Extending the utility of anti-EGFR therapy in metastatic colorectal cancer

The treatment landscape for RAS wild-type (wt) metastatic colorectal cancer (mCRC) has undergone substantial evolution over the past two decades, driven by advances in molecular characterization and the integration of targeted biologic therapies. Among these, monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), including cetuximab and panitumumab, have emerged as critical components of therapy for patients with left-sided RAS wt disease. Initial studies established the efficacy of anti-EGFR therapy in chemotherapy-refractory settings, with subsequent trials demonstrating significant overall survival (OS) benefit when these agents were incorporated into first-line cytotoxic regimens (1-4). As a result, EGFR blockade is now regarded as a preferred therapeutic strategy in appropriately selected patients.

Despite these advances, questions remain regarding the optimal timing, sequencing, and reutilization of anti-EGFR therapy throughout the disease course. Although first-line administration appears to provide the greatest progression-free survival (PFS) benefit, many patients worldwide are unable to access timely molecular testing or receive anti-EGFR therapy early in treatment due to logistical, financial, or institutional limitations. Furthermore, emerging evidence suggests that resistance to EGFR inhibition may be dynamic rather than permanent, raising the possibility that anti-EGFR therapy may retain efficacy when reintroduced after an adequate treatment-free interval and molecular reassessment.

The retrospective analysis by Archwamety et al. provides important real-world insight into outcomes associated with anti-EGFR therapy across multiple lines of treatment in patients with left-sided RAS wt mCRC (5). Their findings, together with recent prospective studies evaluating circulating tumor DNA (ctDNA)-guided anti-EGFR rechallenge, contribute to a growing body of evidence supporting a more adaptive and biologically informed approach to EGFR-directed therapy across the continuum of mCRC care.

Archwamety et al. included patients 18 years of age or older with histologically confirmed metastatic primary left-sided adenocarcinoma of the colon or rectum with RAS wt status (lacking mutations in KRAS/NRAS exons 2, 3, and 4), diagnosed between January 2008 and December 2023 at Siriraj Hospital, a tertiary referral center in Bangkok, Thailand. Patients exposed to cetuximab or panitumumab during any line of therapy were included in the analysis. Notably, patients with metastatic transverse colon cancer were excluded, in addition to those with right-sided colon tumors, colonic tumors of unknown primary location, and colorectal tumors with RAS mutations. Primary outcomes were PFS, defined as the time from the start of anti-EGFR therapy to the date of radiologic progression or death, and OS, the time from the start of anti-EGFR therapy to the date of death. Descriptive statistics were used for patient characteristics, and Kaplan-Meier analyses were used for survival analysis, stratified based on the line of therapy during which anti-EGFR therapy was used. Variables including performance status (PS), sex, line of therapy, tumor differentiation, and sites of metastatic disease were used in multivariable Cox proportional hazards regression models to determine their association with survival outcomes.

Of more than 6,000 patients diagnosed with mCRC during the predetermined time frame, 1,105 had available RAS mutational data, with 300 patients having RAS wt left-sided primary tumors. The population was nearly two-thirds male, with a median age of 60 years, with a largely equal representation of primary sigmoid (46.3%) and rectal tumors (41%). The majority of patients had metastatic disease in the liver (74.7%), followed in frequency by lung (40%), nodal (20.7%), and peritoneal metastasis (18%). Nearly all patients were diagnosed with moderately differentiated adenocarcinoma (82.7%), with mucinous and signet-ring cell histologies representing a small minority of the patient population (2.3% and 0.7%, respectively). Of note, only approximately one-third of patients had mismatch repair (MMR) testing. Cetuximab and panitumumab were used nearly equivalently (54.3% vs. 45.7%), with 51.7% of patients using anti-EGFR therapy in the third line or later. Surprisingly, 32.7% utilized anti-EGFR therapy in the first line and 15.7% in the second line. Patients treated in the first-line setting largely received in combination with oxaliplatin-based therapy (76.5%). Second-line therapy combined anti-EGFR therapy with irinotecan-based therapy, either in combination with fluoropyrimidine (42.6%) or as monotherapy (48.9%). Nearly all patients in the third line or beyond received anti-EGFR therapy in combination with single-agent irinotecan (97.4%).

At a median follow-up of 30.4 months, patients treated with first-line anti-EGFR-based therapy had a statistically significantly longer PFS than those treated in the second line or greater (11.87 vs. 5.75 and 5.06 months, respectively). This trend was consistent after adjusting for age, sex, differentiation, and site of metastasis. However, no statistically significant difference in OS was found among lines of therapy, with only age ≥65 years associated with worse survival.

The study by Archwamety et al. underscores the importance of exposure to anti-EGFR-based therapy in the treatment paradigm of patients with left-sided RAS wt mCRC, regardless of the line of therapy. Current guidelines recommend the use of cetuximab or panitumumab in combination with cytotoxic therapy in the first-line setting, based on the CRYSTAL and PRIME trials, respectively, both of which showed a significant improvement in OS (3,4). The PARADIGM trial further solidified the preference for anti-EGFR therapy in the first-line treatment setting. It indicated superiority of anti-EGFR therapy over anti-vascular endothelial growth factor (VEGF) therapy (bevacizumab) in combination with cytotoxic therapy in all RAS wt, left-sided primary tumors, demonstrating an OS benefit of 37.9 vs. 34.3 months favoring panitumumab (6). Other studies such as FIRE-3 and post hoc analysis of CALGB/SWOG 80405 also demonstrated the superiority of anti-EGFR therapy in left-sided RAS wt CRC. These trials were based upon proven efficacy of anti-EGFR therapy in the treatment-refractory setting, with cetuximab and panitumumab originally approved as monotherapy, showing survival benefit relative to supportive care alone (1,2,7). This benefit was further elucidated in the second-line therapy in combination with irinotecan (8,9). The longer PFS seen in first-line therapy relative to the similar OS benefit across lines of therapy in the study by Archwamety et al. emphasizes the potential heightened tumor sensitivity to cytotoxic therapy in previously untreated disease and subsequent development of mutational resistance in later lines, which is reinforced by the clear PFS benefit seen in the CRYSTAL and PRIME trials. However, true survival gain, as suggested by the study of Archwamety et al., is present irrespective of the timing of administration during a patient’s treatment journey.

This concept is imperative when considering the equity of treatment on a global scale. For treatment centers across the world that may not have expeditious access to molecular testing, the use of anti-EGFR therapy, when indicated, should be considered irrespective of the current line of therapy and should not be limited to first-line therapy. Additionally, the profound benefit seen with the use of anti-EGFR therapy necessitates ubiquitous access and clinical standardization of next-generation sequencing and real time polymerase chain reaction (PCR) to provide optimal care to all patients. There remains significant heterogeneity in availability of this technology, particularly in Southeast Asian countries, African countries, parts of the Middle East, as well as intracountry variability based on institutional funding (10).

Furthermore, evidence now suggests that even after previous exposure to anti-EGFR therapy, there can be benefit in rechallenge with anti-EGFR-based therapy in subsequent lines of therapy. In the phase 2 CHRONOS trial, patients with previous exposure to anti-EGFR-based therapy and no evidence of ctDNA conferring mutational resistance to anti-EGFR therapy were rechallenged with panitumumab, resulting in 30% of patients with partial response and 63% with disease control (11). The CITRIC trial, evaluating third-line cetuximab plus irinotecan versus standard of care in patients with RAS, BRAF or EGFR mutations detected in ctDNA and previous benefit from first-line anti-EGFR therapy, indicated a higher disease control rate and longer PFS when compared with trifluridine/tipiracil plus bevacizumab (77% vs. 57%, 4.8 vs. 3 months, respectively) (12). The recently published PARERE trial expanded on these findings by prospectively comparing panitumumab retreatment followed by regorafenib versus the reverse sequence of treatment in patients with mCRC who had confirmed RAS/BRAF wt ctDNA (13). Specifically, patients had disease response or stabilization for at least 6 months during a previous first-line exposure to anti-EGFR therapy, had one or more interval lines of therapy, were ≥4 months from prior anti-EGFR therapy, and had previous treatment with fluoropyrimidines, oxaliplatin, irinotecan and anti-angiogenic agents. Notably, OS was equivalent in both arms, with superior PFS, objective response rate, and disease control rate during the intervals when patients received panitumumab. The success of anti-EGFR therapy rechallenge appears to be dependent upon the resolution of mutational resistance that inevitably occurs after exposure in the first-line setting. This warrants an anti-EGFR treatment-free interval to allow for clearance of resistant clones, which have an estimated half-life of 4 months, in addition to confirmation that these clones have not persisted via ctDNA analysis (14-16). Unfortunately, despite both prerequisites, the efficacy of anti-EGFR rechallenge is not assured, as 40% of patients in the PARERE trial did not benefit from a rechallenge despite no obvious resistant mutations. This underscores that mutational resistance to therapy may not be limited to RAS/BRAF alterations.

The findings from Archwamety et al., together with emerging prospective data on anti-EGFR rechallenge, reinforce the enduring therapeutic relevance of EGFR blockade across the continuum of care for patients with left-sided RAS wt mCRC. While first-line administration remains associated with the greatest objective response and disease control, clinically meaningful benefit appears to persist even in later treatment settings and after prior anti-EGFR exposure when guided by molecular selection via ctDNA analysis. These observations support a more dynamic treatment framework in which anti-EGFR therapy is not viewed as a single-use intervention, but rather as a biologically adaptable modality that may be strategically reintroduced throughout the disease course. At the same time, these advances underscore the growing necessity for equitable access to molecular diagnostics, including next-generation sequencing and ctDNA testing, to ensure that patients globally can benefit from precision-guided therapeutic decision-making. Ultimately, further prospective studies are needed to refine optimal sequencing, timing, and biomarker selection strategies that will maximize the long-term efficacy of EGFR-directed therapy in mCRC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0700/coif). Over the last 36 months, C.C. received grant support for clinical trial conduct paid to his institution from the Robert Winn Career Development Award and Colorectal Cancer Coalition; received consulting/advisory board payments from AstraZeneca, Taiho and Regeneron; and received payment for speaker bureau participation from AstraZeneca. Over the last 36 months, N.V. has received grant/research support from Arcus, Exelixis Inc, ITM, Jazz Pharmaceuticals, and Puma Biotechnology. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040-8. [Crossref] [PubMed]
2. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658-64. [Crossref] [PubMed]
3. Van Cutsem E, Lenz HJ, Köhne CH, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015;33:692-700. [Crossref] [PubMed]
4. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697-705. [Crossref] [PubMed]
5. Archwamety A, Akewanlop C, Korphaisarn K. Comparable survival outcome with anti-EGFR therapy in any treatment line in left-sided metastatic colorectal cancer. J Gastrointest Oncol 2026;17:14. [Crossref] [PubMed]
6. Watanabe J, Muro K, Shitara K, et al. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA 2023;329:1271-82. [Crossref] [PubMed]
7. Venook AP, Ou FS, Lenz HJ, et al. Primary (1°) tumor location as an independent prognostic marker from molecular features for overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB / SWOG 80405 (Alliance). J Clin Oncol 2017;35:3503. [Crossref]
8. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:2311-9. [Crossref] [PubMed]
9. Peeters M, Price TJ, Cervantes A, et al. Final results from a randomized phase 3 study of FOLFIRI ± panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol 2014;25:107-16. [Crossref] [PubMed]
10. Horgan D, Hamdi Y, Lal JA, et al. Framework for Adoption of Next-Generation Sequencing (NGS) Globally in the Oncology Area. Healthcare (Basel) 2023;11:431. [Crossref] [PubMed]
11. 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;28:1612-8. [Crossref] [PubMed]
12. Montagut C, Vidal J, Rodriguez C, et al. LBA33 Circulating tumor (ct) DNA-guided anti-EGFR rechallenge strategy in metastatic colorectal cancer (mCRC): Final results of the phase II randomized CITRIC trial. Ann Oncol 2025;36:S1576-7. [Crossref]
13. Ciracì P, Germani MM, Pietrantonio F, et al. Re-treatment with panitumumab followed by regorafenib versus the reverse sequence in chemorefractory metastatic colorectal cancer patients with RAS and BRAF wild-type circulating tumor DNA: the PARERE study by GONO. Ann Oncol 2026;37:79-91. [Crossref] [PubMed]
14. 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;21:827. [Crossref] [PubMed]
15. 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;30:243-9. [Crossref] [PubMed]
16. Misale S, Di Nicolantonio F, Sartore-Bianchi A, et al. Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov 2014;4:1269-80. [Crossref] [PubMed]