First Treatment Approved for the KRAS G12C Mutation in Lung Cancer Previously Considered Treatment-Resistant

On May 28, 2021, the FDA (United States Food and Drug Administration) granted approval for adults with tumors harboring the specific genetic mutation KRAS G12C who had received at least one prior systemic treatment for non-small cell lung cancer (NSCLC), as the first treatment in this setting: sotorasib (Lumakras, Amgen), a targeted drug. This is approved for tumors with any KRAS mutation, which account for approximately 25% of mutations in non-small cell lung cancers, and is the first targeted therapy. KRAS G12C mutations represent approximately 13%of mutations in non-small cell lung cancers.

The FDA also approved the QIAGEN KRAS G12C mutation test, therascreen® KRAS RGQ PCR kit (tissue), and Guardant360® CDx (plasma) as companion diagnostics. If no mutation is detected in the plasma sample, tumor tissue should be tested.

What Is the KRAS G12C Mutation?

KRAS has been among the most frequently mutated of the oncogenes (cancer genes) in human cancers and, until recently, was considered undruggable. However, the KRAS inhibitor sotorasib became a source of hope for tumors positive for G12C, a common KRAS mutation.

Figure 1 description: The KRAS protein is an important molecule involved in normal cell growth. The protein produced by the KRAS gene plays a role in transmitting signals from the external environment to the cell nucleus. When a mutation occurs, the cell undergoes "aggressive" growth. Mutated KRAS continuously sends the "multiply" command even when the cell receives no signal from its external environment. KRAS is also responsible for drug resistance that develops against targeted drugs.

KRAS had been known to play a critical role in cancer development for 30 years. However, because of the unique biology of KRAS mutations, it had not been possible to target and silence them with an anticancer agent.

The discovery of agents that effectively target the KRAS G12C mutation is only a beginning and offers hope that it may be possible to target not only other KRAS mutations but also other mutations previously thought to have been unsuccessful targets.

Although the KRAS p.G12C mutation is most often reported in non-small cell lung cancers (NSCLC), it is also found in other solid tumors, particularly colorectal cancers . Its frequency is 13% in NSCLC and 1-7% in colorectal cancers.

Figure 2 description: The KRAS G12C mutation is most common in NSCLC, followed by colorectal cancers. Following the FDA approval of sotorasib, this mutation will be used clinically as a new biomarker for advanced stages of many solid (organ) cancers.

As the most common cancer type with the highest rate of death, lung cancers (see World Cancer Statistics 2020), can largely be classified according to the genetic mutations that cause them.

Figure 3 description: Above, on the left, lung cancers can be seen to have 5 main histological types. From a genetic perspective, lung adenocarcinoma, a subtype of non-small cell lung cancer, can be seen to have more than 12 types (the pie chart on the right). One of these subtypes is lung cancer positive for the KRA G12C mutation.

The CodeBreaK 100 Trial

The researchers evaluated the efficacy of Lumakras in the clinical trial CodeBreak 100, a study involving 124 patients with locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer whose disease had progressed after an immune checkpoint inhibitor and / or platinum-based chemotherapy. The main outcomes measured were objective response rate (the proportion of patients whose tumors disappeared or shrank) and duration of response.

The objective response rate was 36%, and 58% of these patients had a response lasting six months or longer.

The approved 960-milligram dose is based on the available clinical data as well as pharmacokinetic and pharmacodynamic modeling supporting the approved dose. As part of the assessment of this accelerated approval, the FDA is requesting a postmarketing trial to investigate whether a lower dose would have a similar clinical effect.

The most common side effects of Lumakras include diarrhea, musculoskeletal pain, nausea, fatigue, liver injury, and cough. Lumakras should be withheld if patients develop symptoms of interstitial lung disease and permanently discontinued if interstitial lung disease is confirmed. Doctors should monitor patients' liver function tests before starting Lumakras and while they are taking it. If a patient develops liver injury, Lumakras should be interrupted, the dose reduced, or the drug permanently discontinued. Patients should avoid acid-reducing agents, drugs that induce or are substrates of certain liver enzymes, and drugs that are P-glycoprotein substrates while taking Lumakras.