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Efficacy of VEGF/VEGFR-Targeting Agents in Poor-Risk mRCC Patients
Although initially developed for the prognostic stratification of mRCC patients undergoing cytokine treatment, risk assessment models based on clinical/laboratory parameters have proven to be effective in discriminating patients at different probability of outcomes (either PFS or OS) upon treatment with inhibitors of the VEGF/VEGFR axis, which currently constitute the preferred therapeutic choice in the vast majority of patients diagnosed with mRCC. However, patients with poor-risk features have usually been excluded from clinical trials in mRCC; indeed, the global ARCC trial described above is the only pivotal Phase III trials specifically targeting the population of patients with poor-risk mRCC reported so far, while only limited numbers of patients with poor-risk features have been enrolled in Phase III trials assessing the efficacy of VEGF pathway inhibitors. The impact of VEGF/VEGFR-targeting agents in this particular population is therefore difficult to appreciate.
In the AVOREN trial, comparing bevacizumab plus IFN-α with IFN-α alone, PFS was longer in the bevacizumab plus IFN-α group than in the placebo plus IFN-α group, irrespective of MSKCC risk group. However, only 54 out of 649 patients (8%) were classified as poor risk according to MSKCC criteria. The median OS for the 30 poor-risk patients treated with bevacizumab plus IFN-α was 6 months, while PFS was no different from that achieved in patients treated with placebo plus IFN-α (HR: 0.87; 95% CI: 0.48–1.56). In the CALGB 90206 trial, only 75 out of 732 patients (10.2%) were classified as poor risk according to MSKCC criteria. In these patients, the median OS in the bevacizumab plus IFN-α arm was 6.6 months (95% CI: 5.9–8.9 months) compared with 5.7 months (95% CI: 4.4–9.2 months) in the IFN-α alone arm, without statistically significant differences (p = 0.2439). The HR for death for bevacizumab plus IFN-α versus IFN-α was 0.76 for the small subgroup of poor-risk patients.
In the pivotal Phase III trial comparing sunitinib with IFN-α, sunitinib significantly prolonged PFS in all three prognostic risk categories (favorable, intermediate and poor). In the poor-risk group, the median OS was 5.3 months (95% CI: 4.2–10.0 months) for sunitinib compared with 4.0 months (95% CI: 2.7–7.2 months) for IFN-α (HR: 0.660; 95% CI: 0.360–1.207). In this study, however, only 48 out of the 750 (6.4%) participants met poor-risk criteria. Strikingly, similar results were observed in an expanded access trial of sunitinib, which enrolled 4564 patients with mRCC, 373 of whom (9% of the total) were classified as poor risk according to MSKCC criteria: median PFS for these patients was 4.1 months (95% CI: 3.1–5.0 months) and median OS was 5.3 months (95% CI: 4.6–5.4 months). In another small retrospective study of 61 poor-risk mRCC patients, as determined by MSKCC criteria, sunitinib treatment resulted in a median PFS of 3.9 months and a median OS of 6.4 months.
In the pivotal Phase III trial of pazopanib, PFS was significantly prolonged by pazopanib treatment compared with placebo, regardless of MSKCC risk category. However, only 14 out of 435 participants (3.2%) met poor-risk criteria, and no efficacy data for this specific subpopulation are currently available.
A recent retrospective study enrolling 85 mRCC patients with measurable lesions shows that VEGFR-TKI (mostly sunitinib; 86% of cases) are indeed active in mRCC patients with poor-risk features; median time to progression was 5.0 months and median OS was 9.3 months, with a 1-year survival rate of 41%. However, it has to be noted that the majority (52%) of patients included in this study were classified as intermediate risk, according to the International mRCC Database Consortium classification, while only 48% of patients had truly poor-risk features. At present, two studies are ongoing to investigate pazopanib as first-line therapy in poor-risk mRCC patients: a Phase II trial (ClinicalTrials.gov identifier: NCT01392183) comparing pazopanib and temsirolimus in patients with clear-cell histology and the single-arm FLIPPER Phase IV study (ClinicalTrials.gov identifier: NCT01521715).
The global impact of VEGF axis-targeting agents (also including pazopanib and axitinib) can be indirectly derived from the results of the International mRCC Database Consortium prognostic classification and its recent external validation. Indeed, the 645 patients of the original dataset and the 849 patients of the validation dataset were uniformly treated with anti-VEGF agents: 26–31% of patients were classified as poor risk according to the DC model and, in this patient population, median OS ranged from 7.8 to 8.8 months in the two different datasets.
Overall, available data indicate that VEGF/VEGFR-targeting agents are active and relatively well tolerated in mRCC with poor prognostic features. Although it is reasonable to speculate that some poor-risk patients may benefit from VEGF axis inhibitors, OS with such agents in this particular category of patients remains poor (median OS: ~6 months; Figure 1) and the eventual survival benefit over cytokines (namely IFN-α) uncertain. Thus, their true impact on disease course and possibly other outcome measures, such as quality of life, in mRCC patients with poor prognostic features remains to be firmly established.
(Enlarge Image)
Figure 1.
Median overall survival (with 95% CI) for metastatic renal cell carcinoma patients classified as poor risk by strict Memorial Sloan–Kettering Cancer Center criteria on treatment with selected targeted agents. OS: Overall survival.
Novel, more potent and selective VEGFR inhibitors are entering the therapeutic scenario of mRCC treatment; although no data are currently available with specific regard to the poor-risk subgroup, it will be interesting to see whether more potent and less toxic VEGFR-TKI, such as axitinib and tivozanib, may substantially impact on disease course in this difficult-to-treat mRCC patient population.
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