Selecting Novel Small-Molecule Agents Vs Chemotherapy in KRAS G12C+ NSCLC


Patients with KRAS G12C-mutated non–small cell lung cancer who have brain metastases or intolerability of intravenous infusion may be more suitable to receive a small molecule inhibitor compared with chemotherapy, says Sandip P. Patel, MD.

Although various clinical trials have demonstrated the efficacy of small molecule inhibitors like sotorasib (Lumakras) and adagrasib (Krazati) in those with KRAS G12C-mutated non–small cell lung cancer (NSCLC), it still may not be unreasonable to administer chemotherapy to these patients, according to Sandip Patel, MD.

In a conversation with CancerNetwork® during a recent Tweet Chat, Patel, a professor in the Department of Medicine at the University of California San Diego Health, spoke about relevant clinical trial data pertaining to the use of small molecule inhibitors in the management of KRAS G12C–mutated NSCLC. According to Patel, the only direct comparison between sotorasib and docetaxel in the aforementioned population, which was conducted in the phase 3 CodeBreaK 200 trial (NCT04303780), did not show a substantial survival advantage with the experimental agent. However, Patel suggested that the small molecule inhibitors may be a preferred option for specific subsets of patients, such as those who have concerns with the toxicity associated with chemotherapy.

In October 2023, the FDA’s Oncologic Advisory Drug Committee voted that the progression-free survival data for sotorasib in the CodeBreaK 200 trial could not be reliably interpreted in support of potential full approval status of the agent.


There have been several studies in the KRAS G12C space that have been illustrative of efficacy. There are the CodeBreaK trials for sotorasib and the KRYSTAL studies for adagrasib. Broadly, when we’re talking about non–small cell lung cancer, part of the interest is that, historically, KRAS has been thought to be an undruggable target. This is really the first generation of multiple novel KRAS inhibitors, including pan-KRAS inhibitors, in clinical trials.

When we’re thinking about the data, especially because they are a subset, it’s reasonable to look at the data in totality. However, the only randomized control comparison we have in the second-line setting of sotorasib vs docetaxel did not show a substantial survival advantage. It’s not unreasonable to give chemotherapy to these patients by any means. For patients with brain metastases, those whose tolerability of IV infusion may be an issue or may have concerns around the [adverse] effects of chemotherapy, in my clinic, the general preference may be for an oral small molecule inhibitor. However, reasonable [practices] can think about the best opportunity for their patients and sequencing them in a way that maximizes their quality and quantity of life.


Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. Streamed live October 5, 2023. Accessed February 9, 2024.

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