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KRASG12C Combination Therapy New Hope for Lung Cancer Patients

Updated: Sep 22

Lung cancer is one of the most common causes of cancer globally. The five-year survival rate for lung cancer is 18.6% compared to other common cancers like colorectal cancer, 64.5%, and breast cancer, 89.6%. According to American Lung Association, more than half of the people with lung cancer die within one year of being diagnosed. Late diagnosis of the disease, health insurance, and Medicaid coverage, racial disparities in health care coverage, and lack of treatment are among the major causes of high mortality of lung cancer patients. The prevalence of Non-small cell lung cancer (NSCLC) is in 85% of the total lung cancer, making it the most common lung cancer subtype. The majority of the patients with NSCLC have non-squamous non-small cell lung cancer with driver mutations such as K-RAS, ALK, EGFR, BRAF, ROS, and HER2. Among these, KRAS is the most frequent oncogene, making up 30% of the NSCLC. There are different KRAS driver mutations (Figure 1A). Among these, KRASG12C is the most common KRAS driver mutation that impacts more than 70,000 patients in the U.S. and Europe, which makes up ~14% of all NSCLC patients. More than 40% of the patients with KRASG12C NSCLC driver mutation are associated with brain metastasis leading to poor survival and morbidity. Until recently, there were no treatments targeting KRASG12C mutation in NSCLC. In May 2021, the FDA granted accelerated approval for the first targeted therapy against KRASG12C for Amgen’s sotorasib (LUMAKRAS), a milestone and new hope for cancer that was previously accepted as untreatable cancer. Recent report from Phase III trial show that sotorasib show 25% progression free survival compared to 10% shown by present first line therapeutics docetaxel. The other end points like disease control rate (83% vs. 60%), time to response (TTR, 1.4 vs. 2.8 months) and duration or response (DOR, 8.6 vs. 6.8 months) were superior for sotorasib compared to decetaxel in the recent result from CodeBreak 200 trial. FDA is also reviewing Mirati therapeutic’s adagrasib for accelerated approval. There is a comparatively higher percentage of therapeutic pipelines investigating therapy targeting KRASG12C (38% incidence vs. 81% clinical trials) compared to other KRAS mutations showing an existing gap in the investigational pipeline for other KRAS driver mutations (Figures 1A and 1B).


Figure 1: Comparison of epidemiological incidence and the ongoing clinical trials targeting KRAS driver mutation. (For more information on the clinical trials targeting KRAS driver mutation)


Other biopharmaceutical companies have joined Amgen and Mirati to fight against KRASG12C NSCLC. Figure 2A shows the companies with clinical investigational pipelines and the number of clinical trials in the total for KRASG12C NSCLC. The majority of these companies are based in the U.S. (~60%), followed by China (~24%) and the EU (~16%) (Figure 2B).



Figure 2: Clinical pipeline targeting KRASG12C NSCLC by the company and geographical distribution (For details on the phase and ID of the trials).


There are 53 clinical trials with 14 pipeline drugs and four preclinical drugs in the development pipeline targeting KRASG12C NSCLC. Of these KRASG12C 53 trials, 21 are monotherapy trials, while 32 are combination therapy trials.


KRASG12C combination therapy


KRASG12C NSCLC occurs simultaneously with other mutations. Common concomitant mutations reported with KRAS-mutant NSCLC are TP53 tumor suppressor gene, serine/threonine kinase 11 (STK11), and kelch-like ECH-associated protein 1 (KEAP1). In addition, recent studies have shown increased PDL-1 expression in KRASG12C cancer, indicating checkpoint inhibition can improve the prognosis of the KRASG12C NSCLC. Therefore, many combination trials are testing the efficacy of KRASG12C NSCLC targeting drugs with other drugs (Figure 3), with KRASG12C and PD-1/PDL-1 combination therapy being the top combination therapy.




Figure 3: Ongoing combination trials targeting KRASG12C NSCLC (For complete list of combination trials and associated therapeutics)


Recently, Amgen presented clinical data from its exploratory study CodeBreak 100/101, exploring the combination treatment of LUMAKRAS in combination with Pembrolizumab (Keytruda, Merck) or Atezolizumab (Tecentriq, Roche) in KRASG12C NSCLC patients with (67%) or without prior immunotherapy. The median follow-up time was 12.8 months. 17 of the 58 patients (29%) were responders with a median duration of response (DOR) of 17.9 months. The median overall survival (OS) was 15.7 months (95% CI: 9.8, 17.8). Thus combination therapy showed promising results and improved median DOR and OS. However, patients with pre-treated NSCLC and a combination of LUMAKRAS with immunotherapy also had a higher incidence of grade 3-4 treatment-related adverse events than LUMAKRAS monotherapy, primarily marked by liver toxicity and elevated hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This gives new hope to patients with difficult-to-treat KRASG12C NSCLC that may be treatable by combination therapy in the future.



References:

  1. https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/resource-library/lung-cancer-fact-sheet

  2. American Lung Association, State of Lung Cancer 2020 Report.

  3. https://ir.mirati.com/press-releases/press-release-details/2022/U.S.-Food-and-Drug-Administration-FDA-Accepts-Mirati-Therapeutics-New-Drug-Application-for-Adagrasib-as-Treatment-of-Previously-Treated-KRASG12C-Mutated-Non-Small-Cell-Lung-Cancer/default.aspx

  4. https://www.mirati.com/science/programs/kras-inhibitors/

  5. https://www.amgenoncology.com/targets/kras.html

  6. Finn, S. P., Addeo, A., Dafni, U., et al, Prognostic impact of KRASG12C mutation in patients with NSCLC results from the European thoracic oncology platform lungscape project. Feb 2021. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2021.02.016

  7. Ceddia, S., Landi, L., and Cappuzzo, F. KRAS-mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges. 2022. Int J Mol Sci. https://doi.org/10.3390/ijms23169391

  8. Falk, A.T., Yazbeck, N., Guibert, N. et al, Impact of Kras mutant subtypes on PD-L1 expression in lung adenocarcinoma. 2016. Ann Oncol. https://doi.org/10.1093/annonc/mdw363.40

  9. https://www.mirati.com/wp-content/uploads/KRYSTAL-7-WCLC-2020-POSTER_1.4.21-Final.pdf

  10. OA03.06 - CodeBreaK 100/101: First Report of Safety/Efficacy of Sotorasib in Combination with Pembrolizumab or Atezolizumab in Advanced KRAS p.G12C NSCLC. WCLC

  11. https://clinicaltrials.gov/ct2/show/NCT04185883

  12. https://www.amgen.com/newsroom/press-releases/2022/09/lumakraslumykras-sotorasib-demonstrates-superior-progressionfree-survival-over-docetaxel-in-first-positive-phase-3-trial-of-a-kras-g12c-inhibitor-in-nonsmall-cell-lung-cancer



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