Recent findings from the phase III MARIPOSA trial revealed promising results for a combination of amivantamab and lazertinib as a first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). The combination therapy demonstrated a statistically significant improvement in median progression-free survival (PFS) in the amivantamab-lazertinib group compared with the osimertinib group, from 23.7 vs 16.6 months.1 Overall survival was a secondary endpoint, and although the result was not statistically significant, there was a trend toward improved overall survival at both 18 and 24 months compared with osimertinib monotherapy. The hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05).2
Thoracic medical oncologist, Susan Scott, MD, Assistant Professor of Oncology at Johns Hopkins University School of Medicine, recently spoke with the CHEST Physician® publication about the implications of MARIPOSA in light of previous data from the FLAURA2 study of osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC.2
CHEST Physician: Could you provide an overview of the primary focus of the phase III MARIPOSA trial?
Dr. Scott: The phase III MARIPOSA study compared first-line treatments for lung cancer driven by a classical EGFR mutation, comparing first-line treatment with osimertinib to treatment with a combination of amivantamab and lazertinib. The primary outcome measured was progression-free survival, while secondary outcomes included response rates and overall survival.
CHEST Physician: What do you think the success of the MARIPOSA trial means for the field of lung cancer?
Dr. Scott: I think the finding that amivantamab and lazertinib improved overall survival compared with osimertinib alone is truly exciting. This is great news for patients. We are always looking for more effective combinations to offer additional options. Hopefully, this will allow for further personalization of treatment for each patient.
I believe it remains to be seen who will benefit from which treatment regimen, as they haven’t been directly compared. FLAURA2 and MARIPOSA are two separate combination regimens, both of which demonstrate improved progression-free survival in the frontline setting. Certainly, an improvement in overall survival is exciting news for patients and providers. How we will incorporate this into clinical practice remains to be seen.
Each new drug introduces new side effects. So we would expect that a combination of amivantamab and lazertinib would have more side effects than osimertinib alone. We always have to balance these potential side effects with the expected benefits, as well as consider patient and disease characteristics, along with patient goals and preferences.
There will be a population of patients who may be more interested in or who could benefit more from a combination like amivantamab and lazertinib, and there may be others who benefit more from an osimertinib-chemotherapy combination.
CHEST Physician: Would you consider overall survival to be the gold standard in your practice when determining first-line treatments for patient therapy?
Dr. Scott: Yes, overall survival is undoubtedly the gold standard. It is what we hope to see because it reflects the entire patient course rather than just the first treatment. However, this does need to be considered in the context of when the trial was done, what other therapies the patients received, and what sequential options are available when we think about how to incorporate it into practice in the coming years.
CHEST Physician: Are there any patients for whom you would consider osimertinib as a standalone therapy?
Dr. Scott: Yes, I would still consider osimertinib alone for select patients with lower-risk disease with classical mutations, without brain metastases, and who may have a limited burden of disease. It may be a better option for patients who wish to be more conservative with their therapy, who don’t want to have IV treatments, or who can’t tolerate chemotherapy or the blood thinners that we recommend with the combination of amivantamab and lazertinib.
CHEST Physician: Can you explain your therapeutic algorithm for selecting a first-line therapy for a newly diagnosed patient with a sensitive EGFR mutation in stage IV lung cancer?
Dr. Scott: This is evolving as we gather more data from FLAURA2 and MARIPOSA. I consider all three regimens when I see a patient with newly diagnosed EGFR lung cancer. A patient who seems to have low-risk disease features or is averse to combination therapies due to the additional toxicity and risks that come with that. That would be a patient I would consider appropriate for osimertinib monotherapy.
I’m considering combination therapies more and more, particularly for patients with brain metastases, patients with positive circulating tumor DNA at diagnosis, those with a high burden of disease, or those who are very symptomatic. These are the patients for whom I would prefer a combination regimen.
I’m reviewing additional data to determine which combination regimen is best for which high-risk patient. I think we’ll gain more insights in the coming years. It’s always good to have options, and I believe that treatment is an individualized decision. Some of it comes down to patient preferences, their risk factors for additional combination therapies, as well as specific disease features, which may lean me toward one or the other.
Overall, I think it’s exciting to see the overall survival outcomes from MARIPOSA. I’m hopeful that we’ll see similar results for FLAURA2. More choices are always better for our patients.
CHEST Physician: What are the next steps for this research following these results?
Dr. Scott: We need more data on specific risk subgroups to determine who can safely receive osimertinib monotherapy, and we need more precision in distinguishing between the two combination regimens. I think there is a group of patients who specifically benefit from dual inhibition of EGFR, as well as the addition of the MET inhibition.
I think there are patients who need immediate cytoreduction with the addition of chemotherapy. Additional studies are needed to examine these higher-risk subgroups, ideally comparing the treatment regimens. I know that’s a big ask in the frontline setting when both regimens are approved. But hopefully that data will become available in the coming years as we gain more experience with these different treatment regimens.
References
1. Johnson & Johnson. RYBREVANT® (amivantamab-vmjw) plus LAZCLUZE™ (lazertinib) shows statistically significant and clinically meaningful improvement in overall survival versus osimertinib. https://www.jnj.com/media-center/press-releases/rybrevant-amivantamab-vmjw-plus-lazcluze-lazertinib-shows-statistically-significant-and-clinically-meaningful-improvement-in-overall-survival-versus-osimertinib
2. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434