by Dr. C.H. Weaver M.D. updated 8/2022
Decades of research may have finally determined how to target KRAS, a major genetic driver of lung and other cancers. Initial study results presented at the American Society of Clinical Oncology's annual meeting in Chicago revealed that the novel precision cancer medicine currently known as Lumakras “AMG 510” produced a 50% response rate and follow up data released at AACR 2022 has expanded and confirmed these encouraging results, and data on Lumakras combinations is beginning to become available.1,2,8
The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for Sotorasib which is marketed as Lumakras for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with KRAS G12C mutation.
Results from the CodeBreaK 100 clinical study, evaluating Lumakras (sotorasib) in patients with KRAS G12C-mutant advanced NSCLC, who had failed a median of two prior lines of anti-cancer therapies were updated at the 2022 AACR annual meeting. The data confirmed a response rate of 40% and reported an overall survival rate of 51% at one and 32.5% at 2 years in patients with KRAS G12C–mutant NSCLC the majority of whom were previously treated with both platinum-based chemotherapy and anti–PD-1/PD-L1 treatment. The median duration of response was 12.3 months and 50.6% of responders were in response for at least 12 months.4,9,10
KRAS is an oncogene that impacts the growth of lung, pancreatic and colorectal cancers. AMG510 is the first medication of its kind to reach clinical testing and binds to mutated KRAS protein which “turns off” the signals it sends to trigger cell division and cancer cell growth.
Lumakras irreversibly inhibits KRAS G12C by permanently blocking it in an inactive GDP-bound state and represents a first-in-class novel small molecular inhibitor that specifically binds to a mutant protein in KRAS. G12C occurs in roughly 13% of NSCLC's, 3% to 5% of colorectal cancers, and between 1% and 3% of other cancers.
In the CODEBREAK 100 trial responses also occurred in patients with co-occurring mutations in TP53 (wild-type, 40%; mutant, 39%), STK11 (wild-type, 39%; mutant, 40%), and KEAP1 (wild-type, 44%; mutant, 20%)4,5,6
A Little More Information About the KRAS Oncogene
A pivotal milestone in cancer research was the discovery of a group of genes called the RAS family. RAS is an oncogene—a gene that encodes proteins that function as switches to turn on various genes for cell growth and division. These genes are intricate players in the normal cell cycle, responding to cues both outside and inside the cell that regulate how fast a cell should grow and divide. Furthermore, there are myriad proteins that interact with RAS—including receptors on the cell surface—that pass signals into the cell through complex circuits of protein interactions, with the end result being changes in gene expression. Mutations in the RAS genes result in permanently “turned on” switches that in turn result in uninhibited cell division, which can lead to cancer.
There are three types of RAS oncogenes, designated NRAS, GRAS, and KRAS. Although mutations in all three can cause cancer, KRAS is the most frequently mutated oncogene in human colorectal cancer. About 40 to 50 percent of human colorectal cancers have mutated KRAS genes. Recently developed laboratory assays are able to differentiate those tumors that have this mutation from those that have normal (also called wild-type) KRAS.
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This has had several therapeutic implications. Cancers that have non-mutated, or wild-type, KRAS are susceptible to a class of biologic agents called epidermal growth factor receptor (EGFR) inhibitors. EGFR is a receptor on the surface of the cell that binds to a growth factor called epidermal growth factor (EGF). This receptor activates cellular pathways that promote cell growth and division, with KRAS being one of the key players in the process. Blocking the EGF receptor removes this important signal for the continued growth of cancer cells. The two EGFR-targeting agents studied in colon cancer are Erbitux® (cetuximab) and Vectibix (panitumumab).
Another exciting group of drugs that specifically targets the KRAS protein works by inhibiting an enzyme called farnesyltransferase. This enzyme is involved in activating the RAS proteins. As of yet these drugs are not available for use at the bedside and are currently being tested in animal models.
Other cancers also express the KRAS G12C Mutation
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Lumakras Combination Regimen Data in KRAS G12C-mutated Cancers
The Phase 1b CodeBreaK 101 study evaluated the safety and effectiveness of Lumakras™ in more than 10 different investigational combination regimens for the treatment of patients with KRAS G12C-mutated cancers. Results from Lumakras with afatinib, a pan-ErbB tyrosine kinase inhibitor, and with trametinib, a mitogen-activated protein kinase inhibitor (MEKi) were presented at 2021 Virtual International Conference on Molecular Targets and Cancer Therapeutics, Oct. 9, 2021.8
The LUMAKRAS and afatinib combination arm enrolled 33 heavily pre-treated patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC), including five patients previously treated with LUMAKRAS monotherapy. The objective response rate was 20% in and 35% in the patients evaluated.
The combination of LUMAKRAS and trametinib was evaluated in 41 patients, 18 patients with NSCLC, 18 patients with colorectal cancer and five patients with other solid tumors. In patients with CRC who were KRASG12C inhibitor naïve, 9% achieved partial response, in patients who were previously treated with a KRASG12C inhibitor, 14% achieved partial response. In patients with NSCLC who were KRASG12C inhibitor naïve, 20% achieved partial response.8
- Fakih M, et al. Abstract 3003. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
- Amgen's Sotorasib Granted Breakthrough Therapy Designation For Advanced Or Metastatic Non-Small Cell Lung Cancer Patients With KRAS G12C Mutation
- Amgen's Investigational KRAS G12C Inhibitor Sotorasib Demonstrated Rapid, Deep And Durable Responses In Previously Treated Patients With Advanced Non-Small Cell Lung Cancer
- Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(suppl 15):9003. doi:10.1200/JCO.2021.39.15_suppl.9003
- Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. Published online June 4, 2021. doi:10.1056/NEJMoa2103695
- FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. . https://bit.ly/3c172Ah
- AACR-NCI-EORTC 2021, Abstract LBA6581, and LBA6580.
Dy GK, Govindan R, Velcheti V, et al. Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022, New Orleans, LA. Abstract CT008.
KRAS G12C inhibitor sotorasib may offer long-term clinical benefit in patients with non-small cell lung cancer. News release. American Association for Cancer Research; April 10, 2022. Accessed April 10, 2022. https://bit.ly/3rhUk8a