The cost-effectiveness institute for England and Wales has rejected three biological treatments for metastatic colorectal cancer that has progressed after initial or second-line treatment.
The National Institute for Health and Clinical Excellence said Jan. 24 that cetuximab (Erbitux, Merck Serono), bevacizumab (Avastin, Roche) and panitumumab (Vectibix, Amgen) had all failed to reach the agency’s cost-effectiveness criteria for the treatment of metastatic colorectal cancer that has progressed following initial combination chemotherapy.
All the treatments are monoclonal antibodies licensed for the second- or third-line treatment of metastasized colorectal cancer. Cetuximab was evaluated by NICE as monotherapy or combination therapy, bevacizumab in combination with nonoxaliplatin (Eloxatin) chemotherapy, and panitumumab as monotherapy.
NICE published its final guidance on these drugs Jan 25 in the Lancet Oncology. The negative guidance was widely anticipated after NICE issued draft guidance in September 2011 and again in November against the treatments.
In a news release about its decision, the agency singled out the clinical evidence for bevacizumab as especially wanting. NICE said that evidence from three clinical trials (two observational studies and one randomized, controlled trial) evaluating bevacizumab’s effectiveness as a second- or third-line treatment could not be used to establish overall survival benefit. Because of this, the NICE reviewers did not attempt to quantify bevacizumab’s cost-effectiveness in terms of incremental cost-effectiveness rations (ICERs) or Quality Adjusted Life Years (QALYs).
Despite the negative guidance, NICE has not closed the book on bevacizumab for advanced metastatic bowel cancer, having noted in its draft guidance in November that a phase II clinical trial comparing bevacizumab plus 5-fluorouracil plus folinic acid and irinotecan (FOLFIRI) with panitumumab plus FOLFIRI after first-line treatment was underway, with an expected completion date of August 2012, and said that it would take those results into consideration.
With cetuximab, NICE reviewed evidence from a randomized controlled trial (n = 230) enrolling patients with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. (NICE estimates that 30%-50% of people with colorectal cancer have the KRAS wild-type gene.) Subjects had been previously treated with oxaliplatin-based and irinotecan (Camptosar)-based therapies. Median overall survival was 9.5 months for cetuximab plus best supportive care, compared with 4.8 months for best supportive care alone (hazard ratio, 0.55; 95% confidence interval, 0.41-0.74; P less than .001).
However, the NICE reviewers noted that there were no head-to-head trials of cetuximab plus irinotecan compared with best supportive care in KRAS wild-type colorectal cancer, forcing cetuximab’s manufacturer to submit an indirect comparison combining evidence from multiple clinical trials, including nonrandomized trials. This mixed analysis cast doubt on the robustness of the overall survival estimates, NICE said.
NICE estimated an ICER of £98,000 per QALY gained for cetuximab plus best supportive care, compared with best supportive care alone. For cetuximab plus irinotecan plus best supportive care compared with best supportive care alone, NICE estimated an ICER of £88,000 per QALY gained.
The case for panitumumab monotherapy was derived from a randomized, controlled trial that had a subgroup of 243 patients with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. Patients had been previously treated with oxaliplatin and irinotecan therapies, meaning that panitumumab was given as third- or fourth-line therapy. Panitumumab was associated with a progression-free survival benefit of about 5 weeks, compared with best supportive care; however, this did not reach statistical significance.
The NICE reviewers concluded that absent additional evidence, the true magnitude of panitumumab’s survival benefit was uncertain. Further, panitumumab’s expense – NICE estimated its ICER at between £110,000 and £150,000 per QALY gained – would have meant that NICE could not recommend it even if a survival benefit had been established.
All three medications – cetuximab, bevacizumab, and panitumumab – are administered by intravenous infusion.
The recommended dosage of cetuximab is an initial dose of 400 mg/m2 of body surface area followed by 250 mg/m2 once a week. The U.K. list price of a 100-mg vial of cetuximab is £178.10, and a 500-mg vial is £890.50.
Bevacizumab’s dosage is 5 or 10 mg/kg of body weight once every 2 weeks or 7.5 or 15 mg/kg of body weight once every 3 weeks. The list price of a 100-mg vial is £242.66, and a 400-mg vial is £924.40. Panitumumab’s dosage is 6 mg/kg every 14 days. It costs £379.29 for 100 mg and £1,517 for 400 mg.
In announcing its decisions on bevacizumab, cetuximab, and panitumumab, NICE emphasized that it had six other recommended treatments for various stages of colorectal cancer, metastatic and nonmetastatic.
NICE recommends only two treatments for metastatic cancer that has progressed after first-line treatment: monotherapy with irinotecan for people who previously received FOLFIRI (irinotecan in combination with 5-fluorouracil plus folinic acid), and FOLFOX (oxaliplatin in combination with 5-fluorouracil plus folinic acid) for people who previously received FOLFIRI.