New, long-term outcomes from the CodeBreaK 100 trial of sotorasib (Lumakras®; Amgen), the first and only KRASG12C inhibitor [1] approved for patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), will be presented as a late-breaking oral presentation on Sunday, April 10, 2022 (from 3:00 – 5:00 p.m. CST) at the American Association for Cancer Research (AACR) Annual Meeting from April 8-13 in New Orleans, Louisiana.

The development of sotorasib was one of the toughest challenges for researchers, which took more than last 40 years. The agent has demonstrated a positive benefit-risk profile with rapid, deep, and durable anti-cancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the KRASG12C-mutation with a once-daily oral formulation. [2]

Amgen is progressing the largest and broadest global KRASG12C inhibitor development program with unparalleled speed and exploring more than 10 sotorasib combination regimens, including triplets, with clinical trial sites spanning five continents. To date, over 4,000 patients around the world have received sotorasib through the clinical development program and commercial use.

In May 2021, sotorasib was the first KRASG12C inhibitor to receive regulatory approval anywhere in the world with its approval in the U.S., under accelerated approval. Sotorasib is also being studied in multiple other solid tumors. [3]

Ongoing development
Notable data from Amgen’s oncology pipeline includes the first disclosure of preclinical results from AMG 794, a half-life extended (HLE) bispecific T-cell engager (BiTE®) molecule targeting Claudin 6 (CLDN6) in NSCLC and epithelial ovarian cancer, and TNB-928b, a T-cell engaging bispecific antibody utilizing a bivalent tumor-selective folate receptor alpha binding arm for the treatment of ovarian cancer.

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“Following the approval of sotorasib for KRAS G12C-mutated non-small cell lung cancer in nearly 40 countries around the world, we look forward to sharing the longest follow-up data ever presented with a KRASG12C inhibitor at this year’s AACR conference, further demonstrating the clinical benefit this transformative therapy can bring to patients,” noted David M. Reese, M.D., executive vice president of Research and Development at Amgen.

“Across our oncology pipeline, we also look forward to sharing emerging early research highlighting how Amgen is advancing the next frontier of innovation in the treatment of cancers,” Reese added.

Non-Small Cell Lung Cancer and KRASG12C
Lung cancer is the leading cause of cancer-related deaths worldwide, and it accounts for more deaths worldwide than colon cancer, breast cancer and prostate cancer combined. [4] Overall survival rates for NSCLC are improving but remain poor for patients with advanced disease and 5-year survival is only 7% for those with metastatic disease. [5]

KRASG12C is the most common KRAS mutation in NSCLC.[6] About 13% of patients with NSCLC harbor the KRAS G12C mutation.[7] Unmet medical need remains high and treatment options are limited for NSCLC patients with the KRAS G12C mutation whose first-line treatment has failed to work or has stopped working. The outcomes with other approved therapies are suboptimal, with a median progression-free survival of approximately 4 months following second-line treatment of KRAS G12C-mutated NSCLC. [8]

Clinical development
The CodeBreaK clinical development program for Amgen’s drug sotorasib is designed to study patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers.

  • CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors (NCT03600883) Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of the disease. The primary endpoint for the Phase 2 study was a centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline. [2] The Phase 2 trial in colorectal cancer (CRC) is fully enrolled and results have been published. [9]
  • CodeBreaK 200, the global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRASG12C-mutated NSCLC completed enrollment of 345 patients (NCT04303780). Eligible patients had previously treated, locally advanced, and unresectable or metastatic KRASG12C-mutated NSCLC. The primary endpoint is progression-free survival and key secondary endpoints include overall survival, objective response rate, and patient-reported outcomes.

Amgen also has several Phase 1b studies investigating sotorasib monotherapy and sotorasib combination therapy across various advanced solid tumors (CodeBreaK 101) open for enrollment (NCT04185883) and a Phase 2 randomized study will evaluate sotorasib in patients with stage IV KRAS G12C-mutated NSCLC in need of first-line treatment (CodeBreaK 201; NCT04933695)

Clinical trials
A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of Sotorasib (AMG 510) in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100) – NCT03600883
Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) – NCT04185883
AMG 510 Ethnic Sensitivity Study (CodeBreaK 105) – NCT04380753
Study to Compare AMG 510 “Proposed INN Sotorasib” With Docetaxel in Non Small Cell Lung Cancer (NSCLC) (CodeBreak 200) – NCT04303780
A Study of Sotorasib (AMG 510) in Participants With Stage IV NSCLC Whose Tumors Harbor a KRAS p.G12C Mutation in Need of First-line Treatment (CodeBreaK201) – NCT04933695
Sotorasib and Panitumumab Versus Investigator’s Choice for Participants With Kirsten Rat Sarcoma (KRAS) p.G12C Mutation (CodeBreak 300) – NCT05198934

[1] Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter JD, Volak LP, Houk BE, Fakih MG, O’Neil BH, Price TJ, Falchook GS, Desai J, Kuo J, Govindan R, Hong DS, Ouyang W, Henary H, Arvedson T, Cee VJ, Lipford JR. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 Nov;575(7781):217-223. doi: 10.1038/s41586-019-1694-1. Epub 2019 Oct 30. PMID: 31666701.
[2] Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, Italiano A, Schuler M, Borghaei H, Barlesi F, Kato T, Curioni-Fontecedro A, Sacher A, Spira A, Ramalingam SS, Takahashi T, Besse B, Anderson A, Ang A, Tran Q, Mather O, Henary H, Ngarmchamnanrith G, Friberg G, Velcheti V, Govindan R. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N Engl J Med. 2021 Jun 24;384(25):2371-2381. doi: 10.1056/NEJMoa2103695. Epub 2021 Jun 4. PMID: 34096690.
[3] Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, Falchook GS, Price TJ, Sacher A, Denlinger CS, Bang YJ, Dy GK, Krauss JC, Kuboki Y, Kuo JC, Coveler AL, Park K, Kim TW, Barlesi F, Munster PN, Ramalingam SS, Burns TF, Meric-Bernstam F, Henary H, Ngang J, Ngarmchamnanrith G, Kim J, Houk BE, Canon J, Lipford JR, Friberg G, Lito P, Govindan R, Li BT. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020 Sep 24;383(13):1207-1217. doi: 10.1056/NEJMoa1917239. Epub 2020 Sep 20. PMID: 32955176; PMCID: PMC7571518.
[4] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.
[5] American Cancer Society. Lung Cancer Survival Rates. 2021. Online. Last accessed on March 22, 2022.
[6] Arbour KC, Jordan E, Kim HR, Dienstag J, Yu HA, Sanchez-Vega F, Lito P, Berger M, Solit DB, Hellmann M, Kris MG, Rudin CM, Ni A, Arcila M, Ladanyi M, Riely GJ. Effects of Co-occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2018 Jan 15;24(2):334-340. doi: 10.1158/1078-0432.CCR-17-1841. Epub 2017 Oct 31. PMID: 29089357; PMCID: PMC5771996.
[7] Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C Somatic Mutations across Race, Sex, and Cancer Type. N Engl J Med. 2021 Jan 14;384(2):185-187. doi: 10.1056/NEJMc2030638. PMID: 33497555.
[8] Spira AI, Tu H, Aggarwal S, Hsu H, Carrigan G, Wang X, Ngarmchamnanrith G, Chia V, Gray JE. A retrospective observational study of the natural history of advanced non-small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease. Lung Cancer. 2021 Sep;159:1-9. doi: 10.1016/j.lungcan.2021.05.026. Epub 2021 May 25. PMID: 34293517.
[9] Fakih MG, Kopetz S, Kuboki Y, Kim TW, Munster PN, Krauss JC, Falchook GS, Han SW, Heinemann V, Muro K, Strickler JH, Hong DS, Denlinger CS, Girotto G, Lee MA, Henary H, Tran Q, Park JK, Ngarmchamnanrith G, Prenen H, Price TJ. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022 Jan;23(1):115-124. doi: 10.1016/S1470-2045(21)00605-7. Epub 2021 Dec 15. PMID: 34919824.

Featured image: New_Orleans_Louisiana_AACR16. Photo courtesy: © 2016 – 2022 AACR. Used with permission

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