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Controlled Clinical Trial
. 2024 Apr 1;7(4):e245635.
doi: 10.1001/jamanetworkopen.2024.5635.

Anti-EGFR Rechallenge in Patients With Refractory ctDNA RAS/BRAF wt Metastatic Colorectal Cancer: A Nonrandomized Controlled Trial

Davide Ciardiello  1   2 , Erika Martinelli  2 , Teresa Troiani  2 , Gianluca Mauri  3   4   5 , Daniele Rossini  6   7 , Giulia Martini  2 , Stefania Napolitano  2 , Vincenzo Famiglietti  2 , Sara Del Tufo  2 , Gianluca Masi  6   7 , Daniele Santini  8 , Antonio Avallone  9 , Filippo Pietrantonio  10 , Sara Lonardi  11 , Massimo Di Maio  12 , Maria Giulia Zampino  1 , Nicola Fazio  2 , Alberto Bardelli  5   13 , Salvatore Siena  3   4 , Chiara Cremolini  6   7 , Andrea Sartore-Bianchi  3   4 , Fortunato Ciardiello  2
Affiliations
Controlled Clinical Trial

Anti-EGFR Rechallenge in Patients With Refractory ctDNA RAS/BRAF wt Metastatic Colorectal Cancer: A Nonrandomized Controlled Trial

Davide Ciardiello et al. JAMA Netw Open. .

Erratum in

  • Error in Author Affiliation.
    [No authors listed] [No authors listed] JAMA Netw Open. 2024 May 1;7(5):e2418437. doi: 10.1001/jamanetworkopen.2024.18437. JAMA Netw Open. 2024. PMID: 38776089 Free PMC article. No abstract available.

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr D. Ciardiello reported receiving travel support from Bristol-Myers Squibb, Sanofi, and Merck KgA during the conduct of the study. Dr Martinelli reported receiving personal fees from Amgen, Merck, Sharp & Dohme, Pierre Fabre, Servier, Roche, and AstraZeneca outside the submitted work. Dr Mauri reported receiving honoraria from COR2ED outside the submitted work. Dr Rossini reported receiving honoraria from Merck, Sharp & Dohme and Amgen outside the submitted work. Dr Martini reported receiving personal fees from Servier and Incyte outside the submitted work. Dr Napolitano reported receiving personal fees from Novartis and a travel grant from Amgen outside the submitted work. Dr Avallone reported receiving personal fees from Amgen, AstraZeneca, Merck, Sharp & Dohme, Eisai, and Bristol-Myers Squibb outside the submitted work. Dr Pietrantonio reported receiving grants from Bristol-Myers Squibb, Lilly, Agenus, Amgen, Incyte, and AstraZeneca; and personal fees from AstraZeneca, Daiichi-Sankyo, Bristol-Myers Squibb, Merck, Sharp & Dohme, Takeda, Bayer, Servier, Amgen, Merck-Serono, Ipsen, Seagen, GlaxoSmithKline, Astellas, Johnson & Johnson, Rottapharm, and Pierre-Fabre outside the submitted work. Dr Lonardi reported receiving personal fees from Amgen, Astellas, AstraZeneca, Bayer, Merck-Serono, Lilly, Incyte, Daichii-Sankyo, Pierre-Fabre, GlaxoSmithKline, Merck, Sharp & Dohme, Bristol-Myers Squibb, Takeda, Servier, and Roche outside the submitted work. Dr Di Maio reported receiving personal fees from Novartis, Pfizer, Roche, Amgen, AstraZeneca, and Merck; grants from GlaxoSmithKline; and serving as a consultant for Janssen outside the submitted work. Dr Fazio reported receiving research funds from and serving on an advisory board for Merck outside the submitted work. Dr Bardelli reported receiving grants from AstraZeneca, Boehringer-Ingelheim, and Neophore; receiving honoraria and consultation fees from Guardant Health and Inivata outside the submitted work; being a stock shareholder of Neophore and Kither Biotech; and serving on the advisory boards for Inivata, Neophore, and Roche/Genentech outside the submitted work. Dr Siena reported serving on advisory boards for Agenus, AstraZeneca, Bristol-Myers Squibb, CheckMab, Daiichi-Sankyo, GlaxoSmithKline, Seagen, and T-One Therapeutics outside the submitted work. Dr Cremolini reported receiving grants and personal fees from Merck and Amgen outside the submitted work. Dr Sartore-Bianchi reported receiving personal fees from Amgen, Bayer, Novartis, Servier, and Pierre-Fabre outside the submitted work. Dr F. Ciardiello reported receiving grants from Roche, Servier, Pierre-Fabre, Amgen, Merck, Sharp & Dohme, Pfizer, Merck KGgA, and Takeda during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Enrollment Flowchart
CAVE indicates Avelumab Plus Cetuximab in Pre-treated RAS Wild Type Metastatic Colorectal Cancer; CHRONOS, Rechallenge With Panitumumab Driven by RAS Dynamic of Resistance; CRICKET, Cetuximab Rechallenge in Irinotecan-pretreated mCRC, KRAS, NRAS and BRAF Wild-type Treated in 1st Line With Anti-EGFR Therapy; ctDNA, circulating tumor DNA; IPD, individual patient data; VELO, Phase II Randomized Study Evaluating the Efficacy of Panitumumab (Vectibix) and Trifluridine-Tipiracil (Lonsurf) in Pretreated RAS Wild Type Metastatic Colorectal Cancer Patients.
Figure 2.
Figure 2.. Kaplan-Meier Survival Curves for All Patients
Graphs show progression-free survival (A) and overall survival (B). The median progression-free survival 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). Numbers in parentheses denote censored patients.
Figure 3.
Figure 3.. Kaplan-Meier Survival Curves According to the Presence of Liver Metastasis
Graphs show progression-free survival (A) and overall survival (B). The median progression-free survival was 5.7 months (95% CI, 4.8-6.7 months) for patients without liver metastasis and 3.6 months (95% CI, 3.3-3.9 months) for patients with liver metastasis (hazard ratio, 0.56; 95% CI, 0.37-0.83). The median overall survival was 17.7 months (95% CI, 13.0-22.4 months) for patients without liver metastasis and 11.5 months (95% CI, 9.3-13.9 months) for patients with liver metastasis (hazard ratio, 0.63; 95% CI, 0.41-0.97). Numbers in parentheses denote censored patients.
See this image and copyright information in PMC

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