Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation
Another KRAS G12C inhibitor. Congrats to FCS Director of Drug Development Manish Patel, MD, one of the authors. Durable responses with less adverse events.
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, MD1,2;Carlotta Antoniotti, MD, PhD1,2;Sara Lonardi, MD3;Filippo Pietrantonio, MD4;Roberto Moretto, MD2;Lorenzo Antonuzzo, MD, PhD5;Alessandra Boccaccino, MD1,2;Federica Morano, MD4;Marco Brugia, MD6;Carmelo Pozzo, MD7;Federica Marmorino, MD, PhD1,2;Francesca Bergamo, MD8;Emiliano Tamburini, MD9;Alessandro Passardi, MD10;Giovanni Randon, MD4;Sabina Murgioni, MD8;Beatrice Borelli, MD1,2;Angela Buonadonna, MD11;Mirella Giordano, PhD1,2;Gabriella Fontanini, MD, PhD12;Veronica Conca, MD1,2;Vincenzo Formica, MD, PhD13;Massimo Aglietta, MD14;Roberto Bordonaro, MD15;Giuseppe Aprile, MD16;Gianluca Masi, MD1,2;Luca Boni, MD17;and Chiara Cremolini, MD, PhD1,2
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, ItalyRelated Articles
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If anti PD-L1 was not used as first line treatment, this study shows you can still use it as second line.
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In the SUNLIGHT study, Lonsurf + bevacizumab was found to be superior to bevacizumab alone in the 3L setting of mCRC, independent of mutation status. First 3L mCRC where the control group was an active compound instead of a placebo. OS was superior, with a clinically meaningful difference of 10.8 vs. 7.5 months. This is now the SOC 3L option in mCRC, in my opinion.
