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RYBREVANT®

(amivantamab-vmjw)

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RYBREVANT® (amivantamab-vmjw)
Medical Information

Use of RYBREVANT in Colorectal Cancer - OrigAMI-1 Study

Last Updated: 04/23/2026

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
  • OrigAMI-1 (NCT05379595) is an ongoing, phase 1b/2, open-label, multicenter study evaluating the efficacy and safety of RYBREVANT (administered intravenously in 28-day cycles) monotherapy and in combination with standard of care (SOC) chemotherapy (combination of modified leucovorin, 5-fluorouracil, and oxaliplatin [mFOLFOX6] or combination of leucovorin, 5-fluorouracil, and irinotecan [FOLFIRI]) in patients with advanced or metastatic colorectal cancer (mCRC).2-5
    • Median progression-free survival (PFS) was 5.7 months, 4.6 months, and 3.7 months, and investigator-assessed objective response rates (ORRs) were 29%, 19%, and 22% in the RYBREVANT monotherapy cohorts A, B, and C, respectively, as included in Table: Antitumor Activity in the RYBREVANT Monotherapy Cohorts.4 Median PFS was 9.2 months (95% confidence interval [CI], 5.4-12.9) and confirmed ORR was 51% (95% CI, 36-67) in the RYBREVANT plus chemotherapy combination cohorts (cohorts D or E), as included in Table: Antitumor Activity in the RYBREVANT Plus Chemotherapy Combination Cohorts D or E.5
    • In an EGFR rechallenge analysis in cohort B, improved efficacy was observed in patients who had a longer interval between discontinuation of prior anti-EGFR treatment and RYBREVANT rechallenge, as included in Table: Antitumor Activity in Cohort B by Time to RYBREVANT Rechallenge.4
    • The safety profile for RYBREVANT monotherapy was consistent with previous reports, as included in Table: Summary of TEAEs and Table: Safety Profile for the RYBREVANT Monotherapy Cohorts.4 The safety profile of RYBREVANT plus mFOLFOX6 or FOLFIRI was consistent with that of each individual component, as included in Table: Safety Profile for the RYBREVANT Plus Chemotherapy Combination Cohorts.5
    • The updated results on the antitumor activity of RYBREVANT as monotherapy or in combination with chemotherapy (mFOLFOX6 or FOLFIRI) in patients with right-sided (R-sided) RAS/BRAF wild-type (WT) mCRC are reported. Median PFS was 3.7 (95% CI, 3.4-5.5) and 7.4 (95% CI, 1.8-not estimable [NE]) months, and ORRs were 22% (95% CI, 8-44) and 43% (95% CI, 10-82) in the RYBREVANT monotherapy cohort C and RYBREVANT plus chemotherapy combination cohorts D and E, respectively, as included in Table: Antitumor Activity in the R-Sided mCRC Cohorts. In cohort C, 1 patient with R-sided mCRC achieved a complete response. The safety profile of RYBREVANT in patients with R-sided mCRC was consistent with previous reports, as included in Table: Safety Profile for the R-Sided mCRC Cohorts. The most common grade ≥3 treatment-emergent adverse events (TEAEs) related to EGFR and MET inhibition were rash (cohort C, 4%; cohorts D and E, 14%) and hypoalbuminemia (cohort C, 13%). No treatment-related discontinuations with RYBREVANT were reported in any cohort.6
    • Gene expression data (by whole transcriptome RNA-sequencing analysis) to identify mechanisms of sensitivity and action in response to RYBREVANT monotherapy have been reported.4

ongoing clinical study

OrigAMI-1 Study

Study Design/Methods

  • Ongoing phase 1b/2, open-label, multicenter study designed to assess the efficacy and safety of RYBREVANT monotherapy and in combination with SOC chemotherapy (mFOLFOX6 or FOLFIRI) in patients with advanced or mCRC.2-5
  • The study design is shown in Figure: OrigAMI-1 Study Design.
  • In cohort B, an exploratory analysis also evaluated the effect of time elapsed from the discontinuation of prior anti-EGFR therapy to the start of RYBREVANT treatment.4
    • A previous study showed that the frequency of RAS and EGFR mutant clones declined after stopping prior anti-EGFR treatment (ie, cetuximab or panitumumab). The mutational decay (MD) half-life of these clones was found to be 4.4 months.4,7
    • Patients in Cohort B were divided into 2 groups based on the time interval between discontinuation of prior anti-EGFR therapy and the start of RYBREVANT treatment4:
      • >2 MD half-lives, n=25 (>8.8 months between discontinuation of prior anti-EGFR therapy and the start of RYBREVANT treatment)
      • ≤2 MD half-lives, n=29 (≤8.8 months between discontinuation of prior anti-EGFR therapy and the start of RYBREVANT treatment)

OrigAMI-1 Study Design2-6

OrigAMI-1 (ClinicalTrials.gov Identifier: NCT05379595); data cutoff: October 31, 2024.
Abbreviations: 1L, first-line; 2L, second-line; 5-FU, 5-fluorouracil; AE, adverse event; AMI, amivantamab; C, cycle; CBR, clinical benefit rate; CR, complete response; CRC, colorectal cancer; ctDNA, circulating tumor DNA; DCR, disease control rate; DLT, dose-limiting toxicity; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; FOLFIRI, combination of leucovorin, 5-FU, and irinotecan; ILD, interstitial lung disease; IV, intravenous; mCRC, metastatic colorectal cancer; mFOLFOX6, modified combination of leucovorin, 5-FU, and oxaliplatin; ORR, objective response rate; PFS, progression-free survival; PR, partial response; Q2W, every 2 weeks; QW, weekly; RECIST, Response Evaluation Criteria in Solid Tumors; RP2D, recommended phase 2 dose; SD, stable disease; SOC, standard of care; VEGF, vascular endothelial growth factor.
aCentral ctDNA testing was performed at screening to identify KRAS/NRAS missense alterations (leading to G12X, G13X, Q61X, K117X, A59X, or A146X), BRAF missense alterations (leading to V600X change), or ERBB2/HER2 amplification, as detected by Guardant360 CDx.
bSOC chemotherapy is defined as fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
c1050 mg in patients weighing <80 kg and 1400 mg in patients weighing ≥80 kg, IV QW for the first 4 weeks during C1, with the first dose split over 2 days (350 mg on day 1 and remainder of the dose on day 2 during C1), then Q2W starting C2.
dDose escalation identified AMI dose (1050 mg IV [1400 mg if ≥80 kg] IV QW for the first 4 weeks, then Q2W) in combination with standard mFOLFOX6 or FOLFIRI dosing as the RP2D.
eMaximum of 1 prior line in the metastatic setting.
fmFOLFOX6 includes oxaliplatin (85 mg/m2) IV, leucovorin 400 mg/m2 (or 200 mg/m2 if levoleucovorin) IV, 5-FU bolus (400 mg/m2) IV, and 5-FU (2400 mg/m2 or 1200 mg/m2/day for 2 days).
gFOLFIRI includes irinotecan (180 mg/m2) IV, leucovorin 400 mg/m2 (or 200 mg/m2 if levoleucovorin) IV, 5-FU bolus (400 mg/m2) IV, and 5-FU (2400 mg/m2 or 1200 mg/m2/day for 2 days).
hCR/PR or SD of duration of ≥11 weeks.

Results: RYBREVANT Monotherapy Cohorts (Cohorts A, B, and C)

  • Results are reported as of the clinical cutoff date of October 31, 2024.4
Patient Characteristics
  • A total of 94 patients received RYBREVANT monotherapy (cohort A, n=17; cohort B, n=54; cohort C, n=23).4 
  • A majority of the patients (94%) received prior bevacizumab.4
  • In cohort B, 27/54 (50%) patients responded to prior anti-EGFR treatment in any line. In cohort C, 10/23 (43%) patients had received prior anti-EGFR treatment, and 2/10 (20%) patients responded to prior anti-EGFR treatment.4
  • Patient characteristics are included in Table: Patient Characteristics in the RYBREVANT Monotherapy Cohorts.

Patient Characteristics in the RYBREVANT Monotherapy Cohortsa,4
Characteristic
Cohort A (n=17)
Cohort B (n=54)
Cohort C
(n=23)
Median (range) age, years
63 (45-80)
60.5 (36-79)
60 (34-79)
   <65 years
9 (53)
33 (61)
16 (70)
   ≥65 to <75 years
7 (41)
16 (30)
3 (13)
   ≥75 years
1 (6)
5 (9)
4 (17)
Sex, n (%)
   Female
5 (29)
18 (33)
10 (43)
   Male
12 (71)
36 (67)
13 (57)
Race, n (%)
   Asian
14 (82)
34 (63)
13 (57)
   White
2 (12)
19 (35)
6 (26)
   Black or African American
1 (6)
1 (2)
1 (4)
   American Indian or Alaska Native
0 (0)
0 (0)
1 (4)
   Multiple/not reported
0 (0)
0 (0)
2 (9)
Median (range) body weight, kg
67 (48-91)
69 (44-115)
67 (44-120)
   <80 kg, n (%)
13 (76)
44 (81)
16 (70)
   ≥80 kg, n (%)
4 (24)
10 (19)
7 (30)
ECOG PS, n (%)
   0
11 (65)
26 (48)
9 (39)
   1
6 (35)
28 (52)
14 (61)
History of alcohol use, n (%)
   No
6 (35)
33 (61)
14 (61)
   Yes
11 (65)
21 (39)
9 (39)
Median (range) time from metastatic diagnosis to first dose, months
30 (4-109)
27 (3-87)
26 (12-68)
Median (range) number of prior lines of therapy
2 (2-3)
2 (2-3)
2 (2-3)
Number of prior lines of therapy in metastatic settingb
   Median (range)
2 (2-3)
2 (2-3)
2 (1-3)b
   2, n (%)
10 (59)
30 (56)
13 (57)
   3, n (%)
7 (41)
24 (44)
9 (39)
Location of primary disease, n (%)
   Right sidec
 0 (0)
0 (0)
23 (100)
   Left sided
13 (76)
30 (56)
0 (0)
   Extraperitoneal rectum
4 (24)
24 (44)
0 (0)
Liver metastases, n (%)
13 (76)
39 (72)
18 (78)
Peritoneum metastases, n (%)
0 (0)
11 (20)
8 (35)
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; L-sided, left-sided; R-sided, right-sided.
aL-sided CRC was defined as a primary tumor that arose from the splenic flexure, descending colon, sigmoid colon, or rectum. R-sided CRC was defined as a primary tumor that arose from the cecum, ascending colon, or transverse colon.
bOne patient incorrectly received a higher dose of RYBREVANT in cohort A but was later changed to cohort C despite receiving only 1 prior line of therapy in the metastatic setting.
cR-sided primary disease includes patients with primary tumors located in the ascending colon (cohort C, 39%), hepatic flexure (cohort C, 30%), or transverse colon (cohort C, 30%).
dL-sided primary disease includes patients with primary tumors located in the descending colon (cohort A, 6%; cohort B, 4%), retrosigmoid junction (cohort A, 12%; cohort B, 7%), or sigmoid colon (cohort A, 59%; cohort B, 44%).
Efficacy

Antitumor Activity in the RYBREVANT Monotherapy Cohorts4,8
Outcome
RYBREVANT Monotherapy Cohorts
Cohort A (n=17)
Cohort B (n=54)
Cohort C (n=23)
Median (range) follow-up duration, months
16 (2.3-22.3)
13.7 (0.7-25.2)
8.1 (0.6-20.3)
Median (range) duration of treatment, months
6.9 (1-12.1)
5.1 (0-22.1)
3.3 (0-20.3)
Investigator-assessed ORR, % (95% CI)
29 (10-56)
19 (9-31)
22 (8-44)
Best response, n (%)
   CR
0 (0)
0 (0)
1 (4)
   PR
5 (29)
10 (19)
4 (17)
   SD
10 (59)
29 (54)
13 (57)
   PD
2 (12)
14 (26)
5 (22)
   NE /unknown
0 (0)
1 (2)
0 (0)
Median DOR, months (95% CI)
9 (7.3-NE)
6.1 (1.9-8.9)
9.8 (3.7-NE)
   Duration of response ≥6 months,a n (%)
4 (80)
5 (50)
4 (80)
CBR,b % (95% CI)
71 (44-90)
52 (38-66)
48 (27-69)
Median PFS, months (95% CI)
5.7 (3.6-7.4)
4.6 (3.5-5.6)
3.7 (3.4-5.5)
Median OS, months (95% CI)
16.8 (7.1-NE)
14 (10.4-16.4)
9.2 (6.9-17.5)
Abbreviations: CBR, clinical benefit rate; CI, confidence interval; CR, complete response; DOR, duration of response; NE, not estimable; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
aAmong responders (cohort A, n=5; cohort B, n=10; cohort C, n=5).
bPercentage of patients achieving confirmed CR, PR, or durable SD (duration of ≥11 weeks).
  • In an EGFR rechallenge analysis in cohort B, improved efficacy was observed in patients who had a longer interval between discontinuation of prior anti-EGFR treatment and RYBREVANT rechallenge,4 as included in Table: Antitumor Activity in Cohort B by Time to RYBREVANT Rechallenge.
    • Among patients who received anti-EGFR treatment in their last regimen, prior response to anti-EGFR treatment (complete response [CR] or partial response [PR]) was associated with improved outcomes with RYBREVANT.

Antitumor Activity in Cohort B by Time to RYBREVANT Rechallenge8
Outcome
Time from Prior Anti-EGFR to RYBREVANT Rechallenge
HR (95% CI);
P-Value
≤2 MD Half-Livesa (≤8.8 months, n=29)
>2 MD Half-Livesa
(>8.8 months, n=25)
Best response, n (%)
   CR
0 (0)
0 (0)
-
   PR
2 (7)
8 (32)
-
   SD
15 (52)
14 (56)
-
   PD
12 (41)
2 (8)
-
   NE/unknown
0
1 (4)
-
ORR, n (%)
2 (7)
8 (32)
-
   95% CI
1-23
15-54
-
CBR, n (%)
8 (28)
20 (80)
-
   95% CI
13-47
59-93
-
Median PFS,b months (95% CI)
2.8 (1.8-3.8)
7 (5.3-9)
0.48 (0.28-0.84);
log-rank P=0.0081
Median OS,c months (95% CI)
10.4 (3.2-16.4)
16.1 (11.3-NE)
0.56 (0.29-1.1)
log-rank P=0.0878
Abbreviations: CBR, clinical benefit rate; CI, confidence interval; CR, complete response; EGFR, epidermal growth factor receptor; HR, hazard ratio; MD, mutational decay; NE, not estimable; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.aTime from prior anti-EGFR therapy was determined by ≤2 MD half-lives (≤8.8 months) or >2 MD half-lives (>8.8 months) after EGFR-inhibitor rechallenge among patients in cohort B.
bFor cohort B, median PFS, 4.6 (95% CI, 3.5-5.6).
cFor cohort B, median OS, 14 (95% CI, 10.4-16.4).
Safety
  • The safety profile for RYBREVANT monotherapy was consistent with previous reports, with no new safety signals identified.4
  • Among all TEAEs reported, grade 1-2 events were reported in 47/94 (50%) patients, grade 3 events in 39/94 (41%) patients, and grade 4-5 events in 7/94 (7%) patients. TEAEs occurred due to EGFR and MET inhibition.4
  • Serious TEAEs occurred in 30 (32%) patients, 6 (6%) of which were considered treatment-related.4
  • Grade ≥3 treatment-related adverse events (TRAEs) occurred in 25 (27%) patients.4
  • Discontinuation due to a TRAE (dermatitis) occurred in 1 (1%) patient.4
  • Safety data are summarized in Table: Summary of TEAEs and Table: Safety Profile for the RYBREVANT Monotherapy Cohorts.

Summary of TEAEs4
Event, n (%)
Cohorts A, B, and C
(n=94)
Any TEAE
93 (99)
Grade ≥3 TEAE
46 (49)
Serious TEAE
30 (32)
Any TEAE leading to
   Dose interruption
41 (44)
   Dose reduction
11 (12)
   Discontinuation
2 (2)
Abbreviation: TEAE, treatment-emergent adverse event.

Safety Profile for the RYBREVANT Monotherapy Cohorts4
TEAEs (≥20%) by Preferred Term, n (%)
Cohorts A, B, and C (n=94)
All Grades
Grade ≥3
Infusion-related reaction
51 (54)
1 (1)
Dermatitis acneiform
36 (38)
4 (4)
Rash
29 (31)
7 (7)
Hypoalbuminemia
29 (31)
7 (7)
Paronychia
24 (26)
1 (1)
Peripheral edema
23 (24)
1 (1)
Fatigue
19 (20)
2 (2)
Abbreviation: TEAE, treatment-emergent adverse event.

Results: RYBREVANT Plus Chemotherapy Combination Cohorts (Cohorts D and E)

  • Long-term follow-up results are reported as of the data cutoff date of October 13, 2025.5
    • Cohort D included 20 patients receiving RYBREVANT plus mFOLFOX6. Cohort E included 23 patients receiving RYBREVANT plus FOLFIRI.
Patient Characteristics

Patient Characteristics in the RYBREVANT Plus Chemotherapy Combination Cohorts5
Characteristic
Cohort D (n=20)
Cohort E (n=23)
Total (n=43)
Median (range) age, years
64 (39-79)
61 (36-69)
62 (36-79)
Male, n (%)
14 (70)
17 (74)
31 (72)
Race, n (%)
   Asian
10 (50)
15 (65)
25 (58)
   Black/African American
1 (5)
1 (4)
2 (5)
   White
9 (45)
7 (30)
16 (37)
ECOG PS, n (%)
   0
11 (55)
11 (48)
22 (51)
   1
9 (45)
12 (52)
21 (49)
Tumor side, n (%)
   L-sided
16 (80)
20 (87)
36 (84)
   R-sided
4 (20)
3 (13)
7 (16)
Prior lines of therapy in the metastatic setting, n (%)
   0
8 (40)
3 (13)
11 (26)
   1
12 (60)
20 (87)
32 (74)
Liver metastases, n (%)
14 (70)
17 (74)
31 (72)a
Abbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status; L-sided, left-sided; R-sided, right-sided.
aOne patient had a non-target liver lesion.
Efficacy

Antitumor Activity in the RYBREVANT Plus Chemotherapy Combination Cohorts D or E5
Efficacy Outcome
Total (n=43)
Median follow-up, months (range)
16 (1.2-29.5)
Investigator-assessed response
   Confirmed ORR, % (95% CI)
51 (36-67)
      Median DOR, months (95% CI)
9.3 (5.8-14.7)
      Median time to first response,a weeks
8.3
      CR, n
2
   Median PFS, months (95% CI)
9.2 (5.4-12.9)
   CBR,b % (95% CI)
74 (59-87)
Median OS, months (95% CI)
NE (16.2-NE)
Patients receiving treatment as 1L therapy, n
11
   Median follow-up, months
18.3
   ORR, % (95% CI)
73 (53-86)
   Median DOR, months
NR
   Proceeded to curative intent surgery and censored upon completion, n (%)
4 (36)
Patients receiving treatment as 2L therapy, n
32
   Median follow-up, months
12.7
   ORR, % (95% CI)
44 (26-62)
   Median DOR, months (95% CI)
7.4 (5.4-14.5)
   Proceeded to curative intent surgery, n
2
   Received RYBREVANT >1 year, n
12
   RYBREVANT ongoing, n
4
      Received RYBREVANT >2 years, n
3
Abbreviations: 1L, first-line; 2L, second-line; CBR, clinical benefit rate; 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.
aMajority occurring at the first disease assessment.
bConfirmed response or durable stable disease ≥11 weeks.

Antitumor Activity in the Liver Metastases Subgroup of the RYBREVANT Plus Chemotherapy Combination Cohorts D or E5
Efficacy Outcome
Total (n=43)
Patients with target liver lesions, n
 30
ORR, % (95% CI)
57 (37-75)
   CR, n
1
CBR, % (95% CI)
77 (58-90)
Median PFS, months (95% CI)
11.3 (5.9-16.4)
Median OS, months (95% CI)
NE (18.1-NE)
   12-month rate, %
85
   18-month rate, %
75
Abbreviations: CBR, clinical benefit rate; CI, confidence interval; CR, complete response; NE, not estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
Safety

Safety Profile for the RYBREVANT Plus Chemotherapy Combination Cohorts5
TEAEs (≥30%) by Preferred Term, n (%)
Cohort D (n=20)
Cohort E (n=23)
All Grades
Grade ≥3
All Grades
Grade ≥3
Associated with EGFR inhibition
   Diarrheaa
13 (65)
1 (5)
15 (65)
2 (9)
   Stomatitis
11 (55)
1 (5)
11 (48)
0
   Rash
10 (50)
3 (15)
11 (48)
1 (4)
   Paronychia
10 (50)
0
11 (48)
0
   Dermatitis acneiform
5 (25)
0
8 (35)
2 (9)
Associated with MET inhibition
   Hypoalbuminemia
9 (45)
0
14 (61)
2 (9)
   Peripheral edema
6 (30)
0
8 (35)
0
Associated with chemotherapy (mFOLFOX6 or FOLFIRI)
   Neutropenia
10 (50)
7 (35)
16 (70)
12 (52)
   Anemia
4 (20)
0
11 (48)
2 (9)
   Leukopenia
4 (20)
1 (5)
7 (30)
1 (4)
   Thrombocytopenia
6 (30)
3 (15)
3 (13)
0
Other
   Nausea
6 (30)
1 (5)
14 (61)
0
   IRRs
10 (50)
0
12 (52)
0
   Fatigue
10 (50)
0
7 (30)
2 (9)
   Vomiting
8 (40)
1 (5)
7 (30)
0
   Hypokalemia
7 (35)
1 (5)
8 (35)
2 (9)
   Peripheral sensory neuropathy
7 (35)
0
1 (4)
0
   ALT increased
4 (20)
0
8 (35)
0
   Hypomagnesemia
2 (10)
0
8 (35)
1 (4)
   Constipation
6 (30)
0
7 (30)
0
   Decreased appetite
5 (25)
0
7 (30)
0
   Pyrexia
4 (20)
0
7 (30)
0
   Pain in extremity
6 (30)
0
2 (9)
0
   Hypoesthesia
6 (30)
0
1 (4)
0
Abbreviations: ALT, alanine aminotransferase; EGFR, epidermal growth factor receptor; FOLFIRI, combination of leucovorin, 5-fluorouracil, and irinotecan; IRR, infusion-related reaction; MET, mesenchymal-epithelial transition; mFOLFOX6, modified combination of leucovorin, 5-fluorouracil, and oxaliplatin; TEAE, treatment-emergent adverse event.
aDiarrhea was also associated with irinotecan, a component of the FOLFIRI (chemotherapy) regimen.

Results: RYBREVANT Monotherapy Cohort C and RYBREVANT Plus Chemotherapy Combination Cohorts D and E with R-Sided mCRC

  • Results are reported as of the data cutoff date of October 31, 2024.6
  • The updated results on the antitumor activity of RYBREVANT as monotherapy and in combination with chemotherapy (mFOLFOX6 or FOLFIRI) in patients with R-sided RAS/BRAF WT mCRC are reported.6
  • R-sided disease was defined as a primary tumor arising from the cecum, ascending colon, or transverse colon.6
Patient Characteristics
  • Cohort C included 23 patients with R-sided disease who received RYBREVANT monotherapy. In cohort D, 4 of 20 patients receiving RYBREVANT plus mFOLFOX6 had R-sided disease. In cohort E, 3 of 23 patients receiving RYBREVANT plus FOLFIRI had R-sided disease.6
  • Patient characteristics are included in Table: Patient Characteristics in the R-Sided mCRC Cohorts.

Patient Characteristics in the R-Sided mCRC Cohorts6
Characteristic
Cohort C (n=23)
Cohorts D and E (n=7)
Median (range) age, years
60 (34-79)
61 (36-74)
Male, n (%)
13 (57)
6 (86)
Race, n (%)
   Asian
13 (57)
5 (71)
   Black/African American
1 (4)
1 (14)
   White
6 (26)
1 (14)
   Othera
3 (13)
0
ECOG PS, n (%)
   0
9 (39)
2 (29)
   1
14 (61)
5 (71)
Median prior lines of therapy in the metastatic setting, n (range)
2 (1-3)
1 (1-1)
   Prior EGFRi, n (%)
10 (43)
0
Liver metastases,b n (%)
18 (78)
6 (86)
Primary tumor location, n (%)
   Cecum
0
1 (14)
   Ascending colon
9 (39)
4 (57)
   Hepatic flexure
7 (30)
1 (14)
   Transverse colon
7 (30)
1 (14)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; EGFRi, epidermal growth factor receptor inhibitor; mCRC, metastatic colorectal cancer; R-sided, right-sided.
aIncludes patients who identified as American Indian or Alaska Native, those who identified as multiple races, and those who did not report a race.
bPatients could have metastases at >1 location.
Efficacy

Antitumor Activity in the R-Sided mCRC Cohorts6
Efficacy Outcome
Cohort C (n=23)a
Cohorts D and E (n=7)
Median follow-up, months (range)
8.1 (0.6-20.3)
8.2 (3.2-11.9)
ORR,b % (95% CI)
22 (8-44)
43 (10-82)
   Median DOR,c months (95% CI)
9.8 (3.7-NE)d
NE (5.8-NE)e
DCR, % (95% CI)
78 (56-93)
86 (42-100)
Median PFS, months (95% CI)
3.7 (3.4-5.5)
7.4 (1.8-NE)
Best response, n
   CR
1
0
   PR
4
3
   SD
13
3
   PD
4
1
Abbreviations: CI, confidence interval; CR, complete response; DCR, disease control rate (confirmed responders + patients with confirmed SD); DOR, duration of response; mCRC, metastatic colorectal cancer; NE, not estimable; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; R-sided, right-sided; SD, stable disease.
aOne patient discontinued due to an adverse event prior to the first disease assessment. The patient was response evaluable but did not have evaluable target lesion measurements in any postbaseline disease assessment.
bORR was defined as the proportion of patients achieving PR or CR by investigator assessment at ≥2 consecutive disease assessments.
cAmong confirmed responders.
dOf the 5 responders, 3 remain on treatment and have ongoing response.
eAll 3 responders remain on treatment, with 1 of 3 responders showing ongoing response.
Safety
  • Safety data are included in Table: Safety Profile for the R-Sided mCRC Cohorts.
    • The most common grade ≥3 TEAEs related to EGFR and MET inhibition were rash (cohort C, 4%; cohorts D and E, 14%) and hypoalbuminemia (cohort C, 13%), respectively.6
  • No treatment-related discontinuations with RYBREVANT were reported in any cohort.6

Safety Profile for the R-Sided mCRC Cohorts6
TEAEs (≥20%) by Preferred Term, n (%)
Cohort C (n=23)
Cohorts D and E (n=7)
All Grades
Grade ≥3
All Grades
Grade ≥3
Associated with EGFR inhibition
   Dermatitis acneiform
7 (30)
1 (4)
2 (29)
0
   Diarrheaa
6 (26)
0
5 (71)
1 (14)
   Rash
6 (26)
1 (4)
4 (57)
1 (14)
   Stomatitis
6 (26)
0
6 (86)
0
   Pruritus
5 (22)
0
1 (14)
0
   Paronychia
4 (17)
0
3 (43)
0
Associated with MET inhibition
   Hypoalbuminemia
8 (35)
3 (13)
1 (14)
0
   Peripheral edema
6 (26)
0
0
0
Other
   IRR
14 (61)
0
4 (57)
0
   Fatigue
7 (30)
0
2 (29)
0
   Nausea
6 (26)
0
3 (43)
0
   Constipation
6 (26)
0
2 (29)
0
   ALT increased
5 (22)
1 (4)
1 (14)
0
   Anemia
5 (22)
1 (4)
1 (14)
0
   AST increased
5 (22)
1 (4)
1 (14)
0
   Insomnia
5 (22)
0
1 (14)
0
   Vomiting
5 (22)
0
1 (14)
0
   Ascites
5 (22)
2 (9)
0
0
   Hypokalemia
3 (13)
2 (9)
2 (29)
1 (14)
   Weight decreased
2 (9)
0
3 (43)
0
   Asthenia
2 (9)
0
2 (29)
0
   Thrombocytopenia
1 (4)
0
4 (57)
1 (14)
   Neutropenia
0
0
5 (71)
3 (43)
   Leukopenia
0
0
3 (43)
0
   Dry Mouth
0
0
2 (29)
0
   Flatulence
0
0
2 (29)
0
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; EGFR, epidermal growth factor receptor; FOLFIRI, combination of leucovorin, 5-fluorouracil, and irinotecan; IRR, infusion-related reaction; mCRC, metastatic colorectal cancer; MET, mesenchymal-epithelial transition; mFOLFOX6, modified combination of leucovorin, 5-fluorouracil, and oxaliplatin; R-sided, right-sided; TEAE, treatment-emergent adverse event.
aDiarrhea was also associated with 5-fluorouracil, a component of the mFOLFOX6 regimen, and with irinotecan, a component of the FOLFIRI regimen.

Results: RNA-Sequencing Analysis (Cohorts A, B, and C)

  • An analysis of gene expression data identified mechanisms of sensitivity and action in response to RYBREVANT monotherapy.4
    • Tumor biopsy samples were collected at baseline (screening, mandatory), and at cycle 3 day 1 (C3D1) and time of progression (if clinically feasible).4
    • Gene expression data (by whole transcriptome RNA-sequencing analysis) were analyzed using standard bioinformatic methods to identify genes/signatures associated with RYBREVANT treatment response in baseline tumor samples (n=76) and paired baseline and C3D1 tumor samples (n=17).8 
Efficacy by mRNA Expression
  • Treatment response was associated with high baseline mRNA expression of AREG and EREG (EGFR ligands and biomarkers of anti-EGFR treatment efficacy in mCRC) across all cohorts (n=76).4
  • In cohort A (n=16), the median PFS was longer for patients with high (n=8) vs low (n=8) AREG expression (9.1 vs 4.5 months, respectively; P=0.0076).4
Differential Expression, EGFR Pathway, and Cell Cycle Pathway Signatures
  • Differential expression analyses after RYBREVANT treatment showed significant changes in >800 genes (P<0.01) across all cohorts (n=17).4
  • EGFR pathway (P<0.01) and cell cycle pathway (P<0.01) signatures were significantly downregulated with RYBREVANT treatment, which is consistent with its EGFR-MET targeted antitumor activity.4
Immune-Related Signatures
  • A significant upregulation of dendritic cell (P<0.005) and T cell-inflamed gene signatures (P<0.05) was observed with RYBREVANT treatment, consistent with immune cell infiltration into tumors.4
  • RYBREVANT also significantly increased the natural killer (NK) cell-mediated cytotoxicity (P<0.05) and cytolytic gene signatures (P<0.05).4

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 22 April 2026.

 

References

Show
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 Janssen Research & Development, LLC. A phase 1b/2, open-label study of amivantamab monotherapy and in addition to standard-of-care chemotherapy in participants with advanced or metastatic colorectal cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2026 April 22]. Available from: https://www.clinicaltrials.gov/study/NCT05379595 NLM Identifier: NCT05379595.  
3 Oberstein PE, Eng C, Cutsem EV, et al. A phase 1b/2, open-label study of amivantamab monotherapy or in combination with standard-of-care chemotherapy in patients with advanced or metastatic colorectal cancer. Poster presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA.  
4 Oberstein PE, Hecht JR, Raghav K, et al. Amivantamab monotherapy in chemorefractory RAS/BRAF wild-type metastatic colorectal cancer: results from OrigAMI-1, an open-label, phase 1b/2 study. [published online ahead of print April 21, 2026]. J Clin Oncol. doi:10.1200/jco-25-02187.  
5 Chen EX, Malik RA, Su HY-L, et al. Amivantamab plus FOLFOX or FOLFIRI in RAS/BRAF wild-type metastatic colorectal cancer: Long-term follow-up from the phase 1b/2 OrigAMI-1 study. Poster presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 8-10, 2026; San Francisco, CA.  
6 Raghav K, Cutsem EV, Arnold D, et al. Amivantamab with and without chemotherapy in right-sided advanced or metastatic colorectal cancer: updated results from OrigAMI-1, an open-label, phase 1b/2 study. Poster presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 23-25, 2025; San Francisco, CA.  
7 Parseghian CM, Loree JM, Morris VK, et al. Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge. Ann Oncol. 2019;30(2):243-249.  
8 Oberstein PE, Hecht JR, Raghav K, et al. Supplementary appendix for: Amivantamab monotherapy in chemorefractory RAS/BRAF wild-type metastatic colorectal cancer: results from OrigAMI-1, an open-label, phase 1b/2 study. [published online ahead of print April 21, 2026]. J Clin Oncol. doi:10.1200/jco-25-02187.