Entrectinib Improves Responses in NTRK Fusion-Positive Solid Tumors

Robert C. Doebele, MD, PhD

Robert C. Doebele, MD, PhD

Entrectinib (Rozlytrek) led to clinically meaningful responses in patients withNTRKfusion-positive solid tumors, according to results from a pooled analysis of the phase I ALKA-372-001, the phase I STARTRK-1, and the phase II STARTRK-2 studies published in TheLancet Oncology.

“In this integrated analysis of patients with a wide variety of advanced cancers harboringNTRK1,NTRK2, orNTRK3fusions, we show that entrectinib is active in multiple tumor types, showing both systemic antitumor activity and activity in CNS metastases,” lead author Robert C. Doebele, MD, PhD, and colleagues wrote. “The proportion of patients achieving an objective response was 57%, with a similar proportion (55%) achieving an intracranial response. Antitumor activity was similar in both NTRK1and NTRK3gene fusion-positive cancers.”

The primary end points of the trial were the proportion of patients with an objective response and median duration of response, evaluated by blinded independent central review in the efficacy-evaluable patients. Secondary end points included progression-free survival (PFS), clinical benefit rate, time to central nervous system (CNS) disease progression, and safety. The data cutoff date was May 31, 2018, and the median duration of follow-up was 12.9 months.

Overall, 54 patients were evaluated from the STARTRK-2 (n = 51), STARTRK-1 (n = 2), and ALKA-372-001 (n = 1) trials. Most patients had either anNTRK1or NTRK3fusion, of which the most common gene fusion, ETV6-NTRK3, was reported in 25 patients (46%). The most predominant tumor types in the study included 13 patients with sarcoma (24%), 10 patients with non—small cell lung cancer (NSCLC; 19%), and 7 patients with mammary analogue secretory carcinoma of the salivary gland (13%).

Thirty-one patients achieved an objective response (HR, 57%; 95% CI 43.2-70.8), with 4 patients (7%) demonstrating complete responses (CRs) and 27 patients (50%) demonstrating partial responses (PRs). An additional 9 patients had stable disease (SD) as their best response. The median PFS was 11.2 months (range, 8.0-14.9). The median duration of response (DOR) was 10.4 months (range, 7.1-not estimable). Twenty-nine patients had either disease progression or died at the time of data cutoff. The estimated median OS was 21 months (95% CI 14.9-not estimable).

Of the 12 patients with CNS at baseline, 6 patients had an objective response (50%). Six patients had a PR (50%), and 4 patients had SD (33%). The median PFS was 7.7 months in this patient population (range, 4.7-not estimable), and the median DOR was not estimable. Out of the 42 patients who did not have CNS involvement at baseline, 25 patients had an objective response (60%). Four patients had a CR (10%), 21 patients had a PR (50%), and 5 patients had SD (12%). The median PFS was 12.0 months (range, 8.7-15.7), and the median DOR was 12.9 months (range, 7.1-not estimable).

. Thirteen (59%) patients in theNTRK1arm and 18 (58%) of patients in the NTRK3group achieved a response. Only 1 patient had an NTRK2fusion and did not have a response to entrectinib.

Investigators also evaluated responses by tumor type. Six of 7 patients with mammary analogue secretory carcinoma (86%) had a response (range, 42-100), 5 of 6 patients with breast cancer (83%) had a response (range, 36-100), 7 of 10 patients with NSCLC (70%) had a response (range, 35-93), 2 of 3 patients with pancreatic cancer (67%) had a response (range, 9-99), 6 of 13 patients with sarcoma (46%) had a response (range, 19-75), 1 of 4 patients with colorectal cancer (25%) had a response (range, 1-81), and 1 of 5 patients with thyroid cancer (20%) had a response (range, 1-72).

In addition, 11 out of the 54 patients on the study had brain metastases at baseline (20%), and of these patients, 6 had intracranial response (HR, 55%; 95% CI 23.4-83.3). Investigators also noted that 7 of 11 of these patients (64%) had received prior radiotherapy to the brain. Out of 5 patients with intracranial disease, the median intracranial PFS was 14 months (95% CI 5.1-not estimable).

For the safety analysis, 68 patients were included from theNTRKfusion-positive safety-evaluable population and 355 patients from the overall safety-evaluable population. Patients were then divided into 1 of 4 groups, which included 68 patients who were NTRKfusion-positive (19%), 134 patients who were ROS1fusion-positive (38%), 16 pediatric patients (6%), and 137 patients in a fourth group, which included ROS1fusion-positive non-NSCLC, ALKfusion-positive disease, or no gene fusion (39%).

In theNTRKfusion-positive safety evaluable population, the median duration of treatment was 7.85 months and 5.8 months in the overall safety-evaluable arm, while whereas the median number of entrectinib cycles given was 9.5 and 8, respectively. Safety events were consistent between the 2 arms.

Overall, the most common grade 3/4 adverse events (AEs) were anemia (11%), increased weight (7%), dyspnea (6%), and fatigue (4%). In both safety arms, most treatment-related AEs (TRAEs) were grade 1/2 and were reversible. The most common grade 3/4 TRAEs in theNTRKfusion-positive safety-evaluable and the overall safety-evaluable arms included increased weight in 7 (10%) and 18 patients (5%) and anemia in 8 (12%) and 16 patients (5%), respectively. Three serious TRAEs occurred in the NTRKfusion-positive arm, including 1 cognitive disorder event, 1 cerebellar ataxia event, and 1 dizziness event.

Seven patients in theNTRKfusion-positive safety-evaluable arm (10%) had serious TRAEs, as well as 30 patients in the overall safety-evaluable arm (9%). The most frequent serious TRAE was nervous system disorders in 3 patients in the NTRKfusion-positive safety-evaluable arm (4%) and 10 patients in the overall safety-evaluable arm (3%).

Three patients (4%) in theNTRKfusion-positive safety-evaluable arm discontinued treatment because of TRAEs versus 14 patients (4%) in the overall safety-evaluable arm, and 21 patients (31%) versus 90 patients (25%) had a dose interruption due to TRAEs, respectively. Twenty-seven patients (40%) and 97 patients (27%) had a dose reduction due to TRAEs in the NTRKfusion-positive and overall safety-evaluable arms. The most common AEs reported that led to dose reductions included anemia in 5 patients (7%), increased blood creatinine levels in 4 patients (6%), and fatigue in 4 patients (6%). Six deaths (9%) occurred in the NTRKfusion-positive safety-evaluable arm versus 20 deaths (6%) in the overall safety-evaluable population. However, all deaths were not related to entrectinib.

Patients 18 years or older with metastatic or locally advanced solid tumors harboring anNTRKfusion who received treatment of 600 mg entrectinib orally once daily were included in the analysis. All patients had an ECOG performance status of 0, 1, or 2 and could have received prior therapy, with the exception of TRK inhibitors. For assessment, patients needed to have measurable disease at baseline and at least 6 months of follow-up after the start of treatment.

Based on the analysis of these 3 studies,the FDA granted approval in August 2019 to entrectinibfor the treatment of patients with ROS1-positive metastatic NSCLC and patients with solid tumors harboring anNTRKgene fusion who have no alternative effective therapies available. This analysis further validates the impact of entrectinib in this patient population.

“The results from this integrated analysis of entrectinib clinical trials indicate that entrectinib is an active treatment for patients with NTRK fusion-positive solid tumors either with or without malignant lesions in the CNS,” Doebele et al wrote. “The ongoing STARTRK-2 and STARTRK-NG trials will hopefully provide additional data to support the use of entrectinib as a targeted treatment for patients withNTRKfusion-positive tumors who have, or are at risk of developing, CNS metastases.”

Reference:

Doebele DC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1—2 trials. [Published Online December 11, 2019].The Lancet Oncology. doi.org/10.1016/S1470-2045(19)30691-6.