Entrectinib Continues to Yield Promising Data in NTRK Fusion–Positive Breast Cancer

Entrectinib (Rozlytrek) produced deep and durable responses in patients with breast cancer harboring NTRK fusions, according to updated data from the phase 2 STARTRK-2 trial (NCT02568267) presented at the 2022 ESMO Breast Cancer Congress.¹

At a median duration of survival follow-up of 35.3 months in patients with NTRK fusion–positive disease (n = 7), the overall response rate (ORR) was 71% (95% CI, 29.0%–96.3%). Two patients achieved a complete response (CR), and 3 patients had a partial response (PR). Notably, response data were missing on the other 2 patients. Both patients who achieved a CR had secretory disease, and among the 3 patients to have a PR, 2 had secretory disease and 1 had non-secretory disease. Among the 5 responders, the median duration of response (DOR) was 12.9 months (95% CI, 4.2–not evaluable [NE]).

NTRK gene fusions are drivers in many solid tumors, including breast cancer.² Though less than 1% of all breast cancer cases harbor NTRK fusions, they are present in more than 90% of secretory breast carcinomas.³

Prior data from the ALKA-372-001 trial (EudraCT 2012-000148-88), the phase 1 STARTRK-1 trial (NCT02097810), and STARTRK-2 showed entrectinib demonstrated deep and durable responses in patients with NTRK fusion–positive solid tumors.⁴ Prior data from STARTRK-2 showed patients with NTRK fusion–positive breast cancer achieved an ORR of 83% (n = 5 of 6), a median DOR of 12.9 months (95% CI, 4.2-NE), a median progression-free survival (PFS) of 10.1 months (95% CI, 5.1-NE), and a median overall survival (OS) of 23.9 months (95% CI, 5.1-23.9).⁵

STARTRK-2 enrolled patients with locally advanced or metastatic solid tumors that harbored an NTRK1/2/3, ROS1, or ALK gene fusion, including patients with NTRK fusion–positive breast cancer. Moreover, patients were eligible regardless of central nervous system [CNS] metastases, and patients were required to be naïve to TRK inhibitors.⁶

Enrolled patients received 600 mg of entrectinib once daily. Tumor burden was assessed following the first cycle of therapy, followed by every 8 weeks after by blinded independent central review per RECIST v1.1 criteria. Notably, regular brain scans were required for patients with baseline CNS metastases.

The primary end points of the study were ORR and DOR per blinded independent central review. Secondary end points included PFS, OS, intracranial efficacy, CNS progression, and safety.

Among the 7 patients with NTRK fusion–positive breast cancer, all were female with a median age of 61 years (range, 36-67), and 5 patients were White. Patients had an ECOG performance status of 0 (n = 3), 1 (n = 2), or 2 (n = 2). All patients had received prior chemotherapy, radiotherapy, and hormonal therapy, and 5 patients were administered prior targeted therapy. One patient had previous radiotherapy of the brain.

Prior lines of therapy for metastatic disease included 0 (n = 3), 1 (n = 1), 3 (n = 1), and 4 or more (n = 2). Two patients presented with CNS metastases at baseline, and the median time since diagnosis for all patients was 130.1 months (range, 32.6-309.1). Histology included non-secretory (n = 2), secretory (n = 4), and not specified (n = 1).

Additional data showed the median PFS was 10.1 months (95% CI, 5.1-NE), and the median OS was 19.2 months (95% CI, 5.1–NE).

In the 2 patients with CNS metastases at baseline, the first had HER2-positive, estrogen receptor (ER)–positive, PGR-negative disease and received whole brain radiation 2-6 months prior to beginning entrectinib. This patient received no prior lines of systemic therapy for metastatic disease, and she achieved a PR and an intracranial non-CR and non–progressive disease. The second patient had HER2-negative, ER-positive, PGR-positive disease and received 6 prior lines of systemic therapy for metastatic disease. This patient did not have response data after dying 1.7 months following the first dose of entrectinib, though her death was not considered related to treatment.

Notably, no patients experienced a CNS progression event, regardless of baseline status.

Among 12 patients who received at least 1 dose of entrectinib and were evaluable for safety, 4 patients experienced a grade 3 or higher treatment-related adverse effect (TRAE). These included anemia (n = 2), fatigue (n = 1), and increased alanine aminotransferase (n = 1). There were no grade 5 TRAEs recorded. Only 1 patient had a series TRAE.

The most common TRAEs of any grade included dizziness (n = 5), nausea (n = 5), anaemia (n = 4), constipation (n = 4), vomiting (n = 4), dysgeusia (n = 3), diarrhoea (n = 3), increased alanine aminotransferase (n = 3), increased aspartate aminotransferase (n = 3), increased blood creatinine (n = 3), Paraesthesia (n = 3), and increased weight (n = 3).

Treatment related adverse events resulted in the dose interruptions in 6 patients, a dose reduction in 5 patients, and treatment discontinuation in 1 patient.

“In line with previous reports, entrectinib was associated with a manageable safety profile in patients with NTRK fusion-positive breast cancer,” lead study author, Min Janice Lu, MD, of USC Norris Comprehensive Cancer Center, wrote in the poster.

References

1. Lu J, Blakely CM, Barve M, et al. Entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer: updated data from STARTRK-2. Presented at: 2022 ESMO Breast Cancer Congress; May 3-5, 2022; Berlin, Germany. Poster 173P.
2. 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
3. Wu S, Shi X, Ren X, Li K, Pang J, Liang Z. Evaluation of NTRK gene fusion by five different platforms in triple-negative breast carcinoma. Front Mol Biosci. 2021;8:654387. doi:10.3389/fmolb.2021.654387
4. Demetri GD, Braud FD, Drilon A, et al. Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors. Clin Cancer Res. 2022;28(7):1302-1312. doi:10.1158/1078-0432.CCR-21-3597
5. Lu J, Blakely CM, Le Tourneau C, et al. Efficacy and safety of entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PS11-28.
6. Basket study of entrectinib (RXDX-101) for the treatment of patients with solid tumors harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK gene rearrangements (fusions) (STARTRK-2). ClinicalTrials.gov. Updated May 3, 2022. Accessed May 11, 2022. https://clinicaltrials.gov/ct2/show/NCT02568267