Toxicity From Sotorasib After Immune Checkpoint Inhibitors: A Note of Caution and Reflections of Future Advancements in the Field.

NSCLC, a leading global cause of cancer mortality, has seen significant improvements in patient outcomes with the introduction of targeted therapies, particularly for patients with oncogene-addicted advanced NSCLC.1Sung H. Ferlay J. Siegel R.L. et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Google Scholar The oncogenic driver KRAS, one of the most frequently mutated oncogenes across all human malignancies, is present in approximately 20% to 30% of NSCLC diagnoses.2Campbell J.D. Alexandrov A. Kim J. et al.Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas.Nat Genet. 2016; 48: 607-616Google Scholar Despite KRAS being previously considered “undruggable,” recent advancements have led to the Food and Drug Administration approval of two therapies—sotorasib and adagrasib—for patients with KRAS G12C-mutant, locally advanced, or metastatic NSCLC who have undergone at least one systemic therapy previously.3Nakajima E.C. Drezner N. Li X. et al.FDA approval summary: sotorasib for KRAS G12C-mutated metastatic NSCLC.Clin Cancer Res. 2022; 28: 1482-1486Google Scholar,4Jänne P.A. Riely G.J. Gadgeel S.M. et al.Adagrasib in non–small-cell lung cancer harboring a KRASG12C mutation.N Engl J Med. 2022; 387: 120-131Google Scholar The CodeBreaK 100 phase 2 trial exhibited the efficacy of sotorasib in KRAS G12C-positive NSCLC, achieving an objective response rate of 37.1% and a median response duration of 11.1 months. Notably, 81% of trial participants had prior treatments with both platinum-based chemotherapy and programmed cell death protein 1 or programmed death-ligand 1 (PD-[L]1) inhibitors.5Skoulidis F. Li B.T. Dy G.K. et al.Sotorasib for lung cancers with KRAS p. G12C mutation.N Engl J Med. 2021; 384: 2371-2381Google Scholar The subsequent phase 3 CodeBreaK 200 trial further reinforced the therapeutic benefit of sotorasib, revealing a significant increase in progression-free survival compared with docetaxel (5.6 mo versus 4.5 mo) in patients with advanced, previously treated NSCLC harboring the KRAS G12C mutation.6Langen AJd Johnson M.L. Mazieres J. et al.Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS G12C mutation: a randomised, open-label, phase 3 trial.Lancet. 2023; 401: 733-746Google Scholar Sotorasib was well tolerated, with a reduced incidence of grade 3 or higher adverse events (AEs) (33%) compared with docetaxel, the most common of which were diarrhea (12%) and increases in alanine aminotransferase level (8%) and aspartate aminotransferase level (5%). Given prior suggestions of sotorasib potentially inducing immune-related hepatotoxicity,7Begum P. Goldin R.D. Possamai L.A. Popat S. Severe immune checkpoint inhibitor hepatitis in KRAS G12C-mutant NSCLC potentially triggered by sotorasib: case report.JTO Clin Res Rep. 2021; 2100213Google Scholar particularly in patients with prior exposure to immune checkpoint inhibitors (ICIs), these findings carry clinical significance as most patients with KRAS G12C-positive advanced NSCLC are currently treated with first-line chemoimmunotherapy or single-agent immunotherapy. It is important to note that the CodeBreaK 100 and CodeBreaK 200 trials mandated a minimum washout period of 28 days after prior treatment with ICIs before commencing sotorasib therapy. This condition might not be practically feasible in real-world clinical settings outside of trial constraints; thus, real-world data on the toxicity linked with sequential use of ICI and sotorasib are required. In the article accompanying this editorial, Chour et al.8Chour A. Denis J. Mascaux C. et al.Severe sotorasib-related hepatotoxicity and non-liver adverse events associated with sequential Anti–Programmed Cell Death (Ligand)1 and sotorasib therapy in KRASG12C-mutant lung cancer.J Thorac Oncol. 2023; 18: 1408-1415Google Scholar conducted a multicenter, retrospective analysis of 102 patients with advanced KRAS G12C-mutant NSCLC who underwent sotorasib treatment across 16 French medical centers. The patients were categorized into the following two cohorts: those who had received anti–PD-(L)1 as the last line of treatment before initiating sotorasib (sequence group) and those who did not (control group). The study revealed a significantly higher incidence of severe sotorasib-related AEs, notably hepatotoxicity, in the sequence group compared with the control group (50% versus 13%, p < 0.001). This rise in severe AEs was particularly pronounced in patients who received their last anti–PD-(L)1 infusion within 30 days before initiating sotorasib therapy. Therefore, this study underscores the potential risk associated with sequential anti–PD-(L)1 and sotorasib therapy, manifesting as an increase in both severe hepatotoxicity and other non–liver-related AEs. These insights affirm the necessity of carefully considering the sequencing and timing of treatments when managing patients with advanced KRAS G12C-mutant NSCLC. The potential augmented risk of anti–PD-(L)1 and sotorasib therapy, as illustrated in the study by Chour et al.,8Chour A. Denis J. Mascaux C. et al.Severe sotorasib-related hepatotoxicity and non-liver adverse events associated with sequential Anti–Programmed Cell Death (Ligand)1 and sotorasib therapy in KRASG12C-mutant lung cancer.J Thorac Oncol. 2023; 18: 1408-1415Google Scholar is further corroborated by findings from the CodeBreaK 100/101 analysis.9Li B.T. Falchook G.S. Durm G.A. et al.OA03.06 CodeBreaK 100/101: first report of safety/efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC.J Thorac Oncol. 2022; 17: S10-S11Google Scholar The analysis explored the combination of sotorasib with either pembrolizumab or atezolizumab and exhibited an elevated incidence of treatment-related AEs when compared with monotherapy. Notably, the rate of grade 3 toxicities was higher when both drugs were administered concurrently, as opposed to a lead-in strategy (50% versus 30% for atezolizumab combinations and 74% versus 53% for pembrolizumab combinations). In the case of the lead-in strategy, lower doses of sotorasib (120 mg, 240 mg, and 360 mg) were associated with better tolerability across different dose cohorts. Despite the enhanced toxicity, deep and durable responses were observed across all combinations and dose cohorts, with an objective response rate of 29% (95% confidence interval, 18–43) and a median duration of response of 17.9 months (95% confidence interval, 5.6–not evaluable). These findings are in line with the observed pattern of heightened hepatotoxicity within 90 days since the last ICI administration. The aforementioned findings align well with our own single-center study, which observed a similar trend in hepatotoxicity rates among patients receiving sequential ICI and sotorasib therapy. In our cohort, 31% (10 of 32 patients) exhibited grade 3 or higher hepatotoxicity. Interestingly, the temporal pattern of hepatotoxicity occurrence was markedly skewed toward the initial period after immunotherapy, with 75% occurring within 30 days, 64% within the 31-to-90–day range, and no instances recorded beyond 90 days.10Rakshit S. Bansal R. Potter A. et al.MA13. 09 time from immune checkpoint inhibitor to sotorasib use correlates with risk of hepatotoxicity in non-small cell lung cancer.J Thorac Oncol. 2022; 17: S92Google Scholar This further solidifies the notion of an additive hepatotoxic effect arising from overlapping sotorasib and immunotherapy, particularly within the early phase postimmunotherapy administration. The study by Chour et al.8Chour A. Denis J. Mascaux C. et al.Severe sotorasib-related hepatotoxicity and non-liver adverse events associated with sequential Anti–Programmed Cell Death (Ligand)1 and sotorasib therapy in KRASG12C-mutant lung cancer.J Thorac Oncol. 2023; 18: 1408-1415Google Scholar noted that sotorasib-related AEs were substantial enough to necessitate dose modification in 38% of patients and definitive discontinuation in 31%. Most of these events occurred between 41 and 91 days after sotorasib initiation. Furthermore, the median duration of sotorasib treatment was slightly shorter in the sequence group compared with the control group (3.5 versus 4.4 mo, respectively, p = 0.1) and significantly shorter in patients experiencing severe sotorasib-related AEs (2.8 versus 4.7 mo, p = 0.018). These observations raise the question of whether a lower dose of sotorasib might be better tolerated and in turn prove more efficacious when administered close to immunotherapy. Sotorasib operates by covalently binding to a unique cysteine residue present only in KRAS G12C, thus inhibiting the oncogenic effects of this mutation.11Lanman B.A. Allen J.R. Allen J.G. et al.Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors.J Med Chem. 2020; 63: 52-65Google Scholar The drug displays nonlinear, time-dependent pharmacokinetics across a dose range of 180 mg to 960 mg (0.19–1 time the approved recommended dose) once daily, with consistent systemic exposure (area under the curve 0–24 h and Cmax) across doses at a steady state.3Nakajima E.C. Drezner N. Li X. et al.FDA approval summary: sotorasib for KRAS G12C-mutated metastatic NSCLC.Clin Cancer Res. 2022; 28: 1482-1486Google Scholar In the CodeBreaK 100 trial, patients received daily doses of 180, 360, 720, and 960 mg, and responses were observed even at the lower dose levels. This leads us to consider whether a lower dose of sotorasib could improve tolerability while still maintaining efficacy. This hypothesis is currently under investigation in the postmarketing dose comparison study CodeBreaK 201 (NCT04933695), which will evaluate daily doses of sotorasib at 960 and 240 mg.12Ratain M.J. Tannock I.F. Lichter A.S. Dose optimization of sotorasib: is the US Food and Drug Administration sending a message?.J Clin Oncol. 2021; 39: 3423-3426Google Scholar Preclinical studies suggest that sotorasib enhances antitumor efficacy by fostering a proinflammatory tumor microenvironment, leading to durable responses when used in combination with immunotherapy.13Canon J. Rex K. Saiki A.Y. et al.The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity.Nature. 2019; 575: 217-223Google Scholar Thus, it is important to consider whether this may also potentiate immune-related AEs in patients with recent immunotherapy exposure. This interaction raises a crucial query: Could this mechanism also intensify immune-related AEs, particularly in patients recently treated with immunotherapy? The precise cause of hepatocellular injury associated with sotorasib is yet to be defined. It is postulated to stem from direct drug-induced liver damage and hepatitis, typically manageable through treatment suspension and dose reduction. Nevertheless, the French cohort indicates that sotorasib-induced hepatotoxicity may necessitate permanent drug discontinuation in a proportion of patients. It remains unclear whether dose modification, especially in patients recently treated with immunotherapy, or treatment with corticosteroids could avert liver toxicity. This question warrants further exploration. A critical question is whether hepatotoxicity is exclusive to sotorasib or is a class effect; current evidence seems to favor the former, given the lower toxicity rates reported in the KRYSTAL-7 trial combining adagrasib (another KRAS G12C inhibitor) with pembrolizumab. Therefore, clinical trials designing immunotherapy-based combination strategies for KRAS G12C-mutant advanced NSCLC should consider measures to reduce liver injury risk. It is noteworthy that ICIs have been linked to increased toxicity when administered concurrently or overlapping with other tyrosine kinase inhibitors with varied targets.14Ahn M.J. Cho B.C. Ou X. et al.Osimertinib plus durvalumab in patients with EGFR-mutated, advanced NSCLC: a phase 1b, open-label, multicenter trial.J Thorac Oncol. 2022; 17: 718-723Google Scholar,15Lin J.J. Chin E. Yeap B.Y. et al.Increased hepatotoxicity associated with sequential immune checkpoint inhibitor and crizotinib therapy in patients with non-small cell lung cancer.J Thorac Oncol. 2019; 14: 135-140Google Scholar As the list of KRAS G12C inhibitors in development is growing, the data by Chour et al.8Chour A. Denis J. Mascaux C. et al.Severe sotorasib-related hepatotoxicity and non-liver adverse events associated with sequential Anti–Programmed Cell Death (Ligand)1 and sotorasib therapy in KRASG12C-mutant lung cancer.J Thorac Oncol. 2023; 18: 1408-1415Google Scholar set an important landmark safety check that other drugs in this class will need to be screened against. In conclusion, hepatotoxicity represents a critical AE frequently observed in patients receiving sotorasib, particularly those with recent exposure to immunotherapy. Dose optimization and optimal treatment sequencing hold promise for preventing this complication. Importantly, elucidation of the exact mechanism of hepatotoxicity from sotorasib after treatment with ICIs is the key to develop innovative prophylactic measures that will allow safe introduction of sotorasib in earlier phases of the therapeutic algorithm of NSCLC. By minimizing the risk of hepatotoxicity, these approaches could significantly enhance patient adherence to sotorasib, ultimately leading to improved patient outcomes. The need for continued investigation and refinement of these strategies is evident, reinforcing our commitment to safer and more effective treatment paradigms for patients with KRAS G12C-mutant NSCLC. Aakash Desai: Conceptualization, Writing—original draft preparation. Anastasios Dimou: Conceptualization, Writing—reviewing and editing, Supervision. Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti–Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRASG12C-Mutant Lung CancerJournal of Thoracic OncologyVol. 18Issue 10PreviewSequential anti–programmed cell death protein 1 (PD-1) or anti–programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti–PD-(L)1. This study was designed to address whether sequential anti–PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs. Full-Text PDF