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

Davide Ciardiello; Erika Martinelli; Teresa Troiani; Gianluca Mauri; Daniele Rossini; Giulia Martini; Stefania Napolitano; Vincenzo Famiglietti; Sara Del Tufo; Gianluca Masi; Daniele Santini; Antonio Avallone; Filippo Pietrantonio; Sara Lonardi; Massimo Di Maio; Maria Giulia Zampino; Nicola Fazio; Alberto Bardelli; Salvatore Siena; Chiara Cremolini; Andrea Sartore-Bianchi; Fortunato Ciardiello

doi:10.1001/jamanetworkopen.2024.5635

. 2024 Apr 9;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 ¹, Alberto Bardelli ^5,¹³, Salvatore Siena ^3,⁴, Chiara Cremolini ^6,⁷, Andrea Sartore-Bianchi ^3,⁴, Fortunato Ciardiello ²

¹Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy

²Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy

³Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milano, Italy

⁴Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milano, Italy

⁵IFOM ETS–The AIRC Institute of Molecular Oncology, Milan, Italy

⁶Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

⁷Division of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

⁸Medical Oncology Department, La Sapienza University of Rome, Rome, Italy

⁹Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori–IRCCS–Fondazione G. Pascale, Napoli, Italy

¹⁰Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

¹¹Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy

¹²Department of Oncology, University of Turin, Molinette Hospital, Turin, Italy

¹³Department of Oncology, Università degli Studi di Torino, Turin, Italy

Accepted for Publication: February 12, 2024.

Published: April 9, 2024. doi:10.1001/jamanetworkopen.2024.5635

Correction: This article was corrected on May 22, 2024, to fix Nicola Fazio’s affiliation.

^✉

Corresponding Author: Davide Ciardiello, MD, PhD, Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Via Ripamonti 435, Milan 20141, Italy (davide.ciardiello@ieo.it).

Author Contributions: Drs D. Ciardiello and F. Ciardiello had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: D. Ciardiello, Masi, Bardelli, F. Ciardiello.

Acquisition, analysis, or interpretation of data: D. Ciardiello, Martinelli, Troiani, Mauri, Rossini, Martini, Napolitano, Famiglietti, Del Tufo, Masi, Santini, Avallone, Pietrantonio, Lonardi, Di Maio, Zampino, Fazio, Siena, Cremolini, Sartore-Bianchi.

Drafting of the manuscript: D. Ciardiello, Mauri, Rossini, F. Ciardiello.

Critical review of the manuscript for important intellectual content: D. Ciardiello, Martinelli, Troiani, Mauri, Martini, Napolitano, Famiglietti, Del Tufo, Masi, Santini, Avallone, Pietrantonio, Lonardi, Di Maio, Zampino, Fazio, Bardelli, Siena, Cremolini, Sartore-Bianchi, F. Ciardiello.

Statistical analysis: D. Ciardiello, Famiglietti.

Obtained funding: Bardelli.

Administrative, technical, or material support: Rossini, Masi, Siena, F. Ciardiello.

Supervision: Martinelli, Troiani, Martini, Napolitano, Masi, Santini, Avallone, Lonardi, Zampino, Fazio, Cremolini, Sartore-Bianchi, F. Ciardiello.

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.

Funding/Support: This study was supported by Merck KGaA, Amgen, Servier, and Regione Campania (I-Cure Research Project, grant Cup 21C17000030007). The research leading to these results has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (TARGET, grant 101020342 to Dr Bardelli); Associazione Italiana Ricerca sul Cancro (AIRC) under 5 per Mille 2018 (ID 21091 program, principal investigator Dr Bardelli); AIRC under investigator grant 2018 (ID 21923 project, principal investigator Dr Bardelli); International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (grants A26825 and A28223), FC AECC (grant GEACC18004TAB), and AIRC (grant 22795 to Dr Bardelli); and IMI (contract 101007937 PERSIST-SEQ to Dr Bardelli).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the patients and their families who participated in the clinical trials and all the investigators. We thank Gruppo Oncologico dell’Italia Meridionale, a nonprofit group that had a fundamental role in the conduct of the CAVE trial, for supporting the current study.

^✉

Corresponding author.

PMCID: PMC11004834 PMID: 38592721

Key Points

Question

Is rechallenge with anti–epidermal growth factor receptor (EGFR) inhibitors a therapeutic option in patients with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) colorectal cancer (CRC)?

Findings

This nonrandomized controlled trial used a pooled analysis of individual patient data from 114 patients with ctDNA RAS/BRAF wt metastatic CRC receiving anti-EGFR rechallenge therapy in 4 prospective, phase 2 Italian trials. The treatment strategy was associated with tumor shrinkage, a high rate of disease control, and promising progression-free and overall survival, with a significant improvement in patients without liver involvement.

Meaning

These findings suggest that rechallenge with anti-EGFR inhibitors has promising antitumor activity in patients with refractory ctDNA RAS/BRAF wt metastatic CRC.

This nonrandomized controlled trial evaluates anti–epidermal growth factor receptor (EGFR) rechallenge therapy in patients in Italy with circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) metastatic colorectal cancer.

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

Introduction

Treatment with anti–epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in combination with chemotherapy is a standard of care as first-line treatment for patients with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC).¹ Despite an initial antitumor activity with high overall response rate (ORR), disease progression almost inevitably occurs as a result of cancer cells acquiring resistance.^2,3

It is well known that the most frequent resistance alterations are associated with the EGFR signaling cascade, such as the EGFR extracellular domain (ECD) or alterations in downstream effectors like KRAS/NRAS and BRAF. Nevertheless, the spectrum of the molecular alterations may change over time depending on the treatment received. By use of serial liquid biopsy of circulating tumor DNA (ctDNA) status, it has been shown that RAS/BRAF/EGFR ECD alteration cancer cell clones have a half-life of approximately 4 months.^4,5 Therefore, after disease progression, during a so-called anti-EGFR therapeutic holiday, resistant clones might decay, thereby potentially restoring sensitivity to EGFR blockade.^3,4,5 Consequently, over the last decade, different groups have investigated the role of anti-EGFR rechallenge therapy in patients with refractory RAS wt mCRC.^{6,7,8,9,10,11,12,13,14,15,16} The main clinical criteria for patient selection in these trials were receiving an anti-EGFR–based therapy, experiencing a clinical benefit followed by progressive disease, and then receiving a subsequent EGFR-free treatment. In an unselected population with refractory disease, the combination of chemotherapy with anti-EGFR rechallenge was associated with heterogenous responses, with an ORR ranging from 0% to 54%.

Translational retrospective analyses of these studies showed that patients with RAS/BRAF wt ctDNA showed the highest clinical benefit from this treatment.^{9,10,11,13,14,15} To date, the CHRONOS (Rechallenge With Panitumumab Driven by RAS Dynamic of Resistance) trial, in which patients with RAS/BRAF wt mCRC with received panitumumab rechallenge, is the only study that prospectively used liquid biopsy for patient selection.¹²

Despite the strong rationale, the quality of the available evidence on the role of anti-EGFR rechallenge in ctDNA RAS/BRAF wt tumors is poor, because it has been mainly derived via post hoc analysis performed with limited numbers of patients. Consequently, caution is required when interpreting these results, and further validation is needed. Moreover, in a molecularly selected population, the identification of other variables potentially associated with clinical activity represents an unmet need.

To fill this gap, we conducted a pooled analysis of individual patient data (IPD) from 4 prospective phase 2 trials. Only patients with ctDNA RAS/BRAF wt tumors confirmed by liquid biopsy at baseline were included. Finally, exploratory subgroup analyses were performed to identify further potential biomarkers.

Methods

Study Population

In this nonrandomized controlled trial, we conducted a pooled analysis of IPD from 4 multicenter, phase 2 studies: CRICKET (Cetuximab Rechallenge in Irinotecan-pretreated mCRC, KRAS, NRAS and BRAF Wild-type Treated in 1st Line With Anti-EGFR Therapy), CAVE (Avelumab Plus Cetuximab in Pre-treated RAS Wild Type Metastatic Colorectal Cancer), CHRONOS, and VELO (Phase II Randomized Study Evaluating the Efficacy of Panitumumab [Vectibix] and Trifluridine-Tipiracil [Lonsurf] in Pretreated RAS Wild Type Metastatic Colorectal Cancer Patients) trials. Patients who received rechallenge with EGFR inhibitors and exhibited RAS/BRAF wt ctDNA tumors at baseline were included.

The 4 studies were conducted in accordance with the principles of the Declaration of Helsinki¹⁷ and were approved by the ethical committees of all participating centers. Patients provided written informed consent for trial participation. This study followed the Transparent Reporting of Evaluations With Nonrandomized Designs (TREND) reporting guideline.

The CRICKET study was a single-group phase 2 trial that investigated rechallenge with cetuximab plus irinotecan as third-line treatment in patients with RAS/BRAF wt mCRC.⁹ The study provided the first prospective evidence of rechallenge therapy in refractory mCRC. Post hoc analysis showed that confirmed responses were observed only in patients without resistance alterations detected at liquid biopsy analysis. The CAVE trial was a single-group, multicenter, phase 2 study that evaluated rechallenge with cetuximab plus the anti–programmed cell death ligand 1 mAbs avelumab in patients with heavily pretreated RAS wt mCRC.¹¹ The study met its primary end point, and an increase in survival of more than 3 months compared with historical controls was reported. The CHRONOS study was the first trial that prospectively selected patients amenable for rechallenge therapy with panitumumab on the basis of the results of liquid biopsy using highly sensitive digital droplet polymerase chain reaction (ddPCR) to detect RAS/BRAF/EGFR ECD alterations in the plasma.¹² The trial was positive, with an ORR of 30%. The VELO trial was a randomized phase 2 study that compared rechallenge with panitumumab plus trifluridine-tipiracil vs trifluridine-tipiracil as third-line treatment in RAS wt mCRC.^13,14 The trial reached its primary end point, demonstrating a significant increase in progression-free survival (PFS) of the experimental group compared with the standard of care. The full study protocols with inclusion and exclusion criteria have been previously published^{9,11,12,13,14} and are shown in Supplement 1.

The procedure for patient selection is displayed in Figure 1. Among the 194 patients enrolled in the 4 trials, 80 patients did not meet the inclusion criteria (ie, having received an anti-EGFR rechallenge treatment with baseline RAS/BRAF alteration ctDNA at liquid biopsy analysis) and were excluded. In the group of patients not eligible for the current analysis, 15 were from the CRICKET trial (3 were not evaluable for tumor response, and 12 showed RAS/BRAF alteration ctDNA), 29 from the CAVE trial (10 did not have available baseline plasma samples, and 19 displayed RAS/BRAF alteration ctDNA), and 36 from the VELO trial (31 did not receive anti-EGFR rechallenge, and 5 exhibited RAS/BRAF alteration ctDNA). To facilitate data gathering and analysis, a study data set including key information from the 4 trials was set up. The following data were extrapolated from each trial: age, sex, Eastern Cooperative Oncology Group performance status, primary tumor sidedness, resection of primary tumor, microsatellite status, number of previous lines of treatment, type of anti-EGFR treatment received as first-line or second-line therapy, number of metastatic sites, metastasis location (liver, lung, peritoneum, and lymph nodes), carcinoembryonic antigen levels, treatment efficacy (ORR, PFS, and overall survival [OS]), and toxic effects.

Efficacy and Safety of the Treatments

The ORR was defined as the percentage of patients who achieved complete or partial response during treatment according to RECIST version 1.1.¹⁸ PFS was defined as the time from the initiation of study treatment to disease progression or death. OS was determined as the time from the beginning of the experimental therapy to death. In the absence of events, PFS and OS were censored at the time of last follow-up.

Tumor measurements were done at baseline and were repeated every 8 weeks in the CRICKET, CHRONOS, and VELO studies. In the CAVE trial, tumor measurements were performed at baseline, and every 8 weeks for the first 40 weeks and subsequently every 12 weeks. Adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0 for CRICKET, version 4.03 for CAVE and CHRONOS, and version 5.0 for VELO studies.¹⁹

Molecular Analysis

In the CRICKET study, baseline plasma samples were available for 25 patients and were analyzed using the next-generation sequencing Ion AmpliSeq Cancer Hotspot Panel (Thermo Fisher).⁷ For the CAVE trial, pretreatment plasma samples were collected for 67 patients and were analyzed using a reverse transcriptase–PCR test (IdyllaTM Biocartis platform).^11,20 In the CHRONOS trial, baseline liquid biopsy analysis was performed during the screening procedures. Overall, ctDNA from 52 patients was assessed using a ddPCR-based assay (Bio-Rad) for the identification of the most frequent KRAS, BRAF, and EGFR ECD alterations. Finally, for the 31 patients enrolled in the VELO trial who received rechallenge therapy, ctDNA was retrospectively evaluated using the IdyllaTM Biocartis assay.^13,14,20

Statistical Analysis

Descriptive statistics were used to summarize clinical and pathological outcomes. The Kaplan-Meier method was used to estimate PFS and OS. The subgroup exploratory analyses were conducted by using the Cox hazard ratio (HR) regression model. Comparison of treatment efficacy in the patient subgroups with or without liver metastases was performed with the log-rank test for PFS and OS. Statistical analyses were performed using SPSS statistical software version 23.0 (IBM). The threshold for statistical significance was set at 2-sided P < .05.

Results

Patient Characteristics

Overall, 114 patients (median [IQR] age, 61 [29-88] years; 66 men [57.9%]) met the specified criteria and were included in the pooled data set: 13 patients from the CRICKET trial received irinotecan plus cetuximab, 48 patients from the CAVE trial received cetuximab plus avelumab, 27 patients from the CHRONOS trial received panitumumab monotherapy, and 26 patients from the VELO trial received trifluridine-tipiracil plus panitumumab. Baseline clinical characteristics of the study population are detailed in Table 1. Eighty-three patients (72.8%) received 2 previous lines of therapy, and 31 (27.2%) patients received 3 or more anticancer treatments. In total, 36 patients (31.6%) had 3 or more different metastatic sites. Liver was the most frequent metastatic site (72 patients [63.2%]), followed by lung (63 patients [55.3%]), lymph nodes (47 patients [41.2%]), and peritoneum (26 patients [22.8%]). Increased carcinoembryonic antigen levels (>5 ng/mL; to convert to micrograms per liter, multiply by 1.0) were reported in 76 patients (66.7%). The type of previous anti-EGFR treatment was balanced in the study population; 57 patients (50.0%) received cetuximab, 56 patients (49.0%) received panitumumab, and 1 patient (0.9%) received both drugs.

Table 1. Baseline Characteristics of Patients With Metastatic Colorectal Cancer Receiving Anti-EGFR Challenge Therapy in 4 Italian Trials.

Characteristic	Patients, No. (%)
Characteristic	CRICKET (n = 13)	CAVE (n = 48)	VELO (n = 26)	CHRONOS (n = 27)	Pooled analysis (N = 114)
Sex
Female	4 (30.8)	23 (47.9)	10 (38.5)	11 (40.7)	48 (42.1)
Male	9 (69.2)	25 (52.1)	16 (61.5)	16 (59.3)	66 (57.9)
Age, median (IQR), y	68 (45-86)	60 (30-88)	63 (39-81)	59 (29-78)	61 (29-88)
Eastern Cooperative Oncology Group performance status
0	10 (76.9)	34 (70.8)	18 (69.2)	14 (51.9)	76 (66.7)
1	2 (15.4)	14 (29.2)	8 (30.8)	12 (44.4)	36 (31.6)
2	1 (7.7)	0	0	1 (3.7)	2 (1.8)
Tumor sidedness
Right rectum	3 (23.1)	1 (2.1)	1 (3.8)	5 (18.5)	10 (8.8)
Left rectum	10 (76.9)	47 (97.9)	25 (96.2)	22 (81.5)	104 (91.2)
Resection of primary tumor
No	1 (7.7)	16 (33.3)	4 (15.4)	2 (7.2)	23 (20.2)
Yes	12 (92.3)	32 (66.7)	22 (84.6)	25 (92.6)	91 (79.8)
Microsatellite status
Microsatellite stable	0	44 (91.7)	12 (46.2)	27 (100.0)	83 (72.8)
Microsatellite instable	0	2 (4.2)	1 (3.8)	0	3 (2.6)
NA	13 (100.0)	2 (4.2)	13 (50)	0	28 (24.6)
No. of previous lines of treatment
2	13 (100.0)	33 (68.8)	26 (100.0)	11 (40.7)	83 (72.8)
≥3	0	15 (31.3)	0	16 (59.3)	31 (27.2)
Previous anti-EGFR treatment
Panitumumab	0	25 (52.1)	17 (65.4)	15 (55.6)	57 (50.0)
Cetuximab	13 (100.0)	23 (47.9)	9 (34.6)	11 (40.7)	56 (49.1)
Both	0	0	0	1 (3.7)	1 (0.9)
No. of metastatic sites
≤2	8 (61.5)	32 (66.7)	20 (76.9)	18 (66.7)	78 (68.4)
>2	5 (38.5)	16 (33.3)	6 (23.1)	9 (33.3)	36 (31.6)
Liver metastasis
No	3 (23.1)	18 (37.5)	10 (38.5)	11 (40.7)	42 (36.8)
Yes	10 (76.9)	30 (62.5)	16 (61.5)	16 (59.3)	72 (63.2)
Lung metastasis
No	8 (61.5)	16 (33.3)	13 (50.0)	14 (51.9)	51 (44.7)
Yes	5 (38.5)	32 (66.7)	13 (50.0)	13 (48.1)	63 (55.3)
Peritoneal metastasis
No	9 (69.2)	36 (75.0)	21 (80.8)	22 (81.5)	88 (77.2)
Yes	4 (30.8)	12 (25.0)	5 (19.2)	5 (18.5)	26 (22.8)
Lymph node metastasis
No	7 (53.8)	29 (60.4)	21 (80.8)	10 (37.0)	67 (58.8)
Yes	6 (46.2)	19 (39.6)	5 (19.2)	17 (63.0)	47 (41.2)
Carcinoembryonic antigen level
<5 ng/mL	1 (7.7)	7 (14.6)	3 (11.5)	5 (18.5)	16 (14.0)
≥5 ng/mL	11 (84.6)	24 (50.0)	20 (76.9)	21 (77.8)	76 (66.7)
NA	1 (7.7)	17 (35.4)	3 (11.5)	1 (3.7)	22 (19.3)

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Abbreviations: CAVE, 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; EGFR, epidermal growth factor receptor; NA, not available; VELO, Phase II Randomized Study Evaluating the Efficacy of Panitumumab (Vectibix) and Trifluridine-Tipiracil (Lonsurf) in Pretreated RAS Wild Type Metastatic Colorectal Cancer Patients.

SI conversion factor: To convert carcinoembryonic antigen to micrograms per liter, multiply by 1.0.

Efficacy and Safety Analysis

The median (IQR) follow-up was 28.1 (25.8-35.0) months. The ORR in the pooled population was 17.5% (20 patients), with 1 patient who achieved complete response and 19 patients who achieved partial response (Table 2). Stable disease was observed in 65 patients (57.0%). 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) in the study population overall (Figure 2). Of note, a subset of patients experienced prolonged disease control upon anti-EGFR rechallenge therapy, with a 6-month PFS rate of 32.5% that led to an 18-month OS rate of 36.0% (eTable 1 in Supplement 2).

Table 2. Tumor Response of Patients With Metastatic Colorectal Cancer Receiving Anti–Epidermal Growth Factor Receptor Challenge Therapy in 4 Italian Trials.

Study	Patients, No. (%)
Study	Complete response	Partial response	Stable disease	Progressive disease	Overall response rate	Disease control rate
CAVE (n = 48)	1 (2.1)	3 (6.25)	31 (64.5)	13 (27.1)	4 (8.3)	35 (73.0)
VELO (n = 26)	0	3 (11.5)	18 (69.2)	5 (19.2)	3 (11.5)	21 (81.0)
CRICKET (n = 13)	0	5 (38.5)	5 (38.5)	3 (23.1)	5 (38.5)	10 (77.0)
CHRONOS (n = 27)	0	8 (30.0)	8 (30.0)	11 (41.0)	8 (30.0)	16 (59.3)
Pooled analysis (N = 114)	1 (0.9)	19 (16.7)	65 (57.0)	32 (28.0)	20 (17.5)	82 (72.3)

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Abbreviations: CAVE, 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; 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. — 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.

Subsequently, we conducted an exploratory subgroup analysis to evaluate the association of several clinical variables (including performance status, number of previous line of treatments, tumor burden, resection of primary tumor, primary tumor sidedness, location of metastatic sites, and carcinoembryonic antigen) with treatment outcomes (eFigure 1 and eFigure 2 in Supplement 2). The absence of liver metastases was the only variable associated with improved PFS and OS. In the subgroup of patients without liver metastasis, the median PFS was 5.7 months (95% CI, 4.8-6.7 months) compared with 3.6 months (95% CI, 3.3-3.9 months) in patients with liver metastases (HR, 0.56; 95% CI, 0.37-0.83; P = .004) (Figure 3A). The median OS was 17.7 months (95% CI, 13-22.4 months) in patients without liver metastases compared with 11.5 months (95%, CI 9.3-13.9 months) in patients with liver metastases (HR, 0.63; 95% CI, 0.41-0.97; P = .04) (Figure 3B). Finally, in patients without liver involvement, the 12-month PFS rate was 21.0%, whereas the 30-month OS rate was 21.6% (eTable 2 in Supplement 2).

Figure 3. — 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.

The safety profiles of the pooled analysis of the 4 clinical trials were in line with previous findings and were manageable (eTable 3 in Supplement 2). Skin rash (grade 3-4, 24 patients [21%]) and diarrhea (grade 3-4, 9 patients [8%]) were the most frequent adverse events related to the use of anti-EGFR mAbs. Grade 3 to 4 neutropenia was observed in 19 patients (17%), only among the 39 patients who received a backbone chemotherapy.

Discussion

Over the last 2 decades, the identification of the molecular factors underlying disease and the clinical development of more effective treatments have led to substantial improvement in the treatment of patients with mCRC.²¹ Now, after progression to first-line and second-line therapies, more than one-half of patients maintain good performance status and are amenable to receiving further therapies.^22,23

In the continuum of care for mCRC, even in later lines of treatment, fluoropyrimidine-based therapies and the blockade of angiogenesis are the main therapeutic choices.^24,25,26,27 The use of the antiangiogenic drugs regorafenib and fruquintinib, or the chemotherapy compound trifluridine-tipiracil, is associated with a modest but significant clinical benefit compared with placebo.^24,26,27 To date, SUNLIGHT is the only randomized phase 3 trial that demonstrated an improvement in both PFS and OS over an active treatment in patients with chemorefractory mCRC.²⁵

In this scenario, novel and more effective therapeutic options are required. To answer to this unmet need, in this nonrandomized controlled trial, we conducted a pooled analysis of IPD from patients enrolled in 4 prospective Italian phase 2 studies that investigated different anti-EGFR rechallenge strategies.^{9,11,12,13,14} Because the presence of RAS/BRAF alterations at baseline liquid biopsy is associated with unresponsiveness to anti-EGFR mAbs, only patients with plasma ctDNA RAS/BRAF wt mCRC were included in this analysis. Here we provide evidence based on the largest data set available that anti-EGFR rechallenge therapy exerts antitumor activity.

The expected survival for patients with refractory mCRC who received trifluridine-tipiracil, regorafenib, or fruquintinib as single agents is approximately 7 to 9 months, whereas patients who were treated with trifluridine-tipiracil plus bevacizumab as third-line therapy had a median OS of 10.8 months.^22,24,26,27 Furthermore, the available options display mainly a cytostatic activity (ORR, 1%-6%).^24,25,26,27 With all the limitations for indirect cross-trial comparisons, in this study we report an OS longer than 12 months, with approximately one-third of the patients experiencing long survival (approximately 18 months).

In the study population, anti-EGFR rechallenge therapy was administered as third or later line of treatment. Interestingly, no difference in terms of survival was observed between patients according to the number of previous lines of therapies. Moreover, in this heavily pretreated population, anti-EGFR rechallenge achieved an ORR of 17.5% and a DCR of 72.3%. Thus, in a potential real clinical scenario, ctDNA-associated rechallenge with EGFR inhibitors could be considered following progression to trifluridine-tipiracil plus bevacizumab or an option as third-line treatment if tumor shrinkage is required. Further evidence regarding the optimal timing of anti-EGFR rechallenge therapy in the continuum of care of refractory mCRC will be provided by the results of the currently ongoing PARERE trial.²⁸ Overall, more than 200 patients with ctDNA RAS/BRAF wt tumors will be randomly assigned to receive either panitumumab as third-line treatment followed by regorafenib at disease progression or the reverse sequence.

To better elucidate the role of potential factors involved in each treatment’s efficacy, we conducted an exploratory analysis investigating. The absence of liver metastasis was associated with a significantly longer median PFS and OS. Remarkably, 1 of 5 patients was still progression free at 12 months and alive beyond 30 months. Of course, owing to the nature of this subgroup analysis, these data require further confirmation by larger prospective trials. If confirmed, prospective translational and so-called multi-omics studies (ie, studies using data types derived from different research areas, such as genomics, epigenomics, transcriptomics, proteomics and metabolomics) are required to identify the subset of patients with liver metastases who could respond to anti-EGFR treatment.

Limitations

Our study has several limitations that are intrinsic to its design. First, this pooled analysis has included patients who were enrolled in 4 phase 2 studies administering different therapies, which could have influenced clinical outcomes. In this respect, no evidence is currently available regarding the best anti-EGFR rechallenge regimen. To address this question, our group is currently conducting the CAVE-2 trial, a randomized phase 2 trial, that compares rechallenge with cetuximab plus avelumab vs cetuximab as single agent in patients with refractory plasma ctDNA RAS/BRAF wt microsatellite stable mCRC.²⁹ Second, distinct liquid biopsy tests with different sensitivity thresholds and different panels were used for ctDNA analysis in the 4 trials. In the CHRONOS trial, a highly sensitive ddPCR was used, and only patients with 0 RAS/BRAF/EGFR ECD alteration in ctDNA were included.¹² For the CAVE and VELO trials, the IdyllaTM Biocartis platform was used.²⁰ Nevertheless, the issue of what is the real impact of a very low alteration allele fraction on anti-EGFR drug response is still debated.^30,31 Third, alterations other than RAS/BRAF, such as EGFR ECD, MAP2K1, and ERBB2 alterations or amplification, could constitute mechanisms of cancer cell resistance to EGFR blockade.^{32,33,34,35,36} Future trials using larger next-generation sequencing panels for patient selection will contribute to answer this question.³⁷ Fourth, because of the single-group design of the CRICKET, CAVE, and CHRONOS trials and the reduced number of patients included in the control group of the VELO study, no direct comparison with other therapeutic options could be performed. Fifth, we were not able to evaluate the impact of the burden of hepatic disease (number and dimension of liver metastases) on treatment efficacy. These results should be considered as exploratory and hypothesis generating.

Conclusions

In this pooled analysis of IPD from 4 phase 2 trials, anti-EGFR rechallenge therapy showed a promising antitumor activity in patients with refractory RAS/BRAF wt tumors as confirmed by liquid biopsy. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significantly improved survival. Further randomized studies are currently ongoing to confirm these results.

Supplement 1.

Trial Protocols

jamanetwopen-e245635-s001.pdf^{(6.6MB, pdf)}

Supplement 2.

eFigure 1. Forest Plot of Progression Free Survival in Different Subgroup

eFigure 2. Forest Plot of Overall Survival (OS) in Different Subgroup

eTable 1. Progression Free and Overall Survival Rate in the Study Population

eTable 2. Progression Free and Overall Survival Rate According to the Presence of Liver Metastasis

eTable 3. Adverse Events

jamanetwopen-e245635-s002.pdf^{(1MB, pdf)}

Supplement 3.

Data Sharing Statement

jamanetwopen-e245635-s003.pdf^{(15.1KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocols

jamanetwopen-e245635-s001.pdf^{(6.6MB, pdf)}

Supplement 2.

eFigure 1. Forest Plot of Progression Free Survival in Different Subgroup

eFigure 2. Forest Plot of Overall Survival (OS) in Different Subgroup

eTable 1. Progression Free and Overall Survival Rate in the Study Population

eTable 2. Progression Free and Overall Survival Rate According to the Presence of Liver Metastasis

eTable 3. Adverse Events

jamanetwopen-e245635-s002.pdf^{(1MB, pdf)}

Supplement 3.

Data Sharing Statement

jamanetwopen-e245635-s003.pdf^{(15.1KB, pdf)}

[zoi240225r1] 1.Cervantes A, Adam R, Roselló S, et al. ; ESMO Guidelines Committee . Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10-32. doi: 10.1016/j.annonc.2022.10.003 [DOI] [PubMed] [Google Scholar]

[zoi240225r2] 2.Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A. Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov. 2014;4(11):1269-1280. doi: 10.1158/2159-8290.CD-14-0462 [DOI] [PubMed] [Google Scholar]

[zoi240225r3] 3.Martinelli E, Ciardiello D, Martini G, et al. Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives. Ann Oncol. 2020;31(1):30-40. doi: 10.1016/j.annonc.2019.10.007 [DOI] [PubMed] [Google Scholar]

[zoi240225r4] 4.Parseghian CM, Loree JM, Morris VK, et al. Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge. Ann Oncol. 2019;30(2):243-249. doi: 10.1093/annonc/mdy509 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240225r5] 5.Siravegna G, Mussolin B, Buscarino M, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21(7):795-801. doi: 10.1038/nm.3870 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240225r6] 6.Ciardiello D, Martini G, Famiglietti V, et al. Biomarker-guided anti-EGFR rechallenge therapy in metastatic colorectal cancer. Cancers (Basel). 2021;13(8):1941. doi: 10.3390/cancers13081941 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240225r7] 7.Mauri G, Pizzutilo EG, Amatu A, et al. Retreatment with anti-EGFR monoclonal antibodies in metastatic colorectal cancer: systematic review of different strategies. Cancer Treat Rev. 2019;73:41-53. doi: 10.1016/j.ctrv.2018.12.006 [DOI] [PubMed] [Google Scholar]

[zoi240225r8] 8.Santini D, Vincenzi B, Addeo R, et al. Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance? Ann Oncol. 2012;23(9):2313-2318. doi: 10.1093/annonc/mdr623 [DOI] [PubMed] [Google Scholar]

[zoi240225r9] 9.Cremolini C, Rossini D, Dell’Aquila E, 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. 2019;5(3):343-350. doi: 10.1001/jamaoncol.2018.5080 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240225r10] 10.Sunakawa Y, Nakamura M, Ishizaki M, et al. RAS mutations in circulating tumor DNA and clinical outcomes of rechallenge treatment with anti-EGFR antibodies in patients with metastatic colorectal cancer. JCO Precis Oncol. 2020;4(4):898-911. doi: 10.1200/PO.20.00109 [DOI] [PubMed] [Google Scholar]

[zoi240225r11] 11.Martinelli E, Martini G, Famiglietti V, et al. Cetuximab rechallenge plus avelumab in pretreated patients with RAS wild-type metastatic colorectal cancer: the phase 2 single-arm clinical CAVE trial. JAMA Oncol. 2021;7(10):1529-1535. doi: 10.1001/jamaoncol.2021.2915 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240225r12] 12.Sartore-Bianchi A, Pietrantonio F, Lonardi S, et al. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial. Nat Med. 2022;28(8):1612-1618. doi: 10.1038/s41591-022-01886-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240225r13] 13.Napolitano S, De Falco V, Martini G, 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. 2023;9(7):966-970. doi: 10.1001/jamaoncol.2023.0655 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240225r14] 14.Napolitano S, Ciardiello D, De Falco V, et al. Panitumumab plus trifluridine/tipiracil as anti-EGFR rechallenge therapy in patients with refractory RAS wild-type metastatic colorectal cancer: overall survival and subgroup analysis of the randomized phase II VELO trial. Int J Cancer. 2023;153(8):1520-1528. doi: 10.1002/ijc.34632 [DOI] [PubMed] [Google Scholar]

[zoi240225r15] 15.Tsuji A, Nakamura M, Watanabe T, et al. Phase II study of third-line panitumumab rechallenge in patients with metastatic wild-type KRAS colorectal cancer who obtained clinical benefit from first-line panitumumab-based chemotherapy: JACCRO CC-09. Target Oncol. 2021;16(6):753-760. doi: 10.1007/s11523-021-00845-y [DOI] [PubMed] [Google Scholar]

[zoi240225r16] 16.Rossini D, Germani MM, Pagani F, et al. Retreatment with anti-EGFR antibodies in metastatic colorectal cancer patients: a multi-institutional analysis. Clin Colorectal Cancer. 2020;19(3):191-199.e6. doi: 10.1016/j.clcc.2020.03.009 [DOI] [PubMed] [Google Scholar]

[zoi240225r17] 17.World Medical Association . World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi: 10.1001/jama.2013.281053 [DOI] [PubMed] [Google Scholar]

[zoi240225r18] 18.Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi: 10.1016/j.ejca.2008.10.026 [DOI] [PubMed] [Google Scholar]

[zoi240225r19] 19.Division of Cancer Treatment & Diagnosis . Cancer Therapy Evaluation Program (CTEP) Adverse Events/CTCAE. Accessed March 1, 2024. https://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm

[zoi240225r20] 20.Vitiello PP, De Falco V, Giunta EF, et al. Clinical practice use of liquid biopsy to identify RAS/BRAF mutations in patients with metastatic colorectal cancer (mCRC): a single institution experience. Cancers (Basel). 2019;11(10):1504. doi: 10.3390/cancers11101504 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Anti-EGFR Rechallenge in Patients With Refractory ctDNA RAS/BRAF wt Metastatic Colorectal Cancer

Davide Ciardiello, MD, PhD

Erika Martinelli, MD, PhD

Teresa Troiani, MD, PhD

Gianluca Mauri, MD

Daniele Rossini, MD

Giulia Martini, MD, PhD

Stefania Napolitano, MD, PhD

Vincenzo Famiglietti, Bsc

Sara Del Tufo, MD

Gianluca Masi, MD, PhD

Daniele Santini, MD

Antonio Avallone, MD, PhD

Filippo Pietrantonio, MD, PhD

Sara Lonardi, MD

Massimo Di Maio, MD, PhD

Maria Giulia Zampino, MD

Nicola Fazio, MD, PhD

Alberto Bardelli, PhD

Salvatore Siena, MD, PhD

Chiara Cremolini, MD, PhD

Andrea Sartore-Bianchi, MD, PhD

Fortunato Ciardiello, MD, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Intervention

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Population

Figure 1. Patient Enrollment Flowchart.

Efficacy and Safety of the Treatments

Molecular Analysis

Statistical Analysis

Results

Patient Characteristics

Table 1. Baseline Characteristics of Patients With Metastatic Colorectal Cancer Receiving Anti-EGFR Challenge Therapy in 4 Italian Trials.

Efficacy and Safety Analysis

Table 2. Tumor Response of Patients With Metastatic Colorectal Cancer Receiving Anti–Epidermal Growth Factor Receptor Challenge Therapy in 4 Italian Trials.

Figure 2. Kaplan-Meier Survival Curves for All Patients.

Figure 3. Kaplan-Meier Survival Curves According to the Presence of Liver Metastasis.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases