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(amivantamab-vmjw)

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RYBREVANT® (amivantamab-vmjw)

Medical Information

Use of RYBREVANT in Head & Neck Cancer - OrigAMI-4 Study

Last Updated: 11/25/2025

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
  • Amivantamab for subcutaneous (SC) administration is a coformulation of amivantamab with recombinant human hyaluronidase PH20 (rHuPH20).2
  • OrigAMI-4 (NCT06385080) is an ongoing, phase 1b/2, nonrandomized, open-label, multiarm, multicenter study evaluating the efficacy and safety of amivantamab SC as monotherapy and in combination with pembrolizumab, paclitaxel, or pembrolizumab plus carboplatin in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), who had disease progression on/after prior checkpoint inhibitor and platinum-based chemotherapy (cohorts 1, 3, and 4) or were treatment-naïve (cohorts 2 and 5). Enrollment is planned for approximately 247 patients.3-5
    • The investigator-assessed confirmed objective response rate (ORR) was 45% (95% confidence interval [CI], 29-62), and median progression-free survival (PFS) was 6.8 months (95% CI, 4.2-9) in the amivantamab SC monotherapy cohort 1 (n=38), as included in Table: Antitumor Activity in the Amivantamab SC Monotherapy Cohort 1.3 The ORR was 64% (95% CI, 31-89), and median PFS was not estimable (NE) in the amivantamab SC plus paclitaxel combination cohort 3a (n=11), as included in Table: Antitumor Activity in the Amivantamab SC plus Paclitaxel Combination Cohort 3a.5
    • The recommended phase 2 combination dose (RP2CD) identified in the amivantamab SC plus paclitaxel combination cohort 3a was the initial dose level (DL0) combination: amivantamab SC 2400 mg (3360 mg if body weight ≥80 kg) weekly on cycle (C)1 day (D)8 and C1D15 (initial C1D1 dose: 1600 mg or 2240 mg if body weight ≥80 kg), and every 3 weeks (Q3W) on C2D1 and thereafter, plus paclitaxel IV 175 mg/m2 Q3W.5
      • Dose-limiting toxicities (DLTs) were reported in 1 of 7 evaluable patients (grade 3 mucositis and fatigue, both resolved).
    • The safety profile in cohort 1 (n=86) was consistent with previous reports of amivantamab SC monotherapy, as included in Table: Safety Summary in Cohort 1.3
      • Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 47% of patients.
      • The most common TEAEs were hypoalbuminemia (31%), fatigue (31%), and stomatitis (23%) and were mostly grade 1-2 in severity.
      • The rate of administration-related reactions (ARRs) was 7% (n=6).
      • Treatment-related adverse events (TRAEs) leading to discontinuation (paronychia [n=1] and elevated alkaline phosphatase [n=1]) were reported in 2% of patients.
    • The safety profile in cohort 3a (n=11) was consistent with those of amivantamab SC and paclitaxel, as included in Table: Safety Profile for the Amivantamab SC plus Paclitaxel Combination Cohort 3a.5
      • The most common TEAEs were dermatitis acneiform, paronychia, stomatitis, and fatigue (45% each) and were mostly grade 1-2 in severity.
      • No ARRs related to amivantamab SC were reported.
    • Mean predose amivantamab SC serum concentrations observed were consistent between the amivantamab SC plus paclitaxel combination and amivantamab SC monotherapy cohorts.5

ongoing clinical study

OrigAMI-4 Study

Study Design/Methods

  • Ongoing, phase 1b/2, nonrandomized, open-label, multiarm, multicenter study designed to assess the efficacy and safety of amivantamab SC as monotherapy and in combination with pembrolizumab, paclitaxel, or pembrolizumab plus carboplatin in patients with R/M HNSCC.3-5
  • The study includes cohorts of patients who had disease progression on/after prior checkpoint inhibitor (programmed cell death protein 1 [PD-1]/programmed cell death-ligand 1 [PD-L1] inhibitor) and platinum-based chemotherapy (cohorts 1, 3, and 4) or were treatment-naïve (cohorts 2 and 5).3,5
  • Prophylactic management of dermatologic adverse events (AEs) was optional and left to the discretion of the treating investigator.3 
  • The study design is shown in Figure: OrigAMI-4 Study Design.

OrigAMI-4 Study Design3-5

OrigAMI-4 (ClinicalTrials.gov Identifier: NCT06385080).
Abbreviations: AUC, area under the concentration-time curve; BW, body weight; C, cycle; CBR, clinical benefit rate; D, day; DL0, initial dose level; DLT, dose-limiting toxicity; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus; ILD, interstitial lung disease; ISH, in-situ hybridization; IV, intravenous; ORR, objective response rate; OS, overall survival; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; PFS, progression-free survival; PK, pharmacokinetics; QW, weekly; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; R/M, recurrent/metastatic; RP2D, recommended phase 2 dose; SC, subcutaneous; SET, study evaluation team.
aDefined as having ≥1 nontarget lesion per RECIST version 1.1.
bExcept alopecia, postradiation skin changes (any grade), grade ≤2 peripheral neuropathy, and grade ≤2 hypothyroidism stable on replacement therapy.
c1600 mg (2240 mg if BW ≥80 kg) on C1D1, then 2400 mg (3360 mg if BW ≥80 kg) QW on C1D8 and C1D15, and Q3W on C2D1 and thereafter.
dOn D1 of each 21-day cycle.
eThe RP2CD of amivantamab SC will be determined with SET.
fConfirmed by SET in cohort 3A.
gOn D1 of C1-C6.
hThe maximum required washout is 28 days.

Results: Amivantamab SC Monotherapy Cohort (Cohort 1)

  • Results are reported as of the data cutoff date of July 01, 2025.3
Patient Characteristics
  • Cohort 1 included 86 human papillomavirus (HPV)-unrelated patients with R/M HNSCC in the safety population who had received ≥1 prior line of therapy and were treated with ≥1 dose of amivantamab SC monotherapy, with a median follow-up of 3.5 months (range, 0-13.4).3
  • Patient characteristics are included in Table: Patient Characteristics in the Amivantamab SC Monotherapy Cohort 1.

Patient Characteristics in the Amivantamab SC Monotherapy Cohort 13
Characteristic
Cohort 1
Efficacy Population (n=38)a
Safety Population (n=86)
Median age, years (range)
67 (30-79)
63.5 (30-81)
   <65 years, n (%)
16 (42)
46 (53)
   ≥65 to <75 years, n (%)
16 (42)
30 (35)
   ≥75 years, n (%)
6 (16)
10 (12)
Sex, n (%)
   Male
27 (71)
65 (76)
   Female
11 (29)
21 (24)
Race, n (%)
   Asian
17 (45)
39 (45)
   White
19 (50)
37 (43)
   Black or African American
0
1 (1)
   Not reported/unknown
2 (5)
9 (10)
Region, n (%)
   Eastern Asia
15 (39)
36 (42)
   North America
14 (37)
27 (31)
   Europe
7 (18)
21 (24)
   Southeastern Asia
2 (5)
2 (2)
Median body weight, kg (range)
63 (43-96)
61 (40-96)
   <80 kg, n (%)
35 (92)
78 (91)
   ≥80 kg, n (%)
3 (8)
8 (9)
ECOG PS, n (%)
   0
14 (37)
28 (33)
   1
24 (63)
58 (67)
Median time from initial head and neck diagnosis to first dose, months (range)
27 (4-270)
22 (3-270)
Median time from metastatic disease diagnosis to first dose, months (range)
12 (1-42)
10 (0-43)
Primary tumor location, n (%)
   Hypopharynx
4 (11)
13 (15)
   Larynx
10 (26)
21 (24)
   Oropharynxb
4 (11)
10 (12)
   Oral cavity
20 (53)
42 (49)
Stage at screening, n (%)
   III
2 (5)
2 (2)
   IVA
9 (24)
18 (21)
   IVB
4 (11)
12 (14)
   IVC
23 (61)
54 (63)
Site of recurrence/metastasis,c n (%)
   Bone
7 (21)
14 (17)
   Head and neck
16 (47)
51 (62)
   Liver
0
5 (6)
   Local lymph node
11 (32)
33 (40)
   Distant lymph node
9 (26)
20 (24)
   Lung
21 (62)
45 (55)
   Skin
1 (3)
1 (1)
   Other
7 (21)
17 (21)
≥1 prior therapy,c n (%)
   Prior systemic therapyd
38 (100)
86 (100)
   Prior radiotherapy
35 (92)
76 (88)
   Prior related surgery
33 (87)
71 (83)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed cell death-ligand 1; R/M, recurrent/metastatic; SC, subcutaneous.
an=34 for time since metastatic disease diagnosis to first dose and site of R/M.
ᵇAll patients with oropharynx cancer (n=10; 100%) had confirmed p16-negative status.
ᶜPatients could be counted in >1 category.
dPrior systemic therapy included anti-PD-L1 checkpoint inhibitor and platinum-based chemotherapy; 39 (45%) patients had received prior taxane-based chemotherapy for R/M disease.
Note: Total may not sum to 100% due to rounding.
Efficacy
  • Efficacy outcomes for amivantamab SC monotherapy in cohort 1 are included in Table: Antitumor Activity in the Amivantamab SC Monotherapy Cohort 1.
  • As of the data cutoff, 38 of 86 enrolled patients had ≥2 disease assessments (or discontinued before for any reason) and were included in the efficacy analysis.3
    • The first disease assessment was conducted 6 weeks after the first dose, then every 6 weeks (±1 week) for the first year and every 9 weeks (±1 week) thereafter.
    • The remaining 48 patients continued to receive treatment, as they had either not had their first disease assessment or had insufficient follow-up to reach their second disease assessment.
    • Treatment was discontinued due to progressive disease (n=23; 27%), AEs (n=9; 10%), and patients refusing further treatment (n=1; 1%).
  • Among the efficacy population3:
    • In the R/M setting, 17 patients received 1 prior line of therapy and 19 received 2 prior lines.
    • Majority of patients (23 of 38; 61%) received prior immunotherapy with platinum-based chemotherapy (18 of 23 also received taxane or fluorouracil); 8 of 38 (21%) patients received prior immunotherapy with nonplatinum-based chemotherapy, and 7 of 38 (18%) patients received immunotherapy as monotherapy either before or after platinum-based chemotherapy.
    • Site of recurrence data were available for 34 patients: locoregional only disease (n=5; 15%), distant only disease (n=10; 29%), and both (n=19; 56%).
  • As of the data cutoff, 16 of 38 (42%) efficacy-evaluable patients and 11 of 17 (65%) confirmed responders remained on amivantamab SC monotherapy.3

Antitumor Activity in the Amivantamab SC Monotherapy Cohort 13
Efficacy Outcome
Cohort 1
Efficacy Population (n=38)
Median follow-up, months (range)
8.3 (1.1a-13.4)
Investigator-assessed response
  Confirmed ORR,b % (95% CI)
45 (29-62)
   Best response, n (%)
      CR
1 (3)
      PR
16 (42)
      SD
17 (45)
      PD
2 (5)
      Not evaluable
2 (5)
   Median time to first response, weeks (range)
6.4 (5.7-18.3)
   Confirmed CBR,c % (95% CI)
76 (60-89)
      Median DOR,d months (95% CI)
7.2 (5.3-NE)
         DOR ≥6 months,d n (%)
8 (47)
Median PFS, months (95% CI)
6.8 (4.2-9)
Median OS, months
NR
Abbreviations: CI, confidence interval; CBR, clinical benefit rate; CR, complete response; DOR, duration of response; NE, not estimable; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SC, subcutaneous; SD, stable disease.
aThe lower value in the range was from a censored observation.
bORR was defined as the percentage of patients achieving confirmed CR or PR.
cCBR was defined as the percentage of patients achieving confirmed CR, PR, or durable SD (≥11 weeks) at the second assessment.
dDOR was defined as the time from confirmed CR or PR until the date of progression or death and was measured among the 17 confirmed responders.
  • Tumor shrinkage of target lesions was observed in 31 of 38 (82%) patients.3
  • A 48-year-old female patient diagnosed with oral cavity cancer and metastases in the lung, who was previously treated with surgery, cisplatin/radiation, and nivolumab, exhibited a 65% tumor reduction on computed tomography (CT) scan after 6 weeks of amivantamab SC monotherapy.6 
Safety
  • The safety profile in cohort 1 was consistent with previous reports of amivantamab SC monotherapy (Table: Safety Summary in Cohort 1).3
  • The safety population (n=86) included patients who received ≥1 dose of amivantamab SC monotherapy.3
  • Median treatment duration was 2.7 months (range, 0-11.3).3

Safety Summary in Cohort 13
TEAE, n (%)
Cohort 1
Safety Population (n=86)
Any TEAE (≥1 event)
79 (92)
   Grade 1-2 TEAE
39 (45)
   Grade ≥3 TEAE
40 (47)
   Serious TEAE
29 (34)
Any TEAE leading to:
   Dose interruption
37 (43)
   Dose reduction
15 (17)
   Treatment discontinuation
6 (7)
Abbreviation: TEAE, treatment-emergent adverse event.

Summary of TEAEs in Cohort 13
TEAEs (≥10%) by Preferred Term, n (%)
Cohort 1
Safety Population (n=86)
All Grades
Grade ≥3
Associated with EGFR inhibition
   Stomatitis
20 (23)
1 (1)
   Dermatitis acneiforma
17 (20)
6 (7)
   Rasha
16 (19)
2 (2)
   Paronychia
15 (17)
1 (1)
   Diarrhea
13 (15)
0
   Pruritus
11 (13)
2 (2)
Associated with MET inhibition
   Hypoalbuminemia
27 (31)
2 (2)
   Peripheral edema
12 (14)
1 (1)
Other
   Fatigue
27 (31)
4 (5)
   Anemia
15 (17)
5 (6)
   Hypocalcemia
13 (15)
0
   ALT increased
11 (13)
3 (3)
   Nausea
11 (13)
0
   Weight decreased
11 (13)
1 (1)
   Decreased appetite
10 (12)
0
   Dyspnea
10 (12)
2 (2)
   AST increased
9 (10)
2 (2)
   Lymphopenia
9 (10)
4 (5)
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; EGFR, epidermal growth factor receptor; MET, mesenchymal-epithelial transition; SC, subcutaneous; TEAE, treatment-emergent adverse event.
aDermatitis acneiform and rash are subcategories of the grouped rash term, which occurred in 41 (48%) patients. The subcategories of dermatitis acneiform and rash are not mutually exclusive, and patients could have >1 type of rash.
  • ARRs occurred in 6 (7%) patients, all were grade 1-2 (grade 1, n=4; 5%; grade 2, n=2; 2%); no grade ≥3 events were reported.3
  • TRAEs leading to discontinuation (paronychia [n=1] and elevated alkaline phosphatase [n=1]) were reported in 2% of patients.3
  • TEAEs leading to amivantamab SC discontinuation unrelated to study treatment included pneumonia aspiration and myocardial ischemia (n=1), pneumonia aspiration (n=1), cerebrovascular accident (n=1), sudden death (n=1), and cardiac arrest and postprocedural hemorrhage (n=1).3

Results: Amivantamab SC plus Paclitaxel Combination Cohort (Cohort 3a)

  • Results are reported as of the data cutoff date of August 6, 2025.5
Patient Characteristics

Patient Characteristics in the Amivantamab SC plus Paclitaxel Combination Cohort 3a5
Characteristic
Cohort 3a (n=11)a
Median age, years (range)
58 (39-69)
Sex, n (%)
   Male
9 (82)
   Female
2 (18)
Race, n (%)
   Asian
7 (64)
   White
3 (27)
   Unknown
1 (9)
Primary tumor location, n (%)
   Hypopharynx
1 (9)
   Larynx
1 (9)
   Oral cavity
8 (73)
   Oropharynx
1 (9)
Abbreviation: SC, subcutaneous.
DLTs
  • DL0 was identified as the RP2CD.5
  • Of the 7 DLT-evaluable patients, 1 experienced DLTs (grade 3 mucositis and fatigue, both resolved).5
Safety

Safety Profile for the Amivantamab SC plus Paclitaxel Combination Cohort 3a5
TEAEs (≥20%) by Preferred Term, n (%)
Cohort 3a (n=11)
All Grades
Grade ≥3
Associated with EGFR inhibition
   Dermatitis acneiform
5 (45)
1 (9)
   Paronychia
5 (45)
0
   Stomatitis
5 (45)
2 (18)
   Rash
4 (36)
0
   Diarrhea
3 (27)
1 (9)
Associated with MET inhibition
   Hypoalbuminemia
3 (27)
0
Other
   Fatigue
5 (45)
1 (9)
   Hypophosphatemia
4 (36)
0
   Neutropenia
3 (27)
 2 (18)
   Pneumonia
3 (27)
2 (18)
   Leukopenia
3 (27)
1 (9)
   Myalgia
3 (27)
1 (9)
   ALT increased
3 (27)
0
   Anemia
3 (27)
0
   Back pain
3 (27)
0
   Constipation
3 (27)
0
   Hypokalemia
3 (27)
0
   Nausea
3 (27)
0
   Pyrexia
3 (27)
0
Abbreviations: ALT, alanine aminotransferase; EGFR, epidermal growth factor receptor; MET, mesenchymal-epithelial transition; SC, subcutaneous; TEAE, treatment-emergent adverse event.
Efficacy

Antitumor Activity in the Amivantamab SC plus Paclitaxel Combination Cohort 3a5
Efficacy Outcome
Cohort 3a (n=11)
ORR, % (95% CI)
64 (31-89)
Best response, n
   CR
1a
   PR
8
   Not evaluable/unknown
2
Median DOR, months
NR
Median time to first response, weeks (range)
6.6 (6.1-14.6)
Tumor shrinkage of target lesions, n
9
Among confirmed responders, n (%)
7 (64)
   Treatment ongoing, n
4
Median PFS, months
NE
Median OS, months
NE
Abbreviations: CI, confidence interval; CR, complete response; DOR, duration of response; NE, not estimable; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SC, subcutaneous.
aResponse ongoing.
  • Antitumor activity among responders was observed regardless of baseline biomarker status.5
Pharmacokinetics
  • Mean predose amivantamab SC serum concentrations observed were consistent between the amivantamab SC plus paclitaxel combination (n=11) and amivantamab SC monotherapy (n=71) cohorts, suggesting that amivantamab SC pharmacokinetics exposure was not impacted by paclitaxel.5

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 24 November 2025.

References

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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 Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory epidermal growth factor receptor-mutated non-small cell lung cancer: primary results from the phase III PALOMA-3 study. J Clin Oncol. 2024;42(30):3593-3605.  
3 Harrington KJ, Rosenberg AJ, Yang M-H, et al. Subcutaneous amivantamab in recurrent/metastatic head and neck squamous cell cancer after disease progression on checkpoint inhibitor and chemotherapy: preliminary results from the phase 1b/2 OrigAMI-4 study. [published online ahead of print November 22, 2025]. Oral Oncol. doi:10.1016/j.oraloncology.2025.107791.  
4 Janssen Research & Development, LLC. A phase 1b/2, open-label study of amivantamab monotherapy and amivantamab in addition to standard of care therapeutic agents in participants with recurrent/metastatic head and neck squamous cell carcinoma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 November 24]. Available from: https://www.clinicaltrials.gov/study/NCT06385080 NLM Identifier: NCT06385080.  
5 Swiecicki PL, Keam B, Li S-H, et al. Amivantamab plus paclitaxel in recurrent/metastatic head and neck squamous cell cancer after disease progression on checkpoint inhibitor: Identification of the recommended combination dose from the phase 1b/2 OrigAMI-4 study. Poster presented at: European Society for Medical Oncology (ESMO) Congress; October 17-21, 2025; Berlin, Germany.  
6 Harrington KJ, Rosenberg AJ, Yang M-H, et al. Amivantamab in recurrent/metastatic head & neck squamous cell cancer after disease progression on checkpoint inhibition and chemotherapy: results from the phase 1b/2 OrigAMI-4 study. Oral Presentation presented at: European Society for Medical Oncology (ESMO) Congress; October 17-21, 2025; Berlin, Germany.