RYBREVANT®
(amivantamab-vmjw)
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RYBREVANT® (amivantamab-vmjw)
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Use of RYBREVANT in Metastatic NSCLC With MET Mutations or Amplifications
Last Updated: 06/24/2025
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
- CHRYSALIS (NCT02609776) is an ongoing phase 1, open-label, multicenter, dose- escalation and dose-expansion study evaluating the safety, efficacy, and pharmacokinetics of RYBREVANT as monotherapy and in combination with other therapies in adult patients with advanced NSCLC harboring EGFR or MET mutations who had disease progression during or after previous standard of care (SOC) treatment.2
, 3 - Krebs et al (2025)4
reported the final efficacy and safety results for patients with advanced NSCLC harboring MET Exon 14 skipping mutations (METex14) who received treatment with RYBREVANT monotherapy at the recommended phase 2 dose (RP2D) in the CHRYSALIS study (n=97). - At a median follow-up of 12.1 months, objective response rate (ORR) was 32% (95% confidence interval [CI], 23-42) among all patients, 50% (95% CI, 25-75) in treatment naïve patients, 46% (95% CI, 28-66) in patients without prior MET therapies, and 19% (95% CI, 9-32) in patients with prior MET therapies. Clinical benefit rate (CBR) was 69% (95% CI, 59-78) among all patients, 88% (95% CI, 62-98) in treatment-naïve patients, 64% (95% CI, 44-81) in patients without prior MET therapies, and 66% (95% CI, 52-79) in patients with prior MET therapies. For responders, median duration of response (DoR) was 11.2 months (95% CI, 5.3–19.0). Overall, median progressionfree survival (PFS) and median overall survival (OS) was 5.3 months (95% CI, 4.3-7.0) and 15.8 months (95% CI, 14.6-not estimable), respectively.
- No new safety signals were observed. The safety profile for the METex14 cohort was consistent with prior reports.
- Haura et al (2019)5
reported preliminary data from the CHRYSALIS study from a cohort of patients (n=142) with advanced NSCLC who had been treated with RYBREVANT monotherapy. - Among 131 (92%) patients with primary EGFR mutations, 10 (8%) patients had secondary cMET amplification (≥6 copies). A best response of partial response (PR) was observed in 32 of 108 (30%) patients with diverse EGFR mutations; 9 of these patients had concurrent cMET amplification.
- Overall, the safety profile in the analyzed patient population was deemed manageable and consistent with EGFR inhibition.
- Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 49 (35%) patients.
- Treatment-related grade ≥3 adverse events (AEs) were reported in 12 (9%) patients.
- AEs leading to treatment discontinuation and dose reduction occurred in 8% (4% treatment related) and 4% of patients, respectively.
clinical data
CHRYSALIS Study
Krebs et al (2025)4 reported the final efficacy and safety results for patients with METex14 NSCLC who received the RP2D of RYBREVANT in the METex14 dose-expansion cohort (n=97).
Study Design/Methods
- Phase 1, ongoing, dose-escalation, and dose-expansion study4
- In the dose-expansion phase, patients received RYBREVANT 1050 mg (<80 kg) and 1400 mg (≥80 kg) intravenously once weekly (QW) for the first 4 weeks (Cycle 1) and every other week (Q2W) thereafter.
- To mitigate infusion-related reactions (IRRs), the initial dose was split over 2 days, and prophylactic premedications were given.
- Key eligibility criteria for METex14 cohort4: metastatic/unresectable NSCLC; measurable disease; progressed after or declined SOC; primary METex14 mutation by next-generation sequencing (NGS) of tumor or circulating tumor deoxyribonucleic acid (ctDNA)
- Primary endpoints4: ORR, DoR, and CBR
- Secondary endpoints4: PFS and OS
Results
Patient Characteristics
- At a median follow-up of 12.1 months (clinical cutoff: January 31, 2024), a total of 97 patients were enrolled in the METex14 cohort; of whom, 53 had received prior MET therapies.4
- Patient characteristics are included in Table: Demographics and Baseline Disease Characteristics.
| Characteristic | Treatment-naïve (n=16) | Previously Treated | Total (N=97) | |
|---|---|---|---|---|
| No Prior MET Therapiesa | Prior MET Therapiesa (n=53) | |||
| Median age, years (range) | 70 (57-86) | 69 (49-83) | 71 (43-88) | 70 (43-88) |
| Sex, n (%) | ||||
| Male | 8 (50) | 13 (46) | 24 (45) | 45 (46) |
| Female | 8 (50) | 15 (54) | 29 (55) | 52 (54) |
| Race, n (%) | ||||
| Asian | 10 (63) | 16 (57) | 21 (40) | 47 (48) |
| White | 6 (38) | 9 (32) | 23 (43) | 38 (39) |
| Black | 0 | 0 | 2 (4) | 2 (2) |
| Not reported | 0 | 3 (11) | 7 (13) | 10 (10) |
| History of brain metastases, n (%) | 1 (6) | 4 (14) | 9 (17) | 14 (14) |
| ECOG PS, n (%) | ||||
| 0 | 7 (44) | 4 (14) | 8 (15) | 19 (20) |
| 1 | 9 (56) | 23 (82) | 45 (85) | 77 (79) |
| 2 | 0 | 1 (4) | 0 | 1 (1) |
| Smoking history, n (%) | ||||
| Nonsmoker | 6 (38) | 14 (50) | 27 (51) | 47 (48) |
| Smoker | 10 (63) | 14 (50) | 26 (49) | 50 (52) |
| Median number of prior lines of therapy (range) | 0 | 1 (1-4) | 3 (1-10) | 2 (0-10) |
| Median time from metastatic disease diagnosis to first dose, months (range) | 1.8 (0.8-15.5)b | 13.5 (1.4-40.3) | 21.9 (5.7-106.1) | 15.3 (0.8-106.1) |
| Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; MET, mesenchymalepithelial transition. aPrior MET therapies include capmatinib, tepotinib, and investigational drugs. bn=14. Note: Percentages may not sum to 100% due to rounding. | ||||
Efficacy
- Among the 31 evaluable patients, median time to response was 1.5 months (range, 1.2-9.9) and median duration of exposure was 10.2 months (range, 1.9-31.4) (Table: Key Efficacy Endpoints).4
- Overall, 61% (19/31) of responders had a response duration of ≥6 months.
- Durable responses at ≥12, ≥18, and ≥24 months were observed in 11, 7, and 3 patients, respectively.
- Overall, 61% (19/31) of responders had a response duration of ≥6 months.
| Endpoint | Treatment-naïve (n=16) | Previously Treated | Total (N=97) | |
|---|---|---|---|---|
| No Prior MET Therapiesa (n=28) | Prior MET Therapiesa (n=53) | |||
| ORR, % (95% CI) | 50 (25-75) | 46 (28-66) | 19 (9-32) | 32 (23-42) |
| CBR, % (95% CI) | 88 (62-98) | 64 (44-81) | 66 (52-79) | 69 (59-78) |
| DoR, median (95% CI), months | 3.2 (2.8-19.0) | 12.5 (5.3-NE) | 12.3 (2.8-NE) | 11.2 (5.3-19.0) |
| ≥6 months, n (%)b | 2 (25) | 10 (77) | 7 (70) | 19 (61) |
| PFS, median (95% CI), months | 5.0 (4.2-20.6) | 6.9 (2.8-13.9) | 5.3 (4.0-7.2) | 5.3 (4.3-7.0) |
| At 12 months, % (95% CI) | 26 (7-51) | 36 (18-55) | 26 (15-39) | 29 (20-39) |
| OS, median (95% CI), months | 15.6 (8.9-NE) | 18.6 (10.0-NE) | 15.8 (13.9-NE) | 15.8 (14.6-NE) |
| At 12 months, % (95% CI) | 56 (30-76) | 66 (43-82) | 73 (58-83) | 68 (57-77) |
| Abbreviations: CBR, clinical benefit rate; CI, confidence interval; DoR, duration of response; MET, mesenchymal-epidermal transition; NE, not evaluable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. aPrior MET therapies include capmatinib, tepotinib, and investigational drugs. bAmong responders (treatment naïve: n=8; no prior MET therapies: n=13; prior MET therapies: n=10; total: N=31). | ||||
Safety
- Patients received a median of 6 cycles of treatment (range, 1-36) for a median of 4.6 months (range 0.03-33.2).4
- No new safety signals were observed. The safety profile for the METex14 cohort was consistent with prior reports (Tables: Safety Summary and Summary of AEs).4
- Grade ≥3 and serious treatment-related AEs were reported in 21 (22%) and 8 (8%) patients, respectively.4
| TEAEs, n (%) | METex14 Cohort (N=97) |
|---|---|
| Any event | 97 (100) |
| Grade ≥3 event | 47 (48) |
| Any serious event | 34 (35) |
| Any event resulting in deatha | 3 (3) |
| Any treatment-related event leading to: | |
| Interruptions | 27 (28) |
| Reductions | 11 (11) |
| Discontinuations | 9 (9) |
| Abbreviations: METex14, mesenchymal-epithelial transition Exon 14 skipping mutations; TEAE, treatment-emergent adverse event. aGrade 5 events leading to death included staphylococcal bacteremia, asthenia, and decreasedperformance status. None of these events were related to the study treatment. | |
| TEAEs | METex14 Subset (N=97) | |
|---|---|---|
| All Grades | Grade ≥3 | |
| Most Common (≥20%) by Preferred Term, n (%) | ||
| Associated with EGFR inhibition | ||
| Paronychia | 48 (49) | 0 |
| Dermatitis acneiform | 40 (41) | 1 (1) |
| Rash | 37 (38) | 1 (1) |
| Stomatitis | 27 (28) | 0 |
| Pruritus | 20 (21) | 0 |
| Associated with MET inhibition | ||
| Peripheral edema | 39 (40) | 4 (4) |
| Hypoalbuminemia | 38 (39) | 2 (2) |
| Other | ||
| Infusion-related reaction | 70 (72) | 4 (4) |
| Fatigue | 29 (30) | 2 (2) |
| Dyspnea | 24 (25) | 5 (5) |
| Hypokalemia | 23 (24) | 3 (3) |
| Nausea | 22 (23) | 0 |
| Decreased appetite | 21 (22) | 0 |
| Aspartate aminotransferase increased | 21 (22) | 1 (1) |
| Alanine aminotransferase increased | 20 (21) | 2 (2) |
| TEAEs of Special Interest by Grouped Term, n (%) | ||
| Rasha | 77 (79) | 3 (3) |
| VTEb | 8 (8) | 2 (2) |
| ILDc | 5 (5) | 1 (1) |
| Abbreviations: AE, adverse event; EGFR, epidermal growth factor receptor; ILD, interstitial lung disease; MET, mesenchymal-epithelial transition; METex14, MET Exon 14 skipping mutations; TEAE, treatment-emergent adverse event; VTE, venous thromboembolism. aGrouping includes the following related preferred terms: dermatitis acneiform, rash, folliculitis, rash maculopapular, skin exfoliation, rash pustular, skin lesion, dermatitis, aseptic pustule, dermatitis exfoliative generalized, dermatitis infected, dermatosis, erythema, external ear inflammation, rash erythematous, and rash pruritic. bGrouping includes the following related preferred terms: pulmonary embolism, deep vein thrombosis, and embolism; anticoagulant use for either VTE prophylaxis (1/97 [1.0%]) or medical history of VTE (0/97) was infrequent. cGrouping includes the following related preferred terms: ILD and pneumonitis; most common AE associated with discontinuation (n=4). | ||
Haura et al (2019)5 reported preliminary data from a cohort of patients (n=142) with advanced NSCLC in the CHRYSALIS study who had been treated with RYBREVANT monotherapy.
- Among 131 (92%) patients with primary EGFR mutations, 10 (8%) patients had secondary cMET amplification (≥6 copies), defined per central NGS or local fluorescence in situ hybridization findings of tumor biopsy samples.5
- A best response of PR was observed in 32 of 108 (30%) patients with diverse EGFR mutations; 9 of these patients had concurrent cMET amplification.5
- RYBREVANT activity was observed in 58 patients with post third-generation tyrosine kinase inhibitor (TKI) disease.5
- Overall, 16 of 58 (28%) patients had a best response of PR (8 confirmed):
- Eight patients with C797S
- Three patients with cMET amplification (≥6 copies)
- Five patients without identified EGFR- or cMET-based resistance
- Overall, 16 of 58 (28%) patients had a best response of PR (8 confirmed):
- The safety profile in the analyzed patient population was deemed manageable and consistent with EGFR inhibition.5
- Grade ≥3 TEAEs were reported in 49 (35%) patients.
- Treatment-related grade ≥3 AEs were reported in 12 (9%) patients.
- AEs leading to treatment discontinuation and dose reduction occurred in 8% (4% treatment related) and 4% of patients, respectively.
- The most frequently observed TEAEs (≥20%) were IRRs (62%), rash (56%), paronychia (26%), and constipation (22%).
- IRRs were primarily limited to the first infusion (Cycle 1 Day 1).
- No specific details on safety outcomes in patients with cMET amplifications were reported.
Literature Search
A literature search of MEDLINE®
References
| 1 | Moores SL, Chiu ML, Bushey BS, et al. A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors. Cancer Res. 2016;76(13):3942-3953. |
| 2 | |
| 3 | |
| 4 | |
| 5 |
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