Amivantamab-vmjw (Rybrevant) and Amivantamab and Hyaluronidase-lpuj (Rybrevant Faspro)

Number: 0995

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses amivantamab-vmjw (Rybrevant) and amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of amivantamab-vmjw (Rybrevant) and amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) is required of all Aetna participating providers and members in applicable plan designs. For precertification of amivantamab-vmjw (Rybrevant) and amivantamab and hyaluronidase-lpuj (Rybrevant Faspro), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Site of Care Utilization Management Policy applies. For information on site of service for amivantamab and hyaluronidase-lpuj (Rybrevant Faspro), see Utilization Management Policy on Site of Care for Specialty Drug Infusions. 

1. Criteria for Initial Approval

   Non-Small Cell Lung Cancer (NSCLC)

   Aetna considers amivantamab-vmjw (Rybrevant) or amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) medically necessary for treatment of NSCLC when any of the following criteria are met:

   1. For first-line treatment of advanced, recurrent, or metastatic nonsquamous non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations and the requested medication will be used in combination with carboplatin and pemetrexed; 
   2. For treatment of advanced, recurrent, or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutation positive disease and the requested medication will be used in combination with lazertinib (Lazcluze);
   3. For subsequent treatment of advanced, recurrent, or metastatic NSCLC when either of the following criteria are met:

      1. Member has EGFR exon 20 insertion mutation positive disease and both of the following criteria are met:

         1. Disease has progressed on or after platinum-based chemotherapy; and
         2. The requested medication will be used as a single agent; or

      2. Member has nonsquamous NSCLC with EGFR exon 19 deletion or exon 21 L858R mutations and both of the following criteria are met:

         1. Disease has progressed on or after treatment with Tagrisso (osimertinib); and
         2. The requested medication will be used in combination with carboplatin and pemetrexed.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Non-small cell lung cancer (NSCLC)

   Aetna considers continuation of amivantamab-vmjw (Rybrevant) or amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) therapy medically necessary in members requesting reauthorization for EGFR positive NSCLC when any of the following criteria are met:

   1. There is no evidence of unacceptable toxicity or disease progression while on the current regimen; or
   2. The member is requesting the medication in combination with lazertinib (Lazcluze) and there is no evidence of unacceptable toxicity while on the current regimen.

Dosage and Administration

Amivantamab-vmjw (Rybrevant)

Amivantamab-vmjw is available as Rybrevant 350 mg/7 mL (50 mg/mL) solution in a single-dose vial for intravenous infusion.

Non-Small Cell Lung Cancer (NSCLC)

• The recommended dosage of Rybrevant is based on baseline body weight and administered as an intravenous infusion after dilution.
• Administer premedications as recommended.
• Administer via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions.
• Administer Rybrevant in combination with chemotherapy weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 3 weeks starting at Week 7.
• Administer Rybrevant in combination with lazertinib or Rybrevant as a single agent weekly for 5 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks starting at Week 7.
• When administering Rybrevant in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment.
• Administer diluted Rybrevant intravenously.
• Refer to the full prescribing information for Rybrevant for infusion rates.
• Administer Rybrevant until disease progression or unacceptable toxicity where applicable.

Table: Recommended Dosage for Rybrevant in Combination with Carboplatin and Pemetrexed, in Combination with Lazertinib, or as a Single Agent

Body Weight (at baseline)	Dosage	Recommended Dose
Rybrevant in Combination with Carboplatin and Pemetrexed
Less than 80 kg	Weeks 1 - 4	1400 mg
	Week 7 onwards	1750 mg
Greater than or equal to 80 kg	Weeks 1 - 4	1750 mg
	Week 7 onwards	2100 mg
Rybrevant in Combination with Lazertinib or Rybrevant  as a Single Agent
Less than 80 kg	Weeks 1 - 5 Week 7 onwards	1050 mg
Greater than or equal to 80 kg	Weeks 1 - 5 Week 7 onwards	1400 mg

Source: Janssen Biotech, 2025a

Amivantamab and Hyaluronidase-lpuj (Rybrevant Faspro)

Rybrevant Faspro is available as 1,600 mg amivantamab and 20,000 units hyaluronidase per 10 mL (160 mg and 2,000 units/mL) and 2,240 mg amivantamab and 28,000 units hyaluronidase per 14 mL (160 mg and 2,000 units/mL) solution in a single-dose vial injection for subcutaneous use.

• Rybrevant Faspro has different recommended dosage and administration than intravenous amivantamab products.
• Administer each injection of Rybrevant Faspro subcutaneously in the abdomen over approximately 5 minutes.
• The recommended dosage of Rybrevant Faspro is based on baseline body weight.
• Administer premedication as recommended.
• Recommended dosage for Rybrevant Faspro in combination with carboplatin and pemetrexed (every 3-week dosing);
• Recommended dosage for Rybrevant Faspro in combination with lazertinib or for Rybrevant Faspro as a single agent (every 2-week dosing).

Table: Rybrevant Faspro In Combination with Carboplatin and Pemetrexed (Every 3-Week Dosing)

Body Weight at BaselineFootnote1*	Recommended Dose	Dosing Schedule
Less than 80 kg	1,600 mg amivantamab and 20,000 units hyaluronidase	First dose at Week 1 Day 1
	2,400 mg amivantamab and 30,000 units hyaluronidase	Weekly (total of 2 doses) from Weeks 2 to 3  – Weeks 2 to 3 - Injection on Day 1
		Every 3 weeks starting at Week 4 onwards
Greater than or equal to 80 kg	2,240 mg amivantamab and 28,000 units hyaluronidase	First dose at Week 1 Day 1
	3,360 mg amivantamab and 42,000 units hyaluronidase	Weekly (total of 2 doses) from Weeks 2 to 3  – Weeks 2 to 3 - Injection on Day 1
		Every 3 weeks starting at Week 4 onwards

Footnote1* Dose adjustments not required for subsequent body weight changes.

Table: Recommended Dosage for Rybrevant Faspro in Combination with Lazertinib or for Rybrevant Faspro as a Single Agent (Every 2-Week Dosing)

Body Weight at BaselineFootnote2**	Recommended Dose	Dosing Schedule
Less than 80 kg	1,600 mg amivantamab and 20,000 units hyaluronidase	Weekly (total of 4 doses) from Weeks 1 to 4  – Weeks 1 to 4 - Injection on Day 1
Greater than or equal to 80 kg	2,240 mg amivantamab and 28,000 units hyaluronidase	Weekly (total of 4 doses) from Weeks 1 to 4  – Weeks 1 to 4 - Injection on Day 1
		Every 2 weeks starting at Week 5 onwards

Footnote2** Dose adjustments not required for subsequent body weight changes.

Refer to full prescribing information for dosage modifications for adverse reactions and preparation instructions.

Source: Janssen Biotech, 2025b

Experimental, Investigational, or Unproven

Aetna considers amivantamab experimental, investigational, or unproven for the treatment of gastro-esophageal cancer.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
81235	EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q)
96413 - 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
Amivantamab and hyaluronidase-lpuj (Rybrevant Faspro)- no specific code
J9061	Injection, amivantamab-vmjw, 2 mg
Other HCPCS codes related to the CPB:
Lazertinib, Osimertinib, Tagrisso (osimertinib) - no specific code
J9045	Injection, carboplatin, 50 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9263	Injection, oxaliplatin, 0.5 mg
J9294	Injection, pemetrexed (hospira) not therapeutically equivalent to j9305, 10 mg
J9296	Injection, pemetrexed (accord) not therapeutically equivalent to j9305, 10 mg
J9297	Injection, pemetrexed (sandoz), not therapeutically equivalent to j9305, 10 mg
J9305	Injection, pemetrexed, not otherwise specified, 10 mg
J9314	Injection, pemetrexed (teva) not therapeutically equivalent to J9305, 10 mg
J9322	Injection, pemetrexed (bluepoint) not therapeutically equivalent to j9305, 10 mg
J9323	Injection, pemetrexed ditromethamine, 10 mg
J9324	Injection, pemetrexed (pemrydi rtu), 10 mg
ICD-10 codes covered if selection criteria are met:
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [non-small cell lung cancer]
ICD-10 codes not covered if selection criteria are met:
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 - C16.9	Malignant neoplasm of stomach
D00.1	Carcinoma in situ of esophagus
D00.2	Carcinoma in situ of stomach

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

Amivantamab-vmjw (Rybrevant) 

• Rybrevant is indicated in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.
• Rybrevant is indicated in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor.
• Rybrevant is indicated in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test.
• Rybrevant is indicated as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

Amivantamab and Hyaluronidase-lpuj (Rybrevant Faspro)

• Rybrevant Faspro is indicated in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.
• Rybrevant Faspro is indicated in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor.
• Rybrevant Faspro is indicated in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test.
• Rybrevant Faspro is indicated as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

Compendial Uses for Amivantamab-vmjw (Rybrevant) and Amivantamab and Hyaluronidase-lpuj (Rybrevant Faspro)

• First-line therapy for recurrent, advanced, or metastatic EGFR exon 20 insertion mutation positive nonsquamous NSCLC
• Subsequent therapy for recurrent, advanced, or metastatic EGFR exon 20 insertion mutation positive NSCLC
• Subsequent therapy for recurrent, advanced, or metastatic EGFR exon 19 deletion or exon 21 L858R mutation positive nonsquamous NSCLC
• Recurrent, advanced, or metastatic EGFR exon 19 deletion or exon 21 L858R mutation positive NSCLC in combination with lazertinib

Amivantamab-vmjw (Rybrevant)

Amivantamab-vmjw is available as Rybrevant (Janssen Biotech, Inc.) and is a low-fucose human immunoglobulin GI-based bispecific antibody that binds the extracellular domains of epidermal growth receptor factor (EGFR) and mesenchymal-epithelial transition (MET). In in vitro and in vivo studies, amivantamab-vmjw was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. Tumor cells with EGFR and MET on their surface are targeted for destruction by immune effector cells through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms. Amivantamab-vmjw is produced by mammalian cell line (Chinese Hamster Ovary [CHO] using recombinant DNA technology (Janssen Biotech, 2024).

Per the prescribing information, amivantamab-vmjw (Rybrevant) carries the following warnings and precautions:

• Infusion-related reactions (IRR): In clinical trial, IRR was noted in 66% of patients treated with Rybrevant and 97% of the reported IRRs were Grade 1 to 2, 2.2% were Grade 3, and 0.4% were Grade 4;
• Interstitial lung disease (ILD)/pneumonitis: In clinical trial, ILD/pneumonitis was noted in 3.3% of patients treated with Rybrevant, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis;
• Dermatologic adverse reactions: In clinical trial, rash was noted in 74% of patients treated with Rybrevant, including Grade 3 rash in 3.3% of patients;
• Ocular toxicity: The occurrence of ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis has been noted with Rybrevant therapy; keratitis occurred in 0.7% of patients and uveitis occurred in 0.3% of patients with all events being Grade 1 to 2;
• Embryo-fetal toxicity.

The most frequent adverse reactions (≥20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting (Janssen Biotech, 2024).

The most frequent Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium(Janssen Biotech, 2024).

Amivantamab and Hyaluronidase-lpuj (Rybrevant Faspro)

The fixed-combination drug product containing amivantamab and hyaluronidase (human recombinant) is available as Rybrevant Faspro (Janssen Biotech, Inc.). The amivantamab component is a low-fucose human immunoglobulin G1-based bispecific antibody that binds to the extracellular domains of epidermal growth factor receptor (EGFR) and MET. In vitro and in vivo studies have shown amivantamab's ability to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertion mutation models, degradation of EGFR and MET. Tumor cells with EGFR and MET on their surface are targeted for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytoxicity (ADCC) and trogocytosis mechanisms, respectively. The hyaluronidase component is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. Hyaluronidase increases subcutaneous tissue permeability by depolymerizing hyaluronan. Specifically when Rybrevant Faspro is administered, hyaluronidase works transiently and locally. The hyaluronidase effects are reversible with restoration of subcutaneous tissue permeability within 24 to 48 hours (Janssen Biotech, 2025b).

The prescribing information for Rybrevant Faspro carries the following contraindications, warnings and precautions, and adverse reactions.

Contraindications

• Patients with known hypersensitivity to hyaluronidase or to any of its excipients.

Warnings and precautions

• Hypersensitivity and Administration-Related Reactions (ARR): Premedicate with antihistamines, antipyretics, and glucocorticoids. Monitor patients for any signs and symptoms of ARRs. Resume treatment upon resolution of symptoms or permanently discontinue Rybrevant Faspro based on severity.
• Interstitial Lung Disease (ILD)/pneumonitis: Monitor for new or worsening symptoms indicative of ILD/pneumonitis. Immediately withhold Rybrevant Faspro in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.
• Venous Thromboembolic (VTE) events with concomitant use with lazertinib: Prophylactic anticoagulation is recommended for the first four months of treatment. Monitor for signs and symptoms of VTE and treat as medically appropriate. Withhold Rybrevant Faspro and lazertinib based on severity. Once anticoagulant treatment has been initiated, resume Rybrevant Faspro and lazertinib at the same dose at the discretion of the healthcare provider. Permanently discontinue Rybrevant Faspro and continue lazertinib for recurrent VTE despite therapeutic anticoagulation.
• Dermatologic adverse reactions: Can cause severe rash including toxic epidermal necrolysis (TEN) and dermatitis acneiform. At treatment initiation, prophylactic and concomitant medications are recommended. Withhold, dose reduce or permanently discontinue Rybrevant Faspro based on severity.
• Ocular toxicity: Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue Rybrevant Faspro based on severity.
• Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception.

Refer to full prescribing information for use in specific populations.

On December 17, 2025, the U.S. Food and Drug Administration (FDA) approved amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) for subcutaneous injection in adult patients across all indications approved for the intravenous formulation of amivantamab (Rybrevant). The FDA approval was based on supporting data from the PALOMA-3 study (FDA, 2025).

In the PALOMA-3 study, a randomized, open-label, multicenter, multiregional trial, investigators evaluated the safety and efficacy of amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR-exon 19 deletions or exon 21 L858R substitution mutations. The patients (n = 418) were randomized (1:1) to receive either subcutaneous Rybrevant Faspro plus lazertinib or intravenous (IV) amivantamab plus lazertinib. Primary outcome measures included the following: were trough concentrations at steady state (Ctrough were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). The observed geometric mean ratio (GMR) (90% confidence interval [CI]) for Cycle 2 AUCDay 1-Day15, at the recommended every two-week dosage, was 1.03 (0.98, 1.09) and for steady-state Ctrough on Cycle 4 Day 1 was 1.43 (1.27, 1.61). The simulated GMRs (90% CI) for the average concentration of Cycle 2 Day 1 to Day 21 was 1.20 (1.15, 1.26) and for steady-state Ctrough, at the recommended every three-week dosage, was 1.32 (1.23, 1.42), with the lower limits of the GMRs (90% CI) also above the pre-specified threshold of 0.8 for comparability. The investigators noted no differences in descriptive analyses of ORR and PFS, and no evidence of a potential detrimental effect on OS, observable in patients receiving subcutaneous Rybrevant Faspro compared to those receiving intravenous amivantamab. The safety profile in the subcutaneous Rybrevant Faspro arm was similar overall to the safety profile of the IV amivantamab arm. A notable exception was that systemic administration reactions (AARs) occurred at a lowere incidence than infusion related reactions (IRRs) for IV amivantamab. Any grade systemic AARs occurred at 13% in the subcutaneous Rybrevant Faspro arm compared to 66% in IRRs in the IV amivantamab arm (FDA, 2025; Janssen Biotech, 2025b).

Non-Small Cell Lung Cancer (NSCLC)

Globally, lung cancer is the most prevalent cancer type and the leading cause cancer-related mortality, of which, non-small cell lung cancer is responsible for 80% to 85% of all lung cancers per the American Cancer Society. An estimated 2% to 3% of patients with non-small cell lung cancer will have epidermal growth factor receptor (EGFR) exon 20 insertion mutations, which are a group of mutations on a protein that result in rapid cell proliferation and ensuing cancer spread. EGFR exon 20 insertion mutations are the third most prevalent type of EGFR mutation (FDA, 2021).

On May 21, 2021, the U.S. Food and Drug Administration (FDA) approved Rybrevant (amivantamab-vmjw) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The FDA granted accelerated approval based on Priority Review and Breakthrough Therapy designation for the non-small cell lung cancer indication. The FDA approval was based on supporting data from the ongoing Phase I CHRYSALIS study (Janssen Biotech, 2021).

The Phase I CHRYSALIS study consisted of a multicenter, open-label, multi-cohort clinical trial which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Rybrevant was administered as an intravenous infusion at 1050 mg (for patient baseline body weight < 80 kg) or 1400 mg (for patient baseline body weight ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. The efficacy of Rybrevant was evaluated in a population of 81 patients with NSCLC with EGFR exon 20 insertion mutation with measurable disease who received prior platinum-based chemotherapy. The primary efficacy outcome measure was overall response rate (ORR) with an additional efficacy outcome measure as duration of response (DOR). The confirmed ORR was 40% (95% confidence interval [CI], 29% to 51%), with 3.7% achieving complete responses (CR) and 36% having partial responses (PR). The median DOR was 11.1 months (95% CI, 6.9 months to not estimable) with 63% of patients having a DOR of 6 months or more (Janssen Biotech, 2024).

On March 1, 2024, the U.S. Food and Drug Administration (FDA) approved amivantamab-vmjw (Rybrevant) with carboplatin and pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test. The FDA approval was based on supporting data from PAPILLON study, a phase 3, randomized, open-label, multicenter trial (FDA, 2024a; Janssen Biotech 2024).

In the PAPILLON study, Zhou et al. (2023) evaluated the efficacy of Rybrevant in 308 participants who had previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertions. The participants were randomized 1:1 to receive Rybrevant with carboplatin and pemetrexed (n=153) or carboplatin and pemetrexed (n=155).

The primary efficacy outcome was progression-free survival (PFS) according to blinded independent central review. Participants in the carboplatin and pemetrexed group who had disease progression were allowed to cross over to receive Rybrevant monotherapy.

PFS was significantly longer in the Rybrevant with carboplatin and pemetrexed group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; p<0.001). At 18 months, PFS was reported in 31% of the participants in the Rybrevant with carboplatin and pemetrexed group and in 3% in the carboplatin and pemetrexed group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; p<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for Rybrevant with carboplatin and pemetrexed as compared with carboplatin and pemetrexed was 0.67 (95% CI, 0.42 to 1.09; p = 0.11).

The investigators concluded that the use of Rybrevant with carboplatin and pemetrexed resulted in superior efficacy as compared with carboplatin and pemetrexed alone as first-line treatment of participants with advanced NSCLC with EGFR exon 20 insertions.

On September 19, 2024, the FDA approved amivantamab-vmjw (Rybrevant) with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor. The FDA approval was based on supporting data from the MARIPOSA-2 study (FDA, 2024b).

In the MARIPOSA-2 study, a randomized, open-label, multicenter, phase 3 trial, Passaro et al. (2024) evaluated the efficacy of amivantamab-vmjw (Rybrevant) in 657 patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations and disease progression on or after receiving osimertinib. Patients were randomized 2:2:1 to receive Rybrevant with carboplatin and pemetrexed (Rybrevant + CP), carboplatin and pemetrexed (CP), or Rybrevant as part of another combination regimen. In total, 394 patients were randomized between the Rybrevant + CP (n = 131) and CP (n = 263) arms.

The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR) for the comparison between Rybrevant + CP and CP for metastatic NSCLC. Key secondary efficacy outcome measures included overall response rate (ORR) per BICR and overall survival (OS). Median PFS was 6.3 months (95% Confidence Interval [CI]: 5.6, 8.4) in the Rybrevant + CP arm and 4.2 months (95% CI: 4.0, 4.4) in the CP arm (hazard ratio 0.48 [95% CI: 0.36, 0.64], p < 0.0001). The confirmed ORR was 53% (95% CI: 44, 62) in the Rybrevant + CP arm and 29% (95% CI: 23, 35) in the CP arm (p < 0.0001). The median OS was 17.7 months (95% CI: 16.0, 22.4) in the Rybrevant + CP arm and 15.3 months (95% CI: 13.7, 16.8) in the CP arm, with a hazard ratio of 0.73 (95% CI: 0.54, 0.99) (FDA, 2024b; Janssen Biotech, 2024).

At the prespecified second interim analysis of OS, with 85% of the deaths needed for the final analysis, there was no statistically significant difference in OS (FDA, 2024b; Janssen Biotech, 2024).

Combined Amivantamab and Lazertinib for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer

Cho et al (2022) stated that 3rd-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have shown effectiveness in patients with EGFR-mutant NSCLC; however, almost all patients will eventually relapse. Amivantamab is an EGFR-MET bi-specific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations and MET mutations and amplifications. In the ongoing CHRYSALIS Trial, amivantamab in combination with lazertinib, a potent, brain-penetrant 3rd-generation EGFR TKI, demonstrated anti-tumor activity in the treatment-naive and osimertinib-relapsed setting. These researchers presented the methodology for the MARIPOSA Trial, a randomized, multi-center, phase-III clinical trial designed to compare the safety and effectiveness of amivantamab and lazertinib combination therapy versus single-agent osimertinib as 1st-line treatment for EGFR-mutant NSCLC.

On August 19, 2024, the U.S. Food and Drug Administration (FDA) approved amivantamab-vmjw (Rybrevant) in combination with lazertinib (Lazcluze) for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. The FDA approval was based on supporting data from the MARIPOSA study (FDA, 2024c).

In the MARIPOSA study, a phase 3, randomized, active-controlled, international, multicenter trial, Cho et al. (2024) evaluated the efficacy of amivantamab-vmjw (Rybrevant) in combination with lazertinib (Lazcluze) in patients with previously untreated locally advanced or metastatic NSCLC with either exon 19 deletions or exon 21 L858R substitution EGFR mutations not amenable to curative therapy. Patients were randomized in a 2:2:1 ratio to receive Rybrevant in combination with Lazcluze (n = 429) in an open-label fashion, osimertinib monotherapy (n = 429) in a blinded fashion, or Lazcluze monotherapy (n = 216), an unapproved regimen for NSCLC in a blinded fashion, to assess the contribution of treatment components. The primary efficacy outcome measure was progression-free survival in the Rybrevant in combination with Lazcluze group versus the osimertinib group, as assessed by blinded independent central review. The median progression-free survival was significantly longer in the Rybrevant in combination with Lazcluze group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; p<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the Rybrevant in combination with Lazcluze group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the Rybrevant in combination with Lazcluze group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of Rybrevant in combination with Lazcluze versus osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). The main adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with Rybrevant in combination with Lazcluze and 3% with osimertinib. The investigators concluded that Rybrevant in combination with Lazcluze demonstrated superior efficacy compared to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC.

Gastro-Esophageal Cancer

Maron et al (2022) noted that subset analyses from phase-III clinical trials of EGFRi suggested improved outcomes in patients with EGFR-amplified gastro-esophageal adenocarcinoma (GEA); however, large-scale analyses are lacking. In a multi-center analysis , these investigators examined the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to-date. A total of 60 patients from 15 tertiary cancer centers in 6 countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments (CLIA)-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing (NGS), plasma circulating tumor DNA NGS, and/or fluorescence in-situ hybridization (FISH) carried out by a CLIA- approved laboratory. Treatment patterns and outcomes analysis was also carried out using a de-identified clinic-genomic database (CGDB). A total of 60 patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52 %) with concurrent chemotherapy. Across treatment lines, patients achieved a 43 % ORR with a median progression-free survival (PFS) of 4.6 months (95 % CI: 3.5 to 6.4). Patients receiving EGFRi in 1st-, 2nd-, and 3rd-line therapy achieved a median overall survival (OS) of 20.6 months (95 % CI: 13.5 to not reached [NR]), 9 months (95 % CI: 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95 % CI: 8.7 to 14.2) median OS from 1st-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011 to December 2020) suggested that only 5 % of patients with EGFR-amplified GEA received EGFRi. The authors concluded that patients with EGFR-amplified GEA derived significant benefit from EGFRi. Moreover, these researchers stated that further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

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References