Early Zidesamtinib Data Appear Promising for ROS1+ NSCLC

The novel ROS1 inhibitor zidesamtinib (formally NVL-520) demonstrated promising early activity in heavily pretreated patients with advanced ROS1-fusion–positive non–small cell lung cancer (NSCLC), including in those treated with other next-generation TKIs, according to findings from the phase 1/2 ARROS-1 study (NCT05118789) presented at the 2024 ESMO Congress.¹

Benjamin Besse, MD, PhD

In the preliminary evaluation across evaluable patients (n = 71), the overall response rate (ORR) with zidesamtinib was 44%, which included 2 complete responses. The duration of response (DOR) was not yet reached, with 67% of patients continuing to respond at 12 months or more. In patients treated with only prior crizotinib (n = 11) as their ROS1 inhibitor, the ORR was 73%. In this group, the DOR was not yet reached with all patients continuing to respond at 12 months or more.

"Zidesamtinib is a ROS1-selective, brain-penetrant, and TRK-sparing TKI with durable responses observed in a heavily pre-treated population and across all subgroups of patients," lead investigator Benjamin Besse, MD, PhD, head of Clinical Research at Institute Gustave, said during a presentation of the results. "Encouraging clinical activity in this heavily pretreated population supports further investigation earlier in the ROS1-positive NSCLC treatment paradigm."

In preclinical studies, zidesamtinib showed activity against ROS1 at both the kinase and mutant levels. The agent was designed to avoid other targets like TRK and to have a high level of brain penetrance. Based on a preliminary assessment, the FDA granted the agent a breakthrough therapy designation in February 2024. This designation is specifically for patients with ROS1-positive metastatic NSCLC previously treated with 2 or more ROS1 TKIs.²

In the dose escalation portion of the study, doses ranged from 25 mg daily to 150 mg daily, with a maximum tolerated dose not reached. The full study enrolled patients with all types of ROS1-postive solid tumors, with NSCLC making up 95% of the study population. After analysis, the 100 mg daily dose was selected as the RP2D. Across doses, there were 104 patients, with 71 being considered response-evaluable; all of which had NSCLC. Of these patients, 24 received the RP2D.

Holographic concept of lung cancer: © catalin - stock.adobe.com

The median age of patients across the full study (N = 104) was 57 years and nearly two-thirds were female (63%). The ECOG performance status was 0 (32%), 1 (66%), and 2 (2%). More than half of patients had a history of central nervous system (CNS) metastases (52%) and 38% had a secondary ROS1 resistance mutation. The median number of prior anti-cancer therapies was 3 (range, 1-11) with two-thirds having received chemotherapy (66%). One prior ROS1 TKI was received by 30% of patients with 69% having received 2 or more. The most common prior agents were crizotinib (Xalkori; 65%) or entrectinib (Rozlytrek; 41%). Outside of these, 68% received another ROS1 TKI, including lorlatinib (Lorbrena; 55%) and repotrectinib (Augtyro; 21%).

In those who had not received repotrectinib (n = 53), the ORR with zidesamtinib was 51% and the DOR was not yet reached, with 71% responding at 12 months or more. In patients specifically with a ROS1 G2032R resistance mutation, the ORR was 38% in those who received prior repotrectinib (3 of 8) and was 72% in those who had not received repotrectinib (13 of 18).

In patients who received 2 or more prior ROS1 TKIs (n = 51), the ORR with zidesamtinib was 41% with a DOR of 12.1 months and 54% of patients still responding at 12 months. In this group for patients with prior lorlatinib exposure (n = 39), the ORR was 44%. Those receiving lorlatinib or another TKI but not repotrectinib, the ORR was 47% with a DOR not yet reached and 59% of patients still responding at 12 months. "The duration of response was not reached in most of the cohorts," Besse said.

In those with measurable intracranial lesions (n = 8), the intracranial ORR was 50% with zidesamtinib. Of these patients, 7 had received 2 or more prior ROS1 TKIs, including lorlatinib and/or repotrectinib. In the 4 patients with confirmed responses there were no CNS progression events up to 21 months, Besse noted.

The rates of treatment-related adverse events (TRAEs) were relatively low, with most being grade 1 in severity. The most common TRAE was peripheral edema, of which 14% of patients had grade 1 and 5% had grade 2. Grade 1 treatment-related ALT increase and AST increase was seen in 11% of patients each. Weight increase was experienced by 11% of patients, with 1 patient having grade 3 weight gain. There were no TRAEs that led to treatment discontinuation. A dose reduction was required for a TRAE for 8% of patients treated with zidesamtinib.

"The 100 mg daily dose maintained steady state plasma levels at or above the target efficacy thresholds in both ROS1 fusion and ROS1 mutations in the periphery and in the CNS," Besse said.

A phase 2 portion of ARROS-1 continues to enroll for both patients with ROS TKI-naive disease and following 1 or more prior TKIs. The primary end point is ORR by blinded independent central review with secondary end points focusing on various efficacy and safety measures. The study is enrolling with an estimated enrollment goal 359 individuals (NCT05118789).

REFERENCES:

1. Besse B, Drilon AE, Cho BC, et al. Phase I/II ARROS-1 Study of Zidesamtinib (NVL-520) in ROS1 Fusion-Positive Solid Tumours. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation 1256MO.

2. Nuvalent receives U.S. FDA breakthrough therapy designation for NVL-520. News Release. Nuvalent. February 27, 2024. Accessed September 14, 2024. https://tinyurl.com/4knxcwrj