Intermittent or Continuous Panitumumab Plus Fluorouracil, Leucovorin, and Irinotecan for First-Line Treatment of RAS and BRAF Wild-Type Metastatic Colorectal Cancer: The IMPROVE Trial

Author(s): Antonio Avallone, MD¹, Francesco Giuliani, MD², Alfonso De Stefano, MD, PhD¹, Giuseppe Santabarbara, MD³, Guglielmo Nasti, MD⁴, Vincenzo Montesarchio, MD⁵, Gerardo Rosati, MD⁶, Antonino Cassata, MD¹, Silvana Leo, MD⁷, Carmela Romano, MD¹, Emiliano Tamburini, MD⁸, Lucrezia Silvestro, MD¹, Claudio Lotesoriere, MD⁹, Anna Nappi, MD¹, Daniele Santini, MD¹⁰, Antonella Petrillo, MD¹¹, Alfredo Colombo, MD¹², Antonio Febbraro, MD¹³, Alessandra Leone, PhD¹⁴, Francesco Mannavola, MD, PhD¹⁵, Maria Maddalena Laterza, MD¹⁶, Francesco Izzo, MD¹⁷, Alberto Sobrero, MD¹⁸, Paolo Delrio, MD¹⁹, Diana Giannarelli, PhD²⁰, Alfredo Budillon, MD, PhD²¹;

Source: https://doi.org/10.1200/JCO.24.00979

Dr. Anjan Patel's Thoughts

Interesting study where intermittent FOLFIRI + pan was seemingly just as effective as continuous therapy. The ongoing Phase III IMPROVE-2 is the confirmatory trial and if positive could change standard practice. Of note, intermittent meant eight (8) cycles followed by a holiday until progression when it was reinitiated.

PURPOSE

To investigate whether intermittent treatment after an induction phase of first-line schedule of fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus panitumumab (PAN) prevents or delays the onset of resistance and improves safety and compliance with treatment in patients with unresectable RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC).

PATIENTS AND METHODS

IMPROVE (ClinicalTrials.gov identifier: NCT04425239) was an open-label, multicenter, randomized phase II noncomparative trial. Patients with unresectable RAS/BRAF wt mCRC were randomly assigned (1:1) to receive FOLFIRI plus PAN continuously until progression (arm A) or intermittently, with treatment-free intervals (arm B) until progression on treatment, toxicity, or death. The primary end point was progression-free survival on treatment (PFSot) at 12 months. Assuming a null hypothesis of median PFSot time ≤7 months and target PFSot ≥10 months, 65 patients per arm were needed to achieve 80% power and 10% type I error, according to the binomial test.

RESULTS

Between May 2018 and June 2021, 69 patients were randomly assigned to arm A and 68 to arm B. The median number of treatment cycles was 13 in arm A and 16 in arm B. At a median follow-up of 43.2 months (IQR, 35.0-50.5), median PFSot was 11.2 and 17.5 months with 12-month PFSot rates of 45.7% and 58.5%, for arms A and B, respectively. The overall response rates were 68.1% and 61.2%, and median overall survival rates were 36.3 and 35.1 months in arms A and B, respectively. The overall rate of grade >2 skin PAN-related adverse events was 30.3% in arm A and 17.9% in arm B.

CONCLUSION

Intermittent FOLFIRI plus PAN after the induction phase was feasible, and the primary end point was met with reduced toxicity while allowing patients more time off treatment.

Author Affiliations

¹ Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia; ² Medical Oncology Irccs Giovanni Paolo II Bari and Medical Oncology San Paolo Hospital ASL, Bari, Italy; ³ Oncology Unit, San Giuseppe Moscati Hospital, Avellino, Italy; ⁴ Innovative Therapies Liver Metastases Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia; ⁵ Medical Oncology Unit, AORN Ospedali dei Colli-Monaldi-Cotugno-CTO, Napoli, Italy; ⁶ Medical Oncology Unit, S. Carlo Hospital, Potenza, Italy; ⁷ Medical Oncology Unit, Ospedale Vito Fazzi, Lecce, Italy; ⁸ Medical Oncology Department, Tricase City Hospital, Tricase, Italy; ⁹ Medical Oncology Unit, IRCCS Saverio de Bellis Hospital, Castellana Grotte, Italy; ¹⁰ Medical Oncology Unit, Policlinico Umberto I, University of Rome, Sapienza, Rome, Italy; ¹¹ Radiology Unit, Istituto Nazionale Tumori-IRCCS—Fondazione G. Pascale, Napoli, Italia; ¹² Medical Oncology Unit, Casa di Cura Macchiarella, Palermo, Italy; ¹³ Medical Oncology Unit, Ospedale Sacro Cuore di Gesù-Fatebenefratelli, Benevento, Italy; ¹⁴ Experimental Pharmacology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia; ¹⁵ Medical Oncology Unit, A.O.U. Consorziale Policlinico di Bari, Bari, Italy; ¹⁶ ASL Napoli 2 Nord, P.O. “S.M. delle Grazie”, Pozzuoli, Italy; ¹⁷ Hepatobiliary Surgery Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia; ¹⁸ Medical Oncology Unit, IRCCS San Martino General Hospital, Genoa, Italy; ¹⁹ Colorectal Surgical Oncology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia; ²⁰ Statistics, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy; ²¹ Scientific Directorate Istituto Nazionale Tumori IRCCS—Fondazione G. Pascale, Napoli, Italia

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