Subcutaneous Amivantamab and Lazertinib in PALOMA-3: Efficacy, Safety, and Administration: A Vodcast

Abstract

Intravenous (IV) amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody, is approved for multiple indications alone or in combination for patients with EGFR-mutated advanced or metastatic nonsmall cell lung cancer (NSCLC). In the PALOMA-3 study, subcutaneous (SC) amivantamab was investigated to improve tolerability, reduce administration time, maintain efficacy, and improve patient experience. This vodcast reviews the rationale and data supporting SC amivantamab on the basis of the PALOMA-3 study and provides expert-led recommendations for SC amivantamab treatment. The PALOMA-3 study investigated the noninferiority of pharmacokinetics, with other endpoints including efficacy and safety of SC versus IV amivantamab, combined with lazertinib in participants with EGFR-mutated, advanced NSCLC after disease progression on osimertinib and platinum-based chemotherapy. Geometric mean ratios of C_trough for SC to IV amivantamab were 1.15 at Cycle 2 Day 1 (C2D1) and 1.42 at C4D1; C2_AUCD1-D15 was 1.035. Objective response rate (ORR) was 30% in the SC group and 33% in the IV group; median progression-free survival was 6.1 and 4.3 months, respectively. SC amivantamab resulted in fewer patients reporting infusion-related reactions (IRR; 13% versus 66% IV) and venous thromboembolism (VTE; 9% versus 14%) with prophylactic anticoagulation; shorter administration time at C1D1 (< 5 min per SC injection versus ~ 5 h for IV); and higher patient-reported convenience at the end of treatment (85% versus 35%). We discuss clinical considerations for SC amivantamab dosing and administration, including premedications, prophylactic measures, dose modifications, management of adverse reactions, and switching between IV and SC amivantamab. In conclusion, SC amivantamab demonstrated noninferior pharmacokinetics and antitumor responses compared with IV amivantamab in the PALOMA-3 study. SC amivantamab also reduced IRR and VTE, with shorter treatment administration times and enhanced patient convenience compared with IV. Utilizing SC amivantamab, while optimizing treatment efficacy and safety through mitigating and managing adverse events, may enhance the patient experience.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s11523-026-01248-7.

The vodcast and transcript can be viewed below the abstract of the online version of the manuscript. The slide deck is included as an Electronic Supplementary File with the online version of the manuscript. Alternatively, the vodcast and slide deck can be downloaded here: https://doi.org/10.6084/m9.figshare.33106724.

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Welcome and Objectives of the Vodcast

Welcome to our vodcast, “Subcutaneous Amivantamab and Lazertinib in PALOMA-3: Efficacy, Safety, and Administration”. My name is Danny Nguyen, and I’m an oncologist at the City of Hope in Irvine, California.

This vodcast reviews the rationale and data supporting subcutaneous (or SC) amivantamab, based on the PALOMA-3 study of amivantamab plus lazertinib. We will review dosage and administration of SC amivantamab, including pre-medications, concomitant medications, dose modifications, and expert recommendations for managing adverse reactions in clinical practice.

Rationale for SC Amivantamab

Amivantamab is a bispecific antibody targeting EGFR and MET [1–3] and is approved for several indications as a single agent or in combination with other anti-cancer agents for patients with EGFR-mutated advanced or metastatic nonsmall cell lung cancer [4].

Amivantamab was initially approved as an intravenous (or IV) injection [4]; however, SC amivantamab has been investigated in multiple trials to assess tolerability, efficacy, safety, and patient experience.

The PALOMA-3 study investigated the noninferiority of pharmacokinetics, efficacy, and safety of SC versus IV amivantamab, combined with lazertinib in patients with EGFR-mutated, advanced nonsmall cell lung cancer after disease progression on osimertinib and platinum-based chemotherapy [5].

Results of the PALOMA-3 Study

In the PALOMA-3 study, 206 patients were randomized to SC amivantamab plus lazertinib, and 212 patients were randomized to IV amivantamab plus lazertinib [5].

The primary endpoint results demonstrated noninferior pharmacokinetics of SC vs IV amivantamab; geometric mean ratios of C_trough for SC to IV amivantamab were 1.15 at Cycle 2 Day 1 and 1.42 at Cycle 4 Day 1; the Cycle 2 AUC_D1–D15 was 1.03 [5].

Key secondary outcomes were consistent between SC and IV amivantamab [5]: objective response rate was 30% in the SC group and 33% in the IV group; objective response rate in the SC group met the noninferiority criterion by retaining ≥60% of the objective response rate in the IV group. Median progression-free survival was 6.1 and 4.3 months in the SC and IV groups, respectively [5].

While SC amivantamab lowered administration-related reaction rates as expected, adverse events, including EGFR- and MET-related events, were generally consistent or improved for SC versus IV amivantamab [5].

Most patients had at least one adverse event, most commonly nail toxicity, rash, musculoskeletal pain, fatigue, and stomatitis [5].

The most common grade 3 or higher adverse events were dermatitis acneiform (at 9% and 6% in the SC and IV groups, respectively) and lymphopenia (at < 1% and 8%, respectively). Fewer venous thromboembolism events were reported in the SC versus IV groups (at 9% and 14%, respectively), most commonly pulmonary embolism and deep-vein thrombosis [5].

Reduced administration-related reactions were reported with SC versus IV amivantamab: 13% and 66% of patients reported an administration-related reaction; all administration-related adverse events ranged between 0% and 6% in the SC group and 2% and 20% in the IV group. Of those who experienced an administration-related reaction, 89% occurred with the initial dose [5].

At Cycle 1 Day 1, administration time per injection was less than 5 min with SC amivantamab versus 5 h with IV amivantamab; administration time was about 2 h for IV amivantamab in subsequent cycles. Also at Cycle 1 Day 1, SC amivantamab was reported as very convenient or convenient by 85% of patients versus 52% of patients for the IV infusion. SC amivantamab was also reported as very convenient or convenient by 85% of patients at the end of treatment, compared with 35% for the IV infusion [5].

Altogether, the PALOMA-3 study showed noninferior pharmacokinetics, consistent antitumor response, consistent or improved safety, and enhanced patient-reported convenience of SC amivantamab vs the IV infusion, supporting the approval of SC amivantamab in EGFR-mutated nonsmall cell lung cancer [5].

Overview of Dosing and Administration for SC Amivantamab

In clinical practice, treatment decisions often reflect both patient preference and logistical considerations in tandem with the guidance provided in the prescribing information. To optimize tolerability and safety, SC amivantamab should be initiated on a prescribed schedule, following guidance for premedication and prophylactic measures, and modifying dose to mitigate adverse reactions as described in the prescribing information [4].

Dosing and Administration of SC Amivantamab

Amivantamab is coformulated with human recombinant hyaluronidase for SC administration. Hyaluronidase is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. SC amivantamab is available as 160 mg amivantamab and 2000 units/mL hyaluronidase [4].

Recommended dosing of SC amivantamab varies by indication and patient weight [4]. For first-line amivantamab plus lazertinib in patients with locally advanced or metastatic nonsmall cell lung cancer with EGFR exon 19 deletions or exon 21 L858R mutations, amivantamab should be administered at 1600 mg for patients weighing less than 80 kg and 2240 mg for patients 80 kg or more. Amivantamab should be administered weekly during weeks 1–4, then using an every-2-week or every-4-week regimen starting at week 5 onward [4].

This dosing and schedule are also recommended for second-line amivantamab as monotherapy in patients with locally advanced or metastatic nonsmall cell lung cancer with EGFR exon 20 insertion mutations [4].

For first-line amivantamab plus carboplatin and pemetrexed in patients with locally advanced or metastatic nonsmall cell lung cancer with EGFR exon 20 insertion mutations, amivantamab should be administered weekly, with 1600 mg in week 1, 2400 mg in weeks 2–3, and every 3 weeks starting at week 4 onward for patients weighing less than 80 kg. Amivantamab should be administered weekly, with 2240 mg in week 1, 3360 mg in weeks 2–3, and every 3 weeks starting at week 4 onward for patients 80 kg and over [4].

This dosing and schedule are also recommended for second-line amivantamab + carboplatin and pemetrexed in patients with locally advanced or metastatic nonsmall cell lung cancer with EGFR exon 19 deletions or exon 21 L858R mutations [4].

From a clinical perspective, considerations around switching may include factors such as disease control, treatment continuity, tolerability history, adverse event burden, and patient preferences around treatment time and availability for clinic visits. When switching amivantamab dosing [4]:

• Patients currently receiving IV amivantamab every 2 weeks may switch to SC amivantamab at an every-2-week or an every-4-week dosing regimen at their next scheduled dose on or after week 5.

• Patients currently receiving IV amivantamab every 3 weeks may switch to SC amivantamab every 3 weeks at their next scheduled dose on or after week 4.

• Patients receiving SC amivantamab every 2 weeks may switch to an every-4‑week SC dosing regimen at their next scheduled dose on or after week 5.

In all cases, close monitoring is important when switching doses.

Premedications and Prophylactic Measures

Premedication strategies are routinely used as part of treatment administration, particularly in early treatment cycles. To reduce the risk of administration-related reactions, recommended premedications to be given before SC amivantamab include an antihistamine, an antipyretic, and a glucocorticoid [4].

The COCOON study demonstrated the importance of prophylactic strategies in reducing the risk and severity of dermatologic adverse events with amivantamab + lazertinib [6], prompting the recommended regimen of an oral antibiotic for the first 12 weeks of treatment, followed by an antibiotic lotion, plus supportive skin care, and sun protection [4].

When initiating amivantamab SC in combination with lazertinib, anticoagulant prophylaxis is prescribed for the first 4 months of treatment to prevent venous thromboembolic events [4].

Recommended Dose Modification and Management of Adverse Reactions

In practice, dose modifications are frequently used in routine care to manage tolerability while maintaining treatment. SC amivantamab dosing can be modified as needed to mitigate or eliminate particular adverse reactions [4].

Dose interruption and reduction are recommended upon the start of an adverse reaction, with a second dose reduction as needed, and treatment discontinuation for continuing or recurring adverse reactions [4].

Here, we show the recommended dose modifications and management for adverse reactions with SC amivantamab, including guidance on managing hypersensitivity and administration-related reactions as needed. These events are uncommon with SC amivantamab and rarely led to discontinuations in the PALOMA-3 study.

Refer to the prescribing information for amivantamab or lazertinib for further information about dose modifications for each drug [4].

Conclusions

SC amivantamab demonstrated noninferior pharmacokinetics and antitumor responses compared with IV amivantamab in the PALOMA-3 study [5]. SC amivantamab also reduced administration-related reactions and venous thromboembolic events with prophylactic anticoagulation, with shorter treatment administration times and enhanced patient convenience compared with IV. These data support the approved SC indications for amivantamab. Administration, dose modifications for adverse events, and the use of premedications and concomitant medications should follow the approved SC amivantamab labeling [5].

Supplementary Information

Below is the link to the electronic supplementary material.

Funding:

This study was funded by Johnson & Johnson. Medical writing support for this vodcast was provided by Renee E. Granger, PhD, of Envision Ignite, an Envision Medical Communications agency, a part of Envision Pharma Group, and funded by Johnson & Johnson.

Declarations

Conflicts of interest

D. Nguyen reports: honoraria/advisory role: Black Diamond Therapeutics, Johnson & Johnson, Taiho Pharmaceutical; research funding: AstraZeneca, Johnson & Johnson; travel and expenses: Corcept Therapeutics, Johnson & Johnson, Taiho Pharmaceutical; stock or other interests: Johnson & Johnson, Novartis, Pfizer, Seagen, Takeda.

Ethical Approval

The PALOMA-3 study was conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Guidelines of the International Council for Harmonisation. The protocol and amendments were approved by the institutional review board at each study site.

Consent to Participate

All patients provided written informed consent for this study.

Consent for Publication

Not applicable.

Availability of Data and Materials

The data sharing policy of Johnson & Johnson is available at https://innovativemedicine.jnj.com/our-innovation/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.

Code Availability

Not applicable.

Author’s Contributions

D. Nguyen: conceptualization; data curation; writing—original draft; and writing—review and editing.