Highlights

  • Mutated RAS genes have been known significant oncodrivers for over 40 years, but have remained elusive targets for therapeutics

  • Only in the past three years, the first two drugs targeting G12C-mutated KRAS have received FDA approval in non-small cell lung cancer (NSCLC)

  • Clinical trials and real world data reveal only modest response rates of ~30-40% and durability of ~10 months

  • The excitement around the first FDA approvals has resulted in a wave of activity and attention in the space, with up to 65 companies working to develop and test ~100 different candidate drugs

  • With most trials likely to fail, proper patient recruitment, screening, and stratification will be paramount to successfully bringing targeted RAS therapy to market

Cancer’s White Whale

The RAS family is the original “white whale” of cancer drug targets. Since the discovery of RAS genes and their role in promoting cancer over 40 years ago, cancer researchers have been on the hunt for a drug against this behemoth of an oncogene1. Overactivation of KRAS is implicated in 25% of non-small cell lung cancers, 25-35% of colorectal cancers, and up to 95% of pancreatic cancers2. In the United States alone, this amounts to roughly 150,000 patients every year diagnosed with KRAS-mutated cancer.

Driver mutations in the genes leave KRAS proteins “stuck on,” constantly sending growth signals, leading to tumor formation. However, targeting RAS directly has proven incredibly challenging. For one, the KRAS protein lacked obvious binding pockets for drugs, so the chemistry of attaching a molecule to the protein seemed impossible. Secondly, RAS genes are central to the regulation of many essential cellular processes, thus, globally disrupting their function can have serious deleterious effects. Lastly, mutations occur up and down the genes, each with distinct pathological implications, complicating the search for a single anti-RAS agent3.

The Hunters’ Quarry

The tenacity of drug hunters across a broad sea of domain expertise, from medicinal chemists and X-ray crystallographers to computer scientists, has finally paid off. Recent advances in small molecule chemistry have led to major breakthroughs, especially for the predominant oncogenic mutation in KRAS G12C. 

The FDA granted accelerated approval for Amgen’s Lumakras (sotorasib) in May 2021, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation who have received at least one prior systemic therapy4,5. Nineteen months later, in December 2022, Krazati (adagrasib), developed by Mirati Therapeutics, also received FDA approval for the same indication6. The arrival of these drugs represents a huge and long-awaited leap for cancer patients and their families, as well as physicians.

Three’s a Crowd

With the initial floodgates to a RAS-inhibitor opened, many other biotechnology and pharma companies are developing additional drugs targeting KRAS or KRAS-mediated pathways7. Following the approvals of sotorasib and adagrasib, the industry has seen a boom in activity and investment. Most market research firms estimate the KRAS therapeutics market will be in the billions of dollars by 2030, with the potential to support several multi-billion dollar drugs. As of this writing, as many as 65 companies are developing 97 different therapies for up to 18 indications8. These efforts encompass various approaches, including targeting particular mutations (e.g. G12C vs.G12D) or all mutations; focusing on particular diseases (e.g. NSCLC vs.CRC vs. pancreatic cancer); as well as deploying novel chemistries (e.g. small molecule vs. allosteric inhibitors). Many companies are even jumping directly into combination approaches. 

With over 200 clinical trials enrolling or planned, the struggle for unique patient enrollment and clinician education will stretch beyond “simply” inhibiting the overactivity of a major oncogene. The competition for patients and sites may be reminiscent of the fervor in the checkpoint inhibitor space circa 2019.

Clinical Benefit

With such recent and so few approved drugs, and a large clinical trial pipeline still in its early days, it may be too early to draw conclusions about the efficacy and durability of KRAS inhibitors. However, the studies that do exist suggest these drugs likely will yield response rates that, frankly, are typical of targeted cancer agents. In clinical trials targeting patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC), Lumakras achieved an objective response rate (ORR) of 37.1%, including 4 complete responses and 42 partial responses. The median duration of response (DOR) was 11.1 months9. Krazati, meanwhile, in its pivotal trial for KRAS G12C-mutated NSCLC, yielded an ORR of 43%, with 1 complete response and 47 partial responses. The median DOR was 8.5 months10. By way of an apples-to-oranges comparison, the median ORR and DOR for pembrolizumab in NSCLC is ~18-45% and 10-14 months, depending on the stage of disease and line of therapy11

Another challenge for KRAS inhibitors, as with other cancer therapies, is the regularity with which patients develop acquired resistance to the drugs. KRAS sits in the middle of complex molecular/cellular regulatory networks, with many signaling routes around and through the mutation. More data for KRAS inhibitors, especially for other diseases and mutations (e.g. CRC, pancreatic, G12D), will help to clarify the range of efficacy and durability. While those data are pending, clinical researchers are already exploring a range of drug combinations (including with immune checkpoint inhibitors). Further, close monitoring of tumor status through disease progression will be important to guide the sequencing of drug regimens.

Finding the Right Patients

As of this writing, 17 nucleic acid-based diagnostic devices have been cleared by the FDA for the detection of the presence or absence of KRAS mutations, in either lung or colorectal cancers12. If the early clinical results are generalizable to the efficacy of inhibitors in patients harboring KRAS G12C, with about 1 in 3 patients harboring the mutation benefiting from the drug, then one may infer that a diagnostic detecting the mutation might be necessary, but is insufficient, to predict clinical benefit. This is especially true in light of the prevalence of drug resistance and requirement for combination therapy. 

In the KRAS inhibitor arena, complex biomarkers based on gene expression, proteomic or multi-omic signatures may be helpful in guiding patients to the right drugs, and in helping promising drugs find their niche in the market. Taking another cue from checkpoint inhibitors, where pembrolizumab has been approved based on the composite status of MSI and dMMR biomarkers alone, KRAS therapeutics may find the broadest and most responsive patient subgroups based not on the narrowly defined mutation status, but rather by considering a more holistic measurement of the relevant driver biologies.

 

Rafael Rosengarten, Ph.D., CEO of Genialis

1  Chen, K., Zhang, Y., Qian, L., & Wang, P. (2021). Emerging strategies to target RAS signaling in human cancer therapy. Journal of Hematology & Oncology, 14(1), 116. https://doi.org/10.1186/s13045-021-01127-w

2  Chien, S. (2021). Targeting the KRAS mutation for more effective cancer treatment. MD Anderson Cancer Center. Retrieved March 28, 2024, from https://www.mdanderson.org/cancerwise/targeting-the-kras-mutation-for-more-effective-cancer-treatment.h00-159458478.html

3  Zhu, C., Guan, X., Zhang, X., Luan, X., Song, Z., Cheng, X., Zhang, W., & Qin, J.-J. (2022). Targeting KRAS mutant cancers: From druggable therapy to drug resistance. Molecular Cancer, 21(1), 159. https://doi.org/10.1186/s12943-022-01629-2

4  FDA (2021). FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. Food and Drug Administration. Retrieved March 28, 2024, from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc

5  Of note, the FDA has since denied full approval of Lumakras, pending a post-market dose response and confirmatory study due in 2028. Read more here

6  FDA (2022). FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC.  Food and Drug Administration. Retrieved March 28, 2024, from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc

7  Zhu, C., Guan, X., Zhang, X., Luan, X., Song, Z., Cheng, X., Zhang, W., & Qin, J.-J. (2022). Targeting KRAS mutant cancers: From druggable therapy to drug resistance. Molecular Cancer, 21(1), 159. https://doi.org/10.1186/s12943-022-01629-2

8  Data aggregated from BioCentury

9  Skoulidis, F., Li, B. T., Dy, G. K., Price, T. J., Falchook, G. S., Wolf, J., Italiano, A., Schuler, M., Borghaei, H., Barlesi, F., Kato, T., Curioni-Fontecedro, A., Sacher, A., Spira, A., Ramalingam, S. S., Takahashi, T., Besse, B., Anderson, A., Ang, A., … Govindan, R. (2021). Sotorasib for lung cancers with KRAS p.G12C mutation. New England Journal of Medicine, 384(25), 2371–2381. https://doi.org/10.1056/NEJMoa2103695

10  Jänne, P. A., Riely, G. J., Gadgeel, S. M., Heist, R. S., Ou, S.-H. I., Pacheco, J. M., Johnson, M. L., Sabari, J. K., Leventakos, K., Yau, E., Bazhenova, L., Negrao, M. V., Pennell, N. A., Zhang, J., Anderes, K., Der-Torossian, H., Kheoh, T., Velastegui, K., Yan, X., … Spira, A. I. (2022). Adagrasib in non–small-cell lung cancer harboring a KRASg12c mutation. New England Journal of Medicine, 387(2), 120–131. https://doi.org/10.1056/NEJMoa2204619

11  Dang TO, Ogunniyi A, Barbee MS, Drilon A. Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. Expert Rev Anticancer Ther. 2016;16(1):13-20. https://doi.org/10.1586/14737140.2016.1123626

12  FDA (2023). Nucleic Acid Based Tests. Food and Drug Administration. Retrieved March 28, 2024, from https://www.fda.gov/medical-devices/in-vitro-diagnostics/nucleic-acid-based-tests

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