Amivantamab + Chemotherapy vs Cetuximab + Chemotherapy for Colorectal Cancer

(OrigAMI-2 Trial)

Recruiting at 198 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Janssen Research & Development, LLC

Must not be taking: EGFR inhibitors, MET inhibitors

Disqualifiers: ILD, Pneumonitis, Pulmonary fibrosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 4 years and 2 months

1000 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Cetuximab when used with chemotherapy for colorectal cancer?

Cetuximab, when combined with chemotherapy, has shown promising results in treating metastatic colorectal cancer, improving progression-free survival and response rates. It has been effective in patients who have previously been treated with other chemotherapy drugs, restoring sensitivity to irinotecan and enhancing the overall treatment effect. ^{1 2 3 4 5}

What safety information is available for Cetuximab in colorectal cancer treatment?

Cetuximab is generally well tolerated in patients with metastatic colorectal cancer, with common side effects including skin rash and low magnesium levels. Severe side effects are rare, but skin rash severity is linked to how well the treatment works. ^{1 5 6 7 8}

What makes the drug combination of Amivantamab and Cetuximab with chemotherapy unique for colorectal cancer?

The combination of Amivantamab and Cetuximab with chemotherapy is unique because it involves two monoclonal antibodies targeting different pathways: Amivantamab targets the MET and EGFR pathways, while Cetuximab specifically targets the EGFR pathway. This dual targeting approach may offer a novel mechanism to enhance antitumor activity compared to standard treatments that typically focus on a single pathway. ^{1 2 7 9 10}

What is the purpose of this trial?

The purpose of this study is to compare how long the participants are disease-free (progression-free survival) when treated with amivantamab and chemotherapy with 5-fluorouracil, leucovorin calcium (folinic acid) or levoleucovorin, oxaliplatin (mFOLFOX6) or 5-fluorouracil, leucovorin calcium (folinic acid) or levoleucovorin, and irinotecan hydrochloride (FOLFIRI) versus cetuximab and mFOLFOX6 or FOLFIRI in adult participants with Kirsten rat sarcoma viral oncogene homolog (KRAS)/ Neuroblastoma RAS viral oncogene homolog (NRAS) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) wild type (WT) unresectable or metastatic left-sided colorectal cancer.

Research Team

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Eligibility Criteria

This trial is for adults with left-sided colorectal cancer that's spread and can't be removed by surgery. They must have a type of tumor without certain mutations (KRAS/NRAS/BRAF wild-type), be able to provide a fresh tissue sample, have measurable disease, and be in good physical condition (ECOG 0 or 1).

Inclusion Criteria

I agree to provide a fresh sample of my tumor for testing.

Have measurable disease according to RECIST v1.1

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

Has known allergies, hypersensitivity, or intolerance to specific excipients

I have a history of lung conditions not caused by infections.

I have or had another type of cancer besides the one currently being treated.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive amivantamab or cetuximab in combination with chemotherapy (mFOLFOX6 or FOLFIRI) for 28-day treatment cycles until disease progression or other discontinuation criteria are met

Up to 4 years and 2 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 7 years 3 months

Treatment Details

Interventions

• Amivantamab
• Cetuximab

Trial Overview The study compares two treatments: Amivantamab combined with chemotherapy (mFOLFOX6 or FOLFIRI) versus Cetuximab with the same chemo options. The goal is to see which treatment keeps the disease from worsening longer.

Participant Groups

Group I: Arm A: Amivantamab in Combination With Chemotherapy Experimental Treatment 5 Interventions

Participants will receive amivantamab in combination with chemotherapy (mFOLFOX6 \[chemotherapy consisting of 5-fluorouracil, leucovorin calcium (folinic acid) or levoleucovorin, and oxaliplatin\] or FOLFIRI \[chemotherapy consisting of 5-fluorouracil, leucovorin calcium (folinic acid) or levoleucovorin, and irinotecan hydrochloride\]) for 28-days treatment cycles and will continue to receive the treatment until radiographic disease progression or other discontinuation criteria are met.

Group II: Arm B: Cetuximab in Combination With Chemotherapy Active Control 5 Interventions

Participants will receive cetuximab in combination with chemotherapy (mFOLFOX6 or FOLFIRI) for 28-days treatment cycles and will continue to receive the treatment until radiographic disease progression or other discontinuation criteria are met.

Amivantamab is already approved in United States, European Union for the following indications:

Approved in United States as Rybrevant for:

• Locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations
• Locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations

Approved in European Union as Rybrevant for:

• Locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations
• Locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations

Who Is Running the Clinical Trial?

Janssen Research & Development, LLC

Lead Sponsor

Trials

1,022

Recruited

6,408,000+

Giacomo Salvadore

Janssen Research & Development, LLC

Chief Medical Officer since 2023

MD from the University of Rome, Tor Vergata

Ricardo Attar

Janssen Research & Development, LLC

Chief Executive Officer since 2008

PhD in Molecular Biology from the University of Buenos Aires

Findings from Research

In a study involving 65 patients with advanced colorectal cancer who had previously been treated with multiple therapies, the combination of cetuximab and irinotecan showed a response rate of 20% and a median overall survival of 10.4 months, confirming the efficacy of this treatment regimen.

The treatment was associated with low rates of severe toxicity, with only 8% experiencing grade 3 skin toxicity, indicating that cetuximab and irinotecan can be a safe option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. Pfeiffer, P., Nielsen, D., Yilmaz, M., et al.[2018]

Capecitabine, an oral chemotherapy drug, is at least as effective as traditional 5-FU plus leucovorin regimens for metastatic colorectal cancer (mCRC) and has a favorable safety profile.

Combining cetuximab with chemotherapy (like FOLFIRI) has been shown to improve progression-free survival and response rates in mCRC patients, with a recent phase III trial confirming these benefits over chemotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab plus XELIRI or XELOX for first-line therapy of metastatic colorectal cancer. Moosmann, N., Heinemann, V.[2018]

Cetuximab, a monoclonal antibody targeting the EGFR, has shown effectiveness in treating metastatic colorectal cancer when combined with irinotecan, particularly in patients who have previously failed irinotecan-based therapies.

While cetuximab has demonstrated promising results in phase II trials for first-line therapy, further research is needed to confirm its efficacy in larger phase III trials and to optimize patient selection for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab in colon cancer. Giuliani, F., Colucci, G.[2018]

Cetuximab, a monoclonal antibody targeting the EGFR, has shown effectiveness in treating metastatic colorectal cancer when combined with irinotecan, particularly in patients who have previously failed irinotecan-based therapies.

While cetuximab has demonstrated promising results in phase II trials for first-line therapy, further research is needed to confirm its efficacy in larger phase III trials and to optimize patient selection for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab in colon cancer. Giuliani, F., Colucci, G.[2022]

Cetuximab, when combined with irinotecan, can provide patients with metastatic colorectal cancer an additional 1.7 to 2.0 years of life, indicating its efficacy as a treatment option.

However, the cost-effectiveness analysis revealed that the treatment is quite expensive, with costs per life year gained ranging from 205,536 to 323,040 Euros, highlighting the financial considerations of using cetuximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab in the treatment of metastatic colorectal cancer: a model-based cost-effectiveness analysis. Norum, J.[2019]

In a post-marketing surveillance study involving 2126 patients with metastatic colorectal cancer, cetuximab was found to be well tolerated, with a median treatment duration of 15.3 weeks and a high incidence of adverse reactions at 89.6%.

The most common adverse reactions included skin disorders (83.7%) and infusion reactions (5.7%), primarily occurring during the first administration, indicating that while side effects are common, they align with previous reports and suggest that cetuximab is clinically useful in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Ishiguro, M., Watanabe, T., Yamaguchi, K., et al.[2022]

The CIFRA study is investigating the effectiveness of cetuximab combined with irinotecan and fluorouracil in patients with metastatic colorectal cancer who have a specific genetic profile (FcγRIIIa V/V), which may enhance the drug's action through a mechanism called Antibody-Dependent Cell-mediated Cytotoxicity (ADCC).

This phase II trial aims to determine if patients with the FcγRIIIa V/V genotype have a higher response rate to cetuximab, potentially improving treatment outcomes, while also assessing safety and survival metrics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol. Ottaiano, A., Scala, S., Normanno, N., et al.[2020]

Cetuximab is an effective treatment for metastatic colorectal cancer (mCRC), particularly in patients who have not responded to other therapies, and it can improve response rates when added to first-line chemotherapy, potentially increasing chances for curative surgery.

The drug is generally well tolerated, with common side effects like rash and low magnesium levels; interestingly, the severity of the rash may indicate how well the treatment is working, although its effectiveness is not linked to EGFR expression, suggesting the need for additional markers to identify responsive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab in the management of colorectal cancer. Lenz, HJ.[2023]

Bevacizumab, a monoclonal antibody that blocks vascular endothelial growth factor, significantly improved response rates and survival in metastatic colorectal cancer when combined with chemotherapy, based on a randomized phase III trial.

Cetuximab, which inhibits the epidermal growth factor receptor, demonstrated a 22.5% response rate and prolonged progression-free survival in irinotecan-refractory patients, highlighting its effectiveness as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Which role do new therapeutic options play in palliative care of colorectal cancer?]. Verbeek, W., Graeven, U.[2018]

In a study of 146 patients with metastatic colorectal cancer, those with left-sided primary tumors experienced significantly longer overall survival (OS) and progression-free survival (PFS) compared to those with right-sided tumors, particularly among patients with KRAS wild-type mutations.

The results suggest that the location of the primary tumor and the KRAS mutation status interact to influence treatment outcomes, indicating that left-sided tumors may predict better efficacy of cetuximab-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Left-sided primary tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer treated with cetuximab plus chemotherapy: an analysis of the AIO KRK-0104 trial. von Einem, JC., Heinemann, V., von Weikersthal, LF., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Cetuximab plus XELIRI or XELOX for first-line therapy of metastatic colorectal cancer. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Cetuximab in colon cancer. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Cetuximab in colon cancer. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Cetuximab in the treatment of metastatic colorectal cancer: a model-based cost-effectiveness analysis. [2019]

6. England pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol. [2020]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Cetuximab in the management of colorectal cancer. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

[Which role do new therapeutic options play in palliative care of colorectal cancer?]. [2018]

10. Germany pubmed.ncbi.nlm.nih.gov

Left-sided primary tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer treated with cetuximab plus chemotherapy: an analysis of the AIO KRK-0104 trial. [2022]