MARIPOSA: Amivantamab, Lazertinib Shows Improvements in Survival End Points for NSCLC

The MARIPOSA (NCT04487080) study evaluated the combination of amivantamab and lazertinib versus osimertinib in patients with common EGFR mutations and advanced non-small cell lung cancer. These results support the FDA approval of the amivantamab-lazertinib combination as a first-line option for patients with EGFR-mutant advanced non-small cell lung cancer. Shirish M. Gadgeel, MD, chief of the Division of Hematology and Oncology at the Henry Ford Cancer Institute/Henry Ford Health System, discussed the findings presented at the 2024 World Conference on Lung Cancer.

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Q: What were the key findings in progression-free survival (PFS) between amivantamab-lazertinib and osimertinib in the longer follow up for the MARIPOSA study?

Shirish M. Gadgeel: So in the MARIPOSA study, patients with common EGFR mutation exon 19 deletion, L858R mutation, with advanced non-small cell lung cancer. Good treatment, right? Naive [patients] were enrolled, and about and 1074 patients were randomized in a 2:2:1 fashion to amivantamab plus lazertinib, or osimertinib, or lazertinib alone, and the primary endpoint of the study was progression free survival (PFS), as assessed by blinded, independent central review. The previous presentation at ESMO last year and then subsequent New England Journal of Medicine paper discussed the primary endpoint of [PFS], where the combination of amivantamab plus lazertinib significantly improved [PFS] compared to osimertinib with a hazard ratio of 0.70 At the World lung World Conference on lung cancer, 2024 we provided results of a longer follow up with a median follow up of 31 months. But in this presentation, we focused on end points of intracranial efficacy, post progression, end points like time to treatment discontinuation, time to subsequent treatment, and [PFS] too, as well as overall survival (OS). So there was no further analysis done of the primary end point of [PFS]. It was really about these other end points, and what this longer follow up showed is that amivantamab plus lazertinib improved intracranial [PFS]. The 3-year survival rates were 38% with the combination versus 18% with osimertinib. It also improved intracranial duration of response (DOR), so the intracranial [DOR] was not reached with amivantamab plus lazertinib, whereas it was 24.4 months with osimertinib. So as far as intracranial efficacy was concerned, the combination demonstrated improved outcomes as compared to osimertinib. Similarly improved outcomes was also observed with post-progression end points, so time to treatment discontinuation, time to subsequent treatment, each of them were better with the combination of amivantamab plus lazertinib and versus osimertinib particular [PFS] to which was defined as time from randomization to progression on next treatment or death was also longer with the combination. So the 3-year [PFS] 2 rates were 57% with the combination, and 49% with osimertinib. And then finally, with the median follow up of 31 months, there was a promising trend in survival that favored the combination of amivantamab plus lazertinib, wherein the median survival was not reached with the combination, but it was 37.3 months with osimertinib with the hazard ratio of 0.77. What is also interesting to note is that the survival curves with the longer follow up appeared to widen. The 2-year survival rates were 75% and 70% whereas at 3-years, the survival rates were 61% with the combination and 53% so there was somewhat widening of the curves, raising the possibility that with a longer follow up, Significant improvement of survival may be observed. Now, these results, are not the final analysis. There is a pre-specified, final [OS] analysis that is going to be performed in the near future, and that would really assess whether the combination improves survival, but the trends with all the end points, particularly [OS], with this longer follow up, appear to be favoring the combination. Based on the MARIPOSA results, the FDA approved, I mean, amivantamab for the first-line treatment of common EGFR mutation positive, advanced non-small cell lung cancer, and I think these longer follow up, the results of this longer follow up show that this combination continues to improve long-term outcomes compared to simultaneous in this patient population.

Q: What was the favored first subsequent therapy after disease progression for patients in the amivantamab-lazertinib and osimertinib arms, and how did PFS after first subsequent therapy compare between the two groups?

Shirish M. Gadgeel: The proportion of patients who had disease progression and/or discontinued first-line therapy and who then went on to receive subsequent treatment was quite similar in the 2 groups, at 72% and 74%, and the most common subsequent treatment in both arms was chemotherapy. The [PFS], as you mentioned, is time from randomization to progression on subsequent treatment or death. There was also improvement in [PFS] 2 with amivantamab, the median [PFS] tool was not reached with the combination where it was 32.4 months with osimertinib, the hazard ratio of 0.73, and at 3 years, the [PFS] 2 was 57% with amivantamab plus lazertinib whereas it was 49% with osimertinib.

Q: What were the main differences in time to treatment discontinuation and time to subsequent therapy between patients treated with amivantamab-lazertinib and those treated with osimertinib?

Shirish M. Gadgeel: Both end points were longer with the combination of amivantamab plus lazertinib, the time continuation was longer with a hazard ratio of 0.80, and that translated into 40% of the patients who started on amivantamab plus lazertinib, and it continued on treatment at 3 years, whereas that percentage was 29% in patients who started on osimertinib. Similarly, the time to subsequent treatment was longer. The median was 30 months in patients with treated with the combination of amivantamab, where it was 24 months, whereas it was 24 months in patients who started on osimertinib. Among the patients who started on osimertinib, only 32% of the patients at 3 years had not switched to subsequent treatment, whereas that percentage was 45% in patients who started on amivantamab plus lazertinib. So both those end points showed that the combination prolonged both the time on treatment as well as the time to change in treatment.

Q: How did intracranial PFS trend between the amivantamab-lazertinib and osimertinib groups, and why is this finding significant for patients with EGFR-mutated advanced NSCLC?

Shirish M. Gadgeel: [Central nervous system (CNS)] metastases is an important site of metastasis, both from the point of view of morbidity and mortality in EGFR mutation positive lung cancer. Patients previously on radiatio,n and occasionally surgery, was the primary treatment for management of CNS metastasis, and in the past, whole brain radiation was commonly used. Subsequently, there was introduction of stereotactic radiosurgery, and that has definitely provided better outcomes and less toxicity compared to whole brain radiation. There is now increasing use of systemic treatment to manage intracranial metastases, particularly patients with intracranial metastases that are asymptomatic, and so we don't necessarily treat these patients with radiation treatment, be it stereotactic neurosurgery or whole brain radiation. So, even though the outcomes with third-generation EGFR kinase domain with osimertinib, as far as intracranial efficacy is concerned, are quite good. There are patients who eventually have progression in the brain and also develop leptomeningeal metastases, and that can cause significant morbidity and can be a cause of death. So there has always been a need to develop first-line treatment, systemic treatments, that can be even more effective against brain metastases. So in with this combination in the MARIPOSA study, what was noticed is that the intracranial [PFS] rate was longer, was higher, with amivantamab plus lazertinib at 38% as compared to 18% in patients with osimertinib, as far as intracranial [DOR] is concerned. So the response rate, intracranial response rate was identical in the 2 arms, at 77% so osimertinib can shrink brain metastasis quite well. However, when you looked at the median [DOR], it was much longer in patients treated with amivantamab plus lazertinib, and a median intracranial [DOR] was not reached in patients treated with this combination, whereas it was 24.4 months in patients treated with osimertinib, and what that translated into is that among the patients who were treated with aamivantamab plus lazertinib and had an intracranial response, 51% of those patients continued to demonstrate intracranial response at 3 years, whereas that percentage was 0% in patients treated with osimertinib. So that goes on to show that even though osimertinib can have activity in the brain, amivantamab plus lazertinib have just appears to keep that area, keep those metastases, under control for a longer period of time. That is, I think, the major advantage observed, particularly with this longer follow up with the combination compared to osimertinib in the MARIPOSA study.