Renal cell carcinoma is a common malignancy with many treatment options developed during the last decade. Targeting VEGF and PD-L1 signaling have enriched the armamentarium of the therapeutic options and have prolonged both OS and PFS [4, 5, 7, 8, 12]. However, the existence of several TKIs and the addition of Immunotherapy (IO) resulted to a more complex therapeutic algorithm in the treatment of metastatic RCC [12].
Under this perspective data regarding the efficacy of TKIs in the later lines of therapy are important. This is also the case for axitinib that lacks randomized data for efficacy beyond second line and very few published data exist regarding its administration beyond second line. Our study aimed at providing efficacy and safety data for axitinib in this setting. These real world data provide evidence that axitinib is an active agent even in latter lines of therapy in mRCC as objective responses and mPFS is favorably compared to those achieved in second line in the AXIS trial. Our data are also in agreement other case series presented in the literature. A large retrospective study with real world data from the United States, regarding axitinib administration resulted that axitinib was most commonly prescribed as a third line treatment [19], while another cohort of patients that received axitinib as either a 2nd line or 3rd line treatment, showed similar activity and tolerability with clinical trials [20]. The efficacy of axitinib beyond second line in our study prompt us to further investigate possible clinicopathological or treatment-related factors that could influence this result. However, no predictive factor was indicated by the analysis, possibly due to the small number of patients. We should also take into consideration that the population of patients that receive treatment beyond second line is usually already selected for improved survival.
The role of axitinib beyond second line was studied retrospectively in a study of Mclean et al using linked datasets from 22 specialty pharmacies that dispense axitinib with databases of longitudinal medical and pharmacy claims [19]. In this study axitinib was prescribed as third-line therapy in 326 patients and as fourth-line or later therapy in 190 patients resulting in a median duration of treatment of 122 (7-644) and 111 days (10–642). In another retrospective study of third line targeted treatment among 1012 mRCC patients treated at 25 centers from all over the world axitinib was given in 90 patients resulting in 5.9 months PFS (4.6–8.0), 19.2 months OS (13.5–22.7) and 66% RR [21].
Finally in another retrospective analysis of the data of patients participated in NCT00835978 and NCT00920816 studies revealed a subgroup of long- term responders whereas the duration of treatment with axitinib -as a second line treatment- have been found to be associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS [22].
An important finding of our study was though that four out of the 22 patients had clinical benefit from the axitinib treatment for more than a year. Again previous therapeutic options or other clinicopathological data included to our study, failed to prove any predictive value. This kind of analysis, even though it is retrospective and includes a limited number of patients, is a unique attempt to discover predictive factors; in order to choose the responsive subgroup of mRCC patients to axitinb treatment, beyond second line. A retrospective analysis of two clinical trials with mRCC patinets who received axitinib as a first line treatment, revealed a population of 37.8% who were long responders [22]. This response was related ECOG performance status 0, no liver or bone metastases, favorable hematology characteristics and baseline tumor burden below the overall median [22].
Long-term response to axitinib may be related to its greater potency as a TKI. Axitinib and Sunitinib share a common mechanism of action, with Axitinib showing a stronger inhibition of VEGFR1, VEGFR2 and VEGFR3. Molecular studies on human cell lines resistant to sunitinib have shown inhibition of MAPK signaling pathway while treated with axitinib[23]. Furthermore, axitinib inhibits stronger than sunitinib VEGFR-2, which is activated when resistance to sunitinib is developed. The above mentioned changes were also confirmed in vivo in tumors with immunostaining of MAPK and VEGFR-2 [23]. It is intriguing to hypothesize that long responders to axitinib might share as driving oncogenic effectors mutations to MAPK and/or VEGFR-2.
Long-term responses have also been described to other TKIs. Long term response to sunitinib has been studied retrospectively from several authors concluding that the absence of adverse disease characteristics (poor PS, poor MSKCC risk, absence of bone or liver metastases) may predict long responders[24] [25]. An extensive analysis comprising 5714 patients treated with 1st line sunitinib as part of clinical trials or expanded access programs revealed that White race, ECOG performance status 0, time from diagnosis to treatment > 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase < 1.5 upper limit of normal (ULN), corrected calcium < 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index > 25 kg/m2, and low neutrophil-to-lymphocyte ratio were associated with long term response [26].
Analogous results have been presented for Pazopanib [27, 28] and Sorafenib [29], but in no case they could provide clinical guidance for the optimal use of these agents in latter lines of therapy. Probably molecular biomarkers are needed to guide sequence of treatments amidst the complex therapeutic algorithm of mRCC as could be the case of PBRM1 for immunotherapy post TKIs.
No new safety signals were recognized in our cohort of patients. Toxicity profile, dose reductions and treatment discontinuation of our patients was similar to the registrational trial of axitinib as a second line treatment [16]. The most frequent adverse events occurring in more than 30% of patients in Axis study; associated with axitinib were diarrhea, hypertension, fatigue, decreased appetite, nausea, and dysphonia, while grade 3 or higher toxicity included hypertension, diarrhea and fatigue [16]. The five most common toxicities independently of grade in our analysis were fatigue, hypertension, hypothyroidism, hand foot syndrome and hoarseness, with grade 3 or higher toxicities including hypertension and hand foot syndrome. It is evident that axitinib administration beyond second line, even in heavily pretreated patients; is not accompanied by a more severe pattern of adverse effects.
In conclusion, axitinib is an effective treatment option for mRCC patients beyond second line. Axitinib is well tolerated from patients, even heavily pretreated. Further studies including larger numbers of patients, combined with translational research analyses; are needed to discover the subgroup of mRCC patients who are responsive to this treatment beyond second line.