Amivantamab for EGFR-Mutated Metastatic Non–Small Cell Lung Cancer

Introduction

The past decade has witnessed a dramatic shift in the treatment approach for patients with metastatic non–small cell lung cancer (mNSCLC), with the identification and understanding of EGFR mutations paving the way for numerous groundbreaking therapies.¹ However, despite these advances, the 5-year overall survival (OS) rate for mNSCLC is still less than 10%.²

To optimize treatment selection, somatic testing for EGFR mutations for all patients with mNSCLC is recommended because these mutations are strong predictors of response to EGFR inhibitor therapy.³ The most common EGFR mutations in mNSCLC are exon 19 deletions or exon 21 L858R point mutations.¹ These 2 mutations, which account for more than 75% of all EGFR mutations in mNSCLC, are sensitive to treatment with EGFR tyrosine kinase inhibitors (TKIs).¹ Conversely, EGFR exon 20 insertions, the third most common EGFR mutation found in mNSCLC, are associated with poor response to EGFR TKIs.¹ Third-generation EGFR TKIs are the standard-of-care first-line treatment for patients with advanced NSCLC or mNSCLC with EGFR exon 19 deletion or exon 21 L858R point mutations¹, and National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend osimertinib (Tagrisso; AstraZeneca) as the preferred EGFR TKI option for these patients.³

A challenge to treatment with EGFR TKIs is the almost inevitable development of acquired resistance over time. To delay resistance and maximize treatment efficacy and duration of response, combinations of third-generation EGFR TKIs with chemotherapy or other targeted therapies are being explored.¹ One promising option for patients with mNSCLC harboring EGFR mutations is amivantamab-vmjw (Rybrevant; Janssen Biotech, Inc), a bispecific antibody that targets EGFR and MET receptors.⁴

Amivantamab was first approved by the FDA in 2021 for adults with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations who had progressed on or after platinum-based chemotherapy.⁴ In 2024, the FDA approved amivantamab for 3 additional indications: (1) in combination with chemotherapy as first-line treatment for locally advanced or metastatic NSCLC with EGFR 20 insertion mutations⁵; (2) in combination with lazertinib (Lazcluze; Janssen Biotech, Inc) as first-line treatment for locally advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations⁶; and (3) in combination with chemotherapy for patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations with disease progression on or after treatment with an EGFR TKI.⁷

These FDA approvals for more common EGFR mutations have increased the utilization of amivantamab in EGFR-mutated mNSCLC. Due to the agent’s rapidly expanding role in this patient population, a review is warranted of the clinical trials that support its use, its potential administration challenges—such as infusion-related reactions (IRRs), dermatologic toxicities, and venous thromboembolism—and strategies for mitigating its common adverse events (AEs).

Mechanism of Action

Amivantamab is derived from 2 parental monoclonal antibodies, one that targets EGFR and one that targets MET. This combination results in a bispecific antibody that binds to the extracellular domains of both EGFR and MET.⁴ Data from in vitro and in vivo studies have demonstrated that amivantamab disrupts EGFR and MET signaling functions in exon 19 deletions, exon 21 L858R substitution mutations, and exon 20 insertion mutations by blocking ligand binding, triggering degradation of EGFR and MET receptors, and promoting antitumor immune cell–directing activity, such as antibody-dependent cellular cytotoxicity.⁸

Dosage and Administration

Initial administration of amivantamab is split into 2 days due to the risk of IRRs.⁴ See TABLE 1⁴ for the dose and schedule recommendations for amivantamab based on patient weight and indication.

To reduce the risk of IRRs, premedication with a corticosteroid, antipyretic, and antihistamine is recommended prior to the first 2 weekly doses of amivantamab during cycle 1. If patients tolerate the first 2 doses without IRRs, corticosteroids can be omitted, and the antipyretic and antihistamine are continued as premedications (see TABLE 1⁴ for premedication recommendations). The prescribing information recommends infusing via a peripheral line in weeks 1 and 2 to reduce the risk of IRRs. All subsequent infusions may be administered through a central line.⁴

CLINICAL DATA ON AMIVANTAMAB

• Indication: as monotherapy for adults with metastatic or locally advanced NSCLC with EGFR exon 20 insertion mutations who have progressed on or after platinum-based chemotherapy

Amivantamab received accelerated FDA approval in May 2021 based on data from the phase 1 CHRYSALIS trial (NCT02609776),⁹ a multicenter, nonrandomized, open-label study that included 81 patients in the efficacy analysis.¹⁰ These patients were treated with the recommended phase 2 dose of amivantamab 1050 mg (1400 mg for body weight > 80 kg) weekly for 4 weeks and then every 2 weeks starting at week 5. The first dose was split over days 1 and 2.

The overall response rate was 40% (95% CI, 29%- 51%); the median duration of response (DOR) was 11.1 months (95% CI, 6.9-not reached); and the median progression-free survival (PFS) was 8.3 months (95% CI, 6.5-10.9).¹⁰ Study investigators concluded that amivantamab “yielded robust and durable responses,” with a tolerable AE profile in patients with EGFR exon 20 insertion mutations who had progressed on platinum-based chemotherapy.10 Full FDA approval for this indication was granted in March 2024.⁵

• Indication: in combination with carboplatin and pemetrexed as first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations

This March 2024 FDA approval⁵ was based on results from the phase 3 PAPILLON trial (NCT04538664)—a randomized, open-label study of 308 adults with advanced NSCLC harboring EGFR exon 20 insertions.¹¹ Participants were randomly assigned 1:1 to receive amivantamab plus carboplatin/pemetrexed or chemotherapy alone in the firstline setting.¹¹

Amivantamab was administered at a dose of 1400 mg (1750 mg for body weight ≥ 80 kg) weekly for 4 weeks, paused for weeks 5 and 6, and then given at 1750 mg (2100 mg for body weight ≥ 80 kg) every 3 weeks starting in week 7. The first infusion was split between 2 days. The chemotherapy regimen consisted of carboplatin at an area under the concentration-time curve of 5 mg/mL/min (AUC 5) for up to 4 cycles and pemetrexed 500 mg/m² every 21 days until disease progression.¹²

The amivantamab-chemotherapy group demonstrated significantly longer PFS than the chemotherapy-only group (median PFS, 11.4 months vs 6.7 months, respectively; HR, 0.40; 95% CI, 0.30-0.53; P < .001). Although OS results were immature at the time of analysis (HR for death for amivantamab-chemotherapy vs chemotherapy, 0.67; 95% CI, 0.42-1.09; P = .11), the investigators noted that the interim analysis “showed evidence of improved survival with first-line amivantamab-chemotherapy despite a high frequency of crossover to second-line amivantamab monotherapy in the chemotherapy group.”¹²

• Indication: in combination with lazertinib as first-line treatment for locally advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations

This August 2024 FDA approval⁶ was based on data from the phase 3, randomized, open-label MARIPOSA trial (NCT04487080) that evaluated 1074 adults with previously untreated locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations. Patients were randomly assigned to receive amivantamab plus lazertinib, osimertinib monotherapy, or lazertinib monotherapy. Patients in the combination arm received amivantamab 1050 mg (1400 mg for weight ≥ 80 kg) once weekly for 5 weeks, with the first dose split over days 1 and 2, and then every 2 weeks metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations who progressed on or after prior EGFR-directed therapy.

This September 2024 FDA approval⁷ was based on data from the open-label, randomized, phase 3 MARIPOSA-2 trial (NCT04988295) that enrolled 657 adults with locally advanced or metastatic NSCLC harboring exon 19 deletions or L858R substitution mutations who had experienced disease progression on osimertinib. These patients were randomly assigned to receive either amivantamab plus chemotherapy, amivantamab with lazertinib plus chemotherapy, or chemotherapy alone.¹⁴

Amivantamab was administered at 1400 mg (1750 mg for body weight ≥ 80 kg) weekly for the first 4 weeks and then at 1750 mg (2100 mg for weight ≥ 80 kg) every 3 weeks starting with week 7. Oral lazertinib 240 mg was given daily. Chemotherapy was administered intravenously at the start of each cycle, with pemetrexed 500 mg/m² given every cycle and carboplatin AUC 5 given for the first 4 cycles. Patients could continue taking amivantamab, lazertinib, and pemetrexed maintenance until disease progression.¹⁴

Median PFS was 6.3 months (95% CI, 5.6-8.4 months) with amivantamab-chemotherapy and 8.3 months (95% CI, 7.1-9.9 months) with amivantamab-lazertinib-chemotherapy vs 4.2 months (95% CI, 4.0-4.4 months) with chemotherapy alone. PFS was significantly longer with amivantamab-chemotherapy vs chemotherapy (HR for disease progression or death, 0.48; 95% CI, 0.36-0.64; P < .001) and with amivantamab-lazertinib-chemotherapy vs chemotherapy (HR for disease progression or death, 0.44; 95% CI, 0.35-0.56; P < .001). The objective response rate also was significantly higher in the combination arms (64% and 63%, respectively, vs 36% with chemotherapy; P < .001 for both). Early interim OS data, although not statistically significant, showed a favorable trend for amivantamab-chemotherapy vs chemotherapy alone (HR, 0.77; 95% CI, 0.49-1.21), whereas no difference in OS was observed between the triplet and chemotherapy alone (HR, 0.96; 95% CI, 0.67-1.35).¹⁴

Although amivantamab-lazertinib-chemotherapy improved PFS vs chemotherapy alone, interim analysis showed a lack of OS benefit and an increased rate of toxicities, particularly hematologic AEs, with the 3-drug regimen.¹⁴ Overall, the amivantamab-chemotherapy combination demonstrated a more favorable balance of efficacy

Amivantamab AES

The safety profile of amivantamab across the CHRYSALIS, PAPILLON, MARIPOSA, and MARIPOSA-2 trials demonstrates a consistent pattern of AEs that aligns with its dual inhibition of EGFR and MET pathways.^10,12-14

As expected with EGFR inhibition, dermatologic toxicities were among the most commonly observed AEs.⁴ In the MARIPOSA trial, rash (all grades) occurred in 54% to 78% of patients receiving amivantamab-based regimens, with grade 3 or higher severity observed in up to 15% of patients given amivantamab with lazertinib.¹³ Also in the MARIPOSA trial, paronychia (all grades) was reported in 37% to 68% of patients, with grade 3 or higher seen in up to 11% of patients.¹³ Diarrhea, another common EGFR-associated toxicity, was reported in 15% to 30% of patients across all trials.^10,12-14 Other common EGFR-associated toxicities, including stomatitis and pruritus, were reported but were generally mild.^10,12-14

MET-related toxicities were also consistently observed across trials. Hypoalbuminemia (all grades) was reported in 22% to 48% of patients receiving amivantamab, with grade 3 or higher observed in up to 5% of patients. Peripheral edema occurred in 30% to 36% of patients receiving amivantamab; however, severe cases were rare, with grade 3 or higher occurring in 1% to 2% of patients.^4,10,12-14

IRRs were another notable toxicity across the amivantamab trials, occurring in 42% to 65% of patients, but most cases were grade 1 or 2.^4,10,12-14 The rate of more severe reactions was low, but it was slightly higher when amivantamab was combined with lazertinib.⁴ Specifically, the rate of grade 3 or 4 IRRs with amivantamab plus lazertinib was 6% in the MARIPOSA trial compared with 2.6% for amivantamab monotherapy in the CHRYSALIS trial.⁴

In combination regimens that included chemotherapy, hematologic toxicities were frequently observed. Neutropenia occurred in 57% to 59% of patients (with up to 45% experiencing grade ≥ 3), and thrombocytopenia occurred in up to 44% (with up to 15% experiencing grade ≥ 3). Incidence of anemia was generally similar between amivantamab-chemotherapy and chemotherapy-only groups. In the PAPILLON and MARIPOSA-2 trials, these hematologic AEs were largely attributed to the chemotherapy components rather than to amivantamab.^12,14

Treatment modifications due to AEs were common across all trials—with dose interruptions and dose reductions occurring in up to 83% and up to 59% of patients, respectively—particularly in the MARIPOSA trial when amivantamab was combined with lazertinib. Permanent discontinuation due to AEs ranged from 4% to 35%, with a lower rate observed in the monotherapy arm of the CHRYSALIS trial.^10,12-14

Overall, the demonstrated toxicity profile of amivantamab is consistent with its mechanism of action as a dual EGFR and MET inhibitor; specifically, dermatologic and hypoalbuminemia-related effects were prominent. Although hematologic AEs also were common, their incidence was relatively similar to that seen in comparator groups and more likely attributable to the combination chemotherapy.^10,12-14

Place in Therapy

Amivantamab has been integrated into the NCCN guidelines as a preferred therapeutic option for specific subsets of NSCLC. For patients with newly diagnosed, advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, the NCCN recommends amivantamab in combination with carboplatin and pemetrexed as the category 1, preferred first-line therapy in nonsquamous cell carcinoma.³ This recommendation is supported by data from the phase 3 PAPILLON study.¹² The NCCN recommends single-agent amivantamab as a category 2A treatment option for patients with NSCLC with EGFR exon 20 insertion mutations after disease progression or after platinum-based chemotherapy if not received in the first line.³

Additionally, the NCCN includes amivantamab plus lazertinib as a category 1 first-line treatment for NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations,³ which is supported by findings from the MARIPOSA study.¹³ In January 2025, the NCCN guidelines were updated for patients with NSCLC who are already on first-line systemic therapy when an EGFR mutation is detected. The updated guidance recommends completing the planned initial treatment or switching to a preferred targeted regimen, such as osimertinib alone or amivantamab plus lazertinib.³ Soon after, updated OS data from the MARIPOSA trial, presented at European Lung Cancer Congress 2025, showed that at a median follow-up of 37.8 months, amivantamab plus lazertinib demonstrated a statistically significant improvement in OS vs osimertinib (HR, 0.75; 95% CI, 0.61-0.92; P < .005) in patients with advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations,¹⁵ further supporting amivantamab’s utilization in the first-line setting for patients with EGFR-mutated NSCLC.

For patients with advanced NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations (nonsquamous histology) who have experienced disease progression after treatment with osimertinib, NCCN guidelines suggest the use of amivantamab in combination with carboplatin and pemetrexed (category 1, preferred) or amivantamab plus lazertinib (category 2A).³

Amivantamab’s expanded role reflects the growing recognition of its dual-targeted mechanism in overcoming resistance pathways associated with EGFR-driven tumors. The clinical utility of amivantamab lies in its ability to target both EGFR and MET signaling pathways, which play a role in tumor proliferation and resistance,⁸ making the bispecific antibody a critical therapeutic advancement in the management of EGFR-mutated NSCLC.

Clinical Considerations

Amivantamab was first approved by the FDA in 2021 as first-line therapy for patients with metastatic or locally advanced NSCLC harboring EGFR exon 20 insertion mutations, but its initial utilization was minimal due to the relative rarity of this specific mutation, which accounts for less than 10% of all EGFR mutations in mNSCLC.¹ However, amivantamab is gaining favor as an effective treatment option following its recent first- and second-line approvals in mNSCLC with common EGFR mutations and its NCCN recommendations. Despite updated OS data from the MARIPOSA trial showing amivantamab plus lazertinib to be superior to osimertinib in the first-line setting for patients with advanced or metastatic NSCLC with exon 19 deletions and L85R substitution mutations,¹⁵ osimertinib remains the NCCN category 1, preferred first-line recommendation, whereas amivantamab plus lazertinib is a category 1, other-recommended first-line treatment for EGFR-mutated NSCLC.³ It remains to be seen whether future NCCN guideline updates will elevate amivantamab plus lazertinib over osimertinib.

Regardless, as amivantamab becomes more widely used for mNSCLC, clinicians must be mindful of its more common AEs—particularly IRRs, dermatologic toxicities, and venous thromboembolism—as well as their mitigation strategies.

• IRRs—IRRs are common during the first infusion of amivantamab, occurring in more than 60% of patients.^4,10,12-14 To reduce this risk, the package insert recommends premedication with a corticosteroid, antihistamine, and antipyretic 30 to 60 minutes prior to the infusion.⁴

The open-label, phase 2 SKIPPirr study (NCT05663866) is evaluating 4 additional strategies to reduce the risk of IRRs for cycle 1 day 1 (C1D1). Patients receiving amivantamab were pretreated with 1 of 4 preventive therapies: (1) oral dexamethasone 4 mg twice daily 1 day prior to treatment (2 doses); (2) oral dexamethasone 8 mg twice daily starting 2 days prior to treatment and on the morning of C1D1 (5 doses); (3) oral montelukast 10 mg daily starting 4 days prior to treatment and on C1D1 (5 doses); and (4) subcutaneous methotrexate 25 mg anytime between 3 and 7 days prior to treatment (1 dose). The primary end point was the incidence of IRRs during C1D1.¹⁶

Interim results presented at the European Society for Medical Oncology Congress in September 2024 showed that oral dexamethasone 8 mg twice daily for 2 days before infusion and another dose 1 hour before infusion (hereafter referred to as dex8) led to an approximate 3-fold reduction in IRRs from intravenous (IV) amivantamab.¹⁷ The incidence of IRRs in the dex8 group was reduced to 24% vs 83%, 73%, and 83% for dexamethasone 4 mg, montelukast, and methotrexate, respectively.¹⁶ Early data from this trial suggest that clinicians should consider adding dex4 to minimize the risk of IRRs.^16,17 

Because high rates of IRRs may pose a barrier to widespread acceptance of IV amivantamab in the first-line setting for EGFR-mutated mNSCLC, Johnson & Johnson is developing a subcutaneous (SQ) formulation with the goal of reducing administration time and improving tolerability.¹⁸ Results from the phase 3 PALOMA-3 trial (NCT01942135) studying this formulation, reported at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated that SQ amivantamab is noninferior to IV amivantamab, “offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.”¹⁸ Specifically, administration time was reduced to approximately 5 minutes with the SQ formulation vs 5 hours with IV amivantamab, and IRRs were reduced 5-fold with SQ compared with IV amivantamab.¹⁸ Based on these trial results, Johnson & Johnson submitted a biologics license application for SQ amivantamab to the FDA in 2024, but it was rejected due to concerns over manufacturing facility issues. According to a Johnson & Johnson news release, the complete response letter was unrelated to the drug’s safety, efficacy, or formulation, and “the FDA has not requested any additional clinical studies.”¹⁹ Nevertheless, the approval of the formulation has been delayed.

• Dermatologic toxicities—Dermatologic reactions to amivantamab were reported in 74% to 86% of patients across the clinical trials; the median time to onset was 14 days in both the amivantamab monotherapy group of the CHRYSALIS trial and the amivantamab-lazertinib group of the MARIPOSA trial.⁴ To minimize dermatologic reactions from amivantamab, patients should limit sun exposure during treatment with amivantamab, wear protective clothing, and use broad-spectrum sunscreen.⁴ Prophylactic treatments to minimize dermatologic reactions are also being evaluated. Results from the first interim analysis of the phase 2 COCOON trial (NCT06120140) assessing enhanced dermatologic management (DM) in combination with IV amivantamab and lazertinib were presented at the 2025 ASCO Annual Meeting. The trial enrolled patients with advanced, previously untreated NSCLC with exon 19 deletions or exon 21 L858R substitution mutations and randomly assigned them 1:1 to receive COCOON DM or standard-of-care (SOC) DM per site practice.²⁰ 

The COCOON DM group received oral minocycline or doxycycline for 12 weeks, topical clindamycin lotion daily on the scalp starting week 13 for 9 months, chlorhexidine 4% on the toes and fingernails daily for 12 months, and a noncomedogenic ceramide-based moisturizer daily for 12 months. The comparator group received SOC DM, including corticosteroids and systemic antibiotics at the provider’s discretion. The primary end point was the incidence of grade 2 or higher AEs during the first 12 weeks of therapy. At 12 weeks, patients in the COCOON DM group showed a 65% reduction in grade 2 or higher dermatologic AEs on the face or body, a 70% reduction in scalp dermatologic AEs, a 25% reduction in paronychia, and a 50% reduction across all dermatologic AEs compared with those receiving SOC. Based on these promising early data indicating that COCOON DM reduced the severity of dermatologic AEs and the impact of those AEs on quality of life, clinicians should consider implementing COCOON DM for patients receiving amivantamab and lazertinib.²⁰  

• Venous thromboembolism (VTE)—VTE was reported in 36% of patients who received amivantamab in combination with lazertinib in the MARIPOSA trial, including grade 3 in 10% and grade 4 in 0.5% of patients.^4,13 This increased risk of VTE has only been reported in patients receiving amivantamab with lazertinib and not with single-agent amivantamab or with amivantamab in combination with chemotherapy.⁴ In patients taking amivantamab and lazertinib, the prescribing information recommends that they receive prophylactic anticoagulation for the first 4 months of treatment with either a direct oral anticoagulant or low molecular weight heparin and avoid vitamin K antagonists.⁴

Conclusions

Amivantamab is a dual-targeted monoclonal antibody developed to overcome resistance pathways seen in EGFR-mutated mNSCLC. In 2024, the FDA approved it for 3 additional indications, which increased its utility for patients with lung cancer. Patients now have the option to receive amivantamab as first-line therapy and as second-line therapy after failure of an EGFR TKI.

Although the effectiveness of amivantamab has been established, so has its association with a range of toxicities stemming from its dual inhibition of the EGFR and MET pathways, including dermatologic events and IRRs, which require careful management. However, proactive management strategies, such as those evaluated in the SKIPPirr and COCOON trials, have demonstrated success in managing these AEs.^16,20

The availability of the SQ formulation would further mitigate the IRRs seen with IV amivantamab. As demonstrated in the PALOMA-3 trial, SQ amivantamab significantly decreased the incidence of IRRs and further improved patient experience by significantly decreasing chair time in clinic and enhancing patient convenience.¹⁸

Amivantamab marks a crucial advancement in addressing the challenges faced by patients with EGFR-mutated mNSCLC, particularly those with EGFR 20 insertion mutations, exon 19 deletions, and exon 21 L858R substitution mutations who previously had limited targeted therapy options. The continuous refinement of amivantamab, including the convenience and safety offered by the SQ formulation, will help solidify the agent’s position as a valuable treatment modality in the landscape of targeted therapies for lung cancer.

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