Amivantamab With or Without Lazertinib Extends PFS in EGFR+ Advanced NSCLC After Progression on Osimertinib

Antonio Passaro, MD, PhD

Patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC) who experienced disease progression (PD) after treatment with osimertinib (Tagrisso) experienced a progression-free survival (PFS) benefit with amivantamab-vmjw (Rybrevant) plus chemotherapy with or without lazertinib (Leclaza) compared with chemotherapy alone, according to findings from the phase 3 MARIPOSA-2 trial (NCT04988295) presented during the 2023 ESMO Congress. These results met both of the study’s primary end points.

At a median follow-up of 8.7 months, patients who received amivantamab plus lazertinib and chemotherapy (n = 263) achieved a median PFS of 8.3 months by blinded independent central review (BICR) and those who were treated with amivantamab plus chemotherapy (n = 131) achieved a median PFS of 6.3 months compared with 4.2 months in those treated with chemotherapy alone (n = 263), leading to a 56% (HR, 0.44; 95% CI, 0.35-0.56; P < .001) and 52% (HR, 0.48; 95% CI, 0.36-0.64; P < .001) reduction in the risk of progression or death vs chemotherapy, respectively. The 6-month PFS rates in the amivantamab plus lazertinib and chemotherapy, amivantamab plus chemotherapy, and chemotherapy arms were 59%, 51%, and 30%, respectively; the 12-month rates were 37%, 22%, and 13%, respectively.

Notably, the PFS benefit was consistent with that determined by investigator assessment. The median PFS in the amivantamab plus lazertinib and chemotherapy arm was 8.3 months and 8.2 months in the amivantamab plus chemotherapy arm compared with 4.2 months in the chemotherapy arm. This led to a respective 62% (HR, 0.38; P < .001) and 59% (HR, 0.41; P < .001) reduction in the risk of disease progression or death compared with the chemotherapy arm.

“The resistance mechanisms after osimertinib are very diverse and polyclonal,” Antonio Passaro, MD, PhD, a medical oncologist in the Division of Thoracic Oncology of the European Institute of Oncology in Milan, Italy, said during the presentation. “In this particular setting in the present time, we have no targeted therapy approved, and the use of platinum-based chemotherapy—the standard of care—has a poor outcome.”

The global MARIPOSA-2 study enrolled patients with locally advanced or metastatic NSCLC harboring a documented EGFR Ex19del or L858R mutation. Patients must have experienced PD on or after osimertinib monotherapy as their most recent line of therapy and have an ECOG performance status of 1 or less. Those with stable brain metastases were permitted. Eligible patients were stratified by osimertinib line of therapy (first vs second), Asian race (yes vs no), and history of brain metastases (yes vs no).

Once enrolled, patients were randomly assigned in a 2:2:1 manner to receive amivantamab plus lazertinib and chemotherapy, chemotherapy alone, or amivantamab plus chemotherapy. Dosing occurred in 21-day cycles. Amivantamab was given at a dose of 1400 mg (1750 mg if ≥ 60 kg) for the first 4 weeks then at 1750 mg (2100 mg if ≥ 60 kg) every 3 weeks starting at cycle 3. Lazertinib was given at 240 mg was given daily following completion of carboplatin, and chemotherapy consisted of carboplatin at area under the curve of 5 for the first 4 cycles followed by pemetrexed 500 mg/m² until PD. Serial brain MRIs were mandatory for all patients.

The dual primary end points were PFS by BICR in terms of amivantamab plus lazertinib and chemotherapy vs chemotherapy and amivantamab plus chemotherapy vs chemotherapy. Secondary end points included objective response rate (ORR), duration of response (DOR), overall survival (OS), intracranial PFS, time to subsequent therapy, and safety.

The baseline patient characteristics were well balanced between the 3 arms; the median age in the amivantamab plus lazertinib, amivantamab plus chemotherapy, and chemotherapy arms was 61 years (range, 23-83), 62 years (range, 36-84), and 62 years (range, 31-85), respectively. Most patients in all arms were women (64% vs 62% vs 60%), had an ECOG performance status of 1 (65% vs 58% vs 62%), had received osimertinib as first-line therapy (70% vs 74% vs 69%), and had EGFR exon 19 deletions (63% vs 68% vs 70%).

Additional results from the study showed that the addition of amivantamab to chemotherapy led to a PFS benefit in every subgroup compared with chemotherapy alone. The most pronounced benefit was observed in patients with L858R mutations (HR, 0.30; 95% CI, 0.17-0.54), those younger than 65 years old (HR, 0.44; 95% CI, 0.31-0.64), and those with an ECOG performance status of 0 (HR, 0.44; 95% CI, 0.28-0.69).

The ORRs in the amivantamab plus lazertinib, amivantamab plus chemotherapy, and chemotherapy alone were was 63%, 64%, and 36%, respectively, including respective complete response rates of 2%, 2%, and 0.4%. The median DORs were 9.4 months (95% CI, 6.9-not estimable [NE]), 6.9 months (95% CI, 5.5-NE), and 5.6 months (95% CI, 4.2-9.6), respectively.

Notably, both the combinations of amivantamab plus lazertinib and chemotherapy as well as amivantamab plus chemotherapy led to a benefit in terms of intracranial PFS by BICR compared with chemotherapy alone. The median intracranial PFS was 12.8 months vs 12.5 months vs 8.3 months, respectively. This translated to a 42% (HR, 0.58; 95% CI, 0.44-0.78; P < .001) and 45% (HR, 0.55; 95% CI, 0.38-0.79; P = .001) reduction in the risk of disease progression or death vs chemotherapy, respectively.

“This was an unexpected result,” Passaro noted. “Amivantamab is a larger molecule that [has previously displayed] no penetrability activity. However, we are seeing here that the addition of third-generation TKIs is not required to give brain protection to our patients.”

To confirm this, investigators examined intracranial PFS by BICR in only patients with a history of brain metastases and no prior brain radiotherapy. Similarly, the median intracranial PFS was 11.1 months vs NE vs 6.3 months, in the amivantamab plus lazertinib (n = 56), amivantamab plus chemotherapy (n = 24), and chemotherapy alone (n = 61) arms, respectively. This translated to a 56% (HR, 0.44; 95% CI, 0.25-0.79; P = .005) and 64% (HR, 0.36; 95% CI, 0.16-0.84; P = .013) reduction in the risk of disease progression or death vs chemotherapy, respectively.

Early interim OS findings showed that both amivantamab plus lazertinib and chemotherapy as well as amivantamab plus chemotherapy produced an OS benefit compared with chemotherapy alone. The respective reductions in the risk of death were 4% (HR, 0.96; 95% CI, 0.67-1.35) and 23% (HR, 0.77; 95% CI, 0.49-1.21).

Patients in the amivantamab plus lazertinib, amivantamab plus chemotherapy, and chemotherapy alone arms received a median duration of treatment of 5.7 months (range, 0.1-18.6), 6.3 months (range, 0-14.7), and 3.7 months (range, 0-15.9), respectively. In terms of safety, patients in all arms experienced any-grade adverse effects (AEs; 100% vs 100% vs 93%), grade 3 or higher AEs (92% vs 72% vs 48%), serious AEs (52% vs 32% vs 20%), and AEs leading to death (5% vs 2% vs 1%). AEs leading to treatment interruptions (77% vs 65% vs 33%), dose reductions (65% vs 41% vs 15%), and dose discontinuations (34% vs 18% vs 4%) were also reported.

In the amivantamab plus lazertinib arm, the most common any-grade AEs were neutropenia (69%), thrombocytopenia (60%), and infusion-related reactions (56%); the most common grade 3 or higher AEs were neutropenia (55%), thrombocytopenia (37%), and leukopenia (27%). In the amivantamab plus chemotherapy arm, the most common any-grade AEs were infusion-related reactions (58%), neutropenia (57%), and nausea (45%); the most common grade 3 or higher AEs were neutropenia (45%), leukopenia (20%), and thrombocytopenia (15%). Finally, in the chemotherapy alone arm, the most common any-grade AEs were neutropenia (42%), anemia (40%), and nausea (37%); the most common grade 3 or higher AEs were neutropenia (21%), thrombocytopenia (9%), and anemia (9%).

“The safety profile for amivantamab [plus] chemotherapy was consistent with that of the dose that we evaluated before,” Parasso said. “At the present time, we cannot consider giving amivantamab/lazertinib/chemotherapy concurrently, and we need to wait for more follow-up to understand the real impact of the modification of this regimen. Today, comparing and evaluating the efficacy, safety, and intracranial PFS, we can say that amivantamab plus chemotherapy is the new standard of care for patients that are progressing after osimertinib.”

Reference

Passaro A, Cho BC, Banuml JM, et al. Amivantamab plus chemotherapy (with or without lazertinib) vs chemotherapy in EGFR-mutated advanced NSCLC after progression on osimertinib: MARIPOSA-2, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl 2):S1307. doi:10.1016/j.annonc.2023.10.063