First-Line Amivantamab Plus Lazertinib Represents New SOC in Advanced EGFR+ NSCLC

Byoung Chul Cho, MD

In the phase 3 MARIPOSA trial (NCT04487080) amivantamab-vmjw (Rybrevant) combined with lazertinib (Leclaza) led to a reduced risk of disease progression or death by 30% vs osimertinib (Tagrisso) alone when given as a first-line treatment for patients with advanced non–small cell lung cancer (NSCLC) harboring classical EGFR sensitizing mutations, according to findings presented at the 2023 ESMO Congress.¹

At a median follow-up of 22.0 months, the median progression-free survival (PFS) was 23.7 months (95% CI, 19.1-27.7) with the combination vs 16.6 months (95% CI, 14.8-18.5) with osimertinib alone (HR, 0.70; 95% CI, 0.58-0.85; P <.001). The 12- and 24-month PFS rates with the combination were 73% and 48%, respectively, vs 65% and 34% with osimertinib alone. Lazertinib monotherapy led to a median PFS of 18.5 months (95% CI, 14.8-20.1).

Moreover, the combination reduced the risk of extracranial progression or death by 32% vs osimertinib alone. Median extracranial PFS was 27.5 months (95% CI, 22.1-not evaluable [NE]) with the combination vs 18.5 months (95% CI, 16.5-20.3) with osimertinib alone (HR, 0.68; 95% CI, 0.56-0.83; P <.001). The 12- and 24-month extracranial PFS rates were 77% and 53% with the combination, respectively, vs 67% and 38% with osimertinib alone.

Interim overall survival (OS), though not yet mature, showed a trend favoring the combination (HR, 0.80; 95% CI, 0.61-1.05; P =.11). The estimated 24-month PFS rates were 74% and 69% with the combination and osimertinib alone, respectively.

“Amivantamab plus lazertinib represents a new standard of care in patients with first-line, EGFR-mutant advanced NSCLC,” lead study author Byoung Chul Cho, MD, PhD, professor at Yonsei Cancer Center in Seoul, Korea, said in a presentation of the data.

Osimertinib is the standard frontline therapy for the approximately 15% to 50% of patients with EGFR-mutant, advanced NSCLC. However, resistance to therapy remains an unmet need.

Amivantamab is an EGFR-MET bispecific antibody with immune cell–directing activity against a variety of EGFR and MET alterations. Lazertinib is a highly selective, CNS-penetrant and well-tolerated, third-generation EGFR TKI, rendering it an ideal combination partner.

By combining the two agents, investigators expect to see improved activity against resistance mechanisms, resulting in improved outcomes without the need for chemotherapy.

Previously, findings from the phase 1 CHRYSALIS trial (NCT02609776) showed that the combination led to a 100% objective response rate (ORR) in 20 patients with treatment-naïve, EGFR-mutant advanced NSCLC. At a median follow-up of 33.6 months, half of patients were still receiving treatment.²

For the phase 3 MARIPOSA trial, eligibility criteria required patients to have treatment-naïve, locally advanced or metastatic NSCLC; a documented EGFR exon 19 deletion or L858R mutation; and an ECOG performance status (PS) of 0 or 1.

Patients were stratified by EGFR mutation type (exon 19 deletion vs L858R mutation), Asian race (yes vs no), and history of brain metastases (yes vs no). A total of 1074 patients were randomly assigned 2:2:1 to amivantamab plus lazertinib (n = 429), osimertinib alone (n = 429), or lazertinib alone (n = 216). Cho noted that the single-agent lazertinib arm was included to evaluate the contribution of each agent alone to the combination.

Amivantamab was administered at a dose of 1050 mg (1400 mg if 80 kg) weekly for the first 4 weeks, then every 2 weeks; lazertinib was given at a dose of 240 mg daily; and osimertinib was given at the standard 80 mg once-daily dose. Serial brain MRIs were mandated for all patients.

The primary end point was PFS by blinded independent central review per RECIST v1.1 criteria for the combination vs osimertinib. Secondary end points included OS, ORR, duration of response (DOR), PFS after first subsequent therapy (PFS2), symptomatic PFS, intracranial PFS, and safety.

Baseline characteristics were well balanced between the 3 arms. In the combination arm, the median patient age was 64 years (range, 25-88). Most patients were female (64%) and Asian (58%). Additionally, most patients had an ECOG PS of 1 (67%), no smoking history (70%), no history of brain metastases (59%), an EGFR exon 19 deletion (60%), and adenocarcinoma (97%). In the osimertinib monotherapy arm, the median patient age was 63 years (range, 28-88). Most patients were female (59%) and Asian (59%). Similarly, most patients had an ECOG PS of 1 (65%), no smoking history (69%), no history of brain metastases (60%), an EGFR exon 19 deletion (60%), and adenocarcinoma (97%).

Additional results showed PFS benefit across all predefined subgroups. Specifically, consistent PFS benefit was seen in patients regardless of the presence or absence of brain metastases. Among patients with a history of brain metastases, the median PFS was 18.3 months (95% CI, 16.6-23.7) with the combination vs 13.0 months (95% CI, 12.2-16.4) with osimertinib alone (HR, 0.69; 95% CI, 0.53-0.92). Among patients without a history of brain metastases, the median PFS was 27.5 months (95% CI, 22.1-NE) with the combination vs 19.9 months (95% CI, 16.6-22.9) with osimertinib alone (HR, 0.69; 95% CI, 0.53-0.89).

Notably, more patients in the combination arm remained in response at data cutoff (62%) vs those in the osimertinib monotherapy arm (48%). The median DOR was 25.8 months (95% CI, 20.1-NE) with the combination vs 16.8 months (95% CI, 14.8-18.5) with osimertinib alone, “suggesting longer time to resistance and progression,” Cho stated.

The ORR among all responders was 86% (95% CI, 83%-89%) with the combination vs 85% (95% CI, 81%-88%) with osimertinib alone. Confirmed responders experienced an ORR of 80% (95% CI, 76%-84%) with the combination vs 76% (95% CI, 71%-80%) with osimertinib alone. In the combination arm, best responses included complete response (CR; 7%), partial response (PR; 79%), stable disease (SD; 7%), and progressive disease (PD; 2%); 5% of patients were NE. In the osimertinib arm, best responses included CR (4%), PR (81%), SD (10%), and PD (3%); 3% of patients were NE.

The combination also reduced the risk of second disease progression or death by 25% (HR, 0.75; 95% CI, 0.58-0.98; P =.03). At 24 months, 72% of patients in the combination arm remained free from second progression vs 64% in the osimertinib monotherapy arm. Cho stated that the most common first subsequent therapy among the 98 patients who received additional treatment in the combination arm was an EGFR TKI (49%) and chemotherapy (33%). In the 137 patients who received subsequent therapy in the osimertinib monotherapy arm, the most common next-line treatment was chemotherapy (39%) and an EGFR TKI (27%).

The median duration of treatment was 18.5 months with the combination vs 18.0 months with osimertinib.

Regarding safety, grade 3 or greater adverse effects (AEs) occurred in 75% of patients in the combination arm vs 43% of patients in the osimertinib arm. Serious AEs occurred in 49% and 33% of patients in the combination and monotherapy arms, respectively. AEs leading to death occurred in 8% and 7% of patients, respectively. Notably, at least half as many patients in the combination arm vs the osimertinib arm experienced an AE leading to treatment interruption, reduction, or discontinuation.

The most common treatment-related AEs (TRAEs) in the combination arm included paronychia, rash, diarrhea, dermatitis acneiform, stomatitis, pruritus, hypoalbuminemia, peripheral edema, infusion-related reaction, alanine aminotransferase increase, constipation, aspartate aminotransferase increase, COVID-19, decreased appetite, anemia, nausea, hypocalcemia, and cough. 

Cho added that the rates of interstitial lung disease and pneumonitis remained low at approximately 3% in both arms.

Venous thromboembolism (VTE) was an AE of special interest, occurring at a frequency of 37% overall in patients in the combination arm (grade 1, 1%; grade 2, 25%; grade 3, 10%; grade 4, 0.5%; grade 5, 0.5%). The median time to onset of first VTE event was 84 days, with most patients (62%) experiencing an event within the first 4 months of treatment. Cho stated that prophylactic dose anticoagulation is now recommended for the first 4 months of treatment in ongoing trials evaluating the combination.

“Amivantamab plus lazertinib had higher rates of EGFR- and MET-related AEs and venous thrombotic events, [but] the majority were grade 1 and 2. [We also saw] infrequent discontinuations due to TRAEs at 10%,” Cho concluded.

REFERENCES:

1. Cho BC, Felip E, Spira AI, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl 2):S1306. doi:10.1016/j.annonc.2023.10.062

2. Cho BC, Lee SH, Han JY, et al. Amivantamab and lazertinib in treatment-naïve EGFR-mutant non-small cell lung cancer (NSCLC). J Thorac Oncol. 2022;17(suppl 9):S126. doi:10.1016/j.jtho.2022.07.210

3. Lee SH, Cho BC, Han JY, et al. Amivantamab and lazertinib in treatment-naïve EGFR-mutated and advanced non-small-cell lung cancer (NSCLC): long-term follow-up and ctDNA results from CHRYSALIS. J Clin Oncol. 2023;41(suppl 16):9134. doi:10.1200/JCO.2023.41.16_suppl.9134