Amivantamab-based regimens may alter EGFR-mutant NSCLC treatment paradigm in Asia

Updates from two MARIPOSA trials presented at ESMO Asia 2023 underpin the potential of amivantamab-based regimens for the treatment of locally advanced or metastatic EGFR-mutated non-small cell lung cancer (EGFRm NSCLC) in Asian subgroups.

“The therapeutic landscape of EGFRm NSCLC vary widely among Asian countries,” said discussant Dr Noemí Reguart from Hospital Clinic, Barcelona, Spain, at ESMO Asia 2023. “Limitations of available novel drugs is still a challenge; first-line (1L) osimertinib is not accessible everywhere and is restricted to very few countries.”

“[The current subgroup analyses suggest that] amivantamab, when combined with lazertinib or chemotherapy in the 1L and second-line (2L) settings, is just as effective in Asian individuals as it is in the global population,” said Reguart.

MARIPOSA: Amivantamab-lazertinib vs osimertinib

In this trial, 1,074 participants (n=629 Asian) were randomized 2:2:1 to amivantamab*-lazertinib (combo), osimertinib 80 mg daily, or lazertinib 240 mg daily. In the Asian subgroup, median age was 63 years, >60 percent were male, and 44 percent had a history of brain metastases. [ESMO Asia 2023, abstract LBA10]

At a median follow-up of 22.5 months, there was a 35-percent reduction in the risk of disease progression or death with the combo regimen vs osimertinib (hazard ratio [HR], 0.65; p<0.001). The former trumped the latter in terms of median progression-free survival (PFS) by about 9 months (27.5 vs 18.3 months).

“There was a consistent PFS benefit among Asian patients across all predefined subgroups,” said Dr Hidetoshi Hayashi from Kindai University, Osaka, Japan.

Objective response rates (ORR) were similar between the combo regimen and osimertinib arms (88 percent vs 85 percent), but the former fared better in terms of complete response (8 percent vs 4 percent) and ongoing responses (64 percent vs 49 percent).

“Among confirmed responders, amivantamab-lazertinib improved median duration of response by 8.6 months [26.1 vs 17.5 months], suggesting longer time to resistance and progression [and] thus more durable responses,” Hayashi said.

The combo regimen also exhibited a favourable trend for PFS2 (HR, 0.78; p=0.17) and interim overall survival (HR, 0.84; p=0.38).

More grade ≥3 adverse events (AEs) were reported with the combo regimen vs osimertinib (71 percent vs 41 percent), driven mainly by grade 3 events. Except for diarrhoea, VTE** and EGFR- and MET-related*** AE rates were higher with the combo but were mostly grade 1/2, Hayashi said.

MARIPOSA-2: Amivantamab-chemo vs chemo

This trial included 657 EGFRm NSCLC patients who have progressed on or after osimertinib monotherapy. They were randomized 2:2:1 to amivantamab^#-lazertinib-chemo, chemo^##, or amivantamab-chemo. Of these, 315 were Asian (median age 61 years, 62 percent female, 44 percent with prior brain metastases). [ESMO Asia 2023, abstract LBA11]

After a median follow-up of 9.5 months, amivantamab-chemo cut the risk for disease progression or death by 46 percent vs chemo (HR, 0.54; p=0.002), with a median PFS of 6.8 vs 4.2 months.

“The two survival curves separated quite early,” said Dr Victor Ho-Fun Lee from the University of Hong Kong. By month 6, there was a 23-percent difference between arms in terms of the percentage of patients who were progression-free.

Compared with chemo, amivantamab-chemo was tied to a twofold higher ORR (66 percent vs 32 percent; odds ratio, 4.0; p<0.0001) and longer median intracranial PFS (12.5 vs 8.5 months; HR, 0.58; p=0.049). The amivantamab-based regimen also trumped chemo in Asian patients with prior brain metastases but no prior brain radiotherapy (not estimable vs 4.3 months; HR, 0.33; p=0.041).

Similar to MARIPOSA, there were more EGFR- and MET-related AEs with the amivantamab-based regimen vs chemo, noted Lee. Despite the higher rates of neutropenia (60 percent vs 44 percent) and thrombocytopenia (45 percent vs 25 percent) in the amivantamab vs chemo arm, these were “transient and occurred early, with low rates of febrile neutropenia or clinically significant bleeding.”

The incidence of interstitial lung disease (including pneumonitis) was low in both amivantamab-chemo and chemo arms (2 percent and 0 percent), as was the VTE rate (<7 percent). The latter finding suggests that amivantamab alone does not increase VTE risk, noted Lee.

“Consistent with the MARIPOSA-2 primary analysis, compared with chemo, amivantamab-chemo improved PFS among Asian patients … had a consistent PFS benefit across subgroups, significantly higher ORR, and substantially longer intracranial PFS, suggesting that amivantamab may provide antitumor central nervous system effects,” said Lee. “[Moreover,] the safety profile of amivantamab-chemo was consistent with individual agents.”

A new standard of care?

Taken together, these findings underline the potential of an amivantamab-based regimen to be the new standard of care for the treatment of EGFRm NSCLC in the 1L setting (when combined with lazertinib) and after disease progression on osimertinib (when combined with chemo).

Reguart noted that while it is too early to define Asian patient subsets that might have greater gains from amivantamab combinations, the findings “need to be considered in context given the burden of EGFRm disease, restricted reimbursement policies, and limitations in drug access in Asia.”

On the verge of transformation

“Based on the groundbreaking results presented this year, the therapeutic landscape of EGFRm NSCLC is on the verge of a significant transformation, introducing several innovative and improved therapeutic options in both 1L and 2L settings,” commented Dr Antonio Passaro from the European Institute of Oncology, Milan, Italy, in a separate report. [dailyreporter.esmo.org/esmo-asia-congress-2023/latest-news/additional-data-confirm-the-promise-of-combination-therapies-for-egfr-mutated-nsclc]

“While combinations of multiple therapeutic agents have come with increased rates of toxicity, these have not been shown to be dose limiting, and low discontinuation rates have been maintained in all these studies,” Passaro added. “With proper management and proactive, dedicated treatment, the use of new therapeutic agents within these novel combinations cannot be ignored as effective therapeutic strategies.”