Responses to Selpercatinib Still Impressive With Over 20 Months of Follow-Up in RET+ NSCLC

Alexander Drilon, MD

Durable and robust responses were observed with selpercatinib (Retevmo) in patients with RET fusion-positive non–small cell lung cancer (NSCLC) after extended follow-up in the LIBRETTO-001 clinical trial (NCT03157128). According to a report published in the Journal of Clinical Oncology, selpercatinib also achieved intracranial activity in these patients.¹

“With longer follow-up and additional patients, selpercatinib continued to demonstrate marked efficacy, with a high objective response rate, continued durability of response, and substantial CNS activity, as well as a consistent safety profile,” wrote the study authors led by Alexander Drilon, MD, a medical oncologist and chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center.

These findings follow the achievement of a 64% (95% CI, 54-73) objective response rate (ORR) and a 17.5-month median duration of response (DOR) with selpercatinib in previously treated patients assessed during the primary analysis of LIBRETTO-001. Moreover, treatment-naïve patients had an ORR of 85% (95% CI, 70-94), with 90% of responses lasting at the 6-month mark. Mainly low-grade toxicities were observed with selpercatinib in the primary analysis.²

Results from the updated analysis of LIBRETTO-001 included 316 patients with RET fusion-positive NSCLC who were evaluated for 18 months or more. There were 64 patients who were treatment-naïve and 247 who were previously treated with chemotherapy.1

By independent review committee (IRC), the ORR observed with selpercatinib in the treatment-naïve population was 84% (95% CI, 73%-92%), with complete response (CRs) in 6% of patients. Partial responses (PRs) were observed in 78% of patients, while 9% had stable disease (SD), and 4% has progressive disease. The median DOR was 20.2 months (95% CI, 13.0 to not evaluated [NE]). Responses were ongoing in 40% of the treatment-naïve population at the time of data cutoff.

In terms of survival, the median progression-free survival (PFS) among treatment-naïve patients was 22.0 months (95% CI, 13.8 to NE). Thirty-five percent of these patents were alive and progression-free at a median follow-up of 21.9 months. The median overall survival (OS) was not estimable, but 69% (95% CI, 55%-80%) of treatment-naïve patients were alive at 2 years.

Among chemotherapy-pretreated patients, the ORR by IRC was 61% (95% CI, 55%-67%) with CRs in 7% of patients. PRs were seen in 54% of patients, 33% of patients had SD, and 3% had PD. The median DOR in the pretreated group was 28.6 months (95% CI, 20.4-NE).

The median PFS in the chemotherapy pretreated group was 24.9 months (95% CI, 19.3-NE). Thirty-eight percent of patients remained alive and progression-free at a median follow-up of 24.7 months. OS was also not estimable in the pretreated group, but 69% (95% CI, 62%-75%) of patients were alive at 2 years.

The full safety population of the study included 796 patients. The safety profile of selpercatinib was consistent with previous information with longer follow-up. The most common grade 3 or higher treatment-emergent adverse events (AEs) were hypertension (19.7%), alanine aminotransferase increase (ALT; 11.4%), aspartate aminotransferase increase (AST; 8.8%), diarrhea (5.0%), and electrocardiogram QT prolongation (4.8%). In terms of treatment-related AEs, the most common grade 3 or higher events were hypertension (13.2%),AST increase (6.3%), and ALT increase (.0%).

“Given the durable efficacy observed in patients with non–small-cell lung cancer, broad-based genomic profiling should be considered to identify patients with RET fusions who may benefit from selpercatinib,” wrote Drilon et al.

_REFERENCES:

_{1. Drilon A, Subbiah V, Gautschi O, et al. Selpercatinib in patients with RET fusion–positive non–small-cell lung cancer: updated safety and efficacy from the registrational libretto-001 phase I/II trial.Published September 19, 2022. J Clin Oncol. doi:10.1200/JCO.22.00393}

_{2. Drilon A, Oxnard GR, Tan DS, et al. Efficacy of selpercatinib in RET fusion–positive non–small-cell lung cancer. N Engl J Med. 2020; 383(9): 813-824. doi: 10.1056/NEJMoa2005653}