What Is Amivantamab (Rybrevant)? FDA Approval, Authorization in Turkey, and Reimbursement
| Active ingredient | Amivantamab-vmjw (intravenous) · Amivantamab and hyaluronidase-lpuj (subcutaneous) |
| Brand name | Rybrevant (intravenous) · Rybrevant Faspro (subcutaneous) |
| Class | EGFR–MET bispecific monoclonal antibody (low-fucose IgG1) |
| Category | Targeted agent (immune-engaging antibody) |
| Route of administration | Intravenous (IV) or subcutaneous (SC) — the subcutaneous form is approved for all indications |
| Dosing frequency | Varies by regimen; the subcutaneous form also has an approved monthly dosing option |
| Approved cancer type | EGFR-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) |
| FDA approved | Yes — four separate indications (two first-line and two second-line) |
| Drugs frequently used with it | Lazertinib (Lazcluze) · carboplatin + pemetrexed |
| Manufacturer | Janssen Biotech / Johnson & Johnson |
| Turkish Ministry of Health authorization | NONE |
| SGK reimbursement | NONE |
| Access in Turkey | Only through off-label approval + import from abroad (paid by the patient) |
| Half-life | Approximately 11 days |
Amivantamab represents a series of firsts in lung cancer treatment. Until now, almost all treatments for EGFR-mutated non-small cell lung cancer have been oral small-molecule tyrosine kinase inhibitors. Amivantamab is an antibody —and it binds not to a single target, but to two targets at once .
This monograph examines how the drug works, its approved indications, what clinical data show—particularly the MARIPOSA results, which first demonstrated an overall survival advantage and the atypical EGFR mutation data presented at ASCO 2026 —and access to treatment in Turkey in detail.
EGFR (epidermal growth factor receptor) and MET are separate receptors on the cell surface that signal cells to multiply. In EGFR-mutated lung cancers, EGFR remains constantly active; when treatment blocks this pathway, the tumor often develops resistance by activating the MET pathway.
Amivantamab is a bispecific antibody: one arm binds EGFR and the other binds MET. It therefore blocks the main pathway while also preemptively blocking the most common escape route. This dual approach underlies both the drug's therapeutic effect and its resistance-delaying effect.
- Bispecific binding: The low-fucose IgG1 antibody targets tumor cells with high levels of both EGFR and MET receptors ; this density is not found in normal tissues.
- Broad coverage: It inhibits activating and resistant EGFR mutations, MET mutations, and MET gene copy-number increases (amplification). It is the first molecule to show activity in EGFR exon 20 insertion mutations .
- Blocking signaling: Signals involved in cell proliferation, growth, invasion/metastasis, and blood vessel formation are suppressed; resistance to cell destruction decreases.
- Receptor reduction: Receptors bound to the antibody are internalized and broken down, permanently reducing the number remaining on the cell surface.
- Engineered Fc region: The antibody's tail is designed to bind more strongly to activating receptors on immune cells.
- Immune-mediated effects: Antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and trogocytosis (ADCT) may be triggered. In these processes, monocytes and macrophages play a particularly important role.
| Date | Approval | Supporting study |
|---|---|---|
| 21 May 2021 | EGFR exon 20 insertion -mutated NSCLC after platinum-based chemotherapy. The first approved treatment for this mutation. | CHRYSALIS (accelerated approval) |
| 1 March 2024 | NSCLC with EGFR exon 20 insertion mutations; first-line treatment with carboplatin and pemetrexed. On the same day, the 2021 accelerated approval was converted to full approval. | PAPILLON |
| 20 August 2024 | Classical EGFR mutations (exon 19 deletion / exon 21 L858R) first-line treatment, with lazertinib. | MARIPOSA |
| 19 September 2024 | NSCLC progressing after osimertinib with classical EGFR mutations; combined with chemotherapy. | MARIPOSA-2 |
| 17 December 2025 | Subcutaneous formulation (Rybrevant Faspro) —can be used for all approved indications of the intravenous form. | PALOMA-3 |
| 17 February 2026 | For the subcutaneous form, a monthly dosing option was approved. | PALOMA program |
The ultimate measure of targeted treatment is not tumor shrinkage or delayed progression, but length of life. The maturing MARIPOSA results are decisive in this respect.
In the first-line setting, amivantamab + lazertinib was compared with osimertinib , the standard at that time (1,074 patients). After approximately 37.8 months of follow-up, the combination provided a statistically significant overall survival advantage : HR 0.75 (95% CI 0.61–0.92; p=0.0048). In the combination arm, median overall survival had not yet been reached (95% CI 42.9 months–not reached); in the osimertinib arm, it was 36.7 months (95% CI 33.4–41.0). Median survival in the combination arm is expected to exceed four years .
| Study | Patient group | Comparison | Main result |
|---|---|---|---|
| MARIPOSA phase 3 · n=1,074 |
Classical EGFR mutation (exon 19 del / L858R), first-line treatment | Amivantamab + lazertinib vs osimertinib | Overall survival superiority: HR 0.75 (p=0.0048). Significant progression-free survival superiority as well. EGFR- and MET-driven resistance development was significantly reduced. |
| MARIPOSA-2 phase 3 · n=657 |
Classical EGFR mutation progressing after osimertinib | Amivantamab + chemotherapy vs chemotherapy | Median progression-free survival 6.3 months vs 4.2 months (HR 0.48; 95% CI 0.36–0.64; p<0.0001). Significantly higher response rate. Benefit regardless of the mechanism of osimertinib resistance (ASCO 2025). |
| PAPILLON phase 3 · n=308 |
EGFR exon 20 insertion mutation, first-line treatment | Amivantamab + carboplatin/pemetrexed vs chemotherapy | Superiority to chemotherapy demonstrated; the basis for first-line approval in this indication. |
| PALOMA-3 phase 3 · n=418 |
EGFR-mutated NSCLC progressing after osimertinib and platinum | Subcutaneous vs intravenous amivantamab (both with lazertinib) | Co-primary pharmacokinetic endpoints met— equivalent exposure. Response duration, progression-free survival, and overall survival were longer in the subcutaneous arm: survival at month 12 was 65% vs 51% (HR 0.62; 95% CI 0.42–0.92; p=0.02). |
| CHRYSALIS phase 1/1b |
EGFR exon 20 insertion mutation, after platinum | Single-arm | Basis for the initial accelerated approval in 2021. |
The vast majority of EGFR mutations fall into two groups: exon 19 deletion and exon 21 L858R —known as 'classical' mutations, for which most existing treatments were developed.
However, some patients have mutations such as G719X, L861Q, S768I , known as atypical (rare) mutations. This group has long represented an unmet need : responses to existing EGFR-targeted treatments are less consistent and long-term outcomes are poorer.
Longer follow-up results were presented from cohort C of CHRYSALIS-2. The group included 49 previously untreated patients with atypical EGFR mutations (excluding exon 20 insertions and mutations occurring alongside classical mutations). First-line amivantamab + lazertinib:
- Median overall survival: 41.0 months (95% CI 27.7–not reached); median follow-up: 31.3 months.
- At year 3, 55% of patients were alive; at year 4, 46% were alive.
- At data cutoff, 20% of patients (10/49) remained on first-line treatment —with treatment durations ranging from 2.5 to 4.4 years. Seven patients had received amivantamab for more than three years of treatment.
- Previously reported efficacy data: objective response rate 57%, median response duration 20.7 months.
- No new safety signal was detected with longer follow-up.
- Do not directly compare 41.0 months with 19.4 months. For afatinib, an approved treatment for atypical EGFR mutations, the literature reports median overall survival of approximately 19.4 months . The difference looks striking—but this is a cross-trial (historical) comparison. Patient groups, time periods, and subsequent treatments differ. There has been no randomized comparison.
- The sample is small (n=49), and the study is single-arm. These data from a phase 1/1b design are hypothesis-generating; there is not yet an approval for this indication.
Nevertheless, a meaningful observation: In a group that has long had limited options, following nearly a quarter of patients on the same treatment for more than four years is clinically noteworthy.
Absent from the previous version of this monograph, this may be the most important development for the patient experience .
- Administration time fell from hours to minutes. Intravenous administration required prolonged infusions, particularly during the initial cycles.
- Administration-related reactions decreased markedly. These were the most frequent and troublesome problem with the intravenous form.
- The need for intravenous access was eliminated —a major advantage for patients with difficult venous access.
- Efficacy was maintained: Co-primary pharmacokinetic endpoints were met; drug exposure was equivalent to the intravenous form.
- And an unexpected finding: In PALOMA-3, response duration, progression-free survival, and overall survival in the subcutaneous arm were longer . This finding was exploratory and was not the study's primary objective—but it is noteworthy.
- A monthly dosing option has also been approved since February 2026 , offering a dosing frequency unmatched among EGFR-targeted therapies.
Reported mechanisms include increased expression of Shc1 and Gab1 proteins, increased activation and expression of Src-family kinases, and activation of alternative intracellular signaling pathways such as PI3K/Akt and MAPK . In other words, the tumor seeks escape by directly activating pathways downstream of the two blocked receptors.
MARIPOSA resistance analysis showed that patients receiving first-line amivantamab + lazertinib developed significantly fewer acquired EGFR- and MET-driven resistance alterations than those receiving osimertinib —without an increase in other known resistance pathways. This finding supports the biological explanation for the drug's overall survival advantage.
- Skin: Acne-like rash, dry skin, itching. This is the most common group of problems.
- Administration-related reactions: Fever, chills, hives, flushing, headache. These occur particularly with the first administration and are more common with the intravenous form.
- Lungs: Increasing cough, shortness of breath, lung infiltrates. Serious effects: interstitial lung disease (ILD) and pneumonia.
- Eyes: Keratitis, dry eyes, conjunctival redness, blurred vision, uveitis.
- Digestive system: Usually mild nausea/vomiting and diarrhea.
- General: Fatigue and loss of appetite.
- Nails: Paronychia (inflammation around the nail).
- Vascular blockage (thromboembolism): Particular care is needed when combined with lazertinib—see below.
- Administration reactions: Close monitoring is required. If a reaction develops, the administration rate is reduced or treatment is permanently stopped according to severity. Premedication with an antihistamine, an antipyretic, and a corticosteroid may prevent or reduce reactions.
- Lung monitoring: In patients with new or worsening respiratory symptoms, treatment should be interrupted; if treatment-related pneumonia or interstitial lung disease is confirmed, it is permanently discontinued.
- Risk of vascular blockage: Studies of the amivantamab and lazertinib combination have recommended preventive blood-thinning treatment during the first months of therapy . This is a known, manageable risk of the combination; decisions also take the patient's bleeding risk into account.
- Sun protection: Patients should avoid sun exposure during treatment and for 2 months after completion , using broad-spectrum sunscreen and protective clothing.
- Managing skin rash: Topical corticosteroids and topical and/or oral antibiotics may be considered. Rash is usually manageable and should not be a reason to discontinue treatment.
- Eye symptoms: Patients should be monitored for new eye symptoms and, when needed, promptly referred to an ophthalmologist.
- Pregnancy and breastfeeding: There is a risk of embryo-fetal toxicity. Women of reproductive potential should use effective contraception during treatment and for 3 months after the last dose . Use during breastfeeding should be avoided.
- Drug interactions: No formally identified drug interaction has been reported to date.
Route: Intravenous or subcutaneous. Dosing is weight-based (with two dose levels according to body weight). For intravenous treatment, the first administration is split over two days ; treatment is initially weekly and then continues at less frequent intervals. A monthly dosing option is also available for the subcutaneous form. Dosing and scheduling decisions belong solely to the treating oncology team; this monograph does not provide dosage information.
Distribution: Distribution within the body has not been described in detail.
Metabolism and half-life: Metabolism has not been characterized in detail. The half-life is approximately 11 days.
Authorization: Rybrevant, containing amivantamab, and its subcutaneous form, Rybrevant Faspro, are not authorized by the Turkish Ministry of Health.
Reimbursement: Not covered by SGK reimbursement.
Consequently: The drug is not marketed in Turkey. When needed, it must be obtained from abroad and paid for by the patient.
- Applying for off-label approval. The patient's treating medical oncologist applies to the Turkish Ministry of Health for approval of off-label drug use. The application documents the diagnosis, stage, molecular test results, and previous treatments.
- Prescription after approval. Once approval is granted, the physician issues a prescription.
- Import through the Turkish Pharmacists' Association (TEB). The drug is imported from abroad through TEB. The cost is paid by the patient.
- Alternative route: a court order. In some cases, after off-label approval, a court order can also enable the drug to be imported through TEB.
This process is subject to regulations and may change over time. For current procedures, consult the treating center's international patient office or medication procurement unit.
Who Is This Drug For? Only for patients with a confirmed EGFR mutation and advanced non-small cell lung cancer. The drug has no role if no mutation is detected, so molecular testing is essential.
What Can You Expect? Compared with standard treatment, first-line use with lazertinib has demonstrated longer survival . However, the combination also has a higher side-effect burden —particularly skin rash, nail problems, and administration reactions.
What Should You Watch For? New or worsening shortness of breath, cough, or fever : do not wait for your next appointment—notify your oncology team immediately. These may indicate a lung side effect, and early intervention is important. In addition, leg swelling/pain or sudden shortness of breath may indicate a blood clot. Eye symptoms should be reported immediately if they occur. And do not neglect sun protection .
How Can It Be Obtained in Turkey? Because it is not authorized in Turkey, access is possible only if your doctor obtains off-label approval and the drug is imported from abroad; the patient bears the cost. The person who can initiate this process is your treating medical oncologist —strictly avoid attempts to obtain it online.
For many years, treatment of EGFR-mutated NSCLC was based on single-target, oral tyrosine kinase inhibitors . Amivantamab breaks this framework: it is an antibody, binds two targets at once , and engages the immune system. Its activity in EGFR exon 20 insertion mutations as the first molecule and its overall survival superiority to osimertinib in MARIPOSA have reopened the first-line treatment debate.
MARIPOSA (n=1,074): amivantamab + lazertinib was superior to osimertinib in overall survival—HR 0.75 (95% CI 0.61–0.92; p=0.0048); median survival was not reached in the combination arm, versus 36.7 months in the osimertinib arm. Resistance analysis showed significantly fewer EGFR- and MET-driven alterations. MARIPOSA-2 (n=657): PFS after osimertinib was 6.3 vs 4.2 months (HR 0.48; p<0.0001), with benefit regardless of resistance mechanism. PALOMA-3 (n=418): subcutaneous treatment provided exposure equivalent to intravenous treatment; administration fell to minutes and reactions decreased. ASCO 2026 · CHRYSALIS-2 (n=49): median overall survival with first-line treatment for atypical EGFR mutations was 41.0 months; 46% were alive at year 4; no new safety signal.
In MARIPOSA, superiority is real but comes at a cost: the combination carries a higher side-effect burden than osimertinib alone (rash, nail problems, administration reactions, and thromboembolic risk), and preventive anticoagulation in the first months becomes a consideration. The ASCO 2026 atypical EGFR data come from a single-arm cohort, n=49 , with a phase 1/1b design; the comparison with afatinib is historical, not randomized. The survival difference in PALOMA-3 is an exploratory finding; the study's primary aim was pharmacokinetic equivalence. The most decisive limitation is specific to Turkey: the drug is neither authorized nor reimbursed there.
In advanced NSCLC, comprehensive molecular testing is essential —exon 20 insertions and atypical mutations may be missed by narrow panels. Choosing between first-line amivantamab + lazertinib and osimertinib depends on balancing survival benefit against side-effect burden and practical administration considerations ; this balance may differ in frail patients. The subcutaneous formulation has substantially improved this balance , and monthly administration offers an important convenience during long-term treatment. In Turkey, decisions are often determined by accessibility before efficacy.
For atypical EGFR mutations, will randomized confirmation become available, and will approval follow for this indication? Is the survival difference with the subcutaneous form real or due to chance? After amivantamab, what should be the next treatment in the event of resistance ? Who benefits from combination therapy versus a single agent first line— can a predictive biomarker be identified? How do the treatments compare in patients with brain metastases? And the most practical question for Turkey: when will authorization and reimbursement move forward?
- This document contains no dosage information and recommends no treatment regimen.
- The drug is neither authorized nor reimbursed in Turkey; FDA approval does not mean access.
- MARIPOSA's survival advantage must be weighed alongside the greater side-effect burden.
- The ASCO 2026 atypical EGFR data are from a small, single-arm study; there is no approval for this indication.
- The comparison with afatinib is historical —not randomized.
- This applies only to patients with confirmed EGFR mutations.
- The decision to use treatment belongs solely to the medical oncologist who knows the patient.
- Yang JC-H, Lu S, Hayashi H, et al; MARIPOSA Investigators. Overall survival with amivantamab–lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. 2025;393(17):1681–1693. doi:10.1056/NEJMoa2503001
- Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77–90.
- Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated non-small cell lung cancer: primary results from the phase III PALOMA-3 study. J Clin Oncol. 2024;42(30):3593–3605.
- Updated CHRYSALIS-2 cohort C analysis—first-line amivantamab + lazertinib in NSCLC with atypical EGFR mutations. ASCO 2026 Annual Meeting, June 2026.
- Mechanisms of acquired resistance to first-line amivantamab plus lazertinib vs osimertinib: updated analysis from MARIPOSA. IASLC 2025 World Conference on Lung Cancer · J Thorac Oncol. 2025.
- FDA approval announcements (21 May 2021 · 1 March 2024 · 20 August 2024 · 19 September 2024) and manufacturer approval announcements (17 December 2025—subcutaneous formulation; 17 February 2026—monthly dosing).
- NCCN Clinical Practice Guidelines in Oncology — Non-Small Cell Lung Cancer, 2026 edition.
- Chu E, DeVita VT Jr. Physicians' Cancer Chemotherapy Drug Manual. Jones & Bartlett Learning. (Mechanism, pharmacology, and side-effect profile.)
- Related reading (drozdogan.com): FDA approval of the lazertinib and amivantamab combination · Amivantamab + chemotherapy for exon 20 insertion mutations · Second-line amivantamab + chemotherapy · Advances in EGFR-positive lung cancer · First-line approval of osimertinib · Osimertinib + chemotherapy · Oral options for exon 20 mutations.
Editor's note: This monograph is for general information only; it does not constitute medical advice, diagnosis, or a treatment recommendation, nor does it promote any product. All reported data have been verified against primary sources and presented without direct quotation. This document deliberately contains no information on drug doses, dosing schedules, or dose adjustments; this information is solely the responsibility of the treating physician. Amivantamab is not authorized by the Turkish Ministry of Health and is not covered by SGK reimbursement; FDA approval does not mean that a drug is authorized, accessible, or reimbursed in Turkey. Import procedures are governed by regulations and may change over time. The overall survival advantage demonstrated in MARIPOSA must be considered alongside the combination's higher side-effect burden compared with single-agent treatment; treatment selection depends not only on efficacy data but also on the patient's general condition, comorbidities, and preferences. The atypical EGFR mutation data presented at ASCO 2026 come from a single-arm phase 1/1b cohort (n=49); there is no approved use for this indication, and the comparison with afatinib is a cross-trial (historical) comparison, not a randomized one. The survival difference reported in the subcutaneous arm of PALOMA-3 is an exploratory finding; the study's primary endpoint was pharmacokinetic equivalence. This drug is relevant only to patients with confirmed EGFR mutations . Do not stop or change any medication without consulting your physician; contact only your treating medical oncologist about obtaining the drug. Consult the doctor who knows you for every decision concerning your health.
Sources
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