Future Directions in the Management of Non–Small Cell Lung Cancer Harboring Driver Mutations

It has been 20 years since the discovery of EGFR mutations and almost 25 years since we first used EGFR inhibitors in the clinic. This resulted in a paradigm shift regarding the way we think about lung cancer. Now that we have drugs which target growth factor receptors, and we use them to slow the growth of tumors, giving rise to dramatic responses. Recently, these agents have moved forward to earlier stages of disease, and we are seeing large improvements in disease-free survival, such as in the recent phase 3 ADAURA trial (NCT02511106) of osimertinib (Tagrisso) as adjuvant therapy for patients with resected stage IB to IIIA EGFR-positive non–small cell lung cancer (NSCLC).¹

The limitations continue, however, the activity of these drugs continues to improve, providing us with third- and fourth-generation agents. Our understanding of sensitivity, resistance, and tolerability very often allows patients to live with lung cancer and have a very manageable quality of life. Questions still remain, however: What are the next steps in this area? How can we continue to improve? That’s where the next-generation agents will come in.

EGFR Mutations: A Brief History

Lung cancer is the leading cause of death in the United States, with more than 230,000 cases in the US and more than 2 million cases worldwide diagnosed annually.² EGFR-mutated lung cancer accounts for approximately 10% to 15% of the cases in the United States² and as many as 30% to 40% in Asia.^3,4 Clearly, targeting this pathway is important.

Through next-generation sequencing and other approaches, we have learned that mutations are canonically in exon 19 and 21, but there are also a host of aberrations in exon 20. The mutations in exon 21 may or may not be sensitive to the standard agents, a fact that requires continued drug discovery to understand how to better target them. Two agents—amivantamab (Rybrevant) and mobocertinib (Exkivity)^5,6—are approved in the setting of metastatic NSCLC with EGFR exon 20 insertion mutations, and several others are in development.

Treatment Challenges

When targeting lung cancer with these personalized therapies, we see many responses, but they are often short-lived: Patients develop resistance mechanisms and pathways. At the Yale Cancer Center, one of our approaches has been to rebiopsy patients at resistance. With this rebiopsy, we can learn if there is EGFR resistance, either on or off target. On-target resistance would mean a new mutation in the EGFR gene, and in that case we use a targeted agent that best targets that new pathway. In some cases, tumors transform to small cell lung cancer. New mutations, such as c-MET, can also develop. In fact, we see many patients who develop c-MET, RET, or other driver mutations.

How I Treat

I was closely involved in the initial trials examining EGFR inhibitors and in some of the work that led to the discovery of other driver mutations by creating databases and looking at biomarkers. In my practice, I have a very strong focus on biomarkers and precision medicine. Before I treat anyone with nonsquamous histology, especially a patient of Asian descent or with a light or nonsmoking history, I make sure I have EGFR testing results. If they have a mutation in exon 19 or 21, they get osimertinib as first-line therapy. Some trials in early stages, such as FLAURA2 (NCT04035486), are currently looking at targeted agents such as osimertinib plus chemotherapy. If a patient has a noncanonical mutation, meaning a mutation in exon 20 or a rare mutation in exon 19 or 21, I either consult my computer or one of the laboratory scientists who are working with these mutations in the laboratory to determine if it’s an activating mutation. I want to know if it causes the lung tumor to grow or not, and if we have a drug that targets it. I predict that we will get much more personalized in how we target EGFR mutations in lung cancer in upcoming years.

Another consideration with these therapies is toxicity. Despite all the research, we still see a good deal of rash, diarrhea, dermatitis, paronychia on the nails, ingrown eyelashes, and other adverse effects (AEs) of therapy. Those require delicate management. It’s important that patients are made aware of these AEs and possible ameliorators before they are treated. I make sure that the nurse practitioners and nurses in the office are familiar with the AE therapies, as well. This is clearly an area where scientists have gone from the clinic to the laboratory and back again, and we are making great headway.

Key Takeaways

1. Targeted therapy is here to stay. In lung cancer, we want to target all the actionable mutations, and certainly the most commonly occurring aberrations are in EGFR exon 19 and 21, followed by exon 20.
2. Drug development must continue. Having done this for more than a quarter of a century, I have treated many patients who have experienced amazing responses. However, I have never seen someone cured except perhaps in the adjuvant setting, such as in the ADAURA trial, and it’s still too soon for that to be determined. We are waiting for the survival results from that trial; they will be available in the next few years. We continue to raise the bar and develop new and better drugs and combinations.
3. This research requires collaboration across the community, industry, and academia. We need large numbers of patients to figure out which drugs work best in which settings, and how to target the drugs together.
4. There is an issue with access. What good are all these therapies if we don’t get them to the underserved populations? Some patients never get medical attention. These include patients with lung cancer who might see only a pulmonologist, never an oncologist—and the oncologist would be the one who’d have the most expertise to think about how these new therapies could best be molded for that patient’s disease. This will be the challenge of the next several years: giving access to all patients.

In summary, it has been fantastic over my career to see targeted therapies, such as EGFR-targeting agents, being used routinely in oncology. Now we need to think about which agents should be used based on which mutation the patient has and how to target resistance because we must continue to ratchet up our clinical abilities and find better ways to manage lung cancer throughout the world.

Financial Disclosures/Conflicts of Interest:

RSH receives consulting fees from AstraZeneca, Bolt Biotherapeutics, Bristol Myers Squibb, Candel Therapeutics, Inc., Checkpoint Therapeutics, Cybrexa Therapeutics, DynamiCure Biotechnology, LLC, eFFECTOR Therapeutics, Inc., Eli Lilly and Company, EMD Serono, Genentech, Gilead, HiberCell, Inc., I-MAB Biopharma, Immune-Onc Therapeutics, Inc., Immunocore, Janssen, Johnson & Johnson, Loxo Oncology, Merck and Company, Mirati Therapeutics, NextCure, Novartis, Ocean Biomedical, Inc., Oncocyte Corp, Oncternal Therapeutics, Pfizer, Regeneron Pharmaceuticals, Revelar Biotherapeutics, Inc., Ribbon Therapeutics, Roche, Sanofi, and Xencor, Inc. He receives research support to his institution from AstraZeneca; Eli Lilly and Company; Genentech, a member of the Roche Group; and Merck and Company. He serves in leadership roles for the American Association for Cancer Research (board member, committee chair), International Association for the Study of Lung Cancer (board member, committee chair), Society of Immunotherapy for Cancer (committee chair), and SWOG (committee chair, principal investigator). He serves on the board of directors for Immunocore (nonexecutive director) and Junshi Pharmaceuticals (nonexecutive, independent board member).

References

1. Wu YL, Tsuboi M, He J, et al; ADAURA Investigators. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071
2. Lung cancer – non-small cell: statistics. Cancer.net. February 2022. Accessed June 15, 2022. https://bit.ly/3Howgr1
3. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446-454. doi:10.1038/nature25183
4. Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 2021;27(8):1345-1356. doi:10.1038/s41591-021-01450-2
5. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. FDA. May 21, 2021. Accessed June 15, 2022. https://bit.ly/3mQDT00
6. FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. FDA. September 16, 2021. Accessed June 15, 2022. https://bit.ly/3tDfQFu