Anti-EGFR Rechallenge in Patients With Refractory ctDNA RAS/BRAF wt Metastatic Colorectal Cancer: A Nonrandomized
Davide Ciardiello1,2, Erika Martinelli2, Teresa Troiani2
1Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy.
Importance:
The available evidence regarding anti-epidermal growth factor receptor (EGFR) inhibitor rechallenge in patients with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) is derived from small retrospective and prospective studies.
Objective:
To evaluate the efficacy of anti-EGFR rechallenge in patients with refractory ctDNA RAS/BRAF wt mCRC.
Design, Setting, And Participants:
This nonrandomized controlled trial used a pooled analysis of individual patient data from patients with RAS/BRAF wt ctDNA mCRC enrolled in 4 Italian trials (CAVE, VELO, CRICKET, and CHRONOS) and treated with anti-EGFR rechallenge between 2015 and 2022 (median [IQR] follow-up, 28.1 [25.8-35.0] months).
Intervention:
Patients received anti-EGFR rechallenge therapy, including cetuximab plus avelumab, trifluridine-tipiracil plus panitumumab, irinotecan plus cetuximab, or panitumumab monotherapy.
Main Outcomes And Measures:
Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated. Exploratory subgroup analysis evaluating several clinical variables was performed. Safety was reported.
Results:
Overall, 114 patients with RAS/BRAF wt ctDNA mCRC (median [IQR] age, 61 [29-88] years; 66 men [57.9%]) who received anti-EGFR rechallenge as experimental therapy (48 received cetuximab plus avelumab, 26 received trifluridine-tipiracil plus panitumumab, 13 received irinotecan plus cetuximab, and 27 received panitumumab monotherapy) were included in the current analysis. Eighty-three patients (72.8%) had received 2 previous lines of therapy, and 31 patients (27.2%) had received 3 or more previous lines of therapy. The ORR was 17.5% (20 patients), and the DCR was 72.3% (82 patients). The median PFS was 4.0 months (95% CI, 3.2-4.7 months), and the median OS was 13.1 months (95% CI, 9.5-16.7 months). The subgroup of patients without liver involvement had better clinical outcomes. The median PFS was 5.7 months (95% CI, 4.8-6.7 months) in patients without liver metastasis compared with 3.6 months (95% CI, 3.3-3.9 months) in patients with liver metastasis (hazard ratio, 0.56; 95% CI, 0.37-0.83; P = .004). The median OS was 17.7 months (95% CI, 13-22.4 months) in patients without liver metastasis compared with 11.5 months (95% CI, 9.3-13.9 months) in patients with liver metastasis (hazard ratio, 0.63; 95% CI, 0.41-0.97; P = .04). Treatments showed manageable toxic effects.
Conclusions And Relevance:
These findings suggest that anti-EGFR rechallenge therapy has promising antitumor activity in patients with refractory ctDNA RAS/BRAF wt mCRC. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significant improved survival.
Trial Registration:
ClinicalTrials.gov Identifiers: NCT02296203; NCT04561336; NCT03227926; NCT05468892.
Insights
Anti-EGFR rechallenge shows promise for metastatic colorectal cancer patients with refractory ctDNA RAS/BRAF wild-type tumors. Patients without liver metastases experienced significantly improved survival outcomes.
Area of Science:
- Oncology
- Medical Genetics
Background:
- Metastatic colorectal cancer (mCRC) with circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) presents challenges for treatment efficacy.
- Limited evidence exists for anti-epidermal growth factor receptor (EGFR) inhibitor rechallenge in refractory mCRC patients.
Purpose of the Study:
- To evaluate the efficacy of anti-EGFR rechallenge therapy in patients with refractory ctDNA RAS/BRAF wt mCRC.
- To identify clinical factors associated with improved outcomes in this patient population.
Main Methods:
- A pooled analysis of individual patient data from four Italian clinical trials (CAVE, VELO, CRICKET, CHRONOS) was conducted.
- 114 patients with RAS/BRAF wt ctDNA mCRC received anti-EGFR rechallenge therapy between 2015 and 2022.
- Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were assessed.
Main Results:
- The overall response rate (ORR) was 17.5% and the disease control rate (DCR) was 72.3%.
- Median PFS was 4.0 months and median OS was 13.1 months.
- Patients without liver metastases showed significantly improved PFS (5.7 vs 3.6 months) and OS (17.7 vs 11.5 months) compared to those with liver metastases.
Conclusions:
- Anti-EGFR rechallenge therapy demonstrates promising antitumor activity in patients with refractory ctDNA RAS/BRAF wt mCRC.
- The absence of liver metastases is a significant predictor of improved survival in patients undergoing anti-EGFR rechallenge.
- Further research is warranted to optimize rechallenge strategies in mCRC.
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