KRAS Lung Cancer: Taking on Goliath Discussion by Jai Luo MD

By Jai Luo, MD

Hi there, my name is Jai Luo. I'm a thoracic medical oncologist at Dana Farber. It's very nice to speak with you today about my talk at ASCO called, "Taking on Goliath: Targeting KRAS in Lung Cancer." The meaning behind "Goliath" here is that it is a deeply difficult question, but we've made a ton of headway, and I think we need to take advantage of the momentum we've made in the field to keep advancing it forward.

So, my overall takeaway from this talk is that KRAS mutations lung cancer is common and an important question. We have our first FDA-approved treatment, and there are many clinical trials up ahead that will continue to develop new treatments for both KRAS G12C lung cancer and other subsets of KRAS lung cancers.

To summarize my talk overall, the first point I want to emphasize is that KRAS mutations lung cancer is actually the most common form of oncogene-driven non-small cell lung cancer. It's more common than EGFR here in the United States. It accounts for 25% of individuals with non-small cell lung cancer and is about 50,000 individuals in the United States per year alone. Additionally, we think that it's a unique subtype of non-small cell lung cancer. Those with KRAS-driven non-small cell lung cancers tend to have a higher tumor mutation burden. That's thought to be due to the carcinogenesis from tobacco exposure, and they tend to have these C to A transversions that drive the high tumor mutation burden. Additionally, the tumor microenvironment of these tumors tends to have more immune-infiltrated cells. When we examine this by immunohistochemistry or multiplex immunofluorescence, we find that these individuals tend to benefit from immunotherapy-based treatments because of these features. So, the subset analyses of phase 3 studies of the registrational (clinical) trials involving checkpoint inhibitors in the first line - if you look at the KRAS mutation subset, you'll see that those individuals who receive either immunotherapy or immunotherapy and chemotherapy versus those who receive chemotherapy tend to benefit from the immunotherapy-based treatments.

So, this KRAS lung cancer is a distinct subtype. And we're also learning that each allele, such as G12C, which is the most common, is a slightly different type of KRAS lung cancer. In the talk, I will go more in-depth about why it took so long, 30 plus years, to develop our first inhibitor, but it was Sotorasib (clinical trial), which was FDA-approved in 2021. We have Adagrasib (clinical trial) that's already submitted to the FDA as a new drug designation. And in ASCO 2022, there were multiple updates about this promising treatment as well. And there are over a dozen other KRAS G12C inhibitors under development (clinical trials).

Additionally, I go into some of the non-G12C targeting medicines, and I think they highlight the ingenuity and also progress that we've made in medicinal chemistry and drug development. Since some of these approaches include those that are molecules that induce new protein interactions or those that are clever small molecule inhibitors that are targeting the non-G12C isoform.

Overall, I end the talk by saying that due to the many molecules that are being developed in the clinic and great excitement in this field since our breakthrough in 2013 of developing a new KRAS G12C inhibitor, we should keep up the momentum by testing all of our patients who have advanced non-small cell lung cancer for KRAS alterations. And it shouldn't just be the medical oncologists, I think proceduralists, pathologists, and others should be aware of this as well. Please check out my presentation at ASCO 2022, "Taking on Goliath," to find more about KRAS lung cancers. Thank you.

What is KRAS Mutations in Lung Cancer?

KRAS mutation is a gene that plays a critical role in cell signaling pathways that control cell growth, differentiation, and survival. Mutations in the KRAS gene are frequently found in various types of cancer, including lung cancer mutation. In fact, KRAS mutations are the most common genetic alteration found in lung adenocarcinomas, which is a type of non-small cell lung cancer.

The KRAS gene produces a protein called KRAS that helps transmit signals from the cell surface to the nucleus. When a KRAS mutation occurs, the protein becomes overactive, causing cells to grow and divide uncontrollably. This abnormal growth leads to the formation of tumors and contributes to cancer progression.

KRAS mutations are particularly prevalent in smokers and are associated with poor prognosis and resistance to many standard therapies. Unfortunately, targeted therapy against KRAS have been challenging to develop due to the complex nature of the protein and its signaling pathways. However, there is ongoing research into new therapies that may target KRAS mutations directly, and researchers remain hopeful that more effective treatments will emerge in the future.

In conclusion, KRAS mutations play a significant role in the development and progression of lung cancer, particularly in smokers. While targeted therapy against KRAS have been challenging to develop, ongoing research is focused on identifying new approaches to improve outcomes for patients with this devastating disease progression.

10 Key Takeaways from the KRAS Lung Cancer Discussion

1. KRAS lung cancer is the most common form of oncogene-driven non-small cell lung cancer, accounting for 25% of individuals with non-small cell lung cancer in the US.

2. KRAS lung cancer is a distinct subtype of non-small cell lung cancer and those with KRAS-driven non-small cell lung cancers tend to have a higher tumor mutation burden.

3. The tumor microenvironment of KRAS mutation lung cancers tends to have more immune-infiltrated cells, making immunotherapy-based treatments a potential option for treatment.

4. Sotorasib, the first FDA-approved KRAS inhibitor, was approved in 2021 and Adagrasib has already been submitted for new drug designation.

5. There are over a dozen other KRAS G12C inhibitors under development for targeted therapy.

6. Each allele, such as KRAS G12C, is a slightly different type of KRAS lung cancer (KRAS inhibitors).

7. Non-G12C targeting medicines, such as those that induce new protein interactions or clever small molecule inhibitors, are also being developed to help PFS (progression free survival in clinical studies).

8. The breakthrough in 2013 of developing a new KRAS G12C inhibitor has generated great excitement in the field.

9. Testing all patients with advanced non-small cell lung cancer for KRAS alterations is recommended.

10. Proceduralists, pathologists, and other medical professionals should also be aware of KRAS mutation in lung cancer and its potential treatments.

Jia Luo, MD - About The Author, Credentials, and Affiliations

Jia Luo, MD, is a highly accomplished physician and researcher affiliated with Harvard Medical School. She has dedicated her career to advancing the field of medicine through cutting-edge research, innovative treatments, and compassionate patient care.

Dr. Luo earned her medical degree from Harvard Medical School, where she also completed her residency in internal medicine. She then went on to complete a fellowship in oncology at the Dana-Farber Cancer Institute, where she gained expertise in the diagnosis and treatment of a wide range of cancers.

Dr. Luo's research focuses on developing new targeted therapies for cancer, with an emphasis on precision medicine and immunotherapy. Her work has been published in numerous high-profile medical journals, and she has received numerous awards and honors for her contributions to the field.

In addition to her research, Dr. Luo is a skilled clinician who is deeply committed to providing personalized, compassionate care to her patients. She has a reputation for being a thoughtful and empathetic physician who takes the time to listen to her patients' concerns and address their needs.

Overall, Dr. Jia Luo is a gifted physician and researcher whose dedication to advancing the field of medicine is truly inspiring. Her groundbreaking work has the potential to transform the lives of countless patients, and she is widely respected by colleagues and patients alike for her knowledge, expertise, and compassionate care.

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