Significance of KRAS Inhibitors in Non-Small Cell Lung Cancer
A deep dive into Non-Small Cell Lung Cancer treatment and the significance of Somatanib and the future of KRAS Inhibitors
May 28th, 2021, was a big win for patients with Non-Small Cell Lung Cancer (NSCLC). The FDA granted accelerated approval for the first-ever KRAS inhibitor, sotorasib (Lumakras). KRAS inhibitors have been in development for some time now but Amgen is the first company to get approval. Mirati Therapeutics is expected to submit an NDA later this year for their KRAS inhibitor drug while Eli Lilly is starting from scratch after their candidate failed in Phase 1 clinical trial due to patients experiencing unexpected toxicity back in late 2019. If you are unfamiliar with what NSCLC is and how significant KRAS inhibitors are in cancer treatment, then let me break it down for you.
Lung cancer is one of the most common types of cancer worldwide. There are about 2.2 million new cases each year and of that, about 10% of those cases are in the US. NSCLC is the most common form of lung cancer, occurring in about 84% of cases, which means worldwide, there are about 1.6 million newly diagnosed NSCLC patients each year. Treatment is often made up of platinum doublets, like cisplatin or carboplatin, with some additional chemotherapy added, depending on if NSCLC is squamous or non-squamous. When cancer becomes metastatic, additional, targeted therapy will be added based on patients’ mutational status. These mutations can vary from patient to patient and some patients can have multiple mutations. Mutations that you may see clinically are PD-1 expression, EGFR, BRAF, MET, and many more. Most of these mutations have therapies that can target them except for one which is KRAS (until Lumakras was approved).
The EGFR is a common mutation that is targeted in many types of cancer, including colon cancer, lung cancer, pancreatic cancer, head and neck cancer, glioblastoma, and breast cancer. EGFR stands for Epidermal Growth Factor Receptor, which initiates a chain of reactions that results in cell proliferation in the Mitogen-Activated Protein Kinase (MAPK) pathway. Cancers will often overexpress EGFR, causing the cells to proliferate more rapidly at an uncontrolled rate. This is known to be called, “EGFR-positive”. Treatment for EGFR-positive cancers typically contains monoclonal antibodies that target EGFR specifically like Vectibix (panitumumab) or Erbitux (cetuximab), but when EGFR becomes mutated, that is when tyrosine kinase inhibitors (TKIs) come into play. TKIs are small molecule drugs that enter the cancer cell and target various kinases that are associated with EGFR’s chain of reactions. There are multiple classes of TKIs and choosing one depends on which mutation that cancer has. In regards to the MAPK pathway, TKIs can target EGFR, BRAF, MEK, and now KRAS (Figure 1).
Now, you may be asking yourself, “If there are already TKIs and monoclonal antibodies that can be used to treat NSCLC, why do we need a KRAS inhibitor?” If a patient had a KRAS mutation, then all TKIs and EGFR targeting monoclonal antibodies would be ineffective. BRAF inhibitors, like Dabrafenib, are only used when BRAF is mutated which only occurs in about 1-2% of NSCLC. MEK inhibitors can also be used to treat NSCLC but in the SELECT-1 randomized controlled trial that compared the use of docetaxel and a MEK inhibitor, selumetinib, with docetaxel alone in NSCLC patients with KRAS mutations showed that the docetaxel plus selumetinib group did not improve progression-free survival compared to the docetaxel alone treatment group.
KRAS inhibitors are important, especially in NSCLC, because about 20-40% of those patients have a KRAS mutation. In the US, 13% of NSCLC patients have KRAS G12C, which is the mutation that Lumakras specifically targets. This is a major unmet need and it looks like Lumakras is the first step heading in the right direction. Commercially, Lumakras will be sold at $17,900 per month and is expected to make about $100 million in sales this year. Amgen will hold a $6.5 billion market share for KRAS G12C mutation patients in the US alone. Amgen partnered with two companies Guardant Health and Qiagen to create a diagnostic tool to screen NSCLC patients for KRAS G12 C mutation. Amgen is advocating hard to raise awareness about getting patients tested for G12C mutation since one-half of NSCLC patients have a druggable mutation, but often are never screened. Hopefully, this push to promote mutation screening will improve patient outcomes and lead to better decision-making with potential treatments in the future.
So, what does this mean for other types of cancers? Since KRAS mutations are commonly found not only in lung cancer but also colorectal cancer and pancreatic cancer, we will start seeing more KRAS inhibitors targeting different mutations in these disease states in the future. Mirati Therapeutics already has a KRAS inhibitor that targets G12D in the works indicated for pancreatic cancer, colorectal cancer, and non-small cell lung cancer and is expected to submit an IND later in 2022. In addition, Cardiff Oncology’s onvansertib, is a Polo-like Kinase 1 (PLK1) inhibitor that can target KRAS mutations in metastatic colorectal cancer. Currently, it is in Phase 2 clinical trials to be used with second line standard of care. Other upcoming KRAS inhibitors are coming from Loxo Oncology (Eli Lilly’s oncology unit) and Boehringer Ingelheim. KRAS inhibitors will play a major role in the treatment for these types of cancers and we are only seeing the beginning of what these small molecule drugs can do.