December 23, 2020 - Entrectinib continued to demonstrate clinically meaningful, durable responses with a manageable toxicity profile in patients with NTRK fusion–positive sarcoma.
Entrectinib (Rozlytrek) continued to demonstrate clinically meaningful, durable responses with a manageable toxicity profile in patients with NTRK fusion–positivesarcoma, according to data from an analysis of 3 clinical trials presented during the 2020 Connective Tissue Oncology Society Virtual Meeting.1
Results showed that the selective TKI elicited a confirmed objective response rate (ORR) of 56.3% (95% CI, 29.9-80.3) per blinded independent central review (BICR) in the NTRK fusion–positive sarcoma cohort at a median follow-up of 17.74 months.
Moreover, entrectinib resulted in a reduction in tumor lesion size in most patients with sarcoma, including those with central nervous system (CNS) metastases at baseline.
The median progression-free survival (PFS) was 10.1 months (95% CI, 6.5-11.2). The estimated PFS rate with entrectinib at 6 months was 80% (95% CI, 60-100); at 12 months, this rate was 24% (95% CI, 10-48). The median overall survival (OS) with the TKI was 16.8 months (95% CI, 10.6-20.9). The estimated OS rates at 6 and 12 months were 87% (95% CI, 69-100) and 61% (95% CI, 33-88), respectively.
“Entrectinib achieved impressive durable responses in NTRK-positive sarcoma similar to TKIs in gastrointestinal stromal tumor,” Sant P. Chawla, MD, director of the Sarcoma Oncology Research Center, said in a presentation of the data during the meeting. “We hope we will get more drugs like this, [beyond] current chemotherapy [options] in sarcomas.”
Previous results from an updated integrated analysis of the ALKA-372-001 (EudraCT 2012-000148-88), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267) trials indicated that entrectinib elicited deep, durable responses in a subgroup of 74 patients with 12 NTRK-positive solid tumors.2
Specifically, the confirmed ORR achieved with the TKI was 63.5% (n = 47/74) and the median duration of response (DOR) was 12.9 months (95% CI, 9.3–not estimable [NE]). The median PFS was 11.2 months (95% CI, 8.0-15.7), while the median OS was 23.9 months (95% CI, 16.0-NE). Additionally, the intracranial (IC) ORR was 50% (n = 8/16) and the median IC DOR was 8.0 months (95% CI, 6.7-NE); the median PFS in these patients was 8.9 months (95% CI, 5.9-14.3).
Patients aged 18 years or older with locally advanced or metastatic NTRK fusion–positive solid tumors, with and without CNS metastases, who were also naïve to TRK inhibitors were included in the analysis. Responses were evaluated by BICR in accordance with RECIST v1.1 criteria after 4 weeks and then every 8 weeks thereafter. The co-primary objectives of the analysis were ORR and DOR per BICR. Key secondary end points comprise PFS per BICR, OS, and safety.
Of the 18 patients with NTRK fusion–positive sarcoma who were administered entrectinib, 16 were determined to be efficacy evaluable. Of these patients, 93.8% had an ECOG performance status of 0-1 and 75% had previously received 1 or more lines of systemic treatment. The median age of participants was 50.5 years. Fifty percent of patients were male, the majority (87.5%) were white, and 12.5% of patients had CNS metastases at baseline confirmed by BICR.
Additional results from the analysis focused on the NTRK fusion–positive sarcoma cohort showed that of the patients who experienced responses to entrectinib, 56.3% had a partial response (PR; n = 9), 25.0% achieved stable disease (n = 4), while 6.3% (n = 1) had disease progression.
Among the 9 responders, the median time to response was 0.95 months (95% CI, 0.9-2.8) and the median DOR was 9.3 months (95% CI, 4.6-15.0).
Of the 2 patients who had baseline CNS metastases, 1 who had undifferentiated pleomorphic sarcoma and had previously received radiotherapy for less than 2 months before entrectinib experienced an overall PR and IC PR, with an IC DOR of 1.9 months. The other patient, who had spindle cell sarcoma and had not received previous radiotherapy achieved an overall PR and IC non-CR/non-PD. None of the patients in the sarcoma efficacy cohort experienced a CNS progression event while on treatment, irrespective of whether that had metastases at baseline.
A total of 18 patients comprised the safety-evaluable NTRK fusion–positive sarcoma cohort. The majority, or 88.9% (n = 16), of these patients experienced a treatment-related toxicity, although no grade 5 effects were observed. The most commonly experienced treatment-related adverse effects included dysgeusia (44.4%), dizziness (38.9%), fatigue (33.3%), peripheral edema (27.8%), and weight gain (27.8%).
About 22% of patients experienced dose reductions, 16.7% required dose interruptions, and 5.6% had treatment discontinuations. Dose intensity was maintained during the study in this cohort; the median of missed doses was 1.5 and the median dose intensity was 97.0%.
“Entrectinib was well tolerated, with a manageable safety profile,” Chawla concluded. “Although NTRK fusion–positive sarcoma is rare, the evidence demonstrates that entrectinib is an effective treatment option, supporting the value of screening patients with sarcoma for NTRK gene fusions.”