RYBREVANT®
(amivantamab-vmjw)
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RYBREVANT® (amivantamab-vmjw)
Medical Information
Use of RYBREVANT in Combination With Capmatinib
Last Updated: 08/28/2024
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
- METalmark (NCT05488314) is an ongoing, phase 1 (combination dose selection) and phase 2 (dose expansion), global, open-label study evaluating the safety and efficacy of RYBREVANT plus capmatinib in patients with unresectable metastatic NSCLC. The primary endpoints are safety and dose-limiting toxicities (DLTs) in phase 1 and objective response rate (ORR) in phase 2.2
, 3 - The recommended phase 2 combination dose (RP2CD) for RYBREVANT plus capmatinib, along with preliminary safety, efficacy, and pharmacokinetics (PK) results in patients with advanced NSCLC receiving combination therapy at 2 dose levels (DLs; DL 0, n=10; DL +1, n=8) are reported.3
- The RP2CD identified was the DL +1 combination: RYBREVANT 1050 mg intravenous (IV; 1400 mg if body weight ≥80 kg) plus capmatinib 400 mg orally twice daily (PO BID). No DLTs were reported at this DL.
- The most common treatment-emergent adverse events (TEAEs) were associated with EGFR and MET inhibition and were primarily grade 1-2 in severity (Table: Summary of TEAEs).
- No treatment-related adverse events (TRAEs) led to treatment discontinuation.
- ORR was 20% in patients at DL 0 and 13% in patients at DL +1.
- The recommended phase 2 combination dose (RP2CD) for RYBREVANT plus capmatinib, along with preliminary safety, efficacy, and pharmacokinetics (PK) results in patients with advanced NSCLC receiving combination therapy at 2 dose levels (DLs; DL 0, n=10; DL +1, n=8) are reported.3
clinical Study
Study Design/Methods2,3
- Ongoing phase 1/2, global, open-label study designed to assess the safety and efficacy of RYBREVANT plus capmatinib in patients with unresectable metastatic NSCLC.
- For phase 1 combination dose selection, DLs 0 and +1 were assessed to identify the RP2CD.
- For phase 2 dose expansion, the efficacy of RYBREVANT plus capmatinib at the RP2CD (determined in phase 1) will be evaluated.
- The study design is shown in Figure: METalmark Study Design.
METalmark (ClinicalTrials.gov Identifier: NCT05488314); data cutoff: November 8, 2023.
Abbreviations: 1L, first line; 2L+, second line and beyond (no >3 lines of prior systemic anticancer therapy); ALK, anaplastic lymphoma kinase; BID, twice daily; DCR, disease control rate; DL, dose level; DLT, dose-limiting toxicity; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HRQoL, health-related quality of life; IV, intravenous; MET, mesenchymal-epithelial transition; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PO, orally; QW, once a week; Q2W, every 2 weeks; RP2CD, recommended phase 2 combination dose; SET, safety evaluation team; SOC, standard of care; TTST, time to subsequent therapy.
a
b
c
d
Spira et al (2024)3 reported the RP2CD for RYBREVANT plus capmatinib along with preliminary safety, efficacy, and PK results in patients with advanced NSCLC from the combination dose selection phase (phase 1) of the METalmark study.
Results3
Patient Characteristics
- At the data cutoff of November 8, 2023, with a median follow-up of 3.3 months, 18 patients received RYBREVANT plus capmatinib at DL 0 (n=10) and DL +1 (n=8).
- The patient demographics and baseline characteristics are included in Table: Demographics and Baseline Disease Characteristics.
| Characteristic | DL 0 (n=10) | DL +1 (n=8) |
|---|---|---|
| Median age, years (range) | 62 (36-68) | 59 (48-65) |
| Female, n (%) | 8 (80) | 5 (63) |
| Body weight <80 kg, n (%) | 10 (100) | 6 (75) |
| Race, n (%) | ||
| Asian | 7 (70) | 4 (50) |
| White | 2 (20) | 4 (50) |
| Not reported | 1 (10) | 0 |
| ECOG PS, n (%) | ||
| 0 | 2 (20) | 1 (13) |
| 1 | 8 (80) | 7 (88) |
| Median no. of prior systemic therapies (range) | 3 (1-5) | 3 (1-5) |
| Baseline brain metastases, n (%) | 4 (40) | 4 (50) |
| Mutation type, na | ||
| EGFR Ex19del | 4 | 2 |
| EGFR Exon 21 L858R | 2 | 4 |
| MET Exon 14 | 2 | 2 |
| MET amp | 1 | 2 |
| EGFR Ex20ins | 1 | 0 |
| KRAS G12Vb | 1 | 0 |
| Abbreviations: amp, amplification; DL, dose level; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Ex19del, Exon 19 deletion; Ex20ins, Exon 20 insertion; KRAS, Kirsten rat sarcoma viral gene homolog; MET, mesenchymal-epithelial transition. aThe number of patients tested for each individual mutation at baseline varied based on the availability of appropriate samples; patients could have had >1 mutation type. bKRAS mutations were detected by central laboratory testing. | ||
Primary Endpoints: Safety and DLTs
Safety
- The most common TEAEs were associated with EGFR and MET inhibition and were primarily grade 1-2 in severity (Table: Summary of TEAEs).
| TEAEs by Preferred Term, n (%) | DL 0 (n=10) | DL +1 (n=8) | ||
|---|---|---|---|---|
| All Grades | Grade ≥3 | All Grades | Grade ≥3 | |
| EGFR inhibition associated (≥20%) | ||||
| Paronychia | 4 (40) | 0 | 3 (38) | 0 |
| Rasha | 4 (40) | 0 | 4 (50) | 0 |
| Stomatitis | 2 (20) | 0 | 0 | 0 |
| Pruritus | 2 (20) | 0 | 0 | 0 |
| MET inhibition associated (≥20%) | ||||
| Hypoalbuminemia | 5 (50) | 2 (20) | 4 (50) | 0 |
| Generalized edema | 2 (20) | 1 (10) | 0 | 0 |
| Peripheral edema | 2 (20) | 0 | 3 (38) | 0 |
| Other (≥30%) | ||||
| Nausea | 5 (50) | 1 (10) | 3 (38) | 0 |
| IRR | 5 (50) | 0 | 3 (38) | 0 |
| Fatigue | 4 (40) | 0 | 2 (25) | 0 |
| Anemia | 4 (40) | 2 (20) | 1 (13) | 1 (13) |
| Vomiting | 4 (40) | 0 | 1 (13) | 0 |
| Decreased appetite | 4 (40) | 0 | 0 | 0 |
| Constipation | 3 (30) | 0 | 1 (13) | 0 |
| Abbreviations: DL, dose level; EGFR, epidermal growth factor receptor; IRR, infusion-related reaction; MET, mesenchymal-epithelial transition; TEAE, treatment-emergent adverse event. aPreferred term: In total, 6 (60%) and 6 (75%) patients at DLs 0 and +1, respectively, reported grouped term rash (including acne, dermatitis, dermatitis acneiform, erythema, folliculitis, rash, and rash maculopapular), with none being grade ≥3 in severity. | ||||
- The incidence rates of TRAEs are included in Table: Summary of TRAEs.
- None of the patients reported pneumonitis or interstitial lung disease.
- Of the 8 treatment discontinuations, 6 were due to progressive disease and none due to TRAEs.
- One death unrelated to treatment was reported among patients at DL +1.
| TRAEs | DL 0 (n=10) | DL +1 (n=8) |
|---|---|---|
| 4 (40) | 0 | |
| Serious AEs, n | 2 | 0 |
| Abbreviations: AE, adverse event; DL, dose level; TRAE, treatment-related adverse event. | ||
DLTs
- Of the 9 evaluable patients at DL 0, 1 experienced DLT (grade 3 nausea; Table: DLTs).
- No DLTs were reported in any of the 8 evaluable patients at DL +1.
- The DL +1 combination was selected as the RP2CD.
| DL | Patients (n) |
|---|---|
| DL 0 | 10 |
| Before nausea/vomiting recommendations adopted | 5 |
| Evaluable patientsa | 4 |
| DLT | 1c |
| After nausea/vomiting recommendations adopted | 5 |
| Evaluable patientsa | 5 |
| DLT | 0 |
| DL +1b | 8 |
| Evaluable patientsa | 8 |
| DLT | 0 |
| Abbreviations: AE, adverse event; DL, dose level; DLT, dose-limiting toxicity. aThese patients had follow-up for ≥28 days. In cycle 1, patients received either ≥75% of the planned doses of both RYBREVANT plus capmatinib or <75% of the planned doses due to toxicity (dose reduction, dose interruption, dose delay, or treatment discontinuation due to an AE in cycle 1). bDose escalation after the prespecified criteria were met. cGrade 3 nausea. | |
Other Endpoints
Efficacy
- The ORR and disease control rate in patients at DLs 0 and +1 are included in Table: Efficacy Outcomes.
- Antitumor activity was observed in patients with MET Exon 14-mutated NSCLC (n=2), MET-amplified NSCLC (n=1), and EGFR-mutated NSCLC post-osimertinib (n=3).
| DL 0 (n=10) | DL +1 (n=8) | |
|---|---|---|
| Median follow-up, months | 5.6 | 2.8 |
| Median treatment duration, months | 4.4 | 2.2 |
| ORR,a % | 20 | 13 |
| DCR,b % | 70 | 50 |
| Abbreviations: CR, complete response; DCR, disease control rate; DL, dose level; ORR, objective response rate; PR, partial response; SD, stable disease. aIncluding confirmed and unconfirmed CR and PR. bDefined as achieving confirmed or unconfirmed CR, PR, or SD duration of ≥6 weeks during the study. | ||
PK
- Preliminary PK data suggest similar exposure for amivantamab vs historical amivantamab monotherapy data from the CHRYSALIS study.
Literature Search
A literature search of MEDLINE®
05 June 2024.
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 |