CHIMERA

CHIMERA is the first Italian trial conducted in Europe as part of the international ENGIC (European Network In GastroIntestinal Cancer) collaboration.
The European Countries involved are France, Germany, Spain and Italy.
The trial is sponsored and coordinated by GONO GI.
Colorectal cancer (CRC) is a leading cause of cancer-related deaths, worldwide. Approximately 30% of patients are diagnosed with metastatic disease and chemotherapy with a biological agent represents a standard upfront treatment option. According to the specific molecular profile of the disease, along with primary tumor sidedness, anti-EGFR or anti-VEGF monoclonal antibody are added to chemotherapy to enhance treatment efficacy. HER-2 positive metastatic CRC (mCRC) is a rare and aggressive disease, usually associated with primary resistance to anti-EGFR agents; in this context, upfront treatment with the anti-VEGF agent bevacizumab and doublet/triplet chemotherapy is a recommended option by major guidelines. Nonetheless, prognosis is poor and most patients will ultimately experience disease progression. HER-2 positivity is a well characterized druggable molecular alteration and HER-2 directed agents are well integrated in the treatment algorithms of patients with several tumor types such as HER-2 positive gastroesophageal and breast cancer. For patients with HER-2 positive mCRC, double HER-2 blockade or the antibody-drug-conjugate Trastuzumab-Deruxtecan (T-DXd) have demonstrated promising antitumor activity across various phase II trials in the chemo-refractory setting. Furthemore, the association of T-DXd with other agents, including a fluoropyrimidine, was safe and active as a first-line treatment option in patients with HER-2 positive gastroesophageal cancer. Drawing from this, upfront treatment with T-DXd, capecitabine and bevacizumab may represent a novel treatment combination to enhance antitumor activity and ultimately improve patients’ outcomes.

Key Inclusion criteria

1. Subjects must be ≥18 years.
2. Histologically or cytologically confirmed unresectable locally advanced or metastatic colorectal adenocarcinoma eligible for treatment in the first-line setting.
3. Locally-determined HER-2 positive disease defined as immunohistochemistry (IHC) 3+ or 2+/in situ hybridization (ISH) amplified on archival/newly obtained tumor tissue, according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for gastric/gastroesophageal cancer.
4. Have RAS known status and pMMR/MSS status per standard testing
5. ECOG PS ≤ 2
6. Adequate organ function as per protocol
7. Estimated life expectancy > 3 months.
8. Presence of measurable disease assessed by CT scan and/or MRI according to RECIST 1.1
9. Availability of archival tumor sample (primary tumor or metastatic site) for biomarker analysis.
10. No presence of complete dihydropyrimidine dehydrogenase (DPYD) enzyme deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT) with DPYD gene testing mandatory at screening as per national guidelines. Enrolment of patients carriers of variants of DPYD has to be discussed with the Sponsor.

Key Exclusion criteria

1. Previous or concurrent systemic (e.g. cytotoxic or targeted or other experimental drugs) therapy for mCRC
2. Previous treatment with anti-HER-2 agents or a topoisomerase I inhibitor
3. Major surgery or radiation therapy performed within <4 weeks before enrollment.
4. Known allergy or hypersensitivity to study drugs and/or their excipients.
5. Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that requires directed therapy (such as radiotherapy or surgery) or increasing doses of corticosteroids 2 weeks prior to study entry.
6. Any known additional malignancy that is progressing or requires active treatment
7. History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

CHIMERA is a no-profit, CHIMERA is designed as a multinational, open-label, single-arm, phase II trial aimed at investigating the safety, activity, and efficacy of T-DXd in combination with capecitabine and bevacizumab as first-line treatment of patients with HER2-positive mCRC.

Primary endpoint: Overall response rate (ORR) by blinded independent central review (BICR)

Key secondary endpoints:
Progression Free Survival (PFS) by BICR and investigator-assessed, Overall Survival (OS), Treatment safety, Disease Control Rate (DCR), Early Tumor Shrinkage (ETS), Duration of Response (DOR), Depth of Response (DoR)