Sorafenib versus sunitinib as first-line treatment agents in Chinese patients with metastatic renal cell carcinoma: the largest multicenter retrospective analysis of survival and prognostic factors

It is evident that ~30% of renal cell carcinoma (RCC) patients have overt metastases, defined as metastatic RCC (mRCC) [ 1] with a very poor average 5-year survival rate (only 10–12%) [ 2]. The growing evidence on the associations of molecular mechanisms with mRCC and also the abstinence of cytokine-based therapies due to high toxicity profile [ 3– 5] has rationalized several randomized clinical trials on molecular targeted therapies such as sorafenib [ 6], bevacizumab [ 4], temsirolimus [ 7], sunitinib [ 8], pazopanib [ 9], everolimus [ 10], and axitinib [ 11] as first- and second-line treatment, which were found to be efficacious and safer than conventional immunotherapy. The availability of these targeted therapies has resulted in prolonged overall survival (OS) to approximately 2 years, thereby emerging as the standard of care in the management of mRCC. However, efficacy of drugs used in cancer chemotherapy is often associated with distinctive challenges due to infrequent occurrence of measurable disease, prolonged natural history of disease, diverse clinical characteristics and greater likelihood of contrary outcomes when treating elderly patients with more aggressive treatments [ 12, 13]. These challenges also influence regular, as well as accelerated regulatory approvals of drugs, which require extensive evidence of efficacy derived from clinical trials in addition to accommodating integral characteristics of disease and patient population [ 14]. Also, first-line therapies should be strategically chosen in order to devoid the need of sequential therapy with second-line therapies. For this purpose, comparing the efficacy of drugs may offer substantial evidence and guidance on the optimal use of targeted therapies. When evaluated as first-line treatment, axitinib demonstrated clinical efficacy and safety, but no significant progression free survival (PFS) benefit over sorafenib in a Phase III randomized comparison [ 15]. Further, sunitinib had similar efficacy as pazopanib in a non-inferiority trial [ 16]. Moreover, in case of sunitinib failure in advanced RCC, everolimus and axitinib appear to provide second-line PFS benefits [ 17]. On the other hand, recent Phase III Investigating Torisel as Second-Line Therapy (INTORSECT) trial reported no significant benefit of either temsirolimus or sorafenib as second-line treatment after sunitinib failure [ 7], though, temsirolimus demonstrated clinical efficacy as first-line therapy in poor risk patients [ 18]. Although sorafenib is a comparator agent in several clinical trials and often used as a second-line therapy, Chinese patients have been more responsive to sorafenib than western patients, hence, both sunitinib and sorafenib are widely recommended first-line therapies in China [ 19]. However, studies directly comparing efficacy of the two therapies in first-line settings which may guide the clinical decisions of mRCC treatment in Asian patients are limited. Although, a Korean study has reported comparable efficacy of the 2 drugs in mRCC patients, the findings were limited due to small patient population and a single centric retrospective design, warranting additional investigation [ 20]. Hence this study aims to retrospectively elucidate the relationship between clinical variables and disease prognosis by comparing sorafenib versus sunitinib in Chinese patients with mRCC at 3 tertiary hospitals in China.

Sorafenib and sunitinib have been used for mRCC in China since 2007. Since then several studies have tried to elucidate the efficacy of the novel treatments. OS is a reliable endpoint for assessing the efficacy of mRCC with targeted therapy [ 21]. Although, these new therapies have improved the OS and PFS of patients with mRCC, gradual development of drug resistance may often lead to switching one therapy to other, resulting in sequential therapy. Filson et al. reported that patients on first-line sorafenib therapy have high probability of proceeding to second-line therapy with sunitinib [ 22]. This clearly indicates the difference between the efficacies of the two drugs. However, a Korean study revealed comparable efficacy outcomes of sorafenib and sunitinib when used as monotherapy in first-line settings [ 20]. In support to the Korean study, more Asian studies are warranted to elucidate the efficacies of these therapies to inform the choice of first-line therapies.

Evidence-based studies suggest both first- and second-line efficacy of sorafenib. Earlier trials have shown comparable efficacy of sorafenib with interferon alpha-2a (PFS: 5.7 vs 5.6 months respectively), were the sorafenib treatment was well tolerated by the patients [ 23]. Also, in the INTORSECT trial, sorafenib had significantly longer OS compared to temsirolimus in first line therapy [ 7]. Further, a non-randomized open access trial demonstrated that sorafenib provides similar benefits in both first- and second-line setting [ 15]. The recent findings from an Italian study further confirmed that sorafenib prolonged PFS and OS in both first- and second-line routine community practice setting [ 24]. On the other hand, sunitinib also has established efficacy in previous phase 3 trials. Further, the efficacy of sunitinib was found to be superior to IFN-alpha but comparable to pazopanib across the trails, however severe grade 3 or 4 adverse effects were the limitations [ 8, 25].

Though efficacies of both the drugs in first-line setting are well described in retrospective literature, head-to-head comparison of real world clinical outcomes in patients are more heterogeneous than those trailed under controlled conditions, were patients with independent prognostic risk factors such as elderly, ECOG performance status and MSKCC Moderate risk groups were excluded. Considering the limitation of the clinical trials, expanded-access studies were conducted in America [ 26] and Europe [ 27] on sorafenib and one study on sunitinib [ 28], which were close to the real world scenario. Further, patient age may be a pivotal prognostic factor as elderly patients tend to have lower ECOG performance status than younger patients [ 29]. Hence, head-to-head comparisons are needed to inform the choice of treatment for such selected patients.

Our previous report documented higher clinical benefit rate in sorafenib treated patients than sunitinib treated patients (94.67% vs 84.33%) [ 30]. In extension to this, the present retrospective review reported similar effectiveness of sorafenib and sunitinib in treating Chinese patients with mRCC, however, sorafenib therapy was more effective in elderly patients (≥65 years) and in patients with an normal performance status who were classified under MSKCC moderate risk category. A sub analysis of elderly patients in a phase 3 trial revealed a significant PFS advantage of sorafenib regardless of age [ 19]. In contrast, expanded-access studies on the clinical outcomes of sunitinib reproduced consistent efficacy and safety outcomes with previous results, and the outcomes were fairly similar in both elderly and younger populations but with significantly more common adverse effects seen in older population. However the clinical benefits of OS and PFS were inferior compared with placebo [ 28]. In line with our findings, a Swedish register-based demonstrated no difference between sorafenib and sunitinib in the duration of treatment or time to death when used as first-line therapy, however, the impact of the duration of first-line treatment differed in sequential therapy, concluding sorafenib first line treatment as a favorable choice in mRCC [ 31]. Furthermore, comparison of the present mOS findings with sorafenib therapy with other Asian studies demonstrated mixed results, where the mOS was consistent with a Chinese study12 conducted by Yu et al. [ 32], but were lower than the other Chinese [ 33, 34] and Korean studies [ 20]. However, higher mPFS with sorafenib over sunitinib was demonstrated in this study compared to previous Chinese [ 32], Korean [ 20, 35] and Italian [ 24] studies. The discrepancy may be related to diversity of patient populations enrolled in each study differing in many aspects related to prognosis and ethnicity. Furthermore, studies suggest that compared with Western patients, Chinese patients respond better to sorafenib as first-line targeted therapy [ 36, 37] Also, the results from TIVO-1 trial suggested that sorafenib as a first-line mRCC therapy yielded PFS of 9.1 month [ 38], which was lesser than the findings from the present study (PFS 11.1 months). Hence, the present study findings further support the previous findings with regards to superior efficacy of sorafenib in Chinese patients with mRCC.

Furthermore, multivariate regression analysis revealed treatment (Sorafenib vs. Sunitinib), pathology, ECOG performance status, MSKCC scores, HENG criteria of risk, and number of metastases as significant predictors for OS which is in line with the previous studies conducted by Motzar et al., which demonstrated ethnicity, ECOG status, bone metastasis and old age as predictors for OS and PFS in first-line therapy with sunitinib [ 39]. The findings are also consistent with the findings of Yang et al. who reported MSKCC status as prognostic factor for OS and PFS when treated with sunitinib [ 40]. Overall, our study findings support the findings of the Swedish and Italian studies, demonstrating comparable efficacy of sorafenib over sunitinib, but a more favorable sorafenib therapy in elderly and moderate risk mRCC patients.

Our study has several limitations. The retrospective design of the study comes as an inherent limitation; however, relatively large sample size compared to previous retrospective studies may power the study. The favorable outcomes of sorafenib demonstrated in this study may create a conflict in the belief of the clinicians who believe sunitinib as a better first-line option. Further, mOS was chosen as an endpoint and hence, the survival probability at a later time point after treatment initiation could not be established, hence, warranting further long term comparative efficacy studies.

The present study suggests that sorafenib and sunitinib are both effective as first-line therapeutic agents in treating Chinese patients with mRCC. Sorafenib is effective in elderly patients (≥65 years) and in patients with an ECOG status of 0, classified under MSKCC moderate risk. In addition, multivariate analysis suggests that variables such as treatment (sorafenib vs sunitinib), pathology, ECOG performance status, MSKCC scores, Heng’s criteria of risk and number of metastases are significant prognostic factors for OS and PFS.