Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2024

Dose Adjustments and Exposure-Response Associated With Selpercatinib in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) (#262)

Keunchil Park 1 2 , Edurne Arriola 3 , Maurice Perol 4 , Caicun Zhou 5 , Koichi Goto 6 , Herbert Loong 7 , Scott S. Barker 8 , Ashish Massey 8 , Patrick M. Peterson 8 , Dan Liu 8 , Ayman Akil 9 , Ben J. Solomon 10 , Aarohan Pruthi 8
  1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul , South Korea
  3. Servei d’Oncologia, Hospital del Mar, Cancer Research Program IMIM-Hospital del Mar, Barcelona, Spain
  4. Department of Medical Oncology, Centre Léon Bérard, Lyon, France
  5. Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
  6. National Cancer Center Hospital East, Chiba, Japan
  7. The Chinese University of Hong Kong, Hong Kong, China
  8. Eli Lilly, Indianapolis, IN, USA
  9. Certara USA, Inc., Princeton, NJ, USA
  10. Peter MacCallum Cancer Institute, Melbourne, Australia

Selpercatinib is a highly selective RET kinase inhibitor that has demonstrated improved progression-free survival (PFS) in patients with first-line RET fusion-positive NSCLC. This study examines selpercatinib outcomes with variable exposures resulting from dose adjustment.  

NSCLC patients treated with selpercatinib in 2 prospective trials (LIBRETTO-001/LIBRETTO-431) were started at 160mg BID; dose reductions to 120mg, 80mg, and 40mg BID were permitted. Relationship between selpercatinib and efficacy endpoints (overall response rate [ORR] and PFS) were determined using exposure-response models. Steady-state exposure parameters selected for analysis (area under the plasma concentration-time curve over 24 hours at steady state [AUC24] and maximum and minimum selpercatinib concentrations) represented average selpercatinib exposure over time. Additionally, average exposure over the last 10 doses was considered.

Of 504 treated NSCLC patients (LIBRETTO-431, n=150; LIBRETTO-001, n=354), 266 underwent dose reduction. Median time to first dose reduction was 2 months. Patients with dose reduction tended to be older (median age 61 vs 59 years) and had lower body weight (median weight 63 vs 66 kg) and longer time on therapy (median time on treatment [95% confidence interval]: 31.7 vs 21.2 months) versus patients without dose reduction. AST/ALT elevation, QT prolongation, and hypertension were the most common adverse events leading to dose adjustments. Focusing on 502 patients included in the ORR exposure-response analysis, the response rate was 69%; a stepwise multivariate logistic regression showed that probability of response increased with increasing selpercatinib AUC24 (P<0.05). Exploratory analysis of PFS in 504 patients (254 events) by exposure metrics showed no significant relationship with PFS across exposure quartiles.

No correlation found between drug exposure and PFS but did suggest that higher exposure was associated with better response rates. For patients experiencing toxicity on selpercatinib, dose adjustment to reduce exposure may allow ongoing clinical benefit without a decremental impact on PFS.

Previously presented at WCLC 2024.