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Clinical Trial
. 2021 Nov 20;39(33):3693-3704.
doi: 10.1200/JCO.21.01436. Epub 2021 Sep 13.

Capecitabine Versus Active Monitoring in Stable or Responding Metastatic Colorectal Cancer After 16 Weeks of First-Line Therapy: Results of the Randomized FOCUS4-N Trial

Richard A Adams  1 , David J Fisher  2 , Janet Graham  3 , Jenny F Seligmann  4 , Matthew Seymour  4 , Richard Kaplan  2 , Emma Yates  2 , Mahesh Parmar  2 , Susan D Richman  4 , Philip Quirke  4 , Rachel Butler  5 , Ewan Brown  6 , Fiona Collinson  4 , Stephen Falk  7 , Harpreet Wasan  8 , Kai-Keen Shiu  9 , Gary Middleton  10 , Leslie Samuel  11 , Richard H Wilson  3 , Louise C Brown  2 , Timothy S Maughan  12 ; FOCUS4 Trial Investigators
Affiliations
Clinical Trial

Capecitabine Versus Active Monitoring in Stable or Responding Metastatic Colorectal Cancer After 16 Weeks of First-Line Therapy: Results of the Randomized FOCUS4-N Trial

Richard A Adams et al. J Clin Oncol. .

Abstract

Purpose: Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy.

Methods: FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability.

Results: Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups.

Conclusion: Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy.

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Conflict of interest statement

Richard A. AdamsHonoraria: Merck Serono, Servier, AmgenConsulting or Advisory Role: Merck Serono, Amgen, Servier, BayerSpeakers' Bureau: Merck SeronoResearch Funding: Merck Sharp & DohmeTravel, Accommodations, Expenses: Servier, Amgen, Merck Serono, AstraZeneca Janet GrahamHonoraria: Merck Serono, Bristol Myers Squibb, Nucana, BayerConsulting or Advisory Role: Merck KGaATravel, Accommodations, Expenses: Nucana Jenny F. SeligmannHonoraria: Pierre Fabre, Merck Serono, ServierConsulting or Advisory Role: Pierre Fabre, Roche Molecular DiagnosticsTravel, Accommodations, Expenses: Bristol Myers Squibb/Medarex Matthew SeymourResearch Funding: Amgen, AstraZeneca Richard KaplanResearch Funding: AstraZeneca Mahesh ParmarResearch Funding: AstraZeneca, Astellas Pharma, Janssen, Clovis Oncology Philip QuirkeHonoraria: RocheConsulting or Advisory Role: Roche, Adlai Nortye, Avacta Life Sciences, Amgen, BayerResearch Funding: Roche, GeneFirst, ONIPatents, Royalties, Other Intellectual Property: Roche have filed a patent jointly with my UniversityTravel, Accommodations, Expenses: Roche, Bayer, Amgen Rachel ButlerSpeakers' Bureau: Bayer, Pfizer, Roche, AstraZeneca, MSD, Illumina, Lilly, Novartis, Amgen, Boehringer Ingelheim Ewan BrownResearch Funding: MSD Oncology Fiona CollinsonResearch Funding: Bristol Myers Squibb Stephen FalkStock and Other Ownership Interests: GlaxoSmithKlineSpeakers' Bureau: Merck Serono, Servier, AmgenResearch Funding: Gilead SciencesTravel, Accommodations, Expenses: CelgeneOther Relationship: Servier Harpreet WasanHonoraria: Merck KGaA, Celgene, Sirtex Medical, Servier, Array BioPharma, Roche/Genentech, ERYTECH Pharma, Incyte, ZymeworksConsulting or Advisory Role: Roche Pharma AG, ERYTECH Pharma, Shire, Incyte, Sirtex Medical, Pierre Fabre, Pfizer, BayerSpeakers' Bureau: Sirtex Medical, Celgene, Merck KGaA, Servier, IncyteResearch Funding: Sirtex Medical, Merck KGaA, Pfizer, Merck Sharp & Dohme Kai-Keen ShiuHonoraria: Merck Serono, MSD Oncology, Innovent Biologics, Servier, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: MSD Oncology, Roche, Mirati TherapeuticsResearch Funding: MSD Oncology, Roche Gary MiddletonConsulting or Advisory Role: BMS, D2G, MSDSpeakers' Bureau: Roche, BMS, Servier, PierreFabre, AZTravel, Accommodations, Expenses: BMS Leslie SamuelHonoraria: ServierConsulting or Advisory Role: MerckResearch Funding: Merck, Array BioPharma, Tesaro, Servier, Hutchison MediPharma Richard H. WilsonHonoraria: Servier, Amgen, Bristol Myers SquibbConsulting or Advisory Role: Amgen, CV6 Therapeutics, Pierre Fabre, Amphista Therapeutics, NucanaTravel, Accommodations, Expenses: Amgen, Pierre Fabre Louise C. BrownResearch Funding: AstraZeneca Timothy S. MaughanConsulting or Advisory Role: AstraZeneca, Vertex, Pierre FabreResearch Funding: AstraZeneca, PsiOxus Therapeutics, Merck KgAA, Almac DiagnosticsNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Flow diagram showing patient flow through the FOCUS4-N trial. CR, complete response; PR, partial response; SD, stable disease.
FIG 2.
FIG 2.
Kaplan-Meier curve for PFS in FOCUS4-N. Cox regression HR, adjusted for minimization factors = 0.40 (95% CI, 0.21 to 0.75), P < .0001. Minimization factors: location of primary tumor (left, right, and rectum), baseline WHO performance status, baseline disease assessment, No. of metastases, first-line therapy (fluoropyrimidine, oxaliplatin or irinotecan, and monoclonal antibody), and biomarker cohort, stratified for FOCUS4 trial timepoints. AM, active monitoring; HR, hazard ratio; PFS, progression-free survival.
FIG 3.
FIG 3.
Kaplan-Meier curve for OS in FOCUS4-N. Cox regression HR, adjusted for minimization factors = 0.93 (95% CI, 0.69 to 1.27), P = .66. Minimization factors: location of primary tumor (left, right, and rectum); baseline WHO performance status; baseline disease assessment; No. of metastases; first-line therapy (fluoropyrimidine, oxaliplatin or irinotecan, and monoclonal antibody); and biomarker cohort, stratified for FOCUS4 trial timepoints. AM, active monitoring; HR, hazard ratio; OS, overall survival.
FIG 4.
FIG 4.
(A) Forest plot of subgroup analyses for PFS (unadjusted HRs). (B) Forest plot of subgroup analyses for OS (unadjusted HRs). AM, active monitoring; CAPOX, capeciteabine with oxaliplatin; Cet, cetuximab; FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; HR, hazard ratio; OS, overall survival; Pan, panitumumab; PFS, progression-free survival; PTEN, phosphatase and tensin homolog; PTL, primary tumor location.
FIG 5.
FIG 5.
Cumulative reported toxicity by randomized group: (A) active monitoring (n = 127) and (B) capecitabine (n = 127). G, grade; PPE, palmar-plantar erythema.
FIG 6.
FIG 6.
Quality of life measured by EQ-5D by randomized group: (A) mobility: X2 for AUC difference = 0.86(1), P = .35; (B) self-care: X2 for AUC difference = 1.64(1), P = .20; (C) usual activities: X2 for AUC difference = 0.06(1), P = .81; (D) pain and discomfort: X2 for AUC difference = 2.49(1), P = .11; and (E) anxiety and depression: X2 for AUC difference = 1.03(1), P = .31; AUC, area under the curve.
FIG A1.
FIG A1.
Swimmer plot for FOCUS4-N, by location of primary tumor. CT, computed tomography.
See this image and copyright information in PMC

Comment in

References

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