PALOMA-2 Trial Supports SC Amivantamab Q4W as a Patient-Centered Alternative to IV Therapy

The management of advanced non–small cell lung cancer (NSCLC) with EGFR mutations continues to evolve as novel targeted therapies and administration strategies aim to optimize efficacy, safety, and patient convenience. Amivantamab (Rybrevant; Janssen Biotech), a bispecific antibody targeting EGFR and MET, has already demonstrated efficacy in combination with the third-generation EGFR tyrosine kinase inhibitor (TKI) lazertinib (Lazcluze; Janssen Biotech). Intravenous (IV) administration of this regimen every 2 weeks (Q2W) was shown in the phase 3 MARIPOSA trial (NCT04487080) to significantly prolong progression-free survival (PFS) compared with osimertinib (Tagrisso; AstraZeneca), establishing it as a frontline standard for EGFR-mutated NSCLC.1,2

Despite this efficacy, IV dosing poses logistical burdens for patients and may increase the risk of administration-related reactions (ARRs). To address these limitations, the PALOMA-2 trial (NCT05498428) was designed to investigate subcutaneous (SC) delivery of amivantamab, including a once-monthly every-4-week (Q4W) regimen, in combination with daily oral lazertinib.1,3 Findings from cohort 5, which specifically assessed the Q4W dosing schedule of PALOMA-2, were presented at the 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, by Susan Scott, MD, a thoracic medical oncologist at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.1

“SC amivantamab dosed once a month offers a less burdensome treatment option without compromising efficacy,” said Scott at WCLC. “These data [from PALOMA-2] support the potential for Q4W administration to enhance quality of life for patients with EGFR-mutant NSCLC.”1

Study Design and Methods

PALOMA-2 is a multicohort study designed to evaluate the efficacy, pharmacokinetics, and safety of SC amivantamab in combination with lazertinib in treatment-naïve patients with EGFR Ex19del or L858R-mutated advanced NSCLC. In cohort 5, patients received SC amivantamab coformulated with hyaluronidase via abdominal injection, dosed weekly during the first 4 weeks (1600 mg for patients weighing less than 80 kg, 2240 mg for 80 kg or more) followed by Q4W maintenance dosing (3520 mg or 4640 mg, respectively). Lazertinib 240 mg was administered orally once daily.1

SC amivantamab administered every 4 weeks in combination with daily lazertinib provides high response rates, favorable tolerability, and pharmacokinetic equivalence to IV dosing in patients with EGFR-mutated advanced NSCLC. | Image Credit: © Keopaserth - stock.adobe.com

Prophylactic anticoagulation was recommended during the first 4 months of therapy to mitigate risk of venous thromboembolic events (VTEs), a known adverse event (AE) associated with amivantamab. The primary end point was objective response rate (ORR) assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Independent central review (ICR) provided confirmatory efficacy evaluation.1

As of the October 24, 2024, data cutoff, 77 participants had been enrolled in cohort 5, with a median follow-up of 6.5 months. The median patient age was 63 years, 68% were female, and 62% were an Asian ethnicity. Brain metastases were present in 43% of participants at baseline.1

Efficacy Results

The Q4W regimen demonstrated high efficacy, with an ORR of 82% (95% CI, 71%-90%) by the investigator and 87% (95% CI, 77%-94%) by ICR. The confirmed ORRs were 79% and 83%, respectively. Median time to response was 8.1 weeks (range, 7.0-16.5), consistent with expectations for targeted therapy in this population. Median duration of response (DOR), PFS, and overall survival (OS) were not yet estimable at the time of data cutoff. At 6.5 months of follow-up, 87% of participants remained on study treatment, indicating strong ongoing disease control.1

Safety and Tolerability

The Q4W SC regimen was generally well tolerated, with no new safety signals observed. AEs were consistent with the known EGFR/MET inhibition profile of amivantamab and lazertinib. The most common treatment-emergent AEs included paronychia, rash, and hypoalbuminemia.1

ARRs were reported in 12% of participants, substantially lower than typically observed with IV administration. Only 1 grade 3 or higher ARR was reported, underscoring the improved tolerability of the SC route.1

VTEs occurred in 13% of patients, none of which were grade 3 or higher. Prophylactic anticoagulation was administered to 87% of participants. Bleeding events were rare, with only 1% of patients experiencing grade 3 or higher bleeding.1

Treatment discontinuation due to AEs was infrequent, occurring in just 8% of patients. Importantly, mean plasma concentrations of amivantamab measured on cycle 2 day 1 were consistent with levels achieved by IV and SC Q2W dosing, confirming appropriate drug exposure.1

Context Within the Treatment Landscape

The MARIPOSA trial established amivantamab plus lazertinib as an effective frontline option for EGFR-mutant advanced NSCLC, particularly in patients with exon 19 deletions or exon 21 L858R mutations. Notably, the shift from IV to SC delivery is part of a broader movement in oncology to improve treatment accessibility and reduce the health care system burden. The PALOMA-2 results provide evidence that SC Q4W dosing maintains pharmacokinetic equivalence and clinical activity while substantially lowering ARRs.1

These findings are particularly relevant in the context of patients with brain metastases, who represented 43% of the PALOMA-2 cohort 5 population. Although detailed intracranial efficacy results are not yet available, the high systemic response rates are encouraging for this subgroup.1

Limitations and Future Directions

Although the cohort 5 data are promising, longer follow-up is required to determine median DOR, PFS, and OS, according to Scott. The relatively short 6.5-month median follow-up limits interpretation of long-term outcomes.1

In addition, while prophylactic anticoagulation appears to mitigate severe VTE risk, ongoing monitoring of thromboembolic complications is warranted. Future analyses should also assess quality-of-life outcomes, patient-reported measures of treatment convenience, and potential pharmacoeconomic benefits of reduced treatment frequency.1

“These findings support the continued development of SC Q4W amivantamab as a convenient, effective frontline therapy for EGFR-mutated NSCLC,” Scott reported at WCLC.1

Conclusion

Findings from cohort 5 of the PALOMA-2 trial demonstrate that SC amivantamab administered every 4 weeks in combination with daily lazertinib provides high response rates, favorable tolerability, and pharmacokinetic equivalence to IV dosing in patients with EGFR-mutated advanced NSCLC. The reduced incidence of administration-related reactions, low discontinuation rates, and strong early efficacy outcomes highlight the potential of this regimen to alleviate treatment burden while maintaining disease control. Although longer follow-up is needed to confirm durability of benefit and survival outcomes, Scott noted that these results support the viability of once-monthly SC amivantamab as a patient-centered alternative to IV administration, aligning with broader efforts to optimize convenience and quality of life in the management of EGFR-driven NSCLC.1

References

1. Scott SC. First-line subcutaneous amivantamab plus chemotherapy in EGFR exon 20 insertion-mutated advanced NSCLC: results from PALOMA-2. Presented at: World Conference on Lung Cancer; Barcelona, Spain; September 6-9, 2025.
2. A study of amivantamab and lazertinib combination therapy versus osimertinib in locally advanced or metastatic non-small cell lung cancer (MARIPOSA). Clinicaltrials.gov. Updated August 19, 2025. Accessed September 8, 2025. https://clinicaltrials.gov/study/NCT04487080
3. A study of amivantamab in participants with advanced or metastatic solid tumors including epidermal growth factor receptor (EGFR)-MUTATED NON-SMALL CELL LUNG CANCER (PALOMA-2). Clinicaltrials.gov. Updated July 18, 2025. Accessed September 8, 2025. https://www.clinicaltrials.gov/study/NCT05498428