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. 2025 Jan 17;30(1):oyae356.
doi: 10.1093/oncolo/oyae356.

Pooled safety analysis and management of sotorasib-related adverse events in KRAS G12C-mutated advanced non-small cell lung cancer

Ferdinandos Skoulidis  1 , Bob T Li  2 , Maximilian Hochmair  3 , Ramaswamy Govindan  4 , Mark Vincent  5 , Anthonie J van der Wekken  6 , Noemi Reguart Aransay  7 , Kenneth J O'Byrne  8 , Nicolas Girard  9 , Frank Griesinger  10 , Makoto Nishio  11 , Simon Häfliger  12 , Colin Lindsay  13   14 , Niels Reinmuth  15 , Astrid Paulus  16 , Pavlos Papakotoulas  17 , Sang-We Kim  18 , Carlos Gil Ferreira  19 , Giulia Pasello  20 , Michael Duruisseaux  21 , Spyridon Gennatas  22 , Anastasios Dimou  23 , Bhakti Mehta  24 , William Kormany  24 , Chidozie Nduka  24 , Brooke E Sylvester  24 , Christine Ardito-Abraham  24 , Yang Wang  24 , Adrianus Johannes de Langen  25
Affiliations

Pooled safety analysis and management of sotorasib-related adverse events in KRAS G12C-mutated advanced non-small cell lung cancer

Ferdinandos Skoulidis et al. Oncologist. .

Abstract

Introduction: We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks.

Methods: Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment.

Results: In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; grade ≥ 3: 147 [26.8%]). Gastrointestinal and hepatic TRAEs, including diarrhea (171 [31.1%]), nausea (80 [14.6%]), elevated alanine aminotransferase (ALT; 68 [12.4%]), and elevated aspartate aminotransferase (AST; 67 [12.2%]) were the most common (≥10%). Dose interruption and dose reduction of sotorasib resulted in the resolution of >90% of diarrhea events; median time to resolution were 18.0 days and 22.0 days, respectively. Similar trends were observed for elevated ALT and AST events. Patients who stopped immunotherapy <3 months before initiating sotorasib had a higher incidence of treatment-related hepatotoxicity (80/240 [33.3%]) than those who stopped immunotherapy ≥3 months before initiating sotorasib (26/188 [13.8%]). Treatment-related pneumonitis/interstitial lung disease (ILD) and corrected QT (QTc) prolongation were observed in 9 (1.6%) and 4 (0.7%) patients, respectively. Two (0.4%) patients died with TRAEs, 1 with ILD whose ultimate cause of death was disease progression, and the other with an unknown cause.

Conclusions: Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose modification.

Keywords: KRAS G12C; management; non-small cell lung cancer; pooled analysis; safety; sotorasib; treatment-related adverse events.

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Conflict of interest statement

F.S.: Stock and Other Ownership Interests: BioNTech SE; Moderna Therapeutics. Consulting or Advisory Role: Amgen; AstraZeneca; BeiGene; BergenBio; Bridgebio; Calithera Biosciences; Guardant Health; Hookipa Pharma; Merck; Novartis; Novocure; Revolution Medicines; Tango Therapeutics. Research Funding: Amgen (Inst); Merck (Inst); Mirati Therapeutics (Inst); Novartis (Inst); Revolution Medicines (Inst). Other Relationship: American Association for Cancer Research; Amgen; AstraZeneca; Curio LLC; DAVA Oncology; ESMO; Genentech/Roche; IASLC; Ideology Health; Intellisphere; Japanese Lung Cancer; McGill Universite de Montreal; Medscape; Merck; MI and T; MJH Life Sciences; Novartis; PER; Revolution Health Care; RV Mais Promocao Events LTDS; Tango Therapeutics. Bob T Li: Research Funding: Ambrx (Inst); Amgen (Inst); AstraZeneca (Inst); Bolt Biotherapeutics (Inst); Daiichi Sankyo (Inst); Hengrui Therapeutics (Inst); Lilly (Inst); MORE Health (Inst); Roche/Genentech (Inst). Patents, Royalties, Other Intellectual Property: Karger Publishers—Book royalty; Shanghai Jiao Tong University Press—Book royalty; US62/514,661 (Inst); US62/685,057 (Inst). Travel, Accommodations, Expenses: Amgen. Uncompensated Relationships: Amgen; AstraZeneca; Boehringer Ingelheim; Daiichi Sankyo; Lilly. M.H.: Consulting or Advisory Role: AstraZeneca/Daiichi Sankyo; Lilly; Roche; Takeda. Speakers’ Bureau—Lilly; MSD Oncology; Novartis; Roche. M.V.: Serving on advisory boards or receiving consulting or lecture fees from Merck; Bristol Myers Squibb; AstraZeneca; Eli Lilly; Amgen; Apobiologix; Boehringer; Roche; Sanofi; Pfizer. A.J.v.d.W.: Grants or contracts: AstraZeneca; Boehringer-Ingelheim; Pfizer; Roche; Takeda. Consulting fees: AstraZeneca; Janssen; Lilly; Roche; Takeda. Payments or honoraria: AstraZeneca; BMS; Lilly; Pfizer; Roche. Leadership or fiduciary role in the oncology section NVALT, guideline committee NSCLC and CUP, duregeneesmiddelen committee NVALT and FMS. N.R.A.: Honoraria: Amgen; AstraZeneca; Bayer, Bristol-Myers Squibb; Boehringer; Guardant; Janssen; Merck Sharp & Dohme; Novartis; Pfizer; Roche; Sanofi; Takeda. K.J.O.: Founder of Carpe Vitae Pharmaceutical and inventor of provisional patents filed by Queensland Institute of Technology. N.G.: Employment: AstraZeneca (I). Consulting or Advisory Role: Abbvie; AMGEN; AstraZeneca; BeiGene; Bristol-Myers Squibb; Daiichi Sankyo/Astra Zeneca; Gilead Sciences; Ipsen; Janssen; LEO Pharma; Lilly; MSD; Novartis; Pfizer; Roche; Sanofi; Takeda. Research Funding: AstraZeneca (Inst); BMS (Inst); MSDavenir (Inst); Roche (Inst). Travel, Accommodations, Expenses—Janssen Oncology; Roche. Research Funding—AstraZeneca; Novartis. M.N.: Honoraria: Amgen; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb Japan; Chugai Pharma; Daiichi Sankyo/UCB Japan; Eisai; Janssen; Lilly; Merck; MSD; Nippon Kayaku; Novartis; Ono Pharmaceutical; Pfizer; Taiho Pharmaceutical; Takeda. Research Funding: Amgen (Inst); AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Janssen (Inst); Lilly (Inst); Merck (Inst); MSD (Inst); Pfizer (Inst); Taiho Pharmaceutical (Inst); Takeda (Inst). S.H.: Consulting or Advisory Role: Roche; Takeda. Travel, Accommodations, Expenses: Amgen. C.L.: Honoraria: Amgen. Consulting or Advisory Role: Amgen; cbpartners. Research Funding: Revolution Medicines (Inst). Uncompensated Relationships: Amgen. N.R.: Honoraria: AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Merck; Pfizer; Roche; Takeda. Consulting or Advisory Role: AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Merck; Pfizer; Roche; Takeda. Speakers’ Bureau: Amgen; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Merck; Merck KGaA; Pfizer; Roche; Sanofi; Takeda. P.P.: Research Funding: Amgen Greece. G.P.: Personal fees (as consultant and/or speaker bureau): Amgen; Astrazeneca; BMS; Lilly; MSD; Roche; Janssen. Research support: Astrazeneca; Roche unrelated to the current work. A.D.: Honoraria: Intellisphere; Intellisphere (Inst); Roche/Genentech. Consulting or Advisory Role: Anheart Therapeutics; ChromaCode; Guardant Health (Inst); TP Therapeutics (Inst). Research Funding—Anheart Therapeutics (Inst); AstraZeneca (Inst); Guardant Health; Merck; Novartis (Inst); Sorrento Therapeutics (Inst); Syntrix Biosystems (Inst). Travel, Accommodations, Expenses—Guardant Health; Other Relationship—Rising Tide Foundation (Inst). B.M., W.K., C.N., B.E.S., C.A.-A., and Y.W. are employees and shareholders of Amgen Inc. A.J.d.L.: Research support: BMS; MSD; Boehringer; AstraZeneca. Non-financial support from Merck Serono (supply of cetuximab for clinical trial) and Roche (supply of molecular diagnostic [Avenio] for NGS on ctDNA for clinical trial). R.G., A.P., S.-W.K., C.G.F., M.D., and S.G. have nothing to disclose.

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