The treatment of metastatic renal-cell carcinoma (mRCC) has advanced significantly since the era of cytokine therapy, when patient prognosis was poor with 5-year survival rates estimated at 10% . The last decade has seen the advent of therapies targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, heralding significant improvements in progression-free survival (PFS) and overall survival (OS) for patients with mRCC [2–4]. Multiple-targeted agents are now approved for the treatment of mRCC, including tyrosine kinase inhibitors (TKIs) of the VEGF receptor (VEGFR; axitinib, pazopanib, sorafenib, and sunitinib), anti-VEGF antibodies (bevacizumab in combination with interferon-α) and inhibitors of the mTOR pathway (temsirolimus and everolimus). Although these therapies have undoubtedly provided considerable survival benefits for patients with mRCC, most tumors will develop acquired or adaptive resistance to targeted agents, with resistance to first-line VEGFR-TKIs developing within 6–11 months of treatment initiation in the majority of patients [5,6]. When resistance develops, a recognized treatment strategy is the sequential use of different targeted agents, with optimal sequencing being the focus of considerable ongoing research . Growing evidence also suggests that rechallenge with the same agent could be considered in this sequential treatment approach, as resistant tumors can regain sensitivity to first-line (or previous-line) therapy after subsequent lines of alternative treatments. The purpose of this review is to explore the current evidence for rechallenge with targeted therapies in mRCC.
SEQUENTIAL TARGETED THERAPY AFTER THE DEVELOPMENT OF RESISTANCE
Sequential treatment with as many targeted therapies as a patient is likely to benefit from is the current standard of care in mRCC, with the potential to considerably extend patient survival and maximize the duration of disease control [7,8▪–10▪]. On progression of a first-line agent, the European Society for Molecular Oncology (ESMO), European Association of Urology (EAU), and National Comprehensive Cancer Network (NCCN) guidelines recommend alternative VEGFR-TKIs or mTOR inhibitors as second-line treatment (Table 1) [11▪–13▪]. However, specific guidance on the order in which these agents should be selected is less clear, with sequences often determined by treatment availability, the toxicity profile of previous therapies, physician familiarity with specific drugs, treatment costs, and patient comorbidities .
As different VEGFR-TKIs essentially target the same signaling pathway, subsequent therapy with an mTOR inhibitor would seem to be the most logical treatment approach for patients who are refractory to a first-line agent [14▪▪]. However, as each VEGFR-TKI has a distinct molecular target profile and specific binding affinities for shared molecular targets (Fig. 1), successive treatment with an alternative VEGFR-TKI is also a plausible strategy to counteract resistance . Indeed, there is no evidence to suggest cross-resistance between VEGFR-TKIs, and meaningful clinical benefits are observed in patients refractory to first-line VEGFR-TKIs receiving sequential therapy with a second VEGFR-TKI [8▪–10▪]. Furthermore, in a head-to-head, randomized controlled trial, second-line treatment with sorafenib was associated with significantly longer median OS compared with temsirolimus after progression on first-line sunitinib (16.6 versus 12.3 months, respectively; P = 0.01) [15▪].
Limited data are available from randomized studies assessing the comparative efficacy of different VEGFR-TKIs as second-line or third-line agents for mRCC. The AXIS trial was the first phase 3, randomized trial to directly compare second-line treatment of mRCC with two VEGF-targeted agents, axitinib, and sorafenib . Axitinib was associated with improved median PFS compared with sorafenib (6.7 versus 4.7 months, respectively; P < 0.0001), although this did not translate into improved median OS. A longer duration of prior treatment and a smaller tumor burden following initial therapy was generally associated with longer OS for both agents second line [17▪]. In the third-line setting, the phase three GOLD study was conducted to compare the efficacy of dovitinib (a fibroblast growth factor receptor, platelet-derived growth factor receptor, and VEGFR inhibitor) and sorafenib after previous VEGF-targeted therapies and mTOR inhibitors [10▪]. Although both agents provided clinical benefits, no significant differences in efficacy outcomes were noted between groups.
Real world, observational data may also help inform on the optimal sequencing of targeted therapies. In a systematic review and meta-analysis of observational studies comparing sequential treatment strategies for mRCC, some survival benefit was observed with second-line mTOR inhibitors over second-line VEGFR-TKIs among a subset of studies with more controlled design [18▪▪]. However, data for axitinib were limited at the time of this analysis. In contrast, in a retrospective multicenter analysis, a longer duration of response to first-line TKI therapy and receiving a TKI rather than an mTOR inhibitor second line were associated with a longer duration of response and PFS with second-line therapy [19▪▪].
RATIONALE FOR RECHALLENGE: PRECLINICAL EVIDENCE
The precise mechanisms by which resistance to targeted therapies for RCC develops are yet to be fully elucidated. VEGF-targeted therapies are proposed to cause tumor hypoxia, leading to the accumulation of hypoxia-inducible factor 1, which in turn leads to upregulation of factors that stimulate angiogenesis, tumor invasiveness, and epithelial-to-mesenchymal transition [20▪]. Accumulating evidence suggests that these effects are reversible, and that changes in the tumor microenvironment may restore tumor sensitivity to targeted therapies . Preclinical evidence supporting this hypothesis comes from a study in which tumor tissue was transplanted from sunitinib-resistant metastatic skin lesions into nude mice . Interestingly, xenograft tumors regained sensitivity to sunitinib and demonstrated the clear cell phenotype, whereas evidence of epithelial-to-mesenchymal transition was observed in the sunitinib-resistant metastatic tumor tissue . In a clinical setting, the same effect of altering the tumor environment may be affected by switching to a different targeted therapy or with a treatment break followed by rechallenge with the same agent [14▪▪].
Recent research has investigated the impact of the tumor microenvironment on the clinical outcome for patients with RCC. Molecular subtypes of clear cell RCC with poor sensitivity to sunitinib exhibit sarcomatoid differentiation and a suppressive immune microenvironment, with high expression of the immune checkpoint protein, PD-1, and its ligands [22▪]. Similarly, high expression of immune checkpoint proteins and the absence of fully functional mature dendritic cells have been observed in primary or metastatic tumors from RCC patients with a poor prognosis [23▪]. Conversely, low expression of immune checkpoints and mature dendritic cells located in tertiary lymphoid structures were observed in tumors from patients with prolonged survival.
RECHALLENGE IN OTHER TUMOR TYPES
Drug rechallenge has provided meaningful clinical benefits in retrospective studies of other tumor types. In 270 patients with metastatic castration-resistant prostate cancer who progressed after an initial good response to first-line docetaxel, improved rates of symptom relief and stable disease were achieved with docetaxel rechallenge compared with nontaxane-based second-line therapies [24▪]. Similarly, the reintroduction of docetaxel to 72 patients with metastatic breast cancer resulted in a substantial proportion achieving a partial response (42.5%) or stable disease (33.5%) . The survival benefits of rechallenge in this heavily pretreated-patient population needs to be balanced against the risk of exacerbation of chronic toxicities and impaired quality of life.
Key considerations determining whether a patient may be suitable for rechallenge include the length of time that has passed between completion of initial therapy and subsequent rechallenge , and the duration of the progression-free interval (PFI) achieved with first-line chemotherapy [27,28]. In patients with advanced ovarian cancer who achieve a PFI of more than 6 months with first-line paclitaxel in combination with a platinum analogue can achieve response rates of 30–50% on retreatment with a platinum-based therapy after progression . Similarly, for patients with advanced small-cell lung cancer and a PFI of at least 3 months after the discontinuation of first-line treatment may be considered for platinum-based rechallenge .
EVIDENCE FOR RECHALLENGE IN METASTATIC RENAL-CELL CARCINOMA: RETROSPECTIVE STUDIES AND CASE REPORTS
Recent ESMO guidelines for RCC include rechallenge with the same TKI used for initial treatment as an option for patients requiring third-line therapies (Table 1) [11▪], although this recommendation is based on limited evidence from retrospective cohort or case–control studies. A summary of studies evaluating rechallenge either with agents from the same class or the same agent are provided in Table 2[16,29–35]. The majority of studies exploring rechallenge with the same agent have focused on sunitinib, and have been summarized in a recent review by Porta et al.[14▪▪]. Initial case report data reported symptomatic relief and disease stabilization with sunitinib rechallenge in patients with mRCC who had progressed on first-line sunitinib [36,37]. Similarly, in a small retrospective analysis, 12 of 13 patients rechallenged with sunitinib experienced a partial response or stable disease, with median PFS of 6.9 months compared with 21 months after first-line sunitinib treatment .
In a further study, five of 23 patients experiencing disease progression or intolerance to first-line sunitinib (and ≥1 subsequent agent) achieved a partial response to sunitinib rechallenge . Median PFS first line was 13.7 months compared with 7.2 months on sunitinib rechallenge, with the length of the interval between first-line sunitinib and rechallenge influencing the duration of PFS. A retreatment interval greater than 6 months was associated with longer median PFS compared with rechallenge within 6 months (16.5 versus 6.0 months, respectively). The type or number of intervening treatments had no significant effect on outcomes and no new toxicities or exacerbation of prior toxicities was noted. Similarly, in another study, sunitinib rechallenge in nine patients who had failed at least two previous targeted therapies was associated with median PFS of 6.8 months compared with 13.7 months for initial sunitinib treatment .
The evidence for rechallenge in mRCC is not limited to sunitinib. In a case series of 12 patients who had failed first-line sorafenib and subsequent anti-VEGF therapies or mTOR inhibitors, eight (67%) achieved stable disease upon sorafenib rechallenge, with median PFS of 5.4 months . In contrast to sunitinib rechallenge, the duration of PFS with sorafenib rechallenge did not correlate with the PFS duration observed with initial sorafenib treatment or with the length of the interval between initial treatment and rechallenge.
In a retrospective analysis of 12 patients with mRCC who progressed on treatment with their first mTOR inhibitor (temsirolimus or everolimus; after ≥1 line of prior VEGFR-TKIs), and then underwent rechallenge with the other agent, a longer median treatment duration was observed with the everolimus–temsirolimus sequence compared with the temsirolimus–everolimus sequence (10.3 versus 5.8 months; respectively) . Of the seven patients treated with everolimus before temsirolimus, 57 and 29% responded to everolimus or temsirolimus only, and 14% responded to both mTOR inhibitors. Among the five patients treated with temsirolimus before everolimus, 20% responded to temsirolimus only, 20% responded to everolimus only, and 60% did not respond to either mTOR inhibitor. Despite the limited number of patients included in this study, the results again highlight the potential feasibility of rechallenge as a sequential therapy option in mRCC.
RECHALLENGE WITH SUNITINIB IN METASTATIC: THE LARGEST STUDY OF RECHALLENGE IN MRCC CONDUCTED TO DATE
REchallenge with SUnitinib in MEtastatic renal-cell carcinoma (RESUME) was a multicenter, observational, prospective, and retrospective study of sunitinib rechallenge in the third line or more. The primary objective was to examine the effect of sunitinib rechallenge on PFS in 52 patients with mRCC who received first-line sunitinib followed by one or more lines of different therapies (temsirolimus, everolimus, sorafenib, pazopanib, axitinib, or bevacizumab) [38▪▪]. On first-line sunitinib, 28 patients (54%) achieved an objective response and median PFS was 18.4 months (Table 3). The median duration of therapy was 14.9 months, with the majority of patients (82%) discontinuing due to disease progression rather than tolerability issues. Rechallenge began a median of 14.6 months after discontinuation of initial sunitinib treatment and constituted fourth-line therapy in the majority of patients (65%).
On sunitinib rechallenge, median OS was 55.9 months with 61% of patients (n = 32) experiencing clinical benefit (Table 3) [38▪▪]. Median PFS was 7.9 months, which is in line with the duration of PFS observed in the smaller retrospective studies of sunitinib rechallenge [33–35]. A shorter duration of PFS with later lines of therapy would be expected compared with first-line therapy as these patients are more likely to have a poorer performance status. Subgroup analyses also revealed significantly improved median PFS on rechallenge in patients who achieved median PFS at least 18.4 months and had a median duration of treatment at least 14.9 months with first-line sunitinib therapy (P < 0.05).
Eight patients (15%) achieved a partial response on rechallenge, with six of these patients having experienced a prior response to first-line sunitinib [38▪▪]. These patients who had achieved a complete or partial response to first-line sunitinib also achieved longer PFS with sunitinib rechallenge compared with first-line nonresponders (15.0 versus 5.0 months, respectively; P = 0.05).
As would be expected for this heavily pretreated patient population, the proportion of patients experiencing serious adverse events was higher on rechallenge compared with on first-line sunitinib (19 versus 4%, respectively; Table 3). Importantly, no new adverse events were reported either at first line or on rechallenge [38▪▪].
Although the results of RESUME provide convincing evidence for the potential clinical benefit of rechallenge in mRCC, there may have been some positive selection bias toward patients more likely to achieve longer OS in this study. Patients with mRCC who are able to receive multiple lines of targeted therapy are often likely to live longer, with a greater duration of PFS [39▪]. Additionally, 80% of patients had a dose reduction when receiving first-line sunitinib, and therefore may not have been truly resistant to the recommended dose of sunitinib. Another key consideration is that as the RESUME study was partly retrospective, adverse event data were only available for some patients (n = 27), meaning that the tolerability profile of sunitinib rechallenge may not have been fully characterized.
To further explore the potential clinical benefits of sunitinib rechallenge in mRCC, two prospective phase 2 studies have been initiated. A Dutch trial (NTR3711) will assess the ability of sunitinib rechallenge to improve PFS in patients who achieved stable disease for at least 6 months on first-line sunitinib but subsequently progressed on sunitinib and second-line therapies [mTOR inhibitors or another therapy (excluding VEGFR TKIs)]. A second Italian study will assess the ability of third-line sunitinib rechallenge after second-line everolimus to provide freedom from disease progression (EudraCT 2012–000473–23/RETRY). It is hoped that the results of these studies will help better inform wherein rechallenge fits in the current treatment algorithm for mRCC, further optimizing the sequential-targeted therapy approach.
Adaptive or acquired resistance to targeted therapies for mRCC is the main barrier preventing patients from achieving maximal survival benefits with these agents. The sequential use of different targeted therapies is a promising approach to bypassing this resistance, potentially by providing continual inhibition of the signaling pathways implicated in tumor angiogenesis, thereby stabilizing disease progression. The accumulated data from case reports, retrospective studies, and the recent RESUME study supports the validity of rechallenge as an additional strategy to be included in this sequential therapy approach for the management of tumor progression in mRCC. Key factors that may be linked to the degree of clinical benefit likely to be observed with rechallenge include a longer duration of response to initial treatment and a greater interval between first-line therapy and rechallenge. The results of ongoing prospective studies of sunitinib rechallenge should further characterize the clinical benefits that could be expected with targeted therapy rechallenge. Future research should also focus on characterizing, which patients are most likely to benefit from rechallenge or other sequential therapy options, with the goal of further enhancing survival outcomes for mRCC patients.
Financial support and sponsorship
Medical writing support was provided by Farah Dalwai at Litmus MME (London, UK).
Funding for medical writing support was provided by Pfizer Inc.
Conflicts of interest
S.O. has received honoraria from Novartis, Pfizer, Bayer, Bristol-Myers, Squibb and GlaxoSmithKline.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
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