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Clinical Trial
. 2023 Jul 1;9(7):966-970.
doi: 10.1001/jamaoncol.2023.0655.

Panitumumab Plus Trifluridine-Tipiracil as Anti-Epidermal Growth Factor Receptor Rechallenge Therapy for Refractory RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial

Stefania Napolitano  1 , Vincenzo De Falco  1 , Giulia Martini  1 , Davide Ciardiello  1   2 , Erika Martinelli  1 , Carminia Maria Della Corte  1 , Lucia Esposito  1 , Vincenzo Famiglietti  1 , Alessandra Di Liello  1 , Antonio Avallone  3 , Claudia Cardone  3 , Alfonso De Stefano  3 , Vincenzo Montesarchio  4 , Maria Giulia Zampino  5 , Roberto Bordonaro  6 , Mario Scartozzi  7 , Daniele Santini  8 , Massimo Di Maio  9 , Ferdinando De Vita  1 , Lucia Altucci  1 , Francesca Marrone  1 , Fortunato Ciardiello  1 , Teresa Troiani  1
Affiliations
Clinical Trial

Panitumumab Plus Trifluridine-Tipiracil as Anti-Epidermal Growth Factor Receptor Rechallenge Therapy for Refractory RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial

Stefania Napolitano et al. JAMA Oncol. .

Erratum in

  • Error in Affiliations.
    [No authors listed] [No authors listed] JAMA Oncol. 2024 Apr 1;10(4):541. doi: 10.1001/jamaoncol.2024.0068. JAMA Oncol. 2024. PMID: 38386352 Free PMC article. No abstract available.

Abstract

Importance: Current third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors for RAS wild-type (WT) MCRC may be valuable for these patients.

Objective: To compare the anti-EGFR monoclonal antibody panitumumab plus standard-of-care trifluridine-tipiracil with trifluridine-tipiracil alone as third-line therapy for RAS WT MCRC.

Design, setting, and participants: This phase 2 randomized clinical trial (RCT) was conducted in 7 Italian centers from June 2019 to April 2022. Patients with refractory RAS WT MCRC who had a partial or complete response to first-line chemotherapy plus an anti-EGFR monoclonal antibody and an anti-EGFR drug-free interval of 4 or more months during second-line therapy were included.

Interventions: Patients were randomized 1:1 to receive panitumumab plus trifluridine-tipiracil or trifluridine-tipiracil alone.

Main outcomes and measures: The primary end point was progression-free survival (PFS). Circulating tumor DNA (ctDNA) extended sequence variation analysis was performed in a subgroup of patients.

Results: Of 62 included patients, 31 received panitumumab plus trifluridine-tipiracil (19 [61.3%] male; median age, 65 years [range, 39-81 years]) and 31 received trifluridine-tipiracil alone (17 [54.8%] male; median age, 66 years [range, 32-82 years]). The primary end point was met. Median PFS was 4.0 months (95% CI, 2.8-5.3 months) in the panitumumab plus trifluridine-tipiracil arm vs 2.5 months (95% CI, 1.4-3.6 months) in the trifluridine-tipiracil only (hazard ratio [HR], 0.48; 95% CI, 0.28-0.82; P = .007). Pretreatment plasma RAS/BRAF WT ctDNA identified patients obtaining prolonged clinical benefit with panitumumab plus trifluridine-tipiracil compared with trifluridine-tipiracil, with PFS rates at 6 months of 38.5% vs 13.0% and at 12 months of 15.4% vs 0%. A ctDNA liquid-biopsy extended mutation analysis by FoundationOne Liquid CDx (profiling 324 genes) was performed in a subgroup of patients with baseline plasma RAS/BRAF WT ctDNA; in 15 of 23 patients (65.2%) whose tumors were WT for KRAS, NRAS, BRAFV600E, EGFR, ERBB2, MAP2K1, and PIK3CA, median PFS was 6.4 months (95% CI, 3.7-9.2 months). Within this group of 15 patients, 2 (13.3%) had partial response, 11 (73.3%) had stable disease, and 2 (13.3%) had disease progression as best response.

Conclusions and relevance: In this RCT, third-line treatment with the anti-EGFR monoclonal antibody panitumumab plus the standard-of-care trifluridine-tipiracil resulted in improved PFS compared with treatment with trifluridine-tipiracil alone among patients with refractory RAS WT MCRC. The findings support the clinical utility of liquid biopsy-guided anti-EGFR rechallenge therapy for refractory RAS WT MCRC.

Trial registration: ClinicalTrials.gov Identifier: NCT05468892.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Napolitano reported receiving travel grants from Amgen and Merck KGaA outside the submitted work. Dr D. Ciardiello reported receiving personal fees (travel support) from Sanofi, Bristol Myers Squibb, and Merck-Serono outside the submitted work. Dr Martinelli reported receiving travel grants from AstraZeneca and Pierre Fabre and being an advisory board member for AstraZeneca, Bayer, Amgen, Merck KGaK, Roche, Sanofi, Servier, and Pierre Fabre outside the submitted work. Dr Della Corte reported receiving personal fees from Roche, MSD, and AstraZeneca and travel grants from Amgen outside the submitted work. Dr Avallone reported receiving personal fees for consulting from Amgen, AstraZeneca, MSD, and Eisai and being an advisory board member for Amgen and Servier outside the submitted work. Dr Cardone reported receiving personal fees from Bayer outside the submitted work. Dr De Stefano reported being a speaker for Amgen outside the submitted work. Dr Scartozzi reported receiving personal fees from Amgen, Servier, Merck, MSD, AstraZeneca, and GSK outside the submitted work. Dr Di Maio reported receiving personal fees from AstraZeneca, Novartis, Roche, Pfizer, Amgen, Merck, Boehringer Ingelheim, and Servier and grants from Tesaro/GSK outside the submitted work. Prof F. Ciardiello reported serving on the advisory board for Amgen and Servier during the conduct of the study and serving on the advisory board for MSD, Merck KGaA, Roche, Pfizer, Bayer, Pierre Fabre, and Eisai outside the submitted work. Dr Troiani reported serving on the advisory board for Amgen, MSD, Pierre Fabre, Roche, Merck, and Sanofi outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
The data cutoff for the interim analysis was September 16, 2022.
Figure 2.
Figure 2.. Kaplan-Meier Estimates of Progression-Free Survival (PFS) in the Study Population
Cross marks show data censored at the time of last disease assessment. ctDNA indicates circulating tumor DNA; ITT, intention to treat; and WT, wild type.
See this image and copyright information in PMC

References

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