In late May 2021, the U.S. Food and Drug Administration (FDA) approved sotorasib (Lumakras™; Amgen), a RAS GTPase family inhibitor, for the treatment of adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.
At the same time, the FDA also approved the QIAGEN therascreen® KRAS RGQ PCR kit (tissue) and the Guardant360® CDx (plasma) as companion diagnostics for sotorasib.
The Kirsten Rat Sarcoma viral oncogene homolog or KRAS p.G12C mutation is one of the most prevalent driver mutations in NSCLC, and occurs in approximately 13% of all patients diagnosed with non-squamous NSCLC and 1%–3% of CRC and other solid tumors. 
The mutation follows a single DNA error which swaps out an important protein building block, placing a cysteine where a glycine should be. Tumors with the KRASG12C-mutation manufacture a version of the KRAS protein that is almost constantly active, driving tumor growth. Sotorasib blocks tumor growth by trapping the KRAS protein in its inactive form.
NSCLC accounts for approximately 84% of the 2.2 million new lung cancer diagnoses each year worldwide, including approximately 236,000 new cases in the U.S. 
Sotorasib (previously known as AMG 510) received accelerated approval based on overall response rate (ORR) and duration of response (DoR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
“The FDA approval of sotorasib is a breakthrough moment for patients with KRASG12C-mutated non-small cell lung cancer because there is now a targeted therapy for this common, but previously elusive, mutation,” noted David M. Reese, M.D., executive vice president of Research and Development at Amgen.
“This [KRASG12C] mutation is difficult to target and this group of patients [has] tumors that have been difficult to treat [because…] we did not have targeted therapies,” said co-senior author and medical oncologist Ramaswamy Govindan, MD, the Anheuser Busch Endowed Chair in Medical Oncology at Washington University.
“Sotorasib is one of the first-in-class small-molecule inhibitors that bind to this mutant protein, locking in anticancer activity. The new drug is addressing an unmet need for these patients, targeting the most common mutation that we can go after. [One of the interesting facts is that it has] fewer toxicities [than] expected,” Govindan explained.
“We’re also continuing to investigate this drug in combination with other experimental drugs to see if we can further improve responses and survival,” he added.
A race against cancer
“KRAS has challenged cancer researchers for more than 40 years with many deeming it as ‘undruggable.’ The sotorasib development program was a race against cancer for Amgen’s scientists and clinical trial investigators who together have now successfully delivered this new medicine to patients in less than three years—from the first patient dosed to U.S. regulatory approval.”
The FDA approval of sotorasib is based on results from a subset of patients in CodeBreaK 100, the largest clinical trial conducted to date exclusively for patients with the KRASG12C mutation.
The results of the study, led by researchers at Washington University School of Medicine in St. Louis, Perlmutter Cancer Center at NYU Langone Health in New York, MD Anderson Cancer Center in Houston, and Memorial Sloan Kettering Cancer Center in New York, will be presented June 4, 2021 at the annual meeting of the American Society of Clinical Oncology (ASCO) and published the same day in The New England Journal of Medicine. 
Most patients participating in the trial had previously been treated with standard chemotherapy along with an immunotherapy drug that targets a protein called PD-1. The results of the study demonstrated favorable efficacy and tolerability in 124 patients with KRASG12C mutation-positive NSCLC who had disease progression after receiving immunotherapy and/or chemotherapy.
In the trial, 960 mg of sotorasib administered orally once-daily demonstrated an ORR (a proportion of patients with ≥ 30% decrease in the tumor) of 36% (95% CI: 28-45) with 81% (95% CI: 73-87) of patients achieving disease control (percentage of patients who have achieved complete response, partial response and stable disease for more than three months). The median DoR was 10 months. The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. Adverse reactions resulting in permanent discontinuation of sotorasib occurred in 9% of patients.
“Sotorasib represents a major advancement in oncology and changes the treatment paradigm for patients with KRASG12C-mutated non-small cell lung cancer,” said Bob T. Li, M.D., Ph.D., MPH, principal investigator at Memorial Sloan Kettering Cancer Center.
“Patients with non-small cell lung cancer who have progressed beyond first-line treatment face a poor prognosis and have limited treatment options available to them. Sotorasib delivers a new option for these patients, and it is the first KRAS-targeted therapy to be approved after nearly four decades of research,” Li concluded.
“The excitement surrounding this trial result is that sotorasib is now the first targeted therapy for lung cancer patients with KRAS mutations,” said Vamsidhar Velcheti, MD, of NYU Langone Health.
“Sotorasib showed clinically significant benefit without any new safety concerns in patients with this specific form of KRAS mutant lung cancer,” noted Govindan.
“Moving forward, [we’ll] seek to inform the development of combination therapies featuring sotorasib and other [emerging therapeutic agents] and to determine which best fit the mix of mutations in each patient’s cancer cells.”
The researchers currently are conducting a phase 3 clinical trial called CodeBreak 200 which is designed to compare the effectiveness of sotorasib with docetaxel (Taxotere®; Sanofi Aventis) in 345 patients who have non-small-cell lung cancer and this specific KRAS mutation.
Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100) – NCT03600883
Study to Compare AMG 510 “Proposed INN Sotorasib” With Docetaxel in Non Small Cell Lung Cancer (NSCLC) (CodeBreak 200) – NCT04303780
Highlights of Prescribing Information
Sotorasib (Lumakras™; Amgen)[Prescribing Information]
Docetaxel (Taxotere®; Sanofi Aventis)[Prescribing Information]
 Hong DS, Kuo J, Sacher AG, Barlesi F, Besse B, Kuboki Y, Dy GK, Dembla V, et al. CodeBreak 100: Phase I study of AMG 510, a novel KRASG12C inhibitor, in patients (pts) with advanced solid tumors other than non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Journal of Clinical Oncology 2020 38:15_suppl, 3511-3511 [Abstract]
 American Cancer Society. Key Statistics for Lung Cancer 2021 Online. Last accessed on May 28, 2021.
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 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 4. doi: 10.1056/NEJMoa2103695. Epub ahead of print. PMID: 34096690.
 Hong DS, Strickler JH, Fakih M, Falchook GS, Li BT, Durm GD, Burns TF, et al. Trial in progress: A phase 1b study of sotorasib, a specific and irreversible KRASG12C inhibitor, as monotherapy in non-small cell lung cancer (NSCLC) with brain metastasis and in combination with other anticancer therapies in advanced solid tumors (CodeBreaK 101). Abstract TPS2669. Presented at: American Society of Clinical Oncology. J Clin Oncol 39, 2021 (suppl 15; abstr TPS2669)