Modified FOLFOXIRI plus panitumumab (mFOLFOXIRI/PAN) versus mFOLFOX6/PAN as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer (mCRC): Results of the phase III randomized TRIPLETE study by GONO.

Author:

Cremolini Chiara1,Rossini Daniele2,Lonardi Sara3,Antoniotti Carlotta2,Pietrantonio Filippo4,Marmorino Federica1,Antonuzzo Lorenzo5,Boccaccino Alessandra2,Randon Giovanni4,Giommoni Elisa6,Pozzo Carmelo7,Moretto Roberto8,De Grandis Maria Caterina9,Viola Massimo Giuseppe10,Passardi Alessandro11,Buonadonna Angela12,Formica Vincenzo13,Aprile Giuseppe14,Boni Luca15,Masi Gianluca1

Affiliation:

1. Department of Translational Research and New Technologies in Medicine and Surgery-Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy;

2. Department of Translational Research and New Technologies in Medicine and Surgery-Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy;

3. Medical Oncology 3, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy;

4. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;

5. Clinical Oncology Unit, Careggi University Hospital - Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;

6. Clinical Oncology Unit, Careggi University Hospital, Florence, Italy;

7. Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy;

8. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy;

9. Medical Oncology 1, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy;

10. Department of Surgery, Cardinale G. Panico Tricase City Hospital, Tricase, Italy;

11. Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy;

12. Medical Oncology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy;

13. Medical Oncology Unit, Tor Vergata University Hospital, Rome, Italy;

14. Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy;

15. Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy;

Abstract

LBA3505 Background: The association of a chemotherapy doublet (FOLFOX/FOLFIRI) with an anti-EGFR monoclonal antibody (cetuximab or panitumumab) is an upfront option for the treatment of RAS and BRAF wt mCRC patients. Phase II studies investigating the combination of the triplet FOLFOXIRI with an anti-EGFR reported promising activity results and an acceptable safety profile when lower doses of 5FU and irinotecan were adopted. The added value of intensifying the upfront chemotherapy when combined with a targeted agent in a molecularly selected population is not established. Methods: TRIPLETE is a prospective, open label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomized to receive mFOLFOX6/pan (arm A) or mFOLFOXIRI (irinotecan 150 mg/sqm, oxaliplatin 85 mg/sqm, L-leucovorin 200 mg/sqm, 5-fluoruracil 2400 mg/sqm 48 h infusion)/pan (arm B) up to 12 cycles, followed by 5FU/LV/pan until disease progression. The primary endpoint is overall response rate (ORR) according to RECIST 1.1 criteria. Secondary endpoints include safety profile, R0 resection rate, PFS and OS. Under the assumption of an ORR of 60% in arm A, to detect an increase of at least 15% in arm B, a sample size of 432 cases provided approximately 90% power to a two-sided chi square test for heterogeneity at the 0.05 significance level. Results: From September 2017 to September 2021, 435 pts were enrolled (arm A/B: 217/218) in 67 Italian sites. Main pts’ characteristics were (arm A/B): median age 59/59, ECOG PS 0 80%/84%, left-sided 88%/88%, synchronous metastases 88%/87%, prior adjuvant 2%/6%, resected primary 43%/51%, liver-only 37%/39%. Main grade > 2 adverse events were diarrhoea 7%/23%, stomatitis 7%/7%, neutropenia 20%/32%, febrile neutropenia 3%/6%, fatigue 2%/7%, skin rash 29%/19%. 160 (73%) out of 218 patients in arm B and 165 (76%) out of 217 patients in arm A achieved RECIST response (OR 0.87, 95%CI 0.56-1.34, p=0.526). No interaction effect between treatment arm and disease spread (liver-limited vs not-liver limited) was evident. No differences in early tumor shrinkage (arm A/B 58%/57%, p=0.878) and deepness of response (median arm A/B: 47%/48%, p=0.845) were reported, nor in R0 resection rate (arm A/B 29%/25%, p=0.317). At a median follow up of 26.5 mos, 305 (arm A/B: 157/148) PFS events were collected, with no significant difference between arms (median PFS: 12.7 vs 12.3 months, HR: 0.88, 95%CI 0.70-1.11, p=0.277). Conclusions: The intensification of the upfront chemotherapy backbone in combination with panitumumab in molecularly selected and mostly (88%) left-sided mCRC patients does not provide any benefit in terms of treatment activity at the price of a non-negligible increase in gastrointestinal toxicity. Clinical trial information: NCT03231722.

Funder

GONO (Gruppo Oncologico Nord Ovest) Foundation.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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