Why the Amivantamab + Lazertinib + Chemotherapy Arm Was Not Presented as a Recommended Option in MARIPOSA-2
The quadruplet regimen of amivantamab + lazertinib + chemotherapy was not recommended due to excessive hematological toxicities (52% serious treatment-emergent adverse events) that necessitated a protocol modification to delay lazertinib initiation until after carboplatin completion, combined with no demonstrated overall survival benefit over chemotherapy alone. 1
The Safety Profile That Led to Protocol Changes
The MARIPOSA-2 trial enrolled 657 patients post-osimertinib progression and randomized them 2:2:1 to three arms: chemotherapy alone, amivantamab + chemotherapy, and amivantamab + lazertinib + chemotherapy. 1
Excessive Hematological Toxicity in the Quadruplet Arm
The amivantamab + lazertinib + chemotherapy arm demonstrated excessive hematological toxicities that were clinically unacceptable, with 52% of patients experiencing serious treatment-emergent adverse events compared to 32% with amivantamab + chemotherapy and only 20% with chemotherapy alone. 1
This toxicity profile necessitated a regimen change during the trial itself, requiring lazertinib to be started only upon completion of carboplatin rather than concurrently, indicating the combination was too toxic as originally designed. 1
The quadruplet regimen required longer follow-up to better understand its risk-to-benefit profile, suggesting the safety concerns were significant enough to prevent immediate clinical adoption. 1
Efficacy Did Not Justify the Toxicity
PFS Benefit Without OS Improvement
While the quadruplet arm achieved a median PFS of 8.3 months (HR 0.44 vs chemotherapy alone at 4.2 months), overall survival results remained premature with no demonstrated OS benefit between any of the arms. 1
The amivantamab + chemotherapy doublet achieved a PFS of 6.3 months (HR 0.48), which was only 2 months shorter than the quadruplet but with substantially better tolerability (32% vs 52% serious adverse events). 1
ASCO guidelines explicitly note that both MARIPOSA-2 and ATTLAS demonstrated improvement in PFS but not OS compared with platinum chemotherapy alone, with significantly increased toxicity including serious adverse events. 1
The Clinical Recommendation That Emerged
ASCO Guideline Position
ASCO recommends platinum-based chemotherapy with or without amivantamab (the triplet, not quadruplet) for patients with progressive disease on osimertinib or other EGFR TKIs without emergent T790M or other targetable alterations (Evidence quality: Moderate; Strength of recommendation: Strong). 1
The guideline panel specifically recommends that platinum-doublet chemotherapy be offered for most patients who experience progression after osimertinib, given the lack of OS difference and increased toxicity profiles seen with intensified regimens. 1
The amivantamab + chemotherapy triplet regimen offers an evidence-based, potentially more effective approach versus doublet chemotherapy alone, but the added adverse event profile needs to be considered on an individual basis. 1
Why the Triplet Was Preferred Over the Quadruplet
The triplet (amivantamab + chemotherapy) achieved clinically meaningful PFS improvement (HR 0.48) with a more manageable toxicity profile compared to the quadruplet's marginal additional PFS benefit at the cost of substantially worse hematological toxicity. 1
The objective response rates were essentially identical between the triplet and quadruplet arms (64% vs 63%), providing no additional efficacy justification for the increased toxicity. 1
Critical Pitfalls to Avoid
Do not assume that adding more agents automatically improves outcomes—the MARIPOSA-2 quadruplet arm demonstrates that excessive toxicity can outweigh modest PFS gains, particularly when OS is not improved. 1
Do not overlook the need for protocol modifications during a trial as a red flag—the fact that lazertinib timing had to be changed mid-study due to toxicity signals fundamental tolerability issues with the regimen. 1
Recognize that serious adverse events requiring hospitalization or intensive management (52% in the quadruplet arm) directly impact quality of life and may negate any progression-free survival benefit in the absence of overall survival improvement. 1