Selpercatinib Maintains PFS Benefit vs Chemotherapy in East Asian Patients With Untreated RET+ NSCLC

David R. Spigel, MD

Patients from East Asia with treatment-naive RET fusion-positive non–small cell lung cancer (NSCLC) who received the RET inhibitor selpercatinib (Retevmo) experienced a progression-free survival (PFS) benefit compared with those who were treated with chemotherapy with or without pembrolizumab (Keytruda), according to findings from the phase 3 LIBRETTO-431 trial (NCT04194944) presented during the 2024 ASCO Breakthrough Conference. Investigators noted that the results were consistent with previously presented data from the overall population of LIBRETTO-431 and support the use of selpercatinib as first-line treatment.^1,2

At a median follow-up of 19.4 months in the selpercatinib arm (n = 75) and 21.2 months in the control arm (n = 41), the median PFS was not yet reached (95% CI, 16.4-not evaluable) vs 11.1 months (95% CI, 7.0-16.8), respectively. The 12-month PFS rates were 72.8% vs 41.7%, respectively. Additionally, the overall response rate (ORR) was 86.7% (95% CI, 76.8%-93.4%) in the selpercatinib arm compared with 61% (95% CI, 44.5-75.8) in the chemotherapy arm.¹

“We cannot always assume that effective therapies in a general population will still be effective and safe in subpopulations,” David R. Spigel, MD, chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee, said in a news release.² “These outstanding results provide confidence that selpercatinib is an effective and safe treatment for East Asian patients with newly-diagnosed RET-altered NSCLC.”

Previously, the FDA granted regular approval to selpercatinib in September 2022 for the treatment of adult patients with locally advanced or metastatic NSCLC harboring a RET gene fusion, as detected by an FDA-approved test. The regulatory decision was supported by findings from the phase 1/2 LIBRETTO-001 trial (NCT03157128).³

LIBRETTO-431 was an open-label study that enrolled adult patients with pathologically confirmed unresectable stage IIIB, IIIC, or IV nonsquamous NSCLC who had not received prior systemic treatment for metastatic disease. Eligible patients had measurable disease per RECIST 1.1 criteria, an ECOG performance status of 2 or less, and adequate organ function; those with brain metastases were included if they were asymptomatic or had been neurologically stable for at least 2 weeks prior to random assignment. Patients with additional oncogenic drivers in NSCLC, those who received prior systemic therapy for advanced disease, and those with active cardiovascular disease, active uncontrolled infections requiring treatment, or uncontrolled disease-related pericardial effusion or pleural effusion were not included in the trial.⁴

Patients were initially randomly assigned 1:1 to receive 160 mg of selpercatinib twice daily via continuous 21-day cycles or 500 mg/m² of pemetrexed with vitamin supplementation along with the investigator’s choice of platinum therapy or cisplatinwith or without 200 mg of pembrolizumab administered every 21 days. After a protocol amendment, patients were randomly assigned 2:1 to the investigational or control arm, for a final ratio of random assignment of 1.6:1. Stratification occurred based on geographic region (East Asia vs elsewhere), brain metastases at baseline (absent or unknown vs present), and whether the investigator had intended to treat the patient with or without pembrolizumab prior to random assignment.

The primary end point was PFS by blinded independent central review. Secondary end points included overall survival, investigator-assessed PFS, ORR, and duration of response.

In terms of safety, the most common any-grade adverse effects (AEs) in the selpercatinib arm (n = 91) included elevated aspartate aminotransferase levels (AST; 73.6%), increased alanine transaminase levels (ALT; 70.3%), hypertension (60.4%), increased blood bilirubin (52.7%) and diarrhea (44.0%). In the control arm (n = 49), the most common any-grade AEs included anemia (61.2%), elevated AST levels (49.0%), leukopenia (49.0%), neutropenia (44.9%) and increased ALT levels (42.9%).¹

The median time on treatment in the selpercatinib arm was 16.6 months (SD ± 7.8) compared with 9.7 months (SD ± 7.9) in the control arm. Patients in both arms experienced at least 1 dose adjustment (86.8% vs 65.3%), AEs of grade 3 or higher severity (76.9% vs 51.0%), and AEs leading to treatment discontinuation (12.1% vs 2.0%), respectively. Two patients in the investigational arm experienced a fatal AE either on treatment or within 30 days of receiving the last dose.

References

1. Cheng Y, Loong HH, Zhou C, et al. Efficacy and safety of 1L selpercatinib in RET fusion-positive NSCLC: LIBRETTO-431 East Asian subgroup analysis. J Clin Oncol. 2024;42(suppl 23):214. doi:10.1200/JCO.2024.42.23_suppl.214
2. ASCO breakthrough to highlight advances in esophageal, nasopharyngeal, lung, cancers new treatment approaches help improve survival, quality of life. News release. ASCO. August 5, 2024. Accessed August 6, 2024. https://society.asco.org/about-asco/press-center/news-releases/asco-breakthrough-highlight-advances-esophageal-nasopharyngeal
3. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive non-small cell lung cancer. FDA. September 21, 2022. Accessed August 6, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive-non-small-cell-lung?utm_medium=email&utm_source=govdelivery
4. Zhou C, Solomon B, Loong HH, et al. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC. N Engl J Med. 2023;389(20):1839-1850. doi:10.1056/NEJMoa2309457