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Clinical Trial
. 2025 Mar;43(7):829-839.
doi: 10.1200/JCO.24.00979. Epub 2024 Nov 22.

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

Antonio Avallone  1 , Francesco Giuliani  2 , Alfonso De Stefano  1 , Giuseppe Santabarbara  3 , Guglielmo Nasti  4 , Vincenzo Montesarchio  5 , Gerardo Rosati  6 , Antonino Cassata  1 , Silvana Leo  7 , Carmela Romano  1 , Emiliano Tamburini  8 , Lucrezia Silvestro  1 , Claudio Lotesoriere  9 , Anna Nappi  1 , Daniele Santini  10 , Antonella Petrillo  11 , Alfredo Colombo  12 , Antonio Febbraro  13 , Alessandra Leone  14 , Francesco Mannavola  15 , Maria Maddalena Laterza  16 , Francesco Izzo  17 , Alberto Sobrero  18 , Paolo Delrio  19 , Diana Giannarelli  20 , Alfredo Budillon  21
Affiliations
Clinical Trial

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

Antonio Avallone et al. J Clin Oncol. 2025 Mar.

Abstract

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.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Antonio Avallone

Honoraria: Bristol Myers Squibb

Consulting or Advisory Role: Amgen, MSD Oncology, AstraZeneca, Bayer, Eisai

Research Funding: Amgen (Inst)

Alfonso De Stefano

Employment: Bristol Myers Squibb (I)

Stock and Other Ownership Interests: Bristol Myers Squibb (I)

Travel, Accommodations, Expenses: Pierre Fabre

Giuseppe Santabarbara

Consulting or Advisory Role: Amgen/Dompé, Merck Serono, Servier

Vincenzo Montesarchio

Employment: Bayer

Honoraria: Bristol Myers Squibb, Italfarmaco

Emiliano Tamburini

Consulting or Advisory Role: Servier, Amgen, AstraZeneca

Alberto Sobrero

Consulting or Advisory Role: Servier, Amgen, Bayer, BMS, MSD Oncology, GlaxoSmithKline

Speakers' Bureau: Bayer, Amgen, AstraZeneca, Bristol Myers Squibb

Travel, Accommodations, Expenses: Bayer

Diana Giannarelli

Consulting or Advisory Role: Amgen, Sanofi

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
CONSORT diagram showing flow of patients through the IMPROVE trial. Data cutoff January 30, 2024. AE, adverse event; FOLFIRI, schedule of fluorouracil, leucovorin, and irinotecan; ITT, intention-to-treat; PAN, panitumumab.
FIG 2.
FIG 2.
Kaplan-Meier curves of (A) PFSot according to the treatment arm in the ITT population and PFSot according to the treatment arm in the (B) right-sided and (C) left-sided ITT population. The + symbol indicates patients censored at the time of data cutoff and analysis (January 30, 2024). FOLFIRI, schedule of fluorouracil, leucovorin, and irinotecan; ITT, intention-to-treat; PAN, panitumumab; PFSot, progression-free survival on treatment.
FIG A1.
FIG A1.
ClinicalTrials.gov identifier: NCT04425239. aOr until unacceptable toxicity or withdrawal of consent. bIrinotecan 180 mg/m2, L-leucovorin 200 mg/m2, and fluorouracil bolus 400 mg/m2 followed by 2,400 mg/m2 continuous infusion over 46 hours plus PAN 6 mg/kg on day 1 every 2 weeks. CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; FOLFIRI, schedule of fluorouracil, leucovorin, and irinotecan; mCRC, metastatic colorectal cancer; PAN, panitumumab; PS, performance status; wt, wild-type.
FIG A2.
FIG A2.
Kaplan-Meier curves of (A) OS according to the treatment arm in the ITT population and OS according to the treatment arm in the (B) right-sided and (C) left-sided ITT population. The + symbol indicates patients censored at the time of data cutoff and analysis (January 30, 2024). FOLFIRI, schedule of fluorouracil, leucovorin, and irinotecan; ITT, intention-to-treat; OS, overall survival; PAN, panitumumab.
FIG A3.
FIG A3.
Kaplan-Meier curves of (A) OS of 13 patients in arm A who discontinued study treatment without progressive disease and received intermittent FOLFIRI plus panitumumab reinduction, and (B) OS of the remaining 56 patients in arm A treated with any other second line of treatment. The + symbol indicates patients censored at the time of data cutoff and analysis (January 30, 2024). FOLFIRI, schedule of fluorouracil, leucovorin, and irinotecan; OS, overall survival.
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References

    1. Morgan E, Arnold M, Gini A, et al. : Global burden of colorectal cancer in 2020 and 2040: Incidence and mortality estimates from GLOBOCAN. Gut 72:338-344, 2023 - PubMed
    1. Biller LH, Schrag D: Diagnosis and treatment of metastatic colorectal cancer: A review. JAMA 325:669-685, 2021 - PubMed
    1. Cervantes A, Adam R, Rosello S, et al. : Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 34:10-32, 2023 - PubMed
    1. Di Nicolantonio F, Vitiello PP, Marsoni S, et al. : Precision oncology in metastatic colorectal cancer—From biology to medicine. Nat Rev Clin Oncol 18:506-525, 2021 - PubMed
    1. Siravegna G, Mussolin B, Buscarino M, et al. : Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 21:827, 2015 - PubMed

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