European Cancer Conference and American College of Gastroenterology: Prostate Cancer
Metastatic castrate-resistant prostate cancers (i.e., those that do not respond to androgen-deprivation therapy) typically overexpress receptors for vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), two of the key cell-surface targets for sunitinib (Sutent, Pfizer). Oral suni-tinib has emerged as a first-line therapy for renal cell carcinoma and as a treatment of gastrointestinal stromal cancer (GIST).
Dr. Zurita reported that adding sunitinib to docetaxel (Tax-otere, Sanofi-Aventis) plus prednisone delayed disease progression and improved prostate-specific antigen (PSA) levels in some men with metastatic castrate-resistant prostate cancer in a clinical trial. The trial was planned on the basis of evidence from case reports that imatinib mesylate (Gleevec, Novartis), which targets only PDGF receptors, significantly reduced PSA levels in some patients.
The trial involved 25 men with metastatic and progressive prostate cancer despite pharmacological or surgical castration. During a six-week lead-in period, patients received sunitinib 50 mg once daily for four weeks, followed by a two-week rest. They were then randomly assigned to one of four treatment groups receiving different doses of intravenous docetaxel with sunitinib:
- docetaxel 60 mg/m2 plus sunitinib 12.5 mg
- docetaxel 60 mg/m2 plus sunitinib 37.5 mg
- docetaxel 60 mg/m2 plus sunitinib 50 mg
- docetaxel 75 mg/m2 plus sunitinib 37.5 mg
Docetaxel injections were given every three weeks. All of the men also took oral prednisone 5 mg twice daily.
During the lead-in period, sunitinib showed a curious tri-valent effect on PSA levels. Seven patients experienced a mean PSA decline of 40%; three among them showed a decrease greater than 50%. In contrast, 12 patients showed a steep rise of (mean) PSA of 273%, followed by a drop during the two-week rest period. Six others showed steady rises of (mean) PSA of 73% that were sustained during the rest period.
The docetaxel/sunitinib combination produced PSA reductions of greater than 50% below baseline levels in 10 of the 25 patients (i.e., in 40%). Four of the 20 patients (20%) with measurable disease at baseline had partial tumor responses, and 11 patients (55%) had stable disease. Tumors progressed in five patients during the one-year follow-up period.
Early-phase results led Dr. Zurita to administer a regimen of docetaxel 75 mg/m2 plus sunitinib 37.5 mg in the ongoing phase 2 portion of the trial. At that dose, sunitinib was generally well tolerated and did not significantly add to the side-effect burden of docetaxel plus prednisone drug.
Which men were most likely to respond well to the combination therapy?
“Preliminary observations suggest that PSA reduction during the lead-in (sunitinib-only) phase likely predicted for later response to the combination,” Dr. Zurita said.
The predictive value of the lead-in PSA kinetics in determining later response is still to be clarified.
Renal Cancer
In a clinical trial of metastatic renal cancer, tumor responses and survival were better with sunitinib than with interferon. At the ECCO meeting, the higher cost of sunitinib was shown to be within accepted limits.
Dr. Negrier’s cost-effectiveness analysis was based on the international outcomes trial of Robert J. Motzer, MD, from Memorial Sloan-Kettering Cancer Center. In that trial, among 750 patients with metastatic renal cancer, median progression-free survival was 11 months for those receiving sunitinib and five months for those receiving interferon. Partial tumor responses were noted in 143 sunitinib-treated patients (39%) and in 29 interferon patients (8%). Within 33 months of follow-up, tumor progression was observed in 57 sunitinib patients (15%) and in 102 interferon patients (27%).
Sunitinib also produced fewer major adverse events. Side effects prompted 86 interferon patients (23%) and 59 sunitinib patients (16%) to discontinue treatment.
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Projections showed that sunitinib treatment would give an advantage, compared with no treatment, of 0.92 progression-free years and of 2.09 total life-years. Interferon was anticipated to provide a progression-free survival advantage of 0.51 years and a total life-year advantage of 1.98 years. Dr. Negrier ex plained that the virtue of sunitinib, therefore, was in delaying inevitable progression.
In this analysis, the total discounted sunitinib cost ($224,970) was 4% higher than that of interferon ($214,436), including all ancillary treatments. Best supportive care costs were higher with interferon, whereas first-line drug costs and routine follow-up costs were higher for sunitinib, partly because of the longer-term treatment and survival.
The estimated cost per progression-free life-year gained with sunitinib was $18,611. Projecting costs and benefits over a 10-year span gave an incremental cost-effectiveness ratio for sunitinib, compared with interferon, of $67,215 per life-year gained and $52,593 per quality-adjusted life-year gained. pharmacy uk
Dr. Negrier concluded, “This [amount] is well within the established threshold of $50,000 to $100,000 per life-year that society is willing to pay.”