Sotorasib, Adagrasib Therapy Is “Reasonable” Strategy in KRAS G12C+ NSCLC

It is a “reasonable” treatment strategy to use FDA-approved small molecule inhibitors such as sotorasib (Lumakras) or adagrasib (Krazati) as second-line treatment for patients with KRAS G12C-mutated non–small cell lung cancer (NSCLC), according to Sandip P. Patel, MD.

As part of a Tweet Chat with CancerNetwork^®, Patel, a professor in the Department of Medicine at the University of California San Diego Health, spoke broadly about developments in the treatment landscape for those with KRAS G12C-mutated NSCLC. He stated that the aforementioned small molecule inhibitors have demonstrated improved tolerability compared with docetaxel, and that adverse effects such as mild liver dysfunction appear to be manageable.

Sotorasib previously received accelerated approval from the FDA as a treatment for those with KRAS G12C-mutated NSCLC in May 2021.¹ Additionally, the FDA granted accelerated approval to adagrasib for the same patient population in December 2022.²

Transcript:

There’s probably no space in oncology that’s had as dramatic of an era of drug development as KRAS mutation–targeted therapies; in particular, with the development of small molecule inhibitors for KRAS G12C. The 2 currently FDA-approved agents are sotorasib and adagrasib.

When we think about KRAS G12C, treating [patients] in the second-line setting with these small molecule inhibitors—whether it’s sotorasib or adagrasib—is a very reasonable treatment strategy. Recent data may have tempered some of the enthusiasm around some of the overall survival data compared with docetaxel. The flipside of many of those studies is the differential loss of patients on the control arm, for example. We need to look further in terms of the details. It’s quite clear that, broadly, the tolerability of the small molecule inhibitors is far superior to that of docetaxel, especially when you think about some of the [adverse] effects like alopecia, neutropenia, and other [adverse] effects that we don’t see with the small molecule inhibitors, which typically have [adverse] effects related to mild liver dysfunction, which we can manage.

Broadly, the first, most important concept is we need to test these patients with metastatic non–small cell lung cancer, with multiplex sequencing, most commonly next-generation sequencing, for all the mutations of which KRAS G12C is a driver that we can target now. However, it’s a driver that we target in the second-line setting optimally. In my clinic, it remains my preferred choice [to use these agents] in the second-line setting. Although chemotherapy is reasonable, the [adverse] effect profile and central nervous system [CNS] activity of drugs like sotorasib and adagrasib are reasons I still would favor the oral agent over IV, but reasonable [practices] can have a discussion on what makes sense for their practice setting.

References

1. FDA approves LUMAKRAS (sotorasib), the first and only targeted treatment for patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer. News release. Amgen. May 28, 2021. Accessed February 9, 2024. http://tinyurl.com/mpcb5ss5
2. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed February 9, 2024. https://bit.ly/3UUVphS