Selpercatinib (LOXO-292), a highly selective and potent RET inhibitor, has significant antitumor activity with a favorable safety profile in pts with advanced RET-altered tumors, regardless of prior treatment (tx). Immune-related toxicities have been reported with vemurafenib, crizotinib, osimertinib, and RXDX-105 for prior CPI-treated pts. We report results for selpercatinib post-CPI tx.
Pts enrolled to the global multicenter phase 1/2 LIBRETTO-001 trial (NCT03157128) received the selpercatinib recommended phase 2 dose (160 mg twice daily). A custom safety clustering analysis of adverse events (AEs) was performed. Prior CPI exposure was evaluated. Data cutoff was 16-DEC-2019.
329 (152 CPI-treated v 177 CPI-naïve, including 60 tx-naïve) pts with RET fusion+ NSCLC were analyzed. Gender, age, ethnicity and race were similar between subgroups as were objective response rates (ORR) (64% CPI-treated v 62% CPI-naïve). Tx-naïve pts ORR was 90%. The overall safety profile was similar between subgroups. The cluster analysis identified tx-related HR (TR-HR) (hypersensitivity/drug hypersensitivity) as an AE of special interest, defined as a constellation of events in the initial treatment weeks: maculopapular rash, often preceded by fever, with associated arthralgias or myalgias followed by thrombocytopenia and/or AST/ALT increase (common) and/or blood pressure decrease, tachycardia, and/or creatinine increase (less common). TR-HRs were reported in 17/152 (11%) CPI-treated v 5/177 (3%) CPI-naive pts. The highest severity was grade 3 in 8 pts (5 CPI-treated, 3 CPI-naïve). TR-HR management recommendations (dose modification and concomitant steroid use) were developed and the majority of pts successfully continued selpercatinib.
Prior CPI did not alter second line selpercatinib efficacy or safety. TR-HRs were uncommon, manageable with recommended guidance and supportive care and mostly reported in CPI-treated pts. Tx sequencing decisions should include consideration of the efficacy of selpercatinib in the first line setting as well as the consideration of immune mediated AEs that appear to occur more often in pts with prior CPI tx.
Clinical trial identification
Susan P. Whitman of Loxo Oncology at Lilly provided medical writing assistance.
Legal entity responsible for the study
Eli Lilly and Company, Loxo Oncology at Lilly.
Eli Lilly and Company, Loxo Oncology at Lilly.
C. McCoach: Honoraria (institution), Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: GEnentech, Takeda (uncompensated), Eli Lilly (uncompensatd); Advisory/Consultancy, Shareholder/Stockholder/Stock options: Guardant Health; Research grant/Funding (self): Revolution Medicine; Full/Part-time employment: UCSF. D.S.W. Tan: Advisory/Consultancy, self: Novartis, Merck, Loxo Oncology, AZ, Roche, Pfizer; Travel/Accommodation/Expenses, self: pfizer, BI, Roche; Honoraria (self): BMS, Takeda, Novartis, Roche, Pfizer; Research grant/Funding (institution): Novartis, GSK, AZ, . B. Besse: Research grant/Funding (institution): ABbvie, Amgen, AZ, BeiGene,Blueprint Biomedicines, BMS, BI, Celgene, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Ignyta, Ipsen, Inivata, Janssen, Merck, KGaA, MSD, Nektar, Onxeo, OSE immunotherapeutics, Pfier, PharmaMar, Roche-Genentech, Sanofi. K. Goto: Advisory/Consultancy, self: Otsuka; Honoraria (self): BMS, AZ, Pfizer, ChugaiPharma, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Eli Lilly, BI, Life Technologies, MSD, Nippon Kayaku, Takeda, Otsuka, IQVIA, Astellas Pharma, Guardant Health, Janssen, Kyowa Hakko Kirin, Daiichi Sankyo; Research grant/Funding (self), Research grant/Funding (institution): MSD, AZ, Taiho Pharmaceutical, Chugai Pharma, BI, Ono, Sumitomo Dainippon Pharma, Takeda, Novartis, Daiichi Sankyo, Kyowa Hakko Kirin, Astellas Oharma Eisai, Eli Lilly, Pfizer, Riken Genesis, BMS, Merck Serono, Ignyta, Life Technolgies, Janssen; Research grant/Funding (self), Research grant/Funding (institution): Xcoo, Loxo, Sysmex, MEdical and Biological Laboratories, Amgen. V.W. Zhu: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: AZ, Roche, Genentech, Takeda; Advisory/Consultancy, Shareholder/Stockholder/Stock options: TP Therapeutics. C.D. Rolfo: Speaker Bureau/Expert testimony, self: MSD, AZ; Advisory/Consultancy, self: ARCHER, Inivata, MD Serono; Advisory/Consultancy, self: Mylan, Oncompass; Research grant/Funding (self): Lung Cancer Res Foundation-Pfizer Grant; Guardant Health and biomarker. J.F. Kherani: Shareholder/Stockholder/Stock options, Full/Part-time employment: Loxo Oncology @ Lilly. V. Soldatenkova: Shareholder/Stockholder/Stock options, Full/Part-time employment: Eli Lilly and Company. E. Olek: Shareholder/Stockholder/Stock options, Full/Part-time employment: Loxo Oncology @ Lilly. P. Lee: Shareholder/Stockholder/Stock options, Full/Part-time employment: Eli Lilly and Company. K. Park: Speaker Bureau/Expert testimony: AZ, BI; Advisory/Consultancy: AbbVie, Amgen, AZ, BMS, BI, Daiichi Sankyo, Eli Lilly, Loxo Oncology,Merck KGaA, MSD; Research grant/Funding (institution): AZ, MSD. All other authors have declared no conflicts of interest.