PALOMA-2: Subcutaneous Amivantamab Plus Lazertinib Delivers MARIPOSA-Level Efficacy with Improved Safety

Precision Oncology Enters the Era of Delivery Innovation

In the era of precision oncology, the progress of targeted therapy is no longer defined solely by molecular breakthroughs but by how effectively those therapies reach patients. The intravenous (IV) formulation of amivantamab, an EGFR/MET bispecific antibody, in combination with the third-generation EGFR tyrosine kinase inhibitor (TKI) lazertinib, set a new first-line standard for EGFR exon 19 deletion (Ex19del) and L858R-mutated non-small cell lung cancer (NSCLC) following the landmark MARIPOSA trial. However, the regimen’s IV administration every two weeks posed practical burdens that weigh heavily on patients and oncology centers, including long chair times, infusion reactions, and frequent visits. 

Today, the PALOMA-2 cohort 5 results presented at the 2025 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer (WCLC) and published in the Journal of Thoracic Oncology demonstrate that a once-every-4-weeks subcutaneous (SC) formulation of amivantamab can deliver equivalent efficacy, pharmacokinetics, and safety, reshaping how targeted therapy can be administered in everyday practice.

Spotlight on PALOMA-2

Phase 2 of the PALOMA-2 trial (NCT05498428) evaluated SC amivantamab (co-formulated with hyaluronidase) along with oral lazertinib. Treatment-naive patients with EGFR Ex19del or L858R-mutated advanced NSCLC were included. Cohort 5 investigated the once-every-4-week regimen designed to extend dosing intervals while maintaining systemic exposure comparable to the prior every 2-week schedule. Anticoagulation prophylaxis was mandatory in the first 4 months. The treatment regimen consisted of SC amivantamab 1600 mg (2240 mg if ≥ 80 kg) weekly for 4 weeks, followed by 3520 mg (4640 mg if ≥ 80 kg) every 4 weeks thereafter, along with once-daily oral lazertinib 240 mg.

The study enrolled 77 participants with a median age of 63 years through October 24, 2024. Participants were 68% women, 32% Asian, and 43% had brain metastases at baseline. The median follow-up duration was 6.5 months, and 87% of patients remained on treatment at the time of data cutoff. Regarding EGFR mutation types, 46 patients (60%) had Exon 19 deletion, and 31 patients (40%) had the L858R mutation.

Trial Outcomes

Cohort 5 demonstrated high efficacy and rapid responses, consistent with the results historically observed with IV amivantamab. The primary endpoint, overall response rate (ORR) per RECIST v1.1 (investigator-assessed), was 82% with a confirmed ORR of 79%. 

For secondary endpoints, the ORR as assessed by independent central review (ICR) was 87%, and the confirmed ORR by ICR was 83%. The median time to response was 8.1 weeks (range, 7.0–16.5 weeks), indicating rapid clinical benefit. At the time of the data cutoff, the median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were not yet reached, as most responses were ongoing. Notably, 93% of confirmed responders remained on treatment at the time of analysis, supporting the durable antitumor activity of the every-4-week SC regimen at this early follow-up.

Amivantamab exposure on cycle 2, day 1, averaged 366 µg/mL (±112), matching historical IV and SC concentrations administered every 2 weeks. These results confirm pharmacokinetics being non-inferior, ensuring that systemic exposure and efficacy remain fully preserved despite reduced dosing frequency.

Safety analysis reinforced the advantages of SC administration. Administration-related reactions (ARRs) occurred in 12% of participants, mostly grade 1–2 with only one grade 3 or higher event, representing a markedly lower incidence compared with 66% observed with IV therapy. Venous thromboembolism (VTE) events were reported in 13% of participants, none of which were grade 3 or higher. Grade 3 or higher bleeding events were infrequent (1%), and treatment discontinuations due to adverse events (AEs) occurred in 8% of participants. 

The most common treatment-related AEs included rash (58%), paronychia (73%), and hypoalbuminemia (64%), predominantly grade 1–2 severity. No new safety challenges were identified. The favorable safety and convenience profile of SC delivery supports a more tolerable and streamlined treatment experience for patients.

Clinical Perspective

The cohort 5 results of the PALOMA-2 study establish that simplifying treatment delivery and frequency can preserve therapeutic precision while reducing side effects. Building upon findings from MARIPOSA, where the IV amivantamab plus lazertinib regimen demonstrated robust efficacy, and from PALOMA cohort 1, which confirmed that SC amivantamab every 2 weeks plus lazertinib achieved comparable pharmacokinetics and response rates with fewer infusion-related reactions, the every 4-week SC schedule represents an advancement in frontline therapy for EGFR-mutated NSCLC. 

Importantly, prophylactic strategies were integral to the PALOMA trial. With experience managing chemotherapy-related AEs, oncologists must adapt to a new paradigm where targeted therapies bring distinct mechanism-based toxicities that require proactive prevention. Three key prophylactic approaches—COCOON, SKIPPirr, and prophylactic anticoagulation—collectively demonstrated meaningful reductions in early-onset AEs.

As targeted therapies, such as SC amivantamab, continue to grow, the oncology community must integrate these evidence-based prophylactic protocols into routine practice. 

Training current and future oncologists to anticipate, prevent, and manage targeted therapy-associated AEs is essential to fully grasp the benefits of these next-generation targeted oncological treatments. Overall, the monthly SC amivantamab dosing regimen could set up a new standard of care by leading to improved adherence, reduced travel and chair time, and broader access, particularly in community oncology settings.

References

1. Girard N, et al. PALOMA-2 Cohort 5: Subcutaneous amivantamab plus lazertinib in EGFR-mutated advanced NSCLC achieves MARIPOSA-level efficacy with improved tolerability. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer IASLC 2025; September 2025; San Diego, CA. 
2. 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. clinicaltrials.gov/study/NCT05498428
3. Girard N, et al. Subcutaneous amivantamab + lazertinib in first-line EGFR-mutated NSCLC: interim results from the phase 2 PALOMA-2 study (Cohorts 1 & 6). J Clin Oncol. 2024;42(17 Suppl):LBA8612. doi:10.1200/JCO.2024.42.17_suppl.LBA8612
4. Park K, Nakagawa K, et al. MARIPOSA: Amivantamab plus lazertinib vs osimertinib in EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(4):312-324. doi:10.1056/NEJMoa2402158
5. 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. clinicaltrials.gov/study/NCT04487080

Table: Comparison of PALOMA-2 Cohort 5 (SC Q4W) and MARIPOSA (IV Q2W) in EGFR-Mutated Advanced NSCLC