Nuvalent's Zidesamtinib Shows Promise in ROS1-Positive NSCLC, Eyes FDA Submission

Massachusetts-based biotech company Nuvalent has reported competitive pivotal data for its investigational drug zidesamtinib in ROS1-positive non-small cell lung cancer (NSCLC), paving the way for a potential FDA rolling submission. The novel tyrosine kinase inhibitor (TKI) demonstrated efficacy in heavily pretreated patients, including those who had received prior ROS1 TKIs.

Impressive Efficacy in Heavily Pretreated Patients

In the primary analysis of the phase 1/2 Arros-1 trial, zidesamtinib achieved a 44% overall response rate (ORR) in a cohort of 117 patients with advanced ROS1-positive NSCLC. Notably, half of the patients had received two or more prior ROS1 TKIs, with or without chemotherapy. Among patients who had tried one prior TKI, the ORR increased to 51%, and in those who had only received Pfizer's Xalkori as their prior TKI, the ORR reached 68%.

The drug also showed promising intracranial efficacy, with a 48% intracranial ORR among 56 patients with measurable brain lesions. This is particularly significant given the high prevalence of brain metastases in ROS1-positive NSCLC.

Durability of Response Sets Zidesamtinib Apart

Zidesamtinib's duration of response (DOR) appears to be a key differentiator from existing ROS1 inhibitors. In patients who had received just one prior TKI, an impressive 93% remained in remission after at least 18 months. For the entire primary analysis cohort, the 12-month DOR rate was 78%, and the 18-month rate was 62%.

These figures compare favorably to Bristol Myers Squibb's Augtyro and Nuvation Bio's Ibtrozi, which showed 12-month DOR rates of 48% and about 45%, respectively, in their separate studies of TKI-pretreated patients.

Selective Targeting and Tolerability Profile

Nuvalent attributes zidesamtinib's long DOR to its selective targeting of ROS1 while avoiding inhibition of the structurally related TRK protein family. This selectivity appears to result in a more favorable tolerability profile, potentially allowing patients to remain on therapeutically relevant doses for longer periods.

The most frequent treatment-emergent adverse events included peripheral edema (36%), constipation (17%), blood CPK increase (16%), fatigue (16%), and dyspnea (15%). Dose reductions due to adverse events occurred in 10% of patients, with only 2% discontinuing treatment due to side effects.

Regulatory Plans and Future Directions

Based on these results, Nuvalent plans to initiate a rolling submission to the FDA in July for zidesamtinib in TKI-pretreated NSCLC, with the goal of completing the filing in the third quarter. The company is also exploring the drug's potential in TKI-naïve patients, with preliminary data showing an 89% ORR and a 96% 12-month DOR in this population.

As Nuvalent moves forward with its regulatory strategy, the company is also seeking commercial partners outside the United States to expand the potential reach of zidesamtinib. With its promising efficacy and tolerability data, zidesamtinib could potentially reshape the treatment landscape for ROS1-positive NSCLC in the coming years.