Treatment of advanced renal cell carcinoma: recent ...

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Oct 26, 2016 - combinations, including a study of atezolizumab in com- bination with bevacizumab vs sunitinib in untreated ad- vanced RCC (Clinical ...
TJ

Tumori 2017; 103(1): 15-21 DOI: 10.5301/tj.5000581

ISSN 0300-8916

REVIEW

Treatment of advanced renal cell carcinoma: recent advances and current role of immunotherapy, surgery, and cryotherapy Alessia Mennitto1, Elena Verzoni1, Giuseppina Calareso2, Carlo Spreafico2, Giuseppe Procopio1 Genitourinary Unit, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy Department of Interventional Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy

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Abstract Renal cell carcinoma (RCC) is the 10th most common cancer in Western countries. The prognosis of metastatic disease is unfavorable but may be different according to several risk factors, such as histology and clinical features (Karnofsky performance status, time from nephrectomy, hemoglobin level, neutrophils and thrombocytes count, lactate dehydrogenase and calcium serum value, sites and extension of the disease). In this review, we focused on some recent developments in the use of immunotherapy, surgery and cryotherapy in the treatment of advanced disease. While RCC is unresponsive to chemotherapy, recent advances have emerged with the development of targeted agents and innovative immunotherapy-based treatments. Surgical resection remains the standard of care for patients with small renal lesions but in patients with significant comorbidities ablative therapies such as cryoablation and radiofrequency ablation may lead to local cancer control and avoid surgical complications and morbidity. In the setting of metastatic RCC, radical nephrectomy, or cytoreductive nephrectomy, is considered a palliative surgery, usually part of a multimodality treatment approach that requires systemic treatments. Keywords: Cytoreductive nephrectomy, Immunotherapy, Multimodal treatment strategy, Renal cell carcinoma, Targeted therapy

Introduction Renal cell carcinoma (RCC) is a common cancer in Western countries, with more than 350,000 new cases per year and a death rate of 140,000 per year (1). Despite a significant increase in the diagnosis of lower stage disease due to the evolution of more accurate imaging techniques, 30% of patients show advanced disease at diagnosis (2). Moreover, an additional 30% of patients will develop metastases after a radical nephrectomy. The prognosis of advanced disease is unfavorable but may be different according to several risk factors. Prognostic factors, histology, and clinical characteristics are commonly used to guide treatment selection. In clinical practice, Karnofsky performance status (PS), time from nephrectomy, hemoglobin level,

Accepted: October 18, 2016 Published online: October 26, 2016 Corresponding author: Giuseppe Procopio, MD Medical Oncology Unit 1 Fondazione IRCCS Istituto Nazionale dei Tumori Via Venezian 1 20133 Milan, Italy [email protected]

© 2016 Wichtig Publishing

neutrophils and thrombocytes count, lactate dehydrogenase and calcium serum value, sites and extension of disease are the most useful parameters to define prognostic risk groups. Accordingly, patients are stratified in 3 risk categories having good, intermediate, and poor prognosis. In clinical practice, the 2 most often used risk group classifications proposed by Heng et al (3) and Motzer et al (4) have been demonstrated to have good correlation with the outcome of the disease. None of the prognostic factors identified is a useful predictor of response to any of the available antitumoral agents; nevertheless, risk group stratification is useful to optimize treatment decisions and maximize patient survival. Different cell types have been identified for RCC. Clear cell histology is apparent in 75% of the cases, papillary type 1 and 2 in 15% of the cases, and chromophobe type in 5% of the cases, whereas other rare histotypes including Bellini ducts carcinoma and medullary and unclassified histotypes are observed in the remaining cases. The biology, pathogenesis, and natural history of all histologies are usually very different. Similarly, the efficacy of antitumoral agents varied largely and generally is more evident in the more common clear cell histologies (5).

The role of immunotherapy Due to the well-known lack of efficacy of chemotherapy, immunotherapy with interferon and interleukin-2 (IL-2) were

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in the past the only treatment approaches used, but with disappointing results in terms of safety and efficacy (6). It is known that RCC is an immunogenic tumor showing a notable infiltration of immune cells, such as dentritic cells, T cells, macrophages, and natural killer cells. In RCC, the VHL protein has an important role: it is downregulated through gene inactivation or epigenetic silencing. Consequently, the hypoxia-inducible factors are stabilized and several proangiogenic factors are upregulated (7). Since its inception, immunotherapy has been conceived as part of a multimodal strategy combined with surgery. The first evidence in favor of such multimodal strategy was documented in 2001, when two randomized phase 3 trials suggested that a cytoreductive nephrectomy followed by interferon was superior to interferon alone in terms of overall survival (8, 9). A combined analysis study demonstrated an overall advantage of 5.8 months (10). Based on these data, in the cytokine era physicians considered to perform cytoreductive nephrectomy before activation of the treatment, when feasible. In the last 10 years, better knowledge of the molecular pathways in RCC led to the development and approval of several targeted agents including multikinase inhibitors, such as sunitinib, pazopanib, sorafenib, axitinib, and cabozantinib, mammalian target of rapamycin (mTOR) inhibitors, such as everolimus and temsirolimus, and a monoclonal antibody against vascular endothelial growth factor (VEGF), bevacizumab (11). All these agents were approved as monotherapy, with the exception of bevacizumab, which has been approved in combination with interferon. The availability of molecular targeted therapies has been associated with better disease control, tumor progression delay (12), and a global improvement of prognosis, with 5-year overall survival (OS) of 25% and 10% with targeted therapies and cytokines, respectively (13). According to results from randomized phase 3 studies, expanded access programs, and retrospective series published with targeted therapies, complete responses (CR) are rather rare events, accounting for less than 5% (14, 15). The achievement of a CR is essential to maximize patient survival and it could support the decision of discontinuation of antitumoral medical therapy (drug holiday) and consequently a benefit for the patient’s quality of life. In the absence of a complete resolution of the disease, every drug is used until progression and a sequential use of the available agents is performed to improve the clinical outcome, but without a general consensus on the best sequence. Therefore, patients will receive these agents continuously until progression of disease and will experience significant adverse events, often detrimental to quality of life. In the past, only high-dose IL-2 was able to obtain longterm complete responses in selected cases such as patients with a good PS and only lung metastases (classified as favorable prognosis) (16). About a quarter of patients are resistant to first-line therapy with tyrosine kinase inhibitors (TKIs) and progress within ≤3 months. The mechanisms of resistance can be intrinsic, when patients exhibit preexisting nonresponsiveness to TKIs resulting in no clinical benefit (17), or acquired, when it follows an initial response. Primary resistance is less common and may be due to an intrinsic redundancy of available angiogenic

Treatment of advanced renal cell carcinoma

signals, while the main acquired resistance mechanisms seem to be due to (1) genetic mutations resulting in structural changes of target proteins that prevent drug binding; (2) the engagement of cancer cells to alternative signaling pathways not targeted by drug therapies thus evading apoptosis and continuing uncontrolled proliferation; (3) the upregulation of the ligand for the targeted receptor; and (4) the constitutive activation of downstream mediators (18). The attempt to overcome resistance mechanisms led to the development of more potent and specific TKIs, novel anti-VEGF antibodies, and agents targeting previously untargeted TORC2, PI3K, and Akt. The new therapeutic approaches with immunomodulatory strategies include inhibitors of immune checkpoint pathways. The interactions between antigen-presenting cells (APCs) and T-cell surface molecules can induce immune tolerance. An example of clinically relevant interaction is that between PD-1 on T cells and PD-L1/PD-L2 on APCs or cancer cells (19). Nivolumab is a fully human immunoglobulin G4 monoclonal antibody that binds the PD-1 receptor and by inhibiting its interaction with PD-L1 and PD-L2, it restores T-cell antitumor activity. In a phase I clinical trial, one patient with heavily pretreated metastatic RCC (mRCC) obtained a partial response (PR), which lasted about 16 months (20). Data from the subsequent phase Ib and phase II trials showed an objective response rate (ORR) of 20% to 29% and an encouraging OS exceeding 2 years; moreover, responses are usually durable, lasting more than 12–20 months (21, 22). Based on these promising data, an open-label, phase III study (The CheckMate 025) evaluating nivolumab versus everolimus was designed in mRCC already treated with antiangiogenic therapy (no more than 3 previous treatments) (23). Nivolumab has shown an improvement in OS in comparison to everolimus (25 months vs 19.6 months, p = 0.002) and in ORR (25 vs 5%), without differences in terms of progressionfree survival (PFS) (4.6 vs 4.4 months, hazard ratio 0.88). The advantage in OS and quality of life was statistically and clinically meaningful and supports the use of this agent as standard treatment in this setting of the disease. Nivolumab has shown an OS benefit across prespecified subgroups, including subgroups defined according to region, Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score, number of previous regimens of antiangiogenic therapy, and sex, with the exception of people aged 75 years and older. Moreover, nivolumab has shown clinical benefit independently from PD-L1 expression. In patients who received prior sunitinib (63%), median OS was 23.6 months with nivolumab vs 19.8 months with everolimus. In patients receiving prior pazopanib (32%), median OS was not measurable in the nivolumab arm and was 17.6 months in the everolimus arm. There were fewer serious (grade 3-4) adverse events (AEs) in nivolumab arm: 19% compared to 37% among patients treated with everolimus. The most common treatment-related AEs were asthenia (33%), severe itching (14%), and nausea (14%) for nivolumab, and fatigue (34%), oral mucositis (30%), and anemia (24%) for everolimus. No treatment-related deaths were observed for nivolumab and 2 among patients receiving everolimus. This is the first time that an immune-checkpoint inhibitor has demonstrated an OS advantage in mRCC, so in November 2015 nivolumab was approved by the Food and Drug Administration (FDA) for pretreated advanced RCC. © 2016 Wichtig Publishing

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Given the complexity of the interaction between the tumor cells and the immune system, combining immunotherapeutic agents may improve clinical benefit. Preclinical studies underline that the dual PD-1 and CTLA-4 receptor blockade reduces regulatory T-cell infiltration and increases effector T-cell infiltration and interferon-γ production, achieving a heightened antitumor effect (24). The CheckMate 016 trial, a phase I trial, evaluated the association of nivolumab plus ipilimumab at different doses in 44 patients with mRCC with favorable/intermediate MSKCC score (25). A total of 18% of patients interrupted therapy due to severe AEs, including pneumonitis, diarrhea, and pancreatic and liver enzymes increase. The ORR was 48% in patients treated with nivolumab 1  mg/kg + ipilimumab 3 mg/kg and 43% in the nivolumab 3  mg/kg + ipilimumab 1 mg/kg arm, with stable disease reported in 35% and 24% of patients, respectively. These data support the development of this combination, leading to initiation of a phase III clinical trial in untreated patients versus sunitinib with OS as the primary endpoint (Checkmate 214) (ClinicalTrials.gov identifier: NCT02231749) that has just completed enrollment (26). The results, in terms of PFS and OS, are awaited to define the potential role of firstline immunotherapy. Indeed, the mechanism of action of nivolumab suggests looking carefully at additional settings including its adjuvant use in high-risk cases postnephrectomy or after a radical metastasectomy in untreated cases for advanced disease. Nivolumab has shown encouraging results also when associated with angiogenesis inhibitors. Vascular endothelial growth factors are involved in angiogenesis and lymphangiogenesis and mediate tumor neovascularization. Moreover, VEGF plays a relevant role in antitumor immunity inducing promotion and expansion of inhibitory immune cells, such as Tregs and myeloid-derived suppressor cells, mitigation of effector T-cell responses, suppression of dendritic cell maturation, and alteration of lymphocyte development and trafficking. Thus, VEGF blockade may not only lead to a decreased angiogenesis but may also potentiate antigen presentation improving the activity of the immune system against tumor cells (27). Considering the rationale for dual VEGF and PD-1/PD-L1 inhibition, a phase I trial evaluated the association of escalating doses of nivolumab with sunitinib (33 patients) or pazopanib (22 patients) in patients with mRCC (28). The sunitinib combination arm enrolled untreated patients who received escalated doses of nivolumab. The pazopanib combination arm was closed due to unacceptable liver toxicity. Grade 3 to 4 AEs were experienced by 82% of patients receiving nivolumab plus sunitinib and by 70% of patients treated with pazopanib and nivolumab. Severe AEs led to discontinuation of treatment in 25% of patients in the pazopanib arm and in 36% of patients in the sunitinib arm. The ORR was 52% in the sunitinib arm and 45% in the pazopanib arm. After 6 weeks from the beginning of the study, PR was reached in 41% of patients in the sunitinib arm and 56% in the pazopanib arm. The PFS at 24 weeks was 78% vs 55% in the 2 arms, respectively. This study showed a higher ORR than those reached by either agent alone, especially considering that many patients were pretreated. Several phase 3 studies are currently ongoing to evaluate the efficacy and safety of other agents in different © 2016 Wichtig Publishing

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combinations, including a study of  atezolizumab  in combination with  bevacizumab  vs sunitinib in untreated advanced  RCC (Clinical Trials.gov identifier: NCT02420821 (29) and a study of  avelumab  with  axitinib  vs sunitinib in advanced RCC (JAVELIN Renal 101; Clinical Trials.gov identifier: NCT02684006 (30). Finally, lenvatinib in combination with everolimus has been approved recently by the FDA for the treatment of advanced RCC following 1 prior antiangiogenic therapy based on a randomized, multicenter phase II study in 153 patients randomized 1:1:1 to lenvatinib 18 mg plus everolimus 5 mg (n  =  1), lenvatinib 24 mg monotherapy (n  =  52), or everolimus 10 mg monotherapy (n = 50). In this study (31), metastases were present in 95% of patients. The hazard ratio for PFS between lenvatinib plus everolimus and everolimus was 0.37 (95% confidence interval [CI] 0.22, 0.62). A study of lenvatinib/everolimus or lenvatinib/pembrolizumab vs sunitinib alone as treatment of advanced  RCC is currently ongoing (Clinical Trials.gov identifier: NCT02811861 (32). Results from the above studies are awaited to further define the role of combination treatment with immunotherapy agents in advanced RCC. Some other aspects of this approach need to be better understood; as an example, the identification of predictive biomarkers to select patients who would benefit most from immunotherapy remains an unmet need. PD-L1 immunohistochemistry (IHC) has been studied as a predictive biomarker, but its use is hindered by multiple unresolved issues, including different expression between primary tumor and metastases, variable IHC cutoff to determine positivity, and differing antibodies and tissue preparation (33).

The role of surgery and its combination with systemic treatment Surgical resection is the only curative treatment for localized RCC, and well-controlled studies have shown that immediate nephrectomy improves survival compared to deferred nephrectomy with neoadjuvant systemic therapy. Regarding metastasectomy some evidence suggests the importance of taking into account some parameters, including time from nephrectomy to the appearance of metastases, number and site of metastases, Karnofsky PS, and comorbidities of the patient, in order to identify cases that could receive more benefit from metastasectomy (34, 35). In the metastatic setting, fewer than 5% of patients present a solitary metastasis. Furthermore, even after definitive local treatment for nonmetastatic RCC, subsequent metastases occur in up to 25% of patients. Lungs, brain, bones, and liver are the sites where metastases spread more frequently. In mRCC, radical nephrectomy, commonly called cytoreductive nephrectomy (CN), is considered a palliative surgery, usually part of a multimodality treatment approach that requires systemic treatment. Resection of the primary tumor may prevent further spreading of the disease and hemorrhage and pain. Moreover, in the study by Choueiri et al (35), CN was associated with a doubling of median OS (19.8 vs 9.4 months) that remained significant on multivariable analysis after adjusting for established prognostic risk factors (adjusted hazard ratio 0.68; 95% CI 0.46, 0.99; p = 0.04).

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While an analysis of 2 prospective randomized trials comparing CN plus immunotherapy with interferon-α versus immunotherapy alone has shown an increased OS in patients who underwent surgery (9), the clinical benefit of nephrectomy in the era of targeted therapy is unknown. Indeed, for CN combined with targeted agents, only retrospective data are available (36). Several prospective ongoing trials are investigating the role of CN for patients treated with targeted agents. The TARIBO trial (ClinicalTrials.gov identifier: NCT02535351) is comparing upfront sunitinib or pazopanib vs CN followed by sunitinib or pazopanib for patients with mRCC who have not received prior systemic treatment for metastatic disease (37). Overall survival is the primary endpoint, and secondary endpoints are PFS, response rate, and safety; moreover, the study has an exploratory objective in order to identify eihter prognostic and predictive biomarkers to better define risk factors and potentially druggable targets. The CARMENA trial (ClinicalTrials.gov identifier: NCT 00930033) is comparing the standard treatment with nephrectomy plus sunitinib to treatment with sunitinib alone without nephrectomy and will clarify whether CN has relevance in the context of VEGF inhibitors (38). Overall survival is the primary endpoint; secondary endpoints are PFS and perioperative complication rates. The SURTIME study (ClinicalTrials.gov identifier: NCT 01099423), completed enrollment in April 2015 and investigates upfront nephrectomy followed by sunitinib vs sunitinib (3 cycles) followed by surgery followed by sunitinib in the absence of distant metastatic disease progression (39). The results will highlight whether patients who respond to targeted therapy should undergo surgical consolidation. While the results of these randomized trials are awaited, CN may be considered in patients with mRCC with good PS, low metastatic burden (no brain or liver metastases), and large primary tumors; it is not recommended in patients with poor PS, severe comorbidities, symptomatic disease, International Metastatic Renal-Cell Carcinoma Database Consortium or MSKCC poor-risk disease, relatively small primary tumors and high metastatic volume, and/or sarcomatoid tumors (35). While no randomized clinical trials have evaluated the role of complete metastasectomy, several retrospective studies have shown that complete resection of metastatic sites, when technically feasible, benefits the OS or the 5-year survival rate in appropriately selected patients. Furthermore, rendering a patient surgically tumor-free may delay or avoid systemic therapy and consequently side effects. The metastasis may be resected at the same time as a radical nephrectomy or in case of recurrence (40). Complete resection of a single metastasis is recommended in selected patients with good PS but a retrospective study showed increased survival even with the resection of multiple lesions. Alt et al (41) studied 887 nephrectomized patients who developed multiple metastatic lesions, of whom 125 (14%) underwent complete surgical resection of all metastases. Cancer-specific survival after complete metastasectomy was prolonged to a median of 4.8 years vs 1.3 years (p1 year, complete metastasectomy, and a solitary lesion or site are independent predictive factors of survival (42). Resection of pulmonary metastases is accompanied by better survival. The number of resected metastases does not change survival when the resection is complete. The most relevant predictive factor remains the completeness of resection. A recent review from an Italian center on the role of pancreatic mRCC suggests that the presence of pancreatic metastasis is associated with better prognosis (43). Moreover, when the metastasis can be totally resected, very high 5-year survival rates are reported. In another retrospective analysis of surgically treated pancreatic metastases in 10 patients, a 75% 5-year survival was reported (44). A review article has confirmed that when the pancreatic metastasis can be radically resected, patients can reach impressive 5-year survival rates (45). Similarly, patients with adrenal metastasis have favorable outcomes after metastasectomy (46). In patients with bone and liver metastases, survival following metastasectomy is lower compared with the other sites. Liver lesions are usually associated with a widespread metastatic disease and limited data are available on their surgical approach. A retrospective analysis has shown improved survival in patients with metachronous metastases who underwent surgery; conversely, patients with synchronous metastases did not benefit from liver surgery (47). Despite the lack of clear improvement in OS and possible postoperative complications, bone metastasectomy may help to improve pain control and functional recovery and to avoid skeletal adverse events (48). The relation between targeting agents and metastasectomy is not defined at present. However, in selected patients with good PS, solitary metastases or significant shrinkage after systemic therapy, and when complete resection of the disease can be achieved, metastasectomy seems feasible with an acceptable morbidity (34). The issue of the ideal interval between systemic and local therapy is still somewhat unresolved, but on the basis of current evidence, an interval off therapy of 2 weeks seems to be the one most often implemented.

The role of cryoablation The incidence of diagnosed small renal masses (SRMs) has been gradually increasing because of the greater utilization of cross-sectional imaging. Surgery remains the standard treatment for small lesions, where partial nephrectomy (PN) is preferred if technically feasible, due to low risk of renal failure, and has been shown to improve OS. However, in patients with substantial comorbidities, the use of less invasive treatment is possible. Ablation techniques such as radiofrequency ablation and cryoablation (CA) have become part of treatment strategies because they may locally control the disease, preventing some of the surgical complications (49). © 2016 Wichtig Publishing

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The American Urological Association considers ablative therapies in patients with cT1a tumors who present major comorbidities and increased surgical risk (50). Cryoablation is the most well-studied of the renal ablative procedures (51). It can be done with a laparoscopic approach or percutaneous approach, depending on the tumor location. The percutaneous approach with smaller cryogenic probes (1.7-2.4 mm) and imaging guide permits decreasing the invasiveness of renal ablation. It is a minimally invasive alternative for surgical resection of a renal cancer in cases that are technically difficult and in patients with relative contraindications to PN. The objective of cryoablation is to induce cell death, with a drop in argon gas pressure that produces temperature below −100°C, with secondary evolution of a lethal iceball. Alternating freeze-thaw cycles lead to cellular dehydration, cell membrane rupture, and vascular thrombosis. The percutaneous approach can be performed under ultrasound guidance, computed tomographic (CT) guidance, or magnetic resonance imaging guidance. Because of its availability and ability to accurately show the ablation area and monitor iceball size and location, CT guidance is the most common method. Percutaneous access is determined by the side of the tumor and by the possible effects on adjacent organs; depending on the tumor size, it is possible to use one or more cryogenic probes, in different gauges and lengths. Patients are treated under moderate sedation or general anesthesia. The treatment considers 2 freezing cycles of 13-15 minutes each, separated by a passive warming cycle of 12-15 minutes. During the freezing cycle, temperatures on the tip of each probe decrease to −100° to −140°C. The total duration of the procedure is about 1 hour. Posttreatment monitoring includes hematologic and biochemistry evaluation 4 hours, 8 hours, and 24 hours after percutaneous approach and CT examination 24 hours after percutaneous approach. The follow-up includes a CT scan with intravenous contrast agent 1, 3, 6, 9, and 12 months after treatment and then every 6 months. The evaluation of the efficacy of the treatment is based on absence of enhancement of the mass (52). Currently, there is a lack of consensus about tumor and patient selection criteria. It is widely acknowledged that CA could be offered to patients with SRMs in solitary or transplant kidney, and in patients with history of tuberous sclerosis and von Hippel-Lindau disease; it is also a safe, feasible option for patients with oligometastatic RCC. Moreover, because of its reliability, CA is an important treatment option for older and frail patients with comorbidities such as hypertension, diabetes, or congestive cardiac failure and for patients with high risk of induction of renal insufficiency by surgery (50). The best lesions to treat with CA are well-circumscribed enhancing SRMs, with size 4 centimeters, cystic tumors, hilar and intrarenal masses, and younger age. Advantages of probe-ablative procedures © 2016 Wichtig Publishing

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include reduced morbidity, shorter hospitalization, shorter convalescence, preservation of renal function, usefulness in patients with significant comorbidity (51), and repeatability of the procedure. Complications related to CA are heterogeneous: major complications are collecting system injury, fistula formation, hemorrhage, and adjacent organ injury. To avoid or mitigate the risk of ureteric injury and strictures in tumors close to the renal hilum and pelvis, it is possible to position ureteral stent for retrograde irrigation of the collecting system. Hemorrhage is associated with central tumor location, large tumor size, and number of probes. Organ injury could be avoided with hydrodissection or cargo dissection with CO2 insufflation to safety displace adjacent organs. Minor complications are usually urinary tract infections, hematuria, hematoma, and pneumonia. The skill of the operator and adequate selection of patients based on size of the mass and comorbidity associated with careful execution (stenting position or hydrodissection) can reduce the likelihood of major complications.

Conclusion The last ten years were exciting in terms of new treatment strategies for RCC in both local and metastatic disease, with the introduction of 7 targeted agents and with an effort to define which types of patients may benefit from a multimodal approach. A new era with immunecheckpoint inhibitors has started and we hope that these agents will lead to a long term survival for more patients with metastatic disease.

Disclosures Financial support: No financial support was received for this submission. Conflict of interest: Giuseppe Procopio reports receiving fees for serving on advisory boards from Bayer, Bristol-Myers-Squibb, Ipsen, Janssen, and Novartis and lecture fees from Astellas and Pfizer. Elena Verzoni reports receiving fees for serving on advisory boards from Pfizer, Janssen, and Novartis.

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