Use of RYBREVANT in Combination with Radiation

SUMMARY

• RYBREVANT (amivantamab-vmjw) is a low fucose, fully human immunoglobulin G1 (IgG1)-based bispecific antibody with immune cell-directing activity that targets epidermal growth factor receptor (EGFR) mutations and mesenchymal-epithelial transition (MET) mutations and amplifications in non-small cell lung cancer (NSCLC).¹
• No prospective, randomized trials evaluating the use of RYBREVANT with radiation in metastatic NSCLC were identified in the published literature.
• A retrospective real-world study assessed the safety and efficacy of RYBREVANT with concurrent radiation therapy in patients with advanced EGFR- or MET-altered NSCLC. A total of 21 irradiations were delivered concurrently with RYBREVANT in these patients (N=14).²
  • Primary endpoints were acute (≤90 days after the first radiation therapy treatment) and late (>90 days) radiation therapy-related adverse events (AEs), graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Secondary endpoints were best clinical response, best radiological response, local (irradiated-lesion) control (LC), progression-free survival (PFS), overall survival (OS), time to treatment discontinuation (TTD), and time to new systemic treatment (TTNT).  
  • After a median observation duration of 8 months (interquartile range [IQR],
    4-9.1), 13 grade 1 acute AEs were reported in 8 patients and 6 grade 2 acute AEs in 3 patients. No radiation therapy-related grade ≥3 acute AEs were observed, and no radiation-related skin toxicity was documented within the irradiated fields.
    • All grade 2 acute AEs occurred in patients receiving stereotactic or hypofractionated radiation therapy for oligoprogressive disease, except for 1 patient with rapidly progressive systemic disease who developed grade 2 nausea and fatigue 9 days after palliative radiation therapy to the left pleura (20 Gray [Gy] in 5 fractions).
  • Three grade 1 late AEs (pneumonitis, diarrhea and lung fibrosis) occurred in 3 patients treated for oligoprogressive disease. No radiation therapy-related grade ≥2 late AEs were observed.
  • The most frequent AEs were acute fatigue (24%), nausea (14%), and lymphopenia (14%).
  • The median follow-up duration for oncologic outcomes was 9.5 months
    (IQR, 4.9-44.8). At data cut-off, 8 of 14 patients were alive, including 4 of 5 treated for oligoprogressive disease.
  • Median OS following radiation therapy was not reached. The estimated 6- and 12-month OS rates were 77% (95% confidence interval [CI], 43-92%) and 50% (95% CI, 15-78%), respectively.
  • Among the 11 patients who continued RYBREVANT following radiation therapy, the estimated median PFS, TTD, and TTNT were 4.5 months (95% CI, 3.4-5.7), 4.8 months (95% CI, 3.6-6) and 5.5 months (95% CI, 1.5-9.5), respectively.
  • Radiation therapy was delivered for oligoprogressive disease in 6 (29%) cases and for palliation in 15 (71%) cases.
    • Among 6 lesions treated for oligoprogression in 5 patients, best radiologic responses included 2 complete responses (CRs), 3 partial responses (PRs), and 1 stable disease (SD). At data cut-off, LC was maintained in 4 (80%) patients, while distant control was maintained in 1 patient.
    • At data cut-off, 2 of 5 patients treated for oligoprogressive disease remained on RYBREVANT, while 2 discontinued treatment due to distant disease progression and 1 due to RYBREVANT-related scalp dermatitis.
    • The only local failure occurred 3.7 years after radiation therapy in a patient treated with 20 Gy in 5 fractions for a left adrenal gland metastasis and was successfully salvaged with stereotactic reirradiation (28 Gy in 4 fractions).
    • Best clinical response was assessed for 15 palliative irradiations delivered to 9 patients, resulting in 5 CRs (all painful bone lesions), 8 PRs (6 painful bone lesions and 2 motor deficits from brain metastases), 1 SD (painful bone reirradiation), and 1 progressive disease (PD; pleuritic pain).
• A real-world study retrospectively evaluated the use of RYBREVANT with or without osimertinib and with or without concurrent radiation therapy in patients with EGFR-mutated NSCLC (N=61).³
  • Of the 61 patients identified in the GEMINI database who received RYBREVANT, 37 (58.7%) received concomitant osimertinib and 25 (39.1%) received concomitant radiation.
  • Among 54 evaluable patients, 23 (43.6%) patients had a clinical response, 9 (16.7%) were clinically stable, and 22 (40.7%) had clinical progression. The overall disease control rate was 59.3%. Efficacy results were not separately reported for patients who received concurrent radiation therapy.
  • Among the 25 patients who received concurrent radiation therapy and were evaluated for safety, the following results were observed:
    • Grade 1 or 2 AEs included infusion reactions (n=12; 48%), rash (n=5; 20%), paronychia (n=5; 20%), fatigue (n=7; 28%), edema (n=4; 17.4%), scalp rash (n=2; 8%), mucositis (n=2; 8%), and nausea (n=4; 10%).⁴
    • Grade ≥3 AEs were reported in 12 (48%) patients, including infusion reactions (n=3; 12%), rash (n=5; 20%), pneumonitis (n=2; 8%), thrombocytopenia (n=1; 4%), and transaminitis (n=1; 4%).⁴
    • No neurological toxicities were noted when RYBREVANT was administered with concomitant intracranial radiation. No additional toxicities were noted during radiation to extracranial sites.³ 
• A singlecenter retrospective case series evaluated the use of RYBREVANT with intracranial or extracranial radiation therapy in patients with EGFRmutated NSCLC (N=17).⁵ 
  • Radiation was administered concurrently (n=6), prior to (n=6), or after RYBREVANT (n=5). The most common site of radiation while on RYBREVANT was the brain (n=9; 53%) followed by bone (n=6; 35%), along with other extracranial sites including lung (n=1) and lymph nodes (n=1).
  • Median duration of RYBREVANT treatment and median follow‑up were both 9 months (range, 1-21). Median survival from the start of RYBREVANT was 10 months (95% confidence interval, 7.6-12.6).
  • Disease progression occurred intracranially in 5 (29%) patients and extracranially in 10 (59%) patients. Median time to intracranial and extracranial progression was 7.1 months (range, 3-33) and 7.6 months (range, 1-24), respectively.
  • Grade 3 drug‑related pneumonitis was reported in 3 patients (2 with prior systemic therapy; none with prior thoracic radiation). No additional grade ≥3 toxicities were reported, including intracranial radiation necrosis.
• A case of a 57-year-old woman with metastatic lung adenocarcinoma harboring EGFR Exon 20 insertion mutations was reported. After first-line treatment with afatinib and second-line treatment with RYBREVANT 1050 mg intravenous every 2 weeks with dose reduction to 700 mg every 2 weeks for grade 3 paronychia, she received a total of 55 Gy hypofractionated chest radiotherapy for a right parahilar lesion and continued RYBREVANT. She further received 19 Gy single-dose radiosurgery for a brain lesion. There was no toxicity, and she continued RYBREVANT beyond the progressive disease.⁶

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 01 September 2026.