In this prospective cohort study of 132 Mexican patients with metastatic RCC treated initially with a TKI as first-line therapy, we observed that sequential TKI therapy with sorafenib as second-line therapy is an acceptable treatment option given the outcomes observed: i.e., a median PFS of almost 9 months and a median survival after the introduction of sorafenib of more than 40 months. In addition, sorafenib administration was safe considering sorafenib-related adverse events.
It is difficult to compare PFS obtained from second-line treatments across observational cohorts and clinical trials, given the variations in the designs, patient characteristics, response criteria, and definitions employed among studies. Nevertheless, some general aspects could be inferred. The median PFS with sorafenib in our cohort seems to be similar to the median PFS of 4 to 7 months obtained in other clinical trials for advanced RCC with everolimus, axitinib, nivolumab, cabozantininb or nivolumab/ipilimumab, (20-24). Only lenvatinib/everolimus (14.6 months)(25) had shown a median PFS longer than other second-line therapies in randomized clinical trials with a higher rate of related adverse events. According to our results, we propose that sorafenib could be considered as a feasible option for advanced RCC in certain clinical scenarios, considering patient preferences, specific comorbidities(26), tolerability, and availability.
We need to understand the clinical benefits of actual treatments to obtain fair comparisons with new agents for second-line therapies, especially in minority populations and elderly patients(3). NCCN guidelines suggest that for subsequent therapy in metastatic RCC, the simplest approach is to change the mechanism of action related to the second-line therapy, e.g., if a subject was treated with a TKI as first-line treatment, a PD-1 agent should be the second option. Nevertheless, observational data support the use of sequential TKIs following the treatment with an initially different TKI(2,27). Treatment of metastatic RCC with two TKIs in sequence, both sharing a similar molecular target yet with different clinical effects, could be comparable to newer, more-expensive agents, which are mostly unavailable in developing countries.
In our cohort, it is possible that the majority of patients showed an acceptable PFS time on sorafenib therapy, which is explained by the favorable risk prognosis when the second-line therapy began. Other studies had shown lower PFS with sorafenib. For example, in the AXIS clinical trial, the median PFS with sorafenib as second-line therapy was 4.7 months, where only 28% had a favorable classification according to the Memorial Sloan-Kettering Cancer Center risk(21). Nevertheless, the intermediate-prognosis group in our study had a median progression time of more than 7 months, which seems to be superior to the AXIS trial results. We believe that our patients were highly selected, and our results should not be over-interpreted.
Despite clinically improved outcomes in advanced RCC, it is believed that resistance to VEGF-targeted treatment develops in nearly all patients with RCC(5). In our study, the occurrence of cross-resistance was not observed in all cases during follow-up. Nearly 21% of subjects did not show absolute cross-resistance between the two sequential TKIs (sunitinib and sorafenib). Multiple studies have shown that second-line sorafenib after sunitinib progression is well tolerated and safe over the long term(28,29). These findings show the urgent need to investigate and understand the acquired resistance to TKIs in patients with RCC.
In a retrospective study with 33 patients who had experienced RCC progression treated with sequential use of either sorafenib or sunitinib, Calvani et al. observed that survival on second-line TKI was longer in the patients who received sorafenib first compared to those treated with sunitinib first (median PFS = 11 vs. 3 months). In our results, the increase in median PFS with sunitinib was longer (15 months) than second-line treatment with sorafenib (8.5 months) and the total PFS (the sum of PFS of first-line sunitinib and second-line sorafenib) was longer compared to the referred study (29.8 vs. 10 months, respectively)(30).
We found a high rate of sorafenib-related adverse effects (93%), although we did not regularly perform echocardiography in all patients. According to other studies, sorafenib could be associated with almost 100% of adverse effects(31–33). These high rates of toxicity could be attributed to differences in methods to report adverse events. In our study, sorafenib treatment was associated with an astounding number of mucocutaneous side effects, especially hand-foot skin disease compared to reports from other clinical studies(21,30,34). In an Asian population, fatigue and hand-foot skin reactions were more common compared to diarrhea, which is the most common adverse effect in non-Asian populations(35). In clinical trials with predominantly non-Asian or non-Latin-American patients, hand-foot skin adverse effects has been observed in between 27% to 30% of patients(21,22).
Our study limitations are related to its observational nature, which could be subject to bias, the absence of a comparative treatment, and the inclusion of subjects treated in only one center. In addition, we did not known if no treatment at all could be similar to sorafenib as a second treatment line in many patients. The absence of a comparison group prevents us from making inferences about the real usefulness of sorafenib. In our study, only 14/132 (11%) of subjects had complete and/or partial response, which is a very low proportion of success which is consistent with prior studies of second line treatment with sorafenib after failure of first line sunitinib (28-29). Nevertheless, in our center, we have limited access to alternative second line therapies (e.g. immune checkpoint inhibitors) which is a common problem in developing countries. Our data from real clinical scenarios could help to improve decision making in RCC patients after failure of first line sunitinib.