Dr Rodriguez, we’re going to finish here. I always love stating in lung cancer where we were, where we are, and where we’re going. And it’s fun because we’re going places now. When I started in lung cancer, it was 3 drugs. And we really didn’t know where we were going. We all know now that science is too fascinating that we’re now heading somewhere. So, what is the future here for uncommon 

 mutations? Are there agents being tested, [are there] trials? Are there challenges that you still see?

: [T]hinking more about what just happened with 

[exon] 20 insertions…we have learned to bypass these difficult-to-treat mutations with the current agents with…better TKIs that understand the structure. So, we saw that in 

[exon] 20 insertions, we have mobocertinib as a new option for those patients. We have amivantamab. That is a different drug. It’s an intravenous drug. We’re used to using pills, but an intravenous drug that targets 

 as an antibody. So, we are finding ways to target the receptor in different ways. Seeing the evolution of 

[exon] 20 insertion gives me a lot of hope for what we will have coming forward for uncommon mutations with antibodies. Patritumab, which is anti-HER3, has a possibility of really targeting the receptor in a different way that is not dependent on the pocket, as I say. I don’t know what trials you have seen that you are interested in. A lot of it is early, but we have seen data for some drugs that we thought will be helpful, like poziotinib, that cause a lot of toxicity. We’re looking forward to drugs like BLU-451, which are better. I call them very designed drugs for

. This company has really done a great job of understanding the structure, understanding the CNS [central nervous system] barrier, and finding better drugs for all our patients. All that benefits our patients with uncommon mutations. So those are some of the drugs I’m watching. We’re all watching antibody-drug conjugates. But I have been seeing great data for 

. We’re seeing antibodies to the receptor. We’re seeing more selective TKIs in the future that will open better options for our patients.

I think we’re just beginning to scratch the surface like we are with a lot of genotypes. We’re just at the beginning here. We’re in the dark ages still, which is fun, because I’m going to be in this field for another 15 years, I hope. And it’s great to see what’s going to come down the pike. Who would’ve [thought] 20 years ago, 15 years ago, that lung cancer would be the poster child for precision medicine? So, it’s an exciting time to be in the field.

: I think the other thing I’m excited about is the idea of combining drugs, combining the best of one TKI with the best of a monoclonal antibody to really find patients [who] will benefit because their mutations are different. So, I think you're right. And the science is moving fast. It’s what I tell our patients. This is moving fast. This is why we must encourage our patients with atypical mutations, and uncommon mutations, to join trials, because if we don’t collect data on these new agents in their group, we’re not going to learn how to use these drugs. So, encourage [patients] to join clinical trials, to really seek out opinions, and look into ClinicalTrials.gov for their mutation and what options are available.

Amazing discussion. I learned a lot. Thank you, Dr.

Videos

Closing out their discussion on uncommon EGFR mutations in non–small cell lung cancer, Benjamin Levy, MD, and Estelamari Rodriguez, MD, MPH, consider how the treatment paradigm will continue to evolve. 

Uncommon EGFR Mutations in NSCLC: Future Directions in Care 

Benjamin P. Levy, MD, associate professor of oncology and clinical director of Medical Oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, discusses the importance of testing for 

 alterations have been included on molecular panels for years, only recently have KRAS inhibitors demonstrated efficacy in targeting 

However, because these inhibitors are not yet approved by the FDA, patients who harbor 

 G12C mutations are treated with immunotherapy alone or in combination with chemotherapy based on their PD-L1 expression, says Levy. 

 mutations have immunogenicity, so immunotherapy is a rationale treatment approach to pursue without FDA-approved KRAS inhibitors, Levy adds. 

To date, the oral KRAS G12C inhibitors sotorasib and adagrasib have demonstrated efficacy in treating patients with advanced stage, 

 G12C–mutant lung cancer, says Levy. The response rates observed with these agents appear to be lower compared with other targeted therapies in lung cancer, Levy explains. As such, novel strategies with these agents in combination with immunotherapy, other oral agents, SHP2 inhibitors, or chemotherapy may enhance the efficacy of sotorasib and adagrasib in the 

Additionally, data evaluating sotorasib and adagrasib in the frontline setting are needed for patients with treatment-naïve lung cancer, Levy says. From there, the field could assess whether combination approaches with KRAS G12C inhibitors could elicit durable responses with minimal toxicity in the newly diagnosed setting, concludes Levy.

Benjamin P. Levy, MD, discusses the importance of testing for KRAS mutations in lung cancer.  



Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center

Articles

Uncommon EGFR Mutations in NSCLC: Future Directions in Care

Dr. Levy on the Importance of Testing for KRAS Mutations in Lung Cancer