Editor’s Note:
The European Society for Medical Oncology (ESMO) annual meeting in Madrid, Spain has proceeded as scheduled. “Oncology Frontier” has selected key research reported at ESMO 2023 for commentary by domestic experts. Professor Xinxiang Li from Fudan University Affiliated Tumor Hospital shared insights and reflections on the challenges of rechallenging with EGFR inhibitors in refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type metastatic colorectal cancer (mCRC).
Abstract:
559MO – Rechallenge with EGFR Inhibitors in ctDNA RAS/BRAF Wild-Type Refractory Metastatic Colorectal Cancer: Individual Patient Data Pooled Analysis from Four Phase II Trials.
Background:
The rechallenge with EGFR inhibitors in refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients has demonstrated clinical activity and is listed as a therapeutic option in clinical guidelines. However, existing evidence (Level III C) is derived from small retrospective/prospective studies.
Methods:
Individual patient data were pooled and analyzed from the CAVE, VELO, CRICKET, and CHRONOS trials, focusing on ctDNA RAS/BRAF wild-type patients receiving anti-EGFR rechallenge therapy. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated. Safety information was reported.
Results:
In total, 114 out of 194 baseline plasma ctDNA RAS/BRAF wild-type patients underwent anti-EGFR rechallenge as experimental treatment (48 with cetuximab plus avelumab, 26 with trifluridine/tipiracil and panitumumab, 13 with irinotecan and cetuximab, and 27 with panitumumab) and were included in the analysis. The study population included a substantial number of pretreated patients: 83/114 (72.8%) and 31/114 (27.2%) had received EGFR inhibitors as third-line or later treatment rechallenge. The median PFS (mPFS) and median OS (mOS) were 4.0 months (95% CI: 3.2~4.7) and 13.1 months (95% CI: 9.5~16.7), respectively. One patient achieved complete response (CR), 19 achieved partial response (PR), 65 and 29 were assessed as stable disease (SD) and disease progression as best response, respectively. The ORR (CR+PR) was 17.5% (20/114), and the DCR (CR+PR+SD) was 74.6% (85/114). Almost one-third of patients significantly benefited from anti-EGFR rechallenge therapy (6-month PFS rate of 32.5%; 18-month survival rate of 31.6%). The treatment exhibited manageable toxicity consistent with previous findings.
Conclusion:
The results of this individual patient data pooled analysis indicate that the rechallenge with EGFR inhibitors has good clinical activity, with nearly one-third of patients experiencing prolonged PFS, leading to an extension in overall survival. Therefore, EGFR inhibitor-based rechallenge strategies may be considered as a therapeutic option in the continuous treatment of refractory ctDNA RAS/BRAF wild-type mCRC patients. (Trial information: NCT05291156; NCT05468892; NCT02296203; NCT03227926)
Professor Xinxiang Li’s Commentary:
This study focuses on the efficacy of EGFR inhibitors in the treatment of ctDNA RAS/BRAF wild-type mCRC patients, integrating survival data from the CAVE, VELO, CRICKET, and CHRONOS clinical studies. Out of 194 ctDNA-positive RAS/BRAF wild-type patients, 114 received treatment with EGFR inhibitors. Among them, 72.8% and 27.2% of patients received EGFR inhibitors as experimental treatment after failure of third-line or earlier therapy. The median PFS and median OS were 4.0 months (95% CI: 3.2~4.7) and 13.1 months (95% CI: 9.5~16.7), respectively. One patient achieved complete response (CR), 19 achieved partial response (PR), 65 and 29 were assessed as stable disease (SD) and disease progression as the best response, respectively. Approximately one-third of patients benefited significantly from EGFR inhibitor treatment (6-month PFS rate of 32.5%; 18-month survival rate of 31.6%), and treatment-related toxicities were manageable.
This data provides new insights into the treatment of metastatic colorectal cancer patients. Since plasma ctDNA testing has good consistency with tissue testing, the question arises whether ctDNA testing could replace tissue-based gene testing for guiding treatment. Additionally, for colorectal cancer patients previously treated with EGFR inhibitors, the potential benefit of reusing EGFR inhibitors based on ctDNA testing results represents a rechallenge for metastatic colorectal cancer patients, offering new hope for some refractory colorectal cancer patients.
However, it is important to note that these data are selected from multiple small-sample retrospective or prospective clinical trials, and further validation is urgently needed through large-sample prospective clinical trials.
559MO – Rechallenge with EGFR inhibitors in ctDNA RAS/BRAF wild type refractory metastatic colorectal cancer: Individual patients’ data pooled analysis from 4 phase II trials
Background
Rechallenge with anti-EGFR inhibitors demonstrated clinical activity in patients (pts) with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild type (wt) metastatic colorectal cancer (mCRC) and it is included as an option in clinical guidelines. However, the available evidence (III C) is derived from small retrospective/prospective studies.
Methods
We conducted an individualized patients’ data pooled analysis of pts enrolled in the CAVE, VELO, CRICKET and CHRONOS trials treated with anti-EGFR rechallenge with RAS/BRAF wt ctDNA. Overall survival (OS), progression free survival (PFS), overall response rate (ORR) and disease control rate (DCR) were calculated. Safety was reported.
Results
Overall, 114/194 pts that received anti-EGFR rechallenge as experimental therapy (48 cetuximab plus avelumab, 26 trifluridine/tipiracil plus panitumumab, 13 irinotecan plus cetuximab and 27 panitumumab) had RAS/BRAF wt baseline plasma ctDNA and were included in the current analysis. The study population included heavily pre-treated pts: 83/114 (72.8%) and 31/114 (27.2%) pts received rechallenge with EGFR inhibitors as third- or later lines of treatment, respectively. Median PFS (mPFS) and median OS (mOS) were 4.0 months (95% CI, 3.2-4.7) and 13.1 months (95% CI, 9.5-16.7). One patient achieved complete response (CR), 19 pts displayed partial response (PR), while 65 and 29 had stable disease (SD) and progressive disease as best response, respectively. The ORR (CR+PR) was 17.5% (20/114); DCR (CR+PR+SD) was 74.6% (85/114). Almost one of three pts significantly benefited from anti-EGFR rechallenge therapy (6-months PFS rate, 32.5%; 18-months OS rate, 31.6%). Treatments showed manageable toxicity, in lines with previous findings.
Conclusions
Results of this individual patients’ pooled analysis demonstrate promising clinical activity of rechallenge with EGFR inhibitors with nearly one-third of the pts experiencing long PFS that lead to prolonged survival. Thus, rechallenge with anti-EGFR-based strategies might be considered as a therapeutic option in the continuum of care of pts with refractory ctDNA RAS/BRAF wt mCRC.
Clinical trial identification
NCT05291156; NCT05468892; NCT02296203; NCT03227926.
References:
[1] S. Napolitano et al., “CAVE-2 (Cetuximab-AVElumab) mCRC: A Phase II Randomized Clinical Study of the Combination of Avelumab Plus Cetuximab as a Rechallenge Strategy in Pre-Treated RAS/BRAF Wild-Type mCRC Patients.,” Front. Oncol., vol. 12, p. 940523, 2022, doi: 10.3389/fonc.2022.940523.
[2] S. Napolitano et al., “Panitumumab Plus Trifluridine-Tipiracil as Anti-Epidermal Growth Factor Receptor Rechallenge Therapy for Refractory RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial.,” JAMA Oncol., vol. 9, no. 7, pp. 966–970, Jul. 2023, doi: 10.1001/jamaoncol.2023.0655.
[3] C. Cremolini et al., “Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan: A Phase 2 Single-Arm Clinical Trial.,” JAMA Oncol., vol. 5, no. 3, pp. 343–350, Mar. 2019, doi: 10.1001/jamaoncol.2018.5080.
[4] A. Sartore-Bianchi et al., “Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial.,” Nat. Med., vol. 28, no. 8, pp. 1612–1618, Aug. 2022, doi: 10.1038/s41591-022-01886-0.
[5] M. Loft, Y. H. To, P. Gibbs, and J. Tie, “Clinical application of circulating tumour DNA in colorectal cancer.,” lancet. Gastroenterol. Hepatol., vol. 8, no. 9, pp. 837–852, Sep. 2023, doi: 10.1016/S2468-1253(23)00146-2.
Professor Xinxiang Li
Director, Department of Colorectal Surgery, Fudan University Affiliated Tumor Hospital
Director, Chinese Society of Clinical Oncology (CSCO)
Deputy Director, CSCO Minimally Invasive Oncology Surgery Committee
Lead Author, CSCO Colorectal Cancer Diagnosis and Treatment Guidelines
Chairman, Colorectal Cancer Professional Committee, China Primary Healthcare Foundation
Deputy Director, Chinese Research Hospital Association Colorectal and Anal Surgery Committee
Standing Committee Member, Chinese Medical Association Coloproctologist Branch
Chairman, Colorectal Cancer Comprehensive Treatment Committee, Chinese Medical Association Coloproctologist Branch
Chairman, Integrative Chinese and Western Medicine Society General Surgery Committee Rectal Cancer Prevention and Treatment Expert Committee
Deputy Director, Chinese Medical Association Colorectal Tumor Committee Laparoscopic Committee
Chairman, Shanghai Anti-Cancer Association Gastrointestinal Tumor Laparoscopic Professional Committee
Director, Shanghai Anti-Cancer Association Tumor Minimally Invasive Committee Laparoscopic Surgery Group
Vice President, International Colorectal Cancer Association (ICRCC) China Branch
