Dr Felip on Sequencing Next-Generation ROS1 TKIs After Progression in NSCLC

“The results are probably slightly higher for patients with secondary ROS1 mutations, but [repotrectinib, taletrectinib, and zidesamtinib] are also active in patients without these secondary mutations. There is data with lorlatinib as well, but with this agent, it seems there is no activity in patients with secondary mutations.”

Enriqueta Felip, MD, PhD, head of the Thoracic and Head and Neck Cancer Unit in the Oncology Department at Vall d’Hebron University Hospital, group leader of the Thoracic Tumors Cancer Group and codirector of the Clinical Research Program at the Vall d’Hebron Institute of Oncology (VHIO), and professor of medicine at the Universitat de Vic–Universitat Central de Catalunya, discussed how first-line treatment choice shapes management of ROS1-positive non–small cell lung cancer (NSCLC), highlighting the next-generation ROS1 tyrosine kinase inhibitors (TKIs) repotrectinib (Augtyro), taletrectinib (Ibtrozi), and zidesamtinib (Jideytro) for patients who progress on crizotinib (Xalkori) or entrectinib (Rozlytrek).

According to Felip, repotrectinib (Augtyro), approved based on data from the phase 1/2 TRIDENT-1 trial (NCT03093116), produced an objective response rate (ORR) of 41% (n = 56) in patients previously treated with a ROS1 TKI, rising to 58% among those with a secondary G2032R resistance mutation. Taletrectinib, evaluated in the phase 2 TRUST-I and TRUST-II trials (NCT04395677; NCT04919811), produced a pooled ORR of 55.8% (n = 113) in the TKI-pretreated population, Felip noted. Zidesamtinib, studied in the phase 1/2 ARROS-1 trial (NCT05118789), produced an ORR of 44% (95% CI, 34%-53%; n = 117) in pretreated patients, increasing to 54% (95% CI, 33%-73%) in those with a G2032R mutation. Felip said all three agents remain active regardless of secondary mutation status, whereas lorlatinib (Lorbrena), not approved by the FDA or the EMA for ROS1-positive disease, appears to lack activity against secondary ROS1 mutations.

Felip noted that rebiopsy to confirm the resistance mechanism is generally attempted in these patients, though it is not always feasible. Because outcomes with next-generation TKIs appear consistent whether or not a secondary ROS1 mutation is identified, she said the more practical driver of second-line selection is which ROS1 TKI a patient received first, and she recommended reserving repotrectinib, taletrectinib, or zidesamtinib for progression in patients not already exposed to a next-generation agent in the frontline setting.