First-line Treatment of mRCC

First-line Treatment for Clear Cell mRCC

A number of first-line treatments have been approved and endorsed in many of the above international guidelines for use in clear cell mRCC patients based mainly on the Memorial Sloan Kettering Cancer Centre (MSKCC) prognostication criteria.1Here is the list of drugs approved and data to support its use. We have also included the NICE Incremental Cost Effectiveness Ratio (ICER) data to give an idea about the estimated relative cost-effectiveness of such drugs in the United Kingdom as there are no equivalent data in the local setting.

Sunitinib

Sunitinib was approved for use in the first-line based on the study by Motzer et al comparing it to interferon-alpha (IFN-).2It is indicated for patients with good and intermediate MSKCC prognostic risk.1Median OS was greater in the sunitinib group than in the IFN- group (26.4 vs 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = 0.051) per the primary analysis of unstratified log-rank test (P = 0.013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = 0.049).3The true benefit of sunitinib was likely more if not for the crossover allowed for in the study for patients who had progressed on IFN-

Pazopanib

Pazopanib was approved for use in the first-line in patients with MSKCC good and intermediate risk based on the study by Sternberg et al, comparing it to placebo.4The difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 vs 20.5 months, respectively; HR = 0.91; 95% CI, 0.71 to 1.16; one-sided P = 0.224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis.5In a recent study comparing sunitinib and pazopanib, pazopanib was found to be noninferior to sunitinib.6

The base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, IFN- and sunitinib were USD $50,702, $59,767 and $2750 per quality-adjusted life year (QALY) gained, respectively.7

Temsirolimus

Temsirolimus was approved for use in the first-line setting specifically for MSKCC poor risk patients as defined by the poor risk criteria set by Hudes and team in that study.8Patients who received temsirolimus alone had longer OS (HR = 0.73; 95% CI, 0.58 to 0.92; P = 0.008) and PFS (P <0.001) than did patients who received interferon alone. OS in the combination-therapy group did not differ significantly from that in the interferon group (HR = 0.96; 95% CI, 0.76 to 1.20; P = 0.70). Median OS in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4months, respectively.8The indirect comparison of temsirolimus with best supportive care produced an ICER of USD $124,781 per QALY gained. 9

Bevacizumab and Interferon

Bevacizumab and interferon combination have been approved in the first-line setting for MSKCC good and intermediate risk patients.10,11A total of 732 patients were enrolled. The median OS was 18.3 months (95% CI, 16.5 to 22.5) for bevacizumab plus IFN- and 17.4 months (95% CI, 14.4 to 20.0) for IFN- monotherapy (unstratified logrank P = 0.097). Adjusting on stratification factors, HR was 0.86 (95% CI, 0.73 to 1.01; stratified log-rank P = 0.069) favouring bevacizumab plus IFN-11

The comparison of bevacizumab plus IFN- with IFN- plus placebo produced a base-case ICER of USD $115,241 per QALY gained.9In Singapore, this combination is rarely used in view of the cost and toxicities related to its use.

High-dose Interleukin-2 (IL-2)

High-dose IL-2 can be used in a selected group of fi t clear cell mRCC patients postnephrectomy with limited disease burden.12,13Median duration for all complete responses has not yet been reached, but was at least 80 months (range, 7-131 months) at the time of this analysis. Median duration for all partial responses remains 20 months (range, 3-126 months). Median survival time for all 255 patients remains 16.3 months, with 10% to 20% of patients estimated to be alive 5 to 10 years after treatment with high-dose IL-2.13

Active Surveillance

Observation after cytoreductive nephrectomy is an option that can be considered in a selected group of asymptomatic clear cell mRCC patients.14 In this local study, 15 patients were put on active surveillance. At a median follow-up of 18 months, 80% of patients had progressed. However, a third of the patients had at least 6 months of progression free interval, and 3 of 15 patients had not progressed at prolonged follow-up durations of 18, 23, and 46 months. A third of the patients remained alive and the median survival for the cohort was 25 months. Preoperative predictive factors for non-progression after debulking nephrectomy included absence of abnormal laboratory indices, single organ system metastases, and good performance status. A recent study of 52 patients by Rini et al also showed that a selected group of mRCC patients can be safely observed before any treatment is started.15

First-line Treatment of Non-Clear Cell mRCC

No standard treatment is available and the patient should be treated in the framework of clinical trials if available. A number of recent randomised studies have shown that vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) like sunitinib may be better than everolimus in treating these patients and are hence a reasonable option for these patients.16,17Best supportive care can be offered as a reasonable option if the patient is not fi t to receive further treatment.

Recommendations for First-line Treatment of mRCC

All the committee members who voted expressed preference for the Canadian guideline (Supplementary Table 1) because they listed clinical trials as the first option, followed by patient stratification by MSKCC, and they included observation as an option for first-line. All committee members agreed that tivozanib should not be a part of the local guidelines as data did not support its use.

For MSKCC Poor Risk Patients

It was noted that temsirolimus and sunitinib have both demonstrated their effectiveness in poor risk patients in clinical trials. Majority in the group (86%) held the opinion that pazopanib can be given to poor risk patients because of its better tolerability. One member (14%), however, disagreed, in view of the poor data supporting its use in poor risk patients. The member further elaborated that low-dose sunitinib18has a higher evidence of efficacy in poor risk patients. In the end, the majority (86%) voted to list pazopanib as a first-line option for poor risk patients, with an indication to mention the lack of strong level of evidence to it, and that pazopanib should only be used as an alternative to sunitinib. All members (100%) agreed everolimus should not be recommended as a first-line drug in poor risk patients. There was a unanimous vote to leave out the Asian resource-stratified guideline as it was broad and not relevant to our local setting (Table 1).

For Non-Clear Cell RCC (CCRCC) Patients

The committee noted that the Canadian guideline did not comment on non-CCRCC, NCCN included all drugs for non-CCRCC, and ESMO indicated the lack of standard therapy for non-CCRCC. The committee also discussed on the inclusion of temsirolimus, sunitinib and IFN- for non-CCRCC. In view of the limited evidence on these drugs, all members who voted (100%) agreed to indicate no standard therapy, clinical trial preferred and best supportive care for non-CCRCC, much like the EAU guidelines. The members agreed that they would treat the mixed histology group as CCRCC as long as there is a predominant clear cell component in the histology, except with regard to the use of high-dose IL-2, where they would only use it on pure clear cell patients. The group emphasised that best supportive care should be added as an option in the local guideline for first-line mRCC management (Table 1).