Dr Drilon on How the ARROS-1 Trial May Affect the Current Paradigm in ROS1+ NSCLC

"The paradigm in lung cancer has always been to use our best drug first, and if this truly is our best drug, then we absolutely have to use it in the first-line setting."

Alexander Drilon, MD, chief of the Early Drug Development Service and the Carol Bassok Lowenstein Chair at Memorial Sloan Kettering Cancer Center, discussed future directions for the ROS1 tyrosine kinase inhibitor (TKI) zidesamtinib (Jideytro) in TKI-naive, ROS1-positive non–small cell lung cancer (NSCLC), building on findings from the phase 1/2 ARROS-1 trial (NCT05118789).

Drilon said he hopes the FDA will approve zidesamtinib for the frontline setting through a supplemental application, though he cautioned that longer follow-up is still needed to characterize the true median duration of response and progression-free survival (PFS) of the agent. He noted that the approved ROS1 TKIs repotrectinib (Augtyro) and taletrectinib (Ibtrozi) have each produced a median PFS exceeding 30 and 40 months, respectively, in TKI-naive patients; because responses with zidesamtinib have been observed even after prior repotrectinib or taletrectinib, Drilon said he is hopeful this more advanced-generation agent could ultimately deliver an even longer median PFS as ARROS-1 data mature.

Quality of life should also factor heavily into the treatment choice, according to Drilon: even if there ends up not being a drastically improved PFS relative to earlier-generation agents, a better likelihood of feeling well while on treatment is a strong argument for selecting zidesamtinib over other options. He pointed to the longstanding paradigm in lung cancer of using the most effective drug first, adding that sequencing an inferior agent followed by a superior one typically yields shorter cumulative disease control than starting with the superior agent alone.

Looking ahead, Drilon said more trials are needed to define what happens after progression on a frontline next-generation TKI, drawing a parallel to the ALK-rearranged NSCLC space, where patients now experience years of disease control. Circulating tumor DNA was collected centrally on ARROS-1, he noted, and will eventually inform understanding of resistance mechanisms in both the TKI-pretreated and TKI-naive cohorts, though he said that analysis is likely still some time away.