Lung Cancer Experts Debate Disease Nuances to Deliver Patient-Centered Care

As the biological understanding of lung cancer subtypes hurtles forward, determining patient-level disease features and knowing how to apply an ever-growing treatment arsenal are key to achieving optimal treatment outcomes and gaining patient trust.

FDA approvals like zidesamtinib (Jideytro) for patients with locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC) in July 2026 further complicate treatment selection in clinical practice.¹

Experts at the 27th Annual International Lung Cancer Congress walked through how they would approach difficult-to-treat lung cancer cases, covering topics like second- and third-line treatment selection following progression on osimertinib (Tagrisso) and how to treat patients harboring P53 mutations.

Panelists in the conversation included:

• Christopher Grant, MD, a Y3 fellow of Hematology/Oncology at the University of California (UC) San Diego School of Medicine in La Jolla
• Narjust Florez, MD, the associate medical director of the Cancer Care Access Program and a thoracic medical oncologist at Dana-Farber Brigham Cancer Center, as well as a faculty member and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts
• Lyudmila A. Bazhenova, MD, a medical oncologist and professor of Medicine at UC San Diego Health in California
• Xiuning Le, MD, PhD, an associate professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston
• Edward B. Garon, MD, MS, a professor in the Department of Medicine, Hematology/Oncology, the director of the Thoracic Oncology Program, and the co-director of Signal Transduction and Therapeutics at the UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles, California
• Pasi A. Jänne, MD, PhD, the senior vice president for Translational Medicine. The scientific director of the Belfer Center for Applied Cancer Science, the director of the Chen-Huang Center for EGFR Mutant Lung Cancers, a senior physician, and the David M. Livingston, MD, Chair at Dana-Farber Cancer Institute; as well as a professor of medicine at Harvard Medical School in Boston

Grant: How should second-line treatment selection be approached for an older patient with EGFR-mutated, MET IHC 3+ NSCLC who has progressed on osimertinib and has no prior carboplatin or pemetrexed exposure?

Florez: I probably would use the [regimen from the phase 3 MARIPOSA-2 trial (NCT04988295)].² The patient has not been exposed to carboplatin or pemetrexed. That was what the study was trying to cover. [Regarding] the MET amplification. The phase 2 SAVANNAH trial [(NCT03778229) regimen of osimertinib plus savolitinib (Orpathys)] is not wrong, but [the patient] may have limited benefit. This brings to attention the importance of rebiopsy at the time of disease progression, because it can open many other option.

Garon: We have [an ongoing] clinical trial of osimertinib plus telisotuzumab vedotin-tllv [(Teliso-V; Emrelis) for patients with progressive NSCLC]. That would be a good option in this case. One thing I worry about is that sometimes the data a practitioner gets from molecular studies can lead to questionable treatment choices. In my personal bias, no evidence of MET amplification on the tissue and a low level based on the plasma would not meet the metrics of what was seen in these clinical trials that showed benefit for adding a METTKI. That’s a complicated approach; it’s not an approved approach here. The data are at best [unclear] for a benefit there. The MARIPOSA-2 regimen is a reasonable option, but at our institution, we would look at enrolling the patient in the trial of osimertinib plus Teliso-V.

Jänne: There are existing data on osimertinib plus Teliso-V as well, and with the high IHC shown for this patient, they qualify for that. I agree that with no MET amplification in tissue and low-level amplification in plasma, which is always a bit harder to interpret, this is not a cancer that’s saying it has MET dependency in an oncogenic fashion despite overexpressing MET.

Grant: How would you approach using chemotherapy in the third-line setting for this patient if they progressed on a doublet TKI regimen in the second-line setting?

Bazhenova: [An example in my experience was] when the discussions were made with the patient, she was clear that she did not want chemotherapy. She said, “If you are considering chemotherapy, I’m going on hospice.” That was one of the main reasons 2 TKIs [in previous lines were being used], because it’s shared decision-making, and the patient was not interested in doing chemotherapy. [That patient experienced an] 11-month progression-free survival. This is an anecdote, but it still tells us that we are not able to predict which of our patients will respond to doublet TKI regimens. Now she is open to the idea of chemotherapy, and that will also play to the decision of what to do [in the third-line setting].

Florez: [Aversion to] chemotherapy is not something rare; it’s rather common. My own mother, when she was diagnosed, said she was not doing chemotherapy. I had to sit her down a few times for her to agree. Chemotherapy has a bad reputation, [and this mindset] is more common that not.

Garon: This context gets though to where the art of oncology is important. This would be a shared decision-making approach. But with a patient you finally coaxed onto chemotherapy, chemotherapy plus amivantamab-vmjw [Rybrevant] has the potential to quickly push them in the other direction. That’s a discussion you would have to have [with the patient] in a case like this.

How do you weigh P53 mutation subtypes when selecting between combination regimens and osimertinib monotherapy in lung cancer?

Bazhenova:I wasn’t [looking for P53 mutations], but I do now. There was a recent publication saying that if the P53 gene has a true loss of function, those patients tend to do worse than those with P53 mutations that do not result in a loss of function. When I look at P53 mutations, my decision is between intensifying [treatment] or not at the time of the diagnosis. The other question is: Am I going to be worried enough about small cell transformation to push for post-progression biopsy? I intensify regardless unless the patient is truly not interested in addition of chemotherapy. The data for P53 mutations are messy because in neither MARIPOSA-2 nor the phase 3 FLAURA2 trial [(NCT04035486) of osimertinib plus chemotherapy in patients with EGFR-mutated advanced NSCLC] were the outcomes based on the type of P53 mutation evaluated.^2,3 We need to start dialing down and looking at [P53 mutations] specifically.

Jänne: I mostly look to see whether there is a TP53 Y220C mutation present because there are now other drugs in clinical development specifically for that P53 mutation that may provide another treatment option down the line. Beyond TP53 Y220C mutations, I don’t typically look at the subtypes of P53 mutations, but I agree that it is an area that needs to be investigated further.

Garon: I do not look at the specific [P53 mutation subtypes]. At least for now, this idea that is conceptually appealing of taking the patients with poor prognostic features and intensifying [treatment in] only those patients, I would argue, is not well supported by the data. When you look at patients with a variety of good prognosis factors vs those with bad prognosis factors, the HR is nearly identical, and for those with P53 mutations [overall, not divided into subsets], in general, that was also true. I don’t generally use [P53 mutation subtypes] in my decision-making.

Le: We usually do simultaneous blood and tissue next-generation sequencing. That can help me to tease apart whether the TP53 alteration is clonal hematopoiesis vs truly occurring in the tissue. That’s the first layer.

Then, if the TP53 mutation is truly in the tissue and the blood, not just clonal hematopoiesis, I have a ballpark of whether it’s a TP53 exon 8 mutation. I tend to think that is pathological and is going to dictate poor prognosis. We are starting to have cumulative data on the need to intensify treatment. For example, at the 2026 European Lung Cancer Congress, Yunpeng Yang, MD, from the Sun Yat-sen University Cancer Center in Guangzhou, China, reported findings from the phase 3 TOP trial [NCT04695925] highlighting the potential benefit of intensification [with osimertinib plus carboplatin and pemetrexed] for patients with P53-altered and EGFR-mutated[nonsquamous NSCLC]. Once I filter out the clonal hematopoiesis, once I know this is a pathological TP53 mutation, I try as hard as possible to offer the FLAURA2 regimen.³

References

1. Jideytro (zidesamtinib) approved in the US for previously treated ROS1-positive non-small cell lung cancer. News release. GSK. July 22, 2026. Accessed July 29, 2026. https://www.gsk.com/en-gb/media/press-releases/jideytro-zidesamtinib-approved-in-the-us-for-previously-treated-ros1-positive-non-small-cell-lung-cancer/?linkId=100000431854785
2. Popat S, Reckamp KL, Califano R, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non-small cell lung cancer after disease progression on osimertinib: second interim overall survival from MARIPOSA-2. Ann Oncol. 2024;35(suppl 2):S1244-S1245. doi:10.1016/j.annonc.2024.08.2296
3. Planchard D, Jänne PA, Kobayashi K, et al. First-line osimertinib + chemotherapy versus osimertinib monotherapy in EGFRm advanced NSCLC: FLAURA2 final overall survival. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 1956.