Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO

Author(s): Daniele Rossini, MD^1,2;Carlotta Antoniotti, MD, PhD^1,2;Sara Lonardi, MD³;Filippo Pietrantonio, MD⁴;Roberto Moretto, MD²;Lorenzo Antonuzzo, MD, PhD⁵;Alessandra Boccaccino, MD^1,2;Federica Morano, MD⁴;Marco Brugia, MD⁶;Carmelo Pozzo, MD⁷;Federica Marmorino, MD, PhD^1,2;Francesca Bergamo, MD⁸;Emiliano Tamburini, MD⁹;Alessandro Passardi, MD¹⁰;Giovanni Randon, MD⁴;Sabina Murgioni, MD⁸;Beatrice Borelli, MD^1,2;Angela Buonadonna, MD¹¹;Mirella Giordano, PhD^1,2;Gabriella Fontanini, MD, PhD¹²;Veronica Conca, MD^1,2;Vincenzo Formica, MD, PhD¹³;Massimo Aglietta, MD¹⁴;Roberto Bordonaro, MD¹⁵;Giuseppe Aprile, MD¹⁶;Gianluca Masi, MD^1,2;Luca Boni, MD¹⁷;and Chiara Cremolini, MD, PhD^1,2

Source: DOI: 10.1200/JCO.22.00839

Interesting lack of deepened response with chemotherapy intensification. Expected increase in GI toxicity, increased cost and diminished options upon progression place this truly a quadruple combination on the shelf.

To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC).

METHODS

TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect ≥ 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722).

RESULTS

From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P = .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in R0 resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277).

CONCLUSION

The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC.

Author Affiliations

¹Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy²Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy³Medical Oncology 3, Veneto Institute of Oncology IOV—IRCCS, Padua, Italy⁴Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy⁵Clinical Oncology Unit, Careggi University Hospital—Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy⁶Medical Oncology Unit, Careggi University Hospital, Florence, Italy⁷Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy⁸Medical Oncology 1, Veneto Institute of Oncology IOV—IRCCS, Padua, Italy⁹Oncology and Palliative Care Department, Cardinale G. Panico Tricase City Hospital, Tricase, Italy¹⁰Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola, Italy¹¹Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy¹²Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy¹³Medical Oncology Unit, Tor Vergata University Hospital, Rome, Italy¹⁴Medical Oncology, Candiolo Cancer Institute, Fondazione del Piemonte per l’Oncologia (FPO)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Torino, Italy¹⁵Medical Oncology Unit, Azienda Ospedaliera di Rilievo Nazionale e Alta Specializzazione (ARNAS), Ospedale Garibaldi, Catania, Italy¹⁶Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy¹⁷Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova, 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

The mature overall survival (OS) data from this Japanese randomized trial answer the question the initial publication left open, and the answer is no, adjuvant mFOLFOX6 after hepatectomy for resectable colorectal liver metastases does not improve overall survival (HR 1.07, P=.74), despite the previously reported DFS benefit. Five-year OS was numerically worse in the chemotherapy arm (73% vs 80%), though not significantly so. The disease-free survival (DFS) benefit was likely confounded by oxaliplatin-induced hepatic changes obscuring imaging and imbalances in post-recurrence therapy. Selection of patients and those with curable vs incurable intent surgery may have led to some bias in my opinion.

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.