Paolo Manca1, Salvatore Corallo1, Giovanni Randon1, Sara Lonardi2, Chiara Cremolini3, Lorenza Rimassa4, Francesca Bergamo2, Carlotta Antoniotti3, Valeria Smiroldo5, Alberto Zaniboni6, Roberto Murialdo7, Marco Tampellini8, Gianluca Tomasello9, Matteo Clavarezza10, Patrizia Racca11, Maria Antista1, Alessandra Raimondi1, Michele Prisciandaro1, Filippo Pagani1, Federica Palermo1, Francesca Gabriella Greco12, Marta Vaiani12, Maria Di Bartolomeo1, Filippo de Braud13, Giuseppina Calareso12, Federica Morano1, Filippo Pietrantonio14. 1. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 2. Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, Padua, Italy. 3. Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy. 4. Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy. 5. Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy. 6. Medical Oncology Unit, Fondazione Poliambulanza, Brescia, Italy. 7. Department of Internal Medicine (Di.M.I.), University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy. 8. Department of Oncology, AOU San Luigi di Orbassano, University of Turin, Italy. 9. Medical Oncology Unit, ASST Ospedale di Cremona, Cremona, Italy. 10. Medical Oncology Unit, Ente Ospedaliero Ospedali Galliera, Genoa, Italy. 11. SSD ColoRectal Cancer Unit - Dipartimento di Oncologia AOU Città della Salute e della Scienza di Torino, Turin, Italy. 12. Radiology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 13. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Oncology and Hemato-oncology Department, University of Milan, Italy. 14. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Oncology and Hemato-oncology Department, University of Milan, Italy. Electronic address: filippo.pietrantonio@istitutotumori.mi.it.
Abstract
BACKGROUND: In patients with metastatic colorectal cancer (mCRC) receiving highly active first-line combination treatments, early tumor shrinkage (ETS) and depth of response (DoR) are associated with survival, but their influence on outcomes during maintenance therapy is unknown. The Valentino study showed inferior PFS in 229 RAS wild-type mCRC patients randomized to panitumumab plus FOLFOX followed by maintenance with panitumumab vs. panitumumab + 5-FU/LV. PATIENTS AND METHODS: After blinded independent central review of ETS (≥20% reduction of the sum of target lesions) and DoR in patients enrolled in Valentino, the prognostic and predictive role of such parameters was investigated, along with their combination with PRESSING panel (uncommon genomic alterations associated with anti-EGFRs resistance beyond RAS and BRAF). RESULTS:One hundred and ninety-six patients were included (ETS in 132 [67.3%], median DoR: 44.1%). Both ETS and DoR ≥34% were associated with longer mPFS (p = 0.010 and p < 0.001) and mOS (p = 0.006 and p < 0.001). The PFS benefit of 5-FU/LV added to panitumumab maintenance, reported in the study, was independent from ETS and DoR status (interaction tests NS for both PFS and OS). However, outcomes were extremely poor in patients who received single-agent panitumumab and had no-ETS (mPFS and mOS: 7.7 and 18.7 months) or DoR < 34% (mPFS and mOS: 6.5 and 18 months). Combining PRESSING panel ('molecular hyperselection') and response dynamics allowed to stratify both PFS (p < 0.001 and p < 0.001 for ETS and DoR, respectively) and OS (p < 0.001 and p = 0.017 for ETS and DoR, respectively). CONCLUSIONS: ETS and DoR allow on-treatment anticipation of outcomes following an anti-EGFR-based strategy planning de-escalation, and poor radiological response may guide enrolment in crossover strategy trials. As in vivo markers of drug sensitivity, ETS and DoR may be integrated with several patient- and tumor-related factors to wisely drive decision-making on upfront treatment duration and intensity.
RCT Entities:
BACKGROUND: In patients with metastatic colorectal cancer (mCRC) receiving highly active first-line combination treatments, early tumor shrinkage (ETS) and depth of response (DoR) are associated with survival, but their influence on outcomes during maintenance therapy is unknown. The Valentino study showed inferior PFS in 229 RAS wild-type mCRC patients randomized to panitumumab plus FOLFOX followed by maintenance with panitumumab vs. panitumumab + 5-FU/LV. PATIENTS AND METHODS: After blinded independent central review of ETS (≥20% reduction of the sum of target lesions) and DoR in patients enrolled in Valentino, the prognostic and predictive role of such parameters was investigated, along with their combination with PRESSING panel (uncommon genomic alterations associated with anti-EGFRs resistance beyond RAS and BRAF). RESULTS: One hundred and ninety-six patients were included (ETS in 132 [67.3%], median DoR: 44.1%). Both ETS and DoR ≥34% were associated with longer mPFS (p = 0.010 and p < 0.001) and mOS (p = 0.006 and p < 0.001). The PFS benefit of 5-FU/LV added to panitumumab maintenance, reported in the study, was independent from ETS and DoR status (interaction tests NS for both PFS and OS). However, outcomes were extremely poor in patients who received single-agent panitumumab and had no-ETS (mPFS and mOS: 7.7 and 18.7 months) or DoR < 34% (mPFS and mOS: 6.5 and 18 months). Combining PRESSING panel ('molecular hyperselection') and response dynamics allowed to stratify both PFS (p < 0.001 and p < 0.001 for ETS and DoR, respectively) and OS (p < 0.001 and p = 0.017 for ETS and DoR, respectively). CONCLUSIONS: ETS and DoR allow on-treatment anticipation of outcomes following an anti-EGFR-based strategy planning de-escalation, and poor radiological response may guide enrolment in crossover strategy trials. As in vivo markers of drug sensitivity, ETS and DoR may be integrated with several patient- and tumor-related factors to wisely drive decision-making on upfront treatment duration and intensity.
Authors: Giovanni Fucà; Francesca Corti; Margherita Ambrosini; Rossana Intini; Massimiliano Salati; Elisabetta Fenocchio; Paolo Manca; Chiara Manai; Francesca Daniel; Alessandra Raimondi; Federica Morano; Salvatore Corallo; Michele Prisciandaro; Andrea Spallanzani; Virginia Quarà; Carmen Belli; Marta Vaiani; Giuseppe Curigliano; Chiara Cremolini; Filippo De Braud; Maria Di Bartolomeo; Vittorina Zagonel; Sara Lonardi; Filippo Pietrantonio Journal: J Immunother Cancer Date: 2021-04 Impact factor: 13.751
Authors: Y Sunakawa; H Satake; J Usher; Y Jaimes; Y Miyamoto; M Nakamura; M Kataoka; M Shiozawa; A Takagane; T Terazawa; T Watanabe; K Ishiguro; C Tanaka; M Takeuchi; M Fujii; K Danenberg; P V Danenberg; H-J Lenz; T Sekikawa; W Ichikawa Journal: ESMO Open Date: 2022-06-07