eUpdate – Metastatic Colorectal Cancer Treatment Recommendations

eUpdate – Metastatic Colorectal Cancer Treatment Recommendations

Published: 20 September 2016. Authors: ESMO Guidelines Committee

Clinical Practice Guidelines

These updates refer to the Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Van Cutsem E, Cervantes A, Nordlinger B and Arnold D, Ann Oncol 2014; 25 (Suppl 3): iii1-iii9.

Update 1

Section

Systemic treatment

Text update

Angiogenesis is an important therapeutic target in colorectal carcinoma. The multicentre, randomised, double-blind, phase III RAISE trial assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) in 1072 metastatic colorectal cancer patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Median overall survival (OS) was 13.3 months (95% CI 12.4–14.5) for patients in the ramucirumab group versus 11.7 months (10.8–12.7) for the placebo group (hazard ratio 0.844 [95% CI 0.730–0.976]; logrank p = 0.0219). Evaluation of the Kaplan-Myer curves for OS reveals an OS advantage of 5%-10% at 2 years. Grade 3 or worse serious adverse events were similar and manageable, in the ramucirumab group (36% vs placebo (31%), while quality of life (QoL) assessment did not reveal differences. Given the OS benefit (at 2 years) observed in the absence of QoL or safety profile improvement, the FOLFIRI+ramucirumab regimen was given an ESMO Magnitude of Clinical Benefit Scale (MCBS) score of 3.

Recommendation

For patients with metastatic colorectal carcinoma progressing on or after 1st line bevacizumab, fluoropyrimidine and oxaliplatin, the addition of ramucirumab to 2nd line FOLFIRI improves survival over placebo and represents a therapeutic choice associated with an MCBS score of 3.

Magnitude of Clinical Benefit Scale (MCBS) table for new therapies/indications in metastatic colorectal cancer*

Therapy Disease setting Trial Control Absolute survival gain HR (95% CI) QoL/toxicity MCBS score**
Ramucirumab, a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2 Metastatic colorectal cancer, 2nd line setting, bevacizumab-pretreated. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study [1]
 
Phase III
 
NCT01183780
FOLFIRI + placebo
 
Median OS: 11.7 months
Median OS gain: 1.6 months
 
2-year survival improvement: 5%-10%
OS HR:
0.84 (0.73-0.97)
Similar toxicity profile
 
No improvement in QoL
3 (Form 2a)

*EMA approvals in 2016 to end August 2016.
**ESMO-MCBS version 1.0 [2]
HR, hazard ratio; CI, confidence interval; QoL, quality of life; IgG-1, Immunoglobulin G-1; VEGF, vascular endothelial growth factor; FOLFIRI, leucovorin, fluorouracil, and irinotecan; OS, overall survival, EMA, European Medicines Agency

References

  1. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 2015; 16: 499–508.
  2. Cherny NI, Sullivan R, Dafni U et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol 2015; 26: 1547–1573.

Update 2

Section

Systemic treatment

Text update

In a double-blind study 800 patients with metastatic colorectal cancer who have been previously treated with, or were not considered candidates for, available therapies including fluoropyrimidine, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents, were randomised in a 2:1 ratio, to receive trifluridine/tipiracil (TAS-102) or placebo. The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P<0.001). Overall, adverse events of grade 3 or higher occurred more frequently in the TAS-102 group than in the placebo group (in 69% vs. 52% of the patients). The observed improvement in overall survival/risk of death along with lack of safety profile improvement results in an ESMO Magnitude of Clinical Benefit Scale (MCBS) score of 2.

Recommendation

In patients with refractory colorectal cancer, trifluridine/tipiracil (TAS-102), as compared with placebo, is associated with a statistically significant improvement in overall survival. However, the observed clinical benefit is associated with an ESMO Magnitude of Clinical Benefit Scale (MCBS) score of 2.

Magnitude of Clinical Benefit Scale (MCBS) table for new therapies/indications in metastatic colorectal cancer*

Therapy Disease setting Trial Control Absolute survival gain HR (95% CI) QoL/toxicity MCBS score**
Trifluridine/tipiracil (TAS-102) Patients with metastatic CRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer [1]
 
Phase III
 
NCT01607957
Placebo
 
Median OS: 5.3 months
Median OS gain: 1.8 months OS HR:
0.68
(0.58-0.81)
Deteriorated toxicity profile 2 (Form 2a)

*EMA approvals in 2016 to end August 2016.
**ESMO-MCBS version 1.0 [2]
HR, hazard ratio; CI, confidence interval; QoL, quality of life; CRC, colorectal cancer; OS, overall survival; EMA, European Medicines Agency

References

  1. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. N Engl J Med 2015; 372:1909-1919.
  2. Cherny NI, Sullivan R, Dafni U et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol 2015; 26: 1547–1573.