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KRAS G12C Now Actionable With New FDA-Approved Therapy

May 28th, 2021

Rebecca Nagy, Vice President Medical Affairs, Guardant Health, Professor Clinical Internal Medicine, Licensed Genetic Counselor

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Forty-five percent of patients with non-small cell lung cancer (NSCLC) now have actionable driver mutations.1 KRAS is the most frequently mutated oncogene in human cancers, and of all KRAS driver-mutations, KRAS G12C is the most common.2 The FDA recently approved the first KRAS G12C inhibitor,3,4 sotorasib (LUMAKRAS™), to treat metastatic NSCLC (mNSCLC). Guardant360® CDx is the first and only liquid companion diagnostic for the drug.5

The Majority of mNSCLC Patients Could Benefit From CGP

Today, when so many mNSCLC patients do have these identifiable oncogenic drivers,6,7 there is a compelling need for comprehensive genomic profiling (CGP) as the standard of care. Most advanced lung cancer patients do not receive complete genotyping before starting treatment, though there are at least 9 mutations they should be tested for.

The history of the KRAS G12C mutation provides a valuable lesson. KRAS G12C occurs in 13% of nonsquamous, non–small-cell lung cancers and in 1 to 3% of colorectal and other cancers2. Until now, KRAS G12C mutations were considered undruggable. “Still,” says Terri Conneran8, who is in remission from KRAS G12C-mutated stage-3 non-small cell lung cancer, “many patients want to understand their disease, mutations and all, whether there is a treatment yet or not.” Conneran founded KRAS Kickers, a non-profit organization for patients with KRAS mutations. She and her organization are passionate advocates for CGP and full transparency with results. “At least half the patients I have met have never been tested for any mutations, while others have been tested but don’t have their results,” she marveled. Conneran urges all oncologists to test every mNSCLC patient, every time.8 Far less invasive and time-consuming than tissue testing, Guardant360 CDx plays a critical role for patients like Conneran, by quickly and accurately identifying those with KRAS G12C mutations who now have a promising treatment option.3,4

Of course, the potential benefits of testing with Guardant360 CDx extend to patients with a wide range of mutations. The test uses proprietary next-generation sequencing technology to detect mutations recommended by guidelines that inform first-line treatment decisions across all advanced solid tumors.9,10

It is critical that patients are not only tested, but are also then treated based on their comprehensive genomic profiling results.11 With the approval of sotorasib4, mNSCLC patients with KRAS G12C now have the option of an FDA-approved targeted therapy.7

With the FDA approval of sotorasib, roughly half of mNSCLC patients will have an actionable biomarker for targeted therapy.

With the growing number of approved and emerging targeted therapies, one wonders how many patients are, in fact, missing comprehensive genomic profiling (CGP) that could guide treatment decisions and improve outcomes. CGP is critical and necessary; dramatic changes in the cancer genomics landscape can only be realized through widespread and routine testing. Guardant360 CDx makes it both fast and easy to incorporate complete genomic profiling into the treatment selection process.7,8

Leading with Guardant360 CDx can deliver tremendous and quantifiable value to oncologists and to the patients who depend on them.7,8 Perhaps no one is more aware of this than the 1 in 8 NSCLC patients with a KRAS G12C mutation.12

Sotorasib (LUMAKRAS™) Prescribing Information

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References

  1. Nature. 2014 July 31; 511(7511): 543–550. doi:10.1038/nature13385.
  2. Haigis KM. KRAS alleles: The devil is in the detail. Trends Cancer. 2017 Oct. 3; 3(10):686-697.
  3. Amgen’s sotorasib granted breakthrough therapy designation for advanced or metastatic non-small cell lung cancer patients with KRAS G12C mutation [press release]. Thousand Oaks, CA: Amgen; Dec. 8, 2020. https://www.amgen.com/newsroom/press-releases/2020/12/amgens-sotorasib-granted-breakthrough-therapy-designation-for-advanced-or-metastatic-nonsmall-cell-lung-cancer-patients-with-kras-g12c-mutation. Accessed February 5, 2021.
  4. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA. KRAS G12C inhibition with sotorasib in advanced solid tumors N Engl J Med 2020 Sept. 24; 383:1207-1217.
  5. Amgen announces global diagnostic collaborations to expand molecular testing for patients with non-small-cell lung cancer [press release]. Thousand Oaks, CA: Amgen; Jan 13, 2020. https://www.amgen.com/newsroom/press-releases/2020/01/amgen-announces-global-diagnostic-collaborations-to-expand-molecular-testing-for-patients-with-non-small-cell-lung-cancer. Accessed February 8, 2021.
  6. Heydt C, Michels S, Thress K, Bergner S, Wolf J, Buettner, R. Novel approaches against epidermal growth factor receptor tyrosine kinase inhibitor resistance. Oncotarget. 2018 March 16; 9(20).
  7. Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Med. 2020 Jan 14; 12(1):8.
  8. Conneran T. Founding KRAS Kickers Interview. 2021.
  9. Guardant. Backgrounder: Guardant360 CDx now FDA approved. n.d.
  10. FDA approves first liquid biopsy next-generation sequencing companion diagnostic test [press release]. Silver Springs, MD: FDA; Aug. 7, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-first-liquid-biopsy-next-generation-sequencing-companion-diagnostic-test. Accessed February 5, 2021.
  11. Panabieres C. The future of liquid biopsy. Nature. 2020; 579,S9.
  12. Lipford, JR. Pre-clinical development of AMG 510: the first inhibitor of KRASG12C in clinical testing. Oral. presentation at AACR 2019, Atlanta, GA. March 29-April 3, 2019.