Anti-EGFR Reintroduction and Rechallenge in Metastatic Colorectal Cancer (mCRC): A Real-World Analysis

Round 1

Reviewer 1 Report

The Authors have addressed all my concerns and I have no further comments.

Reviewer 2 Report

Dear authors, thank you for your modifications. 

Reviewer 3 Report

The manuscript of Dr Schulz et al aims to investigate the outcome of patients with metastatic colorectal cancer (mCRC) after an anti-EGFR retreatment strategy. This retrospective monocentric study was performed on 43 patients diagnosed and treated between the 2011-2019 period. Some limitations of this study concern some clinical and pathological information that was not collected during the period investigated, e.g. HER2 status, liquid biopsies. Several prospective and retrospective studies have previously reported the efficiency of mCRC patient retreatment with anti-EGFR. The originality of this study relies on the distinction between anti-EGFR reintroduction (treatment discontinuation due to intolerance/toxicity) and anti-EGFR rechallenge (disease progression on first-line anti-EGFR therapy), and the assessment of retreatment based on therapy sequence (patients included in the study have received one or more intervening non-EGFR therapy prior to retreatment). The data analysis suggests that all patients benefit from anti-EGFR reexposure independently from the reason for treatment discontinuation. Furthermore, patients receiving reintroduction seem to exhibit a higher overall survival and progression-free survival compared to patients with rechallenge therapy. This study fits the topic of the special issue "metastatic colorectal cancer biological features old new treatments".

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The manuscript entitled "Anti-EGFR reintroduction and rechallenge in metastatic colo-rectal cancer (mCRC): A real-world analysis " highlightedt that anti-EGFR reexposure strategies might benefit patients independently from the reason for prior discontinuation.

 

• The Authors should better describe the criteria adopted to select patients to a reexposure strategic therapy. In particular, the Authors hsould better explain the reason behind the discontinuation and if a molecular testing has been performed before the readministration.
• The Authors should provide the expand forms for all acronyms, including gene acronyms, through the text when they first appear.
• Gene acronyms should be written in italics.

Reviewer 2 Report

Dear authors, 

I have read your article regarding the reintroduction of antiEGFR in mCRC with great interest. Indeed, the reintroduction of cetuximab or panitumumab is of capital importance for our RAS/BRAF wt patients as a treatment strategy. However, I have some concerns regarding the paper:

Due to the modest sample size inclusion criteria should be more detailed. Taking in consideration already reported clinical trials with antiEGFR rechallenge there some important information missing:

Documented RAS/BRAF status was performed in tissue or plasma? Was it terminated by NGS or PCR?

HER2 status should be mentioned because has been suggested that HER2 ampl/mutations are related with antiEGFR resistance. It's ok if was not performed but it should be specifically mentioned

There is no information regarding the antiEGFR (first and rechallenge) response rate. This information is of capital importance. Furthermore, this should be an inclusion criteria. Previous well-designed clinical trial include partial response or stable disease (>6 months) as kay inclusion criteria.

Because you have not include liquid biopsy information, clinical inclusion/exclusion criteria are of critical importance. 

Minor comments:

In the introduction, "EGFR pathway"  could be changed to MAPK pathway

Also in the introduction reexposure could be changed to rechallenge

.."antiEGFR reexposure has emerged as a promising approach" should be modified. There are currently, several trials regarding the reintroduction of antiEGFR that has demonstrated the benefit of this strategy.

 

The Chronos trial should be mentioned: 

Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: The CHRONOS trial. Andrea Sartore-Bianchi, Filippo Pietrantonio, Sara Lonardi, Benedetta Mussolin, Francesco Rua, Elisabetta Fenocchio, Alessio Amatu, Salvatore Corallo, Chiara Manai, Federica Tosi, Paolo Manca, Francesca Daniel, Valter Torri, Angelo Vanzulli, Giovanni Cappello, Caterina Marchiò, Anna Sapino, Silvia Marsoni, Salvatore Siena, and Alberto Bardelli Journal of Clinical Oncology 2021 39:15_suppl, 3506-3506