Second line therapy with axitinib after only prior sunitinib in metastatic renal cell cancer: Italian multicenter real world SAX study final results

Background This multi-institutional retrospective real life study was conducted in 22 Italian Oncology Centers and evaluated the role of Axitinib in second line treatment in not selected mRCC patients. Methods 148 mRCC patients were evaluated. According to Heng score 15.5%, 60.1% and 24.4% of patients were at poor risk, intermediate and favorable risk, respectively. Results PFS, OS, DCR and ORR were 7.14 months, 15.5 months, 70.6% and 16.6%, respectively. The duration of prior sunitinib treatment correlated with a longer significant mPFS, 8.8 vs 6.3 months, respectively. Axitinib therapy was safe, without grade 4 adverse events. The most frequent toxicities of all grades were: fatigue (50%), hypertension (26%), and hypothyroidism (18%). G3 blood pressure elevation significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity. Dose titration (DT) to 7 mg and 10 mg bid was feasible in 24% with no statistically significant differences in mPFS and mOS. The sunitinib-axitinib sequence was safe and effective, the mOS was 41.15 months. At multivariate analysis, gender, DCR to axitinib and to previous sunitinib correlated significantly with PFS; whereas DCR to axitinib, nephrectomy and Heng score independently affected overall survival. Conclusions Axitinib was effective and safe in a not selected real life mRCC population. Trial registration INT – Napoli – 11/16 oss. Registered 20 April 2016. http://www.istitutotumori.na.it


Patients and methods
Our multi-Institutional, retrospective study evaluated the outcomes of mRCC patients all treated in secondline therapy with axitinib after first-line sunitinib failure. Eligible patients were: age ≥ 18 years; histologically confirmed RCC; axitinib for at least 2 months, started between January 2014 and May 2017; at least one radiological assessment (CT scan) of disease (RECIST 1.1 criteria) repeated every 2-3 months; only sunitinib as previous treatment in first line. Axitinib was administered at starting dose of 5 mg bid (10 mg/die). Dose titration (DT) was performed every 2 weeks up to a final step of 10 Table 2). Median (m) PFS was 7.14 months (95% CI 5.78-8.5 months; Fig. 1). Median (m) OS from the start of Axitinib was 15.5 months (95% CI 11-20 months; Fig. 2). The median time of axitinib treatment duration was 8.1 months. The ORR, according to RECIST criteria version 1.1 [25] was 16.6%, with 16% of PR and one patient reached a CR (Table 3) and correlated to a statistically longer (p < 0.0000001) mPFS,   (Table 5). At univariate analysis G3 blood pressure elevation (systolic ≥ 160 mmHg and/or diastolic ≥ 100 mmHg) significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity (mean PFS 28.8 months, p = 0.017-mean 6 OS 38.15 months, p = 0.017median survival times not reached for both analysis).
Noteworthy, men compared to women showed both a longer mPFS (9 vs 5.8 months, p = 0.014) and mOS (19.5 vs 12 months, p = 0.048). The Sunitinib-Axitinib sequence, was well-tolerated, without worsening in side effects, particularly in terms of hypertension and handfoot syndrome, with a mOS of 41.15 months (95% CI

Discussion
Currently the goal of mRCC treatment strategy is represented by the correct use of the approved drugs in a sequential algorithm [26,27]. Axitinib is licensed in Italy for the treatment of mRCC patients only after failure of sunitinib or cytokines therapy. We report herein the retrospective data of axitinib in Italian real-life practice for mRCC: despite our population was more "battered" than the one investigated in AXIS trial, our results are consistent with AXIS ones, confirming the efficacy of axitinib in second line treatment [10,11], with ORR, mPFS and mOS of 16.6%, 7.14 and 15.5 months, respectively. Fifteen percentage of our study population was over 75 years, normally underrepresented in clinical trials [28]. The elderly patients are usually a frail population with a lower performance status (PS), poor tolerance to medical treatments and multiple co-morbidities [29]. To date few data are available concerning the use of axitinib in elderly mRCC patients [30][31][32]. Our results showed no differences in both mPFS [6.4 months (95% CI 4. 95-7.95, p = 0.74)] and mOS [13.0 months (95% CI 5.9-20.15, p = 0.72)] than younger patients. In addition, there was no significant difference in the incidence of AEs or dose reduction, or discontinuation. The efficacy and safety of the VEGF-TKI -VEGF-TKI treatment sequence has been confirmed by various trials, showing a statistically longer mPFS and in some of these mOS too [10,11,26,33,34]. Leung et al. indicated axitinib as more appropriate TTs option, compared to sorafenib and pazopanib, in the second line setting; in particular, axitinib is associated with the lowest risk of withdrawal due to adverse events [35]. In post hoc analysis of the AXIS trial, Escudier et al. evaluated the efficacy of axitinib by response and duration of prior sunitinib or cytokines treatment, showed no statistically significant differences in PFS or OS in responders vs non-responders, although a significantly longer PFS and OS was reported in patients who had received a longer prior cytokines treatment [36]. On the contrary, our analysis showed that longer previous sunitinib duration (≤ vs > median duration), correlated with a statistically significant difference in mPFS (8.8 vs 6.3 months, p = 0.021), without any difference in mOS (p = 0.151). The same conclusion was reached by Elaidi et al. who showed that patients who remained on first-line TKI treatment between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi  (PFS: 9.4 vs 3.9 months, p = 0.003) [37]. Higher ORR (20-30%) was reported with VEGF-TKI compared to mTORi (≤ 10%), which is supported by our analysis [38]. Dose titration to 7 or 10 mg bid was feasible in 24% (35/148) of our patients, lower than the axitinib Asian trial (61.5%) [39] or the AXIS trial (37%) [10], but higher than other real-world studies (16%) [21-23, 40, 41]. We reported no differences in both mOS (p = 0.115) and mPFS (p = 0.1), in accordance to the phase II study of first-line axitinib [17,23] Table 5). Our data showed a lower incidence of AEs than AXIS trial, the higher incidence of fatigue in our experience, was probably due to the difficulty to distinguish and explain to the patients the difference between fatigue and asthenia. All these results suggest that axitinib treatment is feasible and safe in this unselected real-world population. At univariate analysis hypertension G3 blood pressure elevation (systolic ≥ 160 mmHg and/or diastolic ≥ 100 mmHg) significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity (mean PFS 28.8 months, p = 0.017-mean OS 38.15 months, p = 0.017-median survival times not reached for both analysis Table 6, 7). Our data are consistent with other real-world studies [42,43] and AXIS trial, suggesting that the development of hypertension during the treatment could be a surrogate of survival in this population. It was interesting to note that the 18% (27/148) of patients enrolled in our study, adopted a modified schedule of sunitinib in first line (2 weeks on 1 week off ), without showing any difference in outcomes. These data confirm those of others retrospective studies that evaluated sunitinib alternative schedules, showing a reduction in the AEs and   achieving comparable outcomes to the standard schedule [44][45][46]. The identification of effective prognostic factors in mRCC patients receiving axitinib represents a new challenge. In these series we identified the following independent prognostic indicators: gender (male), DCR upon axitinib and prior sunitinib for PFS, and DCR upon axitinib, Heng score (poor prognosis vs intermediate vs good prognosis) and prior nephrectomy for OS. The sequence TKI-TKI (sunitinib-axitinib) was well tolerated without worsening in side effects, the global mOS was 41.15 months, higher than AXIS trial (33.7 months). The main limitation of our analysis was represented by the small patient numbers, selection bias, the retrospective nature, without centralized data review. Recently the results of three major clinical trials involving nivolumab, cabozantinib, and lenvatinib plus everolimus, showed superior efficacy in terms of response rates (RR) and OS in second-line setting [47][48][49][50] and these will change dramatically the therapeutic sequence in second-line setting. To date, there are few data about the best sequential therapeutic algorithm beyond first-line VEGF TKIs, and no headto-head study between these new drugs and the currently approved agents are ongoing [51][52][53][54] [55]. In the new era of Immunotherapy, are VEGF-TKIs still a valid option for mRCC treatment? The angiogenesis plays a central role in the RCC tumorigenesis and immunogenicity. The prevalence of pro-angiogenic factors over anti-angiogenic signals promotes an immunosuppressive tumor microenvironment, through abnormal tumor vessel formation and dysregulation of various immune cells. Therefore, antiangiogenic therapy remains the gold standard in selected patients (VEGF-dependent favourable mRCC in all setting) and increases the efficacy of immunotherapy, modulating immune responses, increasing anticancer immune-trafficking and activity, through the regulation of tumor vessels and reducing suppressing cytokines and infiltrating T regs [54,56,57]. Different phase 3 trials evaluated or are evaluating combination of immune checkpoint inhibitors, such as anti PD-1 nivolumab and anti CTLA-4 ipilimumab, or anti PD-1/ PDL-1 and VEGFR-TKI in first-linetreatment, with impressive results that will dramatically impact on the choice of the first and second-line treatments (Table 8).

Conclusions
Evidences emerging from our retrospective analysis are consistent with the available literature and confirm the efficacy and safety of axitinib in a not selected population, particularly in patients who most benefited from first-line sunitinib (VEGF-dependent mRCC). The advent of new drugs such as nivolumab and cabozantinib has further improved the therapeutic landscape of second line setting. Prospective trial will be needed to assess the right sequence of anti PD-1/PD-L1 and VEGF/VEGFRi and moreover, head to head studies will be needful to determine the best VEGFRi (cabozantinib vs axitinib) in second line setting, mostly after the impressive results of the combination trials of immune checkpoint inhibitors and immune checkpoint inhibitors with VEGFR-TKIs, in first-line therapy.

Funding
No funding for the research to declare.

Availability of data and materials
The datasets during and/or analysed during the current study available from the corresponding author on reasonable request.

Ethics approval and consent to participate
The study was approved by the Institutional Board of National Cancer Institute "G. Pascale" -IRCCS -of Napoli Italy and all patients gave consent to participate.