Dr Drilon on the Efficacy of Zidesamtinib Relative to Other ROS1 Inhibitors in Pretreated ROS1+ NSCLC

"In the 1-prior TKI setting…[efficacy outcomes] look numerically better across multiple metrics with zidesamtinib vs repotrectinib and taletrectinib. [This was notable for] ORR, especially if we pull out patients who are postcrizotinib, which made up the majority of patients treated on [these 3 agents]. Durability also appears to be improved [with zidesamtinib]."

Alexander Drilon, MD, a thoracic medical oncologist and early drug development specialist at Memorial Sloan Kettering (MSK) Cancer Center, discussed data from the phase 1/2 ARROS-1 study (NCT05118789) evaluating the selective ROS1 inhibitor zidesamtinib (NVL-520) for previously treated patients with advanced/metastatic ROS1-positive non–small cell lung cancer (NSCLC).

Pooled findings from the phase 1 and 2 portions, presented during the 2025 IASLC World Conference on Lung Cancer showed that all patients previously treated with between 1 and 4 prior ROS1 TKIs with or without chemotherapy (n = 117) achieved an objective response rate (ORR) of 44% (95% CI, 34%-53%) with zidesamtinib. The duration of response (DOR) rates were 84% (95% CI, 71%-92%) at 6 months, 78% (95% CI, 62%-88%) at 12 months, and 62% (95% CI, 28%-84%) at 18 months.

For patients who had received only 1 prior ROS1 TKI (n = 55), the ORR was 51% (95% CI, 37%-65%), with DOR rates at 6, 12, and 18 months all reaching 93% (95% CI, 74%-98%).

In patients who had received prior crizotinib (Xalkori) only, no progression events occurred among responders, and the progression-free survival (PFS) rate was 89% (95% CI, 70%-96%) at 6, 12, and 18 months, with the median not reached. Zidesamtinib also produced intracranial responses and activity against tumors with a ROS1 G2032R resistance mutation.

Based on the cross-trial comparisons conducted in patients who received 1 prior TKI, zidesamtinib’s efficacy metrics appeared numerically superior to those of repotrectinib (Augtyro) and taletrectinib (Ibtrozi) across multiple measures, including ORR and improved durability, Drilon stated. Most notably, the median PFS in this patient population was approximately 9 months with other agents, whereas zidesamtinib achieved a median PFS of approximately 2 years, which Drilon considered a meaningful advance.

Regarding safety, zidesamtinib was well tolerated, and treatment-emergent adverse effects led to dose reductions in 10% of patients and treatment discontinuation in 2%.