Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study

Author(s): Carmine Pinto, MD¹; Armando Orlandi, MD, PhD²; Nicola Normanno, MD, PhD³; Evaristo Maiello, MD⁴; Maria A. Calegari, MD, PhD²; Lorenzo Antonuzzo, MD, PhD⁵; Roberto Bordonaro, MD⁶; Maria G. Zampino, MD⁷; Sara Pini, MD⁸; Francesca Bergamo, MD⁹; Giuseppe Tonini, MD¹⁰; Antonio Avallone, MD¹¹; Tiziana P. Latiano, MD⁴; Gerardo Rosati, MD¹²; Alessio Aligi Cogoni, MD¹³; Alberto Ballestrero, MD¹⁴; Alberto Zaniboni, MD¹⁵; Mario Roselli, MD¹⁶; Stefano Tamberi, MD¹⁷; Carlo Barone, MD²

Source: https://doi.org/10.1200/JCO.23.01021

Dr. Maen Hussein's Thoughts

Less maintenance is NOT NON-inferior, so it is inferior in patients with wild type BRAF metastatic colon cancer. So it is better to keep on the full regimen. Although, quality of life is better.

PURPOSE

The intensity of anti-EGFR–based first-line therapy for RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC), once disease control is achieved, is controversial. A de-escalation strategy with anti-EGFR monotherapy represents a potential option to maintain efficacy while reducing cytotoxicity.

METHODS

In this multicenter, open-label, phase III trial, patients with untreated RAS/BRAF wt mCRC were randomly assigned to receive either fluorouracil, leucovorin, and irinotecan/cetuximab (FOLFIRI/Cet) until disease progression (arm A) or FOLFIRI/Cet for eight cycles followed by Cet alone (arm B). The coprimary end points were a noninferior progression-free survival (PFS) in the modified per-protocol (mPP) population (>eight cycles) and a lower incidence of grade (G) 3-4 adverse events (AEs) for arm B compared with arm A.

RESULTS

Overall, 606 patients were randomly assigned, with 300 assigned to arm A and 306 to arm B. The median follow-up was 22.3 months. In the mPP population, 291 events occurred with a PFS of 10 versus 12.2 months for arms B and A, respectively (P of noninferiority = .43). In the intention-to-treatment (ITT, ≥one cycle) population, 503 events occurred with a PFS of 9 versus 10.7 months (P = .39). The overall survival was 35.7 versus 30.7 months (P = .119) and 31.0 versus 25.2 months (P = .32) in the mPP and ITT population, respectively. Arm B had lower G3-4 AEs during the maintenance period than arm A (20.2% v 35.1%).

CONCLUSION

The ERMES study did not demonstrate noninferiority of maintenance with Cet alone. Despite a more favorable safety profile, maintenance with single-agent Cet after induction with FOLFIRI/Cet cannot be recommended for all patients but could represent an option in selected cases.

Author Affiliations

¹Medical Oncology, Comprehensive Cancer Centre Azienda USL—IRCCS di Reggio Emilia, Reggio Emilia, Italy; ²Comprehensive Cancer Center, UOC Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy; ³Translational Research Departement, Istituto Nazionale Tumori IRCCS—Fondazione G. Pascale, Napoli, Italy; ⁴Oncology Unit, Foundation IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; ⁵Department of Experimental and Clinical Medicine, University of Florence, Italy Clinical Oncology Unit, Careggi University Hospital, Firenze, Italy; ⁶Medical Oncology, Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy; ⁷Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy; ⁸Ospedale Santa Maria delle Croci, Ravenna, Italy; ⁹Dipartimento Oncologia 1, IOV—Istituto Oncologico Veneto IRCCS, Padova, Italy; ¹⁰Dipartimento di Oncologia, Fondazione Policlinico Campus Bio-Medico, Facoltà di Medicina Università Campus Bio-Medico, Rome, Italy; ¹¹Medical Oncology, Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, Naples, Italy; ¹²Medical Oncology Unit, S. Carlo Hospital, Potenza, Italy; ¹³UO Oncologia AOU Sassari, Sassari, Italy; ¹⁴DiMI Università degli Studi di Genova e Ospedale Policlinico San Martino IRCCS, Genova, Italy; ¹⁵Medical Oncology Unit, Fondazione Poliambulanza, Brescia, Italy; ¹⁶Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; ¹⁷UO Medical Oncology, Area Vasta Romagna Ausl di Ravenna, Presidio Ospedaliero di Faenza, Ospedale Civile degli Infermi, Faenza, Italy

Trastuzumab Rezetecan in Human Epidermal Growth Factor Receptor 2–Expressing Advanced Gastric Cancer or Gastroesophageal Junction Adenocarcinoma and Colorectal Cancer: A Multicenter, Open-Label, Phase I Trial

Encouraging phase I signal for this HER2-targeted Antibody-drug conjugate (ADC) in heavily pretreated GI cancers, 45% overall response rate (ORR) and 16.3mo median overall survival (OS) in HER2-positive gastric compares favorably with T-DXd benchmarks, and the 40.5% objective response rate (ORR) with 22.7mo OS in HER2-positive colorectal cancer (CRC) is notable. The 2% ILD rate looks meaningfully better than T-DXd’s reported range, which could be a real differentiator. Hematologic toxicity is substantial but manageable. Small China-only phase I, but worth watching closely as this advances.

Postoperative Hepatic Arterial Infusion With Oxaliplatin After Surgery of Four or More Colorectal Liver Metastases: A Randomized Phase II Trial

For high-risk patients with four or more colorectal liver metastases, adjuvant hepatic arterial infusion oxaliplatin roughly doubled hepatic recurrence-free survival versus standard IV chemotherapy (25 vs. 12 months), with recurrence-free survival (RFS) benefit as well. Overall survival (OS) didn't reach significance but the absolute difference and 5-year OS of 62% versus 47% suggest a real effect worth confirming in phase III. Toxicity was higher in the hepatic arterial infusion (HAI) arm but manageable with no treatment-related deaths. Generalizability remains the challenge, these needs specialized centers with HAI expertise, but worth keeping in mind for your highest-risk resected liver met patients.

Randomized Phase II/III Trial Comparing Hepatectomy, Followed by mFOLFOX6 With Hepatectomy Alone for Liver Metastasis From Colorectal Cancer: Long-Term Results of JCOG0603

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Tumor Debulking in Combination With Chemotherapy in Multiorgan Metastatic Colorectal Cancer: The ORCHESTRA Randomized Clinical Trial

Open-label, phase 3 clinical trial, 382 patients were randomized to receive chemotherapy alone or chemotherapy plus tumor debulking. The overall survival rates were not statistically different, with a median overall survival in the chemotherapy alone group of 27.5 m vs 30.0 m in the chemotherapy plus tumor debulking group hence tumor debulking added to palliative systemic chemotherapy did not result in significantly improved survival compared with chemotherapy alone in patients with multiorgan metastatic colorectal cancer.

Atezolizumab plus FOLFOX for Stage III Mismatch Repair–Deficient Colon Cancer

This is a strong adjuvant signal in resected stage III dMMR colon cancer, adding atezolizumab to mFOLFOX6 cut the risk of recurrence or death in half and improved 3-year DFS from 76% to 86%. OS hasn’t separated yet, but that may be confounded by immunotherapy at relapse. Toxicity was higher, as expected, with more grade 3–4 events and immune-related adverse events (AE)s, but overall manageable. This feels practice changing for stage III dMMR disease.