FDA analysis of toxicity profiles of oral TKIs recently approved for non-small cell lung cancer based on receipt of prior immune checkpoint inhibitor therapy.

person Yufan Liu United States Food and Drug Administration, Silver Spring, MD info_outline Yufan Liu, Elizabeth Duke, Nicole Lauren Drezner, Harpreet Singh, Paul Kluetz, Richard Pazdur, Erin A. Larkins

Authors person Yufan Liu United States Food and Drug Administration, Silver Spring, MD info_outline Yufan Liu, Elizabeth Duke, Nicole Lauren Drezner, Harpreet Singh, Paul Kluetz, Richard Pazdur, Erin A. Larkins Organizations United States Food and Drug Administration, Silver Spring, MD, Office of Oncologic Diseases, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, Oncology Center of Excellence, Office of the Commissioner, U.S. Food and Drug Administration; Office of Oncologic Diseases, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, MD, Oncology Center of Excellence, U.S. Food and Drug Administration; Office of Oncologic Diseases, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD Abstract Disclosures Research Funding No funding received None. Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 are standard front-line therapy for advanced non-small cell lung cancer (NSCLC). Molecularly targeted tyrosine kinase inhibitors (TKIs) are standard of care for subsets of oncogene-driven NSCLC. Published literature suggests the possibility of increased toxicity in patients who receive ICIs followed by EGFR or ALK TKI treatment. However, the toxicity profile in patients who receive ICIs followed by TKIs with other genomic targets has not been well described. Methods: Marketing applications for TKIs in patients with NSCLC submitted to the Office of Oncologic Diseases between Jan 2019 to Dec 2022 were reviewed. Datasets were analyzed for demographics, treatment-emergent adverse events (TEAE), and prior anti-cancer therapies for TKI-treated patients in the primary efficacy population. Drug classes for which < 5% of patients received prior ICI were excluded. Grade 3-4 TEAE, serious adverse events (SAE), discontinuation TEAE and TEAE of interest (hepatotoxicity, rash, and interstitial lung disease [ILD]) were summarized. Results: 9 applications were identified and 2 were excluded. The remaining applications involved TKIs targeting EGFR exon 20 insertion, KRAS G12C , MET exon 14 skipping, and RET fusion alterations. Analyses included 867 patients; 61% received prior ICI therapy. Patient characteristics and results of analyses are presented in the table. In our pooled analysis, the incidence of Grade 3-4 AEs, SAEs, and hepatotoxicity were slightly higher in the prior ICI group, while the incidence of discontinuation TEAE, ILD, and rash were similar between groups. Analysis for hepatotoxicity was limited to reported AEs (did not include analysis of laboratory data). Review of toxicity data across individual drug classes did not show major differences compared to the overall results. Conclusions: Our analysis of safety data for newer TKIs with varied genomic targets does not appear to show excessive toxicity in patients with NSCLC who received prior ICI compared to those who did not. In future clinical trials evaluating TKIs in this population, inclusion of patients who have received prior ICI therapy should be considered when appropriate. TEAE summary for TKIs in patients with NSCLC based on receipt of prior ICI (N=867). Prior ICI Therapy (N = 528) No Prior ICI Therapy (N = 339) Demographics Sex 54% F 56% F Age (years), median (range) 63 (25-89) 65 (23-90) Race 67% White 25% Asian 4% Black 48% White 46% Asian 2% Black Ethnicity 3% Hispanic or Latino 1% Hispanic or Latino Region 60% U.S. 19% Asia 19% Europe 29% U.S. 44% Asia 25% Europe Prior Radiotherapy 59% 45% Drug Class 35% RET 14% MET exon 14 skipping 42% KRAS G12C 9% EGFR ex20 ins 44% RET 33% MET exon 14 skipping 4% KRAS G12C 19% EGFR ex20 ins Toxicity Grade 3 or 4 TEAE, % 71 63 SAEs, % 56 45 Discontinuation AE, % 12 12 Hepatotoxicity, % 4 1 ILD, % 4 6 Rash, % 26 25