The landmark MARIPOSA study has already sparked discussions about the potential of amivantamab in combination with lazertinib as a first-line treatment for EGFR-positive non-small cell lung cancer (NSCLC).
The latest findings from the MARIPOSA trial revealed a statistically significant and clinically meaningful improvement in overall survival (OS) compared with osimertinib monotherapy. Additionally, the trial projected a median OS benefit of more than 1 year, marking this as the first study to show an OS advantage versus the standard-of-care treatment with osimertinib.
Preliminary findings confirmed a previously documented improvement in median progression-free survival (PFS), with the amivantamab-lazertinib combination achieving 23.7 months versus 16.6 months for osimertinib monotherapy.
James Chih-Hsin Yang, MD, PhD, director and distinguished professor at the Graduate Institute of Oncology at National Taiwan University, presented the highly anticipated final OS results from the MARIPOSA trial during the 2025 European Lung Cancer Congress (ELCC) in Paris.
Prof. Chih-Hsin Yang said the MARIPOSA trial is one of the largest studies conducted in patients with EGFR-positive NSCLC; 1,074 participants were randomized in a 2:2:1 ratio to receive either amivantamab plus lazertinib or osimertinib monotherapy or lazertinib monotherapy.
OS benefits were significantly extended with the amivantamab-lazertinib combination compared with osimertinib monotherapy. At the median follow-up (37.8 months), the median OS for the amivantamab-lazertinib treatment had not yet been reached, whereas the median OS for osimertinib was 36.7 months.
“At 36 months, 60% of patients receiving amivantamab plus lazertinib were still alive, compared with 51% in the osimertinib arm,” Prof. Chih-Hsin Yang said. “And the curves continue to widen. There is a 12% difference at 42 months, with 56% of patients in the amivantamab plus lazertinib arm still alive (compared with 44% for those receiving osimertinib monotherapy).”
A long-term treatment plan following first-line amivantamab plus lazertinib appears feasible, as nearly three-quarters (74%) of participants in the amivantamab-lazertinib group were willing and able to receive subsequent therapy.
The amivantamab-lazertinib combination also demonstrated a clinically significant improvement compared to osimertinib in intracranial progression-free survival (icPFS) of 36% versus 18%, respectively. Additionally, the amivantamab-lazertinib combination yielded greater durability of intracranial response (icDoR) than osimertinib monotherapy.
“The intracranial overall response rate (icORR) was the same in both arms, 78% for amivantamab plus lazertinib and 77% for osimertinib. However, the response durability was longer for the amivantamab with lazertinib arm; the median icDoR was 35.7 months versus 29.6 months for the osimertinib arm.”
Prof. Chih-Hsin Yang highlighted that the amivantamab-lazertinib combination significantly delayed symptomatic progression, which refers to the time until the onset of new or worsening of persistent lung cancer symptoms, by a median of over 14 months.
He also reviewed the safety profile of the amivantamab-lazertinib combination, noting that most patients experienced their key adverse events (AEs) within the first 4 months. The most common AEs included rash, fatigue, dry skin, and dermatitis acneiform. No new safety signals were identified with longer-term follow-up, which supports the feasibility of long-term treatment.
Prophylactic interventions have been shown to reduce the incidence of key AEs substantially. Prof. Chih-Hsin Yang presented examples, including:
- COCOON DM, which reduced grade 2 dermatologic AEs by half in an interim analysis using a pre-emptive regimen (38.6% for COCOON DM vs. 76.5% for standard-of-care, “reactive” dermatological management).
- SKIPPirr, which demonstrated a three-fold reduction in amivantamab infusion-related reactions (IRRs), with a dexamethasone 8-mg IRR prophylaxis regimen (22.5%) compared with SoC IRR management (67.4%).
- Prophylactic anticoagulation, which resulted in a two-fold reduction in venous thromboembolic events (VTEs) from 20% to 11.4%.
“Early-onset AEs can be reduced using these accessible, preventive approaches that were not [utilized] in the MARIPOSA study,” he said.
Maurice Pérol, MD, a medical oncologist at Center Léon Bérard, Lyon, France, in his discussion, recognized the significant PFS improvements; however, these benefits came with a cost of additional toxicities. He also noted that the PFS subgroup analysis did not identify any specific subset of patients who derived greater benefit from the combination treatment.
“The question of the risk-benefit ratio of this combination was legitimately raised, and, of course, the OS analysis was eagerly awaited,” Dr. Pérol said.
“The restricted mean survival time (RMST) should better reflect the OS benefit. And in consideration of the median follow-up between 0 to 3 years, the RMST could provide a better estimate of the mean survival time during the first 3 years,” Dr. Pérol said.
He also noted that three key AEs (dermatologic, IRRs, and VTE risk) require proactive management to reduce the incidence of toxicities, particularly for dermatological side effects. Additionally, these AEs occurred early in treatment, and we lack sufficient data on the actual duration of these side effects.
“The management of dermatological toxicity is difficult, both for the patient and the oncologist. We do not have any data about the duration of toxicity,” Dr. Pérol said. “The daily management of dermatological toxicity with this combination is in itself a constraint for the patient.”
Putting the data into perspective, Dr. Pérol emphasized the significance of having two first-line treatment options for patients with EGFR-mutated NSCLC: the amivantamab-lazertinib combination and the FLAURA-2 regimen (osimertinib plus chemotherapy).
Although the analysis for FLAURA-2 is still pending, he noted that both regimens appear to improve OS by preventing and delaying the development of acquired resistance.
Dr. Pérol concluded by stressing the importance of selecting the optimal first-line treatment upfront, as it influences the treatment sequence and significantly impacts OS. However, he also emphasized the need to consider the risk-benefit ratio, as well as treatment objectives of the patient.
“The magnitude of the PFS benefit achieved by the two frontline intensified options is clearly greater than that obtained from osimertinib alone upfront. We must also take into account the patient attrition rate at each step, especially during frontline treatment,” Dr. Pérol said. “Taken together, these data support the selection of the best frontline treatment.”
