20, 2016; New Orleans, LA. Abstract CT008. ir.loxooncology.com/docs/events/2016_AACR_Conference_Call_Presentation.pdf.
3. 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: AACR Special Conference on Pediatric Cancer Research; December 3-6, 2017; Atlanta, GA. ir.loxooncology.com/docs/events/Loxo_AACR_pediatric_oral_presentation_FINAL.pdf.
4. Ignyta receives orphan drug designation from FDA for entrectinib for the treatment of molecularly defined subsets of colorectal cancer [press release]. San Diego, CA: Ignyta, Inc; February 17, 2015. ignyta.com/investors/press-release-article/896522/. Accessed January 11, 2018.
5. Ahn M-J, Cho BC, Siena S, et al. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). Presented at: IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract 8564.