ROS1-Targeting Lung Cancer Drug Yields 90% Response Rate

Most patients with advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who had not previously received a tyrosine kinase inhibitor (TKI) had an objective response with zidesamtinib (Jideytro), according to updated data from a phase I/II trial.

With a median follow-up of 15.2 months, the objective response rate was 94%, with complete responses seen in 15%, reported Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York City, at the World Conference on Lung Cancer in Seoul, South Korea.

The median duration of response was not reached, with ≥6-, ≥9-, and ≥12-month rates of 96%, 94%, and 86%, respectively. Median progression-free survival was also not reached, with ≥6-, ≥9-, and ≥12-month rates of 95%, 95%, and 90%.

Among 10 central nervous system (CNS) response-evaluable patients:

• All 10 had an intracranial response
• Seven of the 10 had a complete intracranial response
• Intracranial response at ≥6, ≥9, and ≥12 months was 100%, 100%, and 78%, respectively

In addition, there were no CNS progression events among patients who entered the study without brain metastases.

The data “support continued investigation of zidesamtinib as frontline therapy for TKI-naive patients,” Drilon said.

Earlier results from ARROS-1 demonstrated the efficacy of zidesamtinib in patients with previously treated locally advanced or metastatic ROS1-positive NSCLC, leading to FDA approval for that indication.

According to drugmaker GSK, these new findings will support a planned supplemental new drug application to the FDA seeking to expand the agent into the first-line setting.

“We’ve seen the trifecta for zidesamtinib,” said invited discussant Malinda Itchins, MBBS, PhD, of the Royal North Shore Hospital and Chris O’Brien Lifehouse in Sydney.

“We’ve seen early strong efficacy — actually amongst the highest we’ve seen in lung cancer, with an objective response of 94% … and only 10% progressing at 12 months,” she said. “We see a pleasing tolerability profile … and we see CNS activity, and we know how important this is to avoid whole-brain radiation and to preserve people’s quality of life and function.”

Itchins also noted that the efficacy data with zidesamtinib “compares very favorably” to taletrectinib (Ibtrozi) and repotrectinib (Augtyro) — drugs currently being used in the clinic for patients with ROS1-positive NSCLC who are TKI naive.

In explaining the rationale behind the development of zidesamtinib, Drilon observed that the approved frontline TKIs for locally advanced or metastatic ROS1-positive NSCLC have important limitations, “such as suboptimal CNS activity and dose-limiting side effects.”

“Zidesamtinib was designed with the goals of maximizing anti-ROS1 resistance mutation activity and CNS coverage, while attempting to minimize TRK inhibition and decrease CNS side effects compared to other agents,” he said.

The global, single-arm, first-in-human ARROS-1 trial enrolled 629 patients and included a phase II cohort of patients with locally advanced or metastatic ROS1-positive NSCLC who were naive to TKI therapy.

Up to one prior line of chemotherapy and/or immunotherapy was permitted and patients received zidesamtinib 100 mg once daily.

The efficacy population had a median age of 59 years, 59% were women, 59% were never smokers, 17% had baseline metastases, 93% had stage IV disease at study entry, and 27% had received platinum-based chemotherapy and/or immunotherapy. Patients were distributed across North America (40%), Europe (29%), and Asia Pacific (31%).

Among 532 patients in the safety population, the most common treatment-related adverse events were peripheral edema (34%), increased weight (18%), increased blood creatine phosphokinase (18%), dysgeusia (17%), and increased aspartate aminotransferase (15%).

Treatment-related adverse events led to dose reductions in 11% of patients and treatment discontinuation in 1%.