Pharmacist's Application to Practice: Amivantamab and Hyaluronidase-lpuj

FDA approves amivantamab and hyaluronidase-lpuj for subcutaneous injection

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What is the potential role for Amivantamab and Hyaluronidase-lpuj in the treatment of non-small cell lung cancer?

• Lung cancer is the leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. Epidermal growth factor receptor mutation (EGFR) mutations are the most common targetable driver mutations in lung adenocarcinoma, occurring in 10-15% of western patients and 50-62% of East Asian patients. Prevalence was higher in females, never-smokers, and adenocarcinoma histology¹.
• Third-generation EGFR Tyrosine kinase inhibitors (TKI) are first line-standard of care for EGFR-mutant advanced NSCLC. However, resistance to third generation EGFR TKIs eventually develops in all patients. The most common measurable resistance mechanisms are secondary EGFR pathway alterations and mesenchymal-epithelial transition (MET) amplification².
• Amivantamab is a bispecific antibody that targets both EGFR and MET. It binds to the EGFR and MET, disrupting their signaling by blocking ligand binding and promoting receptor degradation. This mechanism has been demonstrated in tumors harboring EGFR exon 19 deletions, exon 21 L858R substitutions, and 20 insertion mutations. Additionally, expression of EGFR and MET on tumor cell surfaces facilitates immune-mediated tumor cell killing, including antibody-dependent cellular cytotoxicity by natural killer cells and trogocytosis by macrophages³.
• The subcutaneous (SC) formulation, Rybrevant Faspro, incorporates recombinant human hyaluronidase to facilitate rapid dispersion and absorption3. This allows for a markedly shorter administration time compared with intravenous infusion while maintaining comparable pharmacokinetics and efficacy⁴.
• Amivantamab and hyaluronidase-lpuj subcutaneous injection may be substituted for IV amivantamab-vmjw, with different dosing and administration instructions³.
• Amivantamab-based regimens are approved by the FDA across multiple EGFR-mutated NSCLC settings:
  • First-line, EGFR exon 19 deletion or L858R: Lazertinib + amivantamab-vmjw is a preferred, category 1 option⁵
    • MARIPOSA trial⁵
      • 1,074 patients were randomized in this open-label, international, phase III trial (2:2:1 ratio) comparing amivantamab-lazertinib (n=429) to osimertinib (n=429) or lazertinib alone (n=216)
      • Patients were eligible if they had previously untreated, locally advanced, or metastatic NSCLC with EGFR exon 19 deletion or L858R substitution mutations
      • The most common adverse events with amivantamab–lazertinib were paronychia (68%), infusion-related reactions (63%), and rash (62%). Grade ≥3 adverse events occurred in 75%–80% of patients in the combination arm versus 43%–52% with osimertinib, driven by skin/nail toxicity, venous thromboembolism, and infusion reactions. Discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab–lazertinib versus 3% with Osimertinib.
    • The other two preferred options are:
      • Osimertinib (Tagrisso) – Based on the FLAURA trial, which demonstrated superior PFS (18.9 vs. 10.2 months; HR 0.46; P<0.001) and OS (38.6 vs. 31.8 months; HR 0.80; P=0.046) versus first-generation EGFR TKIs⁹
      • (Carboplatin or Cisplatin)/Osimertinib/Pemetrexed - Based on the FLAURA2 trial, which showed superior PFS with osimertinib plus chemotherapy versus osimertinib alone (HR 0.62; P<0.0001).¹⁰

_{PFS = progression-free survival; ORR = overall response rate; DOR = duration of response; OS = overall survival; HR = hazard ratio; AE = adverse event; RCT = randomized controlled trial; NSCLC = non-small cell lung cancer.}

• • First-line, EGFR exon 20 insertion: Carboplatin/pemetrexed + amivantamab-vmjw is the preferred, category 1 option.
    • PAPILLON Trial⁶
      • 308 patients were randomized (1:1) in this open-label, international, phase III trial comparing amivantamab-chemotherapy (n=153) to chemotherapy alone (n=155). Crossover to amivantamab monotherapy was allowed upon progression on chemotherapy.
      • Patients were eligible if they had previously untreated, locally advanced, or metastatic NSCLC with EGFR exon 20 insertion mutations.
      • The predominant adverse events with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects. The most common adverse events included neutropenia (59%), paronychia (56%), and rash (54%). Discontinuation of amivantamab due to adverse reactions occurred in 7% of patients.
    • There are no other FDA-approved targeted first-line therapies for this mutation. But, after progression on first-line amivantamab + chemotherapy:
      • Sunvozertinib (Zegfrovy) FDA accelerated approval granted July 2, 2025, for EGFR exon 20 insertion-mutated NSCLC after platinum-based chemotherapy. Based on WU-KONG1B: ORR 46% (95% CI, 35–57) at 200 mg daily, DOR 11.1 months¹²
      • Amivantamab-vmjw monotherapy (if not previously given) FDA-approved for EGFR exon 20 insertions after progression on platinum-based chemotherapy. Based on CHRYSALIS: ORR 40%, median PFS 8.3 months⁶
      • Datopotamab deruxtecan-dlnk – also listed for EGFR exon 20 insertions in the subsequent therapy setting.

_{PFS = progression-free survival; ORR = overall response rate; OS = overall survival; HR = hazard ratio; CI = confidence interval; AE = adverse event; RCT = randomized controlled trial; NSCLC = non-small cell lung cancer; BICR = blinded independent central review; NE = not estimable.}

• • Subsequent therapy for EGFR exon 19 deletion or L858R-mutated NSCLC after progression on osimertinib or lazertinib ± amivantamab (systemic progression):
    • MARIPOSA-2 Trial⁷
      • 657 patients with EGFR-mutated NSCLC whose disease progressed on osimertinib were randomized (2:2:1) to amivantamab–lazertinib–chemotherapy, chemotherapy alone, or amivantamab–chemotherapy.
      • Median intracranial PFS was 12.5 months with amivantamab-chemotherapy and 12.8 months with amivantamab-lazertinib-chemotherapy. The similar intracranial PFS between the two arms indicates that the addition of lazertinib to amivantamab-chemotherapy did not meaningfully enhance CNS control and that amivantamab-chemotherapy alone can prevent or delay CNS recurrence.
      • Predominant adverse events in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Serious treatment-emergent adverse events occurred in 32% of patients treated with amivantamab–chemotherapy versus 20% with chemotherapy alone.
    • The other preferred options are:
      • Carboplatin/Pemetrexed + Amivantamab-vmjw (if not previously given) preferred, category 1
      • Lazertinib + Amivantamab-vmjw (if not previously given) useful in certain circumstances (e.g., if progression on carboplatin/cisplatin/osimertinib/pemetrexed)
      • Datopotamab deruxtecan-dlnk (Datroway) preferred for EGFR mutations (all subtypes). FDA accelerated approval granted June 2025 for EGFR-mutated NSCLC after prior EGFR-directed therapy and platinum-based chemotherapy. Pooled ORR of 45% (95% CI, 35–54) with median DOR of 6.5 months across TROPION-Lung05 and TROPION-Lung01¹¹
      • Standard chemotherapy options: docetaxel, pemetrexed, gemcitabine, docetaxel + ramucirumab, albumin-bound paclitaxel

_{PFS = progression-free survival; ORR = overall response rate; HR = hazard ratio; CI = confidence interval; AE = adverse event; NSCLC = non-small cell lung cancer; EGFR = epidermal growth factor receptor; MET = mesenchymal-epithelial transition; BICR = blinded independent central review}

• The subcutaneous formulation was evaluated in the phase III PALOMA-3 trial, which randomized 418 patients (1:1) with EGFR-mutated advanced NSCLC (progressed after osimertinib and platinum-based chemotherapy) to subcutaneous or intravenous amivantamab, both combined with Lazertinib⁸.
  • Subcutaneous amivantamab demonstrated pharmacokinetic noninferiority to intravenous amivantamab, with a 5-fold reduction in infusion-related reactions (13% vs. 66%), reduced venous thromboembolism (9% vs. 14%), and significantly prolonged overall survival (HR 0.62; nominal P=0.02)⁸. Each subcutaneous injection is administered in the abdomen over approximately 5 minutes³.

_{NSCLC = non-small cell lung cancer; EGFR = epidermal growth factor receptor; PK = pharmacokinetics; AUC = area under the curve; GMR = geometric mean ratio; CI = confidence interval; ORR = overall response rate; PFS = progression-free survival; OS = overall survival; HR = hazard ratio; SC = subcutaneous; IV = intravenous; IRR = infusion-related reaction}

• Amivantamab remains unique as the only FDA-approved EGFR×MET bispecific antibody with immune cell–directing activity for solid tumors, and one of the few subcutaneous antibodies formulated with hyaluronidase in oncology.

What role can the pharmacist play in the management of patients on: Amivantamab and Hyaluronidase-lpuj

• Pharmacists play a significant role in ensuring appropriate dosing of amivantamab and hyaluronidase (Rybrevant Faspro), monitoring adverse events, and helping prevent and manage adverse events when they do occur.
• Dosage forms and strengths³:
  • It is supplied as a sterile, preservative-free, clear to opalescent, colorless to pale yellow solution for subcutaneous injection in single-dose vials.
  • Four commercially available single-dose vial strengths exist:
    • 1,600 mg / 20,000 units per 10 mL
    • 2,240 mg / 28,000 units per 14 mL
    • 2,400 mg / 30,000 units per 15 mL
    • 3,520 mg / 44,000 units per 22 mL
• Preparation instructions³:
  • Administer undiluted.
  • Administer immediately after preparation when possible since it has no antimicrobial preservative.
  • Remove vial(s) from refrigeration and equilibrate to room temperature (15–30°C / 59–86°F) for at least 15 minutes.
  • Do not warm by any other method.
  • Do not shake.
  • Visually inspect for particulate matter and discoloration; do not use if discolored, cloudy, or contains foreign particles.
  • Withdraw required volume using a transfer needle into syringe(s)
  • Maximum 15 mL per syringe >15 mL must be divided into two syringes and administered at separate injection sites.
  • Compatible materials: stainless steel injection needles, polypropylene and polycarbonate syringes, polyethylene/polyurethane/PVC subcutaneous infusion sets
  • Use 21G to 23G needle or infusion set for administration.
  • Use 0.9% Sodium Chloride Injection to flush infusion set if needed.
  • Dose volume reference:

• Storage requirements³:
  • Unopened vials: Store refrigerated at 2–8°C (36–46°F), keep in the original carton to protect from light, do not freeze, and do not shake.
  • Prepared syringes: may be stored refrigerated at 2–8°C (36–46°F) for up to 24 hours, then at room temperature (15–30°C/59–86°F) for up to 24 hours, but must be discarded if stored beyond 24 hours in either condition, and should be allowed to reach room temperature before administration.
• Dosing³
  • The recommended dosage of amivantamab and hyaluronidase is weight-based and varies by treatment regimen:

• • Missed dose guidance
    • Weeks 1–4: Administer within 24 hours if missed.
    • Week 5 onward: Administer within 7 days if missed.
    • If not administered per guidance, skip missed dose and resume at next scheduled time.
  • The IV formulation has different dosing than the SC formulation.
• Administration³
  • Subcutaneous amivantamab (Rybrevant Faspro) must be administered only by a healthcare professional in the abdomen over approximately 5 minutes per injection, avoiding IV use and verifying correct formulation prior to administration.
  • Injections should not be given into tattoos, scars, or areas that are red, bruised, tender, or otherwise compromised, the periumbilical area should be avoided.
  • Multiple injections should be given in separate abdominal quadrants with site rotation at subsequent doses.
  • If pain occurs the rate may be paused or slowed or a second site used
  • Any unused portion is discarded as it is a single-dose vial.
• Premedication to reduce administration-related reactions (ARRs)^3,17
  • Oral dexamethasone 8 mg twice daily starting 2 days prior to first dose (Day -2 and Day -1), and one dose on Day 1¹⁷
  • IV dexamethasone 20 mg 45–60 minutes prior to first injection
  • Diphenhydramine 25–50 mg (oral or IV) 30–60 minutes prior
  • Acetaminophen 650–1,000 mg (oral or IV) 30–60 minutes prior
  • For subsequent doses: diphenhydramine and acetaminophen required; corticosteroids optional unless prior ARR occurred.
• The subcutaneous formulation reduces ARRs compared to IV (13% vs. 66%) and administration time (≤5 minutes vs. up to 5 hours)⁸.
• There are no renal or hepatic dose adjustments specified in the prescribing information.
• There are no clinically significant drug-drug interactions and drug-food interactions³.
• Prophylactic Medications
  • VTE prophylaxis (for combination with Lazertinib)
    • Prophylactic anticoagulation is recommended for the first 4 months of treatment.
    • VTE occurred in 37–40% of patients receiving amivantamab + lazertinib vs. 9–11% with osimertinib; 62% of events occurred in the first 4 months^5,8
    • Vitamin K antagonists are not recommended; DOACs or LMWH are preferred³
    • If VTE does not develop during the first 4 months, consider discontinuation at provider discretion³
    • Mandatory prophylaxis reduced VTE incidence from 18% to 7% in PALOMA-2³
  • Dermatologic Prophylaxis (COCOON regimen)¹⁴
    • Oral doxycycline or minocycline 100 mg twice daily (Weeks 1–12)
    • Clindamycin 1% lotion applied to scalp daily (Weeks 13–52)
    • Chlorhexidine 4% applied to fingernails and toenails daily.
    • Ceramide-based non-comedogenic moisturizer applied to body and face at least daily.
    • The COCOON regimen reduced grade ≥2 dermatologic adverse events from 75% to 42% (OR 0.24; p<0.0001)
• Adverse events
  • Most common adverse reactions (≥20%):
    • EGFR-related: Rash (54–64%), paronychia (56–69%), dermatitis acneiform (29–30%), stomatitis (25–30%), pruritus (24–25%), dry skin (16–17%)
    • MET-related: Hypoalbuminemia (41–51%), peripheral edema (30–38%)
    • General: Infusion/administration-related reactions (13% SC vs. 63–66% IV), constipation (29–40%), nausea (21–36%), fatigue (15–18%)
    • Thromboembolic: VTE (37–40% with lazertinib combination), pulmonary embolism (17–19%), deep vein thrombosis (16%)
  • Most Common grade ≥3 adverse events
    • Rash (11–17%), paronychia (7–12%), pulmonary embolism (8–9%), neutropenia (33% with chemotherapy), hypoalbuminemia (5–6%), infusion-related reactions (5–6%)
• Management
  • Prophylactic management (COCOON regimen¹⁴)
    • The COCOON regimen may be used prophylactically in patients initiating amivantamab‑containing therapy to reduce the incidence and severity of EGFR‑related dermatologic toxicities.
    • In patients who did not receive prophylaxis and subsequently develop dermatologic adverse events, management should follow standard reactive dermatologic treatment guidelines; while individual components of the COCOON regimen may be used, the full COCOON protocol has only been validated in the prophylactic setting.
  • Stepwise management algorithm for dermatologic toxicities¹⁸
    • Acneiform Eruption
      • Grade 1: Continue amivantamab; topical corticosteroids (medium potency) + oral tetracycline (doxycycline/minocycline 100 mg BID)
      • Grade 2: Continue amivantamab; escalate to high-potency topical corticosteroids; continue oral tetracycline; reassess in 2 weeks. If there is no improvement, consider dose reduction.
      • Grade 3: Withhold amivantamab; add oral corticosteroids (e.g., prednisone); dermatology referral; resume at reduced dose upon recovery to ≤ grade 2.
    • Erosive Pustular dermatosis (EPD)-like scalp reactions
      • Mild: Topical corticosteroids (high potency) + topical antibiotics (clindamycin/fusidic acid)
      • Moderate–severe: Add oral tetracycline; consider short course of oral corticosteroids; dermatology referral.
      • Refractory/necrotic lesions: Topical β-blocker wet wrap therapy
    • Paronychia
      • Grade 1: Antiseptic soaks, proper nail care, topical corticosteroids
      • Grade 2: Add topical antibiotics (mupirocin or gentamicin); consider topical β-blockers for pyogenic granuloma-like lesions.
      • Grade 3: Withhold amivantamab; consider silver nitrate cauterization or surgical intervention for granulation tissue; resume at reduced dose upon recovery.
    • Anogenital ulcerations and mucositis: Pragmatic severity-based grading with individualized supportive care, topical corticosteroids, and pain management; treatment modification for severe case
  • Topical Beta-blockers¹⁹
    • Topical timolol (0.5%) or betaxolol (0.25%) ophthalmic solution applied via wet wrap therapy (gauze soaked in ~5 mL, applied 10–15 min daily, covered with semi-occlusive dressing) has shown efficacy for:
      • Amivantamab-induced scalp and facial necrosis: Complete resolution within 35–50 days in case reports, allowing continuation of full-dose cancer therapy without interruption.
      • EGFR inhibitor-induced paronychia/pyogenic granuloma-like lesions: A meta-analysis of 6 studies (96 patients) showed a pooled overall response rate of 94% and complete response rate of 34% within 1 month, with no adverse events reported.
    • Betaxolol 0.25% has been reported to achieve a 97.1% resolution rate for EGFR inhibitor-induced paronychia with notable pain reduction within 1 week.
    • Maintenance therapy is important, as recurrence has been observed upon discontinuation.

• Pertinent counseling points
  • COCOON protocol¹⁴
    • Apply ceramide-based, non-comedogenic moisturizer to face and body at least once daily, start before treatment begins.
    • Wash hands and feet daily with chlorhexidine 4% to prevent nail infections.
    • Apply clindamycin 1% lotion to scalp daily (starting Week 13) to prevent scalp eruptions.
    • Take oral doxycycline or minocycline 100 mg twice daily for the first 12 weeks as prescribed.
    • Use sunscreen (SPF 30+) and avoid excessive sun exposure.
  • Self-care tips¹⁵
    • Use gentle, fragrance-free cleansers and lukewarm water.
    • Avoid hot showers/baths which can worsen dry skin.
    • Wear loose-fitting, soft clothing to minimize skin irritation.
    • Wear cotton-lined gloves for wet work and household chores.
    • Keep nails trimmed short and straight; avoid cutting cuticles.
    • Wear comfortable, well-fitting shoes to reduce nail trauma.
  • Swelling and fluid retention¹³
    • Elevate legs when sitting or lying down.
    • Reduce dietary sodium intake.
    • Wear compression stockings if recommended.
    • Monitor for sudden weight gain (>2–3 lbs. in a day or 5 lbs. in a week)
    • Report significant swelling, shortness of breath, or abdominal distension promptly.
  • Blood clot prevention³
    • Take blood thinner medication exactly as prescribed for the first 4 months.
    • Do not stop anticoagulation without consulting the healthcare team.
    • Report any signs of bleeding (unusual bruising, blood in urine/stool, prolonged bleeding)
    • Warning signs of blood clots — seek immediate medical attention:
      • Sudden shortness of breath or chest pain (pulmonary embolism)
      • Leg pain, swelling, warmth, or redness (deep vein thrombosis)
      • Sudden severe headache, vision changes, or confusion
  • Premedication compliance³
    • Take oral dexamethasone 8 mg twice daily for 2 days before the first injection as prescribed.
  • Symptoms to report during/after injections³
    • Flushing, itching, or hives
    • Difficulty breathing or throat tightness.
    • Fever, chills, or rigors
    • Dizziness or lightheadedness
  • Breathing problems (ILD/Pneumonitis) - rare but serious, report immediately if¹⁶:
    • New or worsening shortness of breath
    • Persistent dry cough
    • Chest pain with breathing
    • Low-grade fever with respiratory symptoms
• Patient Assistance Program
  • Janssen Care Path provides support for patients receiving amivantamab.

Clinical Pearls

• Next‑generation sequencing (NGS)is preferred over polymerase chain reaction (PCR) for exon 20 insertions. Targeted PCR-based approaches under-detect EGFR exon 20 insertion events, and NGS-based strategies are preferred⁶
• Emerging predictive biomarker: MET immunohistochemistry (IHC)
  • In the post-Osimertinib setting, MET overexpression by IHC (3+ staining on ≥25% of tumor cells) may predict response to amivantamab + Lazertinib. In the CHRYSALIS-2 study, MET+ patients had an ORR of 61% vs. 12% for MET patients, with median PFS not reached vs. 4.1 months.²⁰
• Early dose modifications of Amivantamab do not compromise efficacy.
  • Exploratory analyses from the MARIPOSA study demonstrated that early dose interruptions of Amivantamab per protocol guidance did not adversely impact the efficacy of Amivantamab + Lazertinib in the first line setting for EGFR-mutant advanced NSCLC.²¹
• Amivantamab AE profile compared with other EGFR TKIs:
  • All small-molecule EGFR TKIs share class-effect toxicities of rash and diarrhea, but the severity varies by generation:
    • First-generation TKIs (erlotinib, gefitinib) cause rash in ~62% and diarrhea in ~42-44%. They are more hepatotoxic (elevated transaminases ~62% with gefitinib), while newer-generation TKIs have significantly lower hepatotoxicity²²
    • Second-generation TKIs (afatinib, dacomitinib) have the highest rates of diarrhea (~87-92%) and rash (~69-85%)^22,23
    • Third-generation osimertinib has the mildest skin/GI profile (rash ~58%, diarrhea ~58%) but carries a higher risk for cardiotoxicity (QTc prolongation, heart failure) and thrombocytopenia⁹
  • Amivantamab + lazertinib introduces a distinct toxicity profile beyond these small-molecule TKI class effects:
    • In the MARIPOSA trial, grade ≥3 AEs were higher than osimertinib (75–80% vs. 43–52%), driven by EGFR-mediated effects (paronychia 69% vs. 30%, rash 64% vs. 32%), MET-mediated effects unique to amivantamab (hypoalbuminemia 51% vs. 7%, peripheral edema 38% vs. 7%), infusion-related reactions (63–65% with IV formulation; reduced to ~16% with SC), and venous thromboembolism (37–40% vs. 9–11%), toxicities not seen with any small-molecule EGFR TKI. Notably, diarrhea was less common with amivantamab-lazertinib than Osimertinib (32% vs 47%), likely reflecting the lower dose of Lazertinib used in the combination and the distinct mechanism of amivantamab compared to small molecule EGFR TKIs^5,16. 
  • Most amivantamab-specific AEs occur within the first 4 months: IRRs predominantly occur on the first day of treatment, 62% of VTE events occur within the first 4 months, and most cutaneous AEs develop over the initial weeks to 4 months and decrease over time^5,16,17