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Role of immunotherapy in kidney cancer

Nazzani, Sebastianoa,b; Bazinet, Améliea,c; Karakiewicz, Pierre I.a,c

Current Opinion in Supportive and Palliative Care: September 2018 - Volume 12 - Issue 3 - p 325–333
doi: 10.1097/SPC.0000000000000363
RENAL AND UROLOGICAL PROBLEMS: Edited by Fred Saad

Purpose of review To summarize current knowledge on promising immunotherapeutic agents and to provide a brief outline of current use of immunotherapeutic agents in patients with locally advanced or metastatic renal cell carcinoma (RCC).

Recent findings Immunotherapy with mAbs directed against programed death cell protein 1, programed death-ligand 1 (PD-L1) and cytotoxic T-Lymphocyte Antigen 4 has become new first-line standard of care for moderate and poor-risk metastatic RCC patients. Similarly, the combination immune-oncology treatment and vascular endothelial growth factor (VEGF) mAbs also showed promising results in first-line therapy despite relative data immaturity. Finally, immune-oncology monotherapy (nivolumab) already represents second or third-line standard of care after tyrosine kinase inhibitor failure.

Summary Combination immune-oncology therapy represents the standard of care for management of intermediate-to-poor risk clear cell metastatic RCC. In addition, combination of immune-oncology and anti-VEGF antibody represents a treatment option across all risk levels in patient with elevated PD-L1 expression. Finally, nivolumab is one of two ideal treatment options in second-line clear cell metastatic RCC patients.

aCancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Québec, Canada

bAcademic Department of Urology, IRCCS Policlinico San Donato, University of Milan, Milan, Italy

cDepartment of Urology, Université da Montréal, Montreal, Québec, Canada

Correspondence to Sebastiano Nazzani, MD, Academic Department of Urology, IRCCS Policlinico San Donato, University of Milan, Piazza Malan 1, San Donato Milanese, Italy. Tel: +39 3356274997; e-mail: sebastiano.nazzani@yahoo.com

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.supportiveandpalliativecare.com).

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INTRODUCTION

In 2018, combination immunotherapy has become first-line standard of care for intermediate-to-poor risk clear cell metastatic renal carcinoma (ccmRCC). In addition, single-agent immune-oncology treatment represents the standard of care for second or third-line therapy in patient with ccmRCC. Moreover, a recent phase 3 trial of immune-oncology agents and antivascular endothelial growth factor (VEGF) antibody combination also reported very promising results, despite relative data immaturity [1▪▪]. Finally, four phase 3 studies comparing immune-oncology and tyrosine kinase inhibitors (TKI) combinations or immune-oncology-epacadostat combination to sunitinib monotherapy are also ongoing.

These observations indicate the beginning of a novel era in the management of mRCC, in which immunotherapy plays a central and highly promising role with potential for durable and complete responses (CRs), that have previously not seen with TKI therapy. Based on these considerations, we will review and summarize the status of completed and ongoing trials.

Box 1

Box 1

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IMMUNOTHERAPY IN LOCALLY ADVANCED OR METASTATIC KIDNEY CANCER

Immune-oncology agents block antibodies directed against the programed cell death protein 1 (PD-1) receptor, its ligand (PD-L1) as well as against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Specifically, PD-1 and PD-L1 interaction results in inhibition of cellular immune response, in which tumors with elevated PD-L1 expression have worse prognosis [2]. The interruption of this signal pathway, through immune-oncology therapy, may restore immune response and reactivate innate antitumor activity. Conversely, CTLA-4 is expressed by T cells, and its activity is based on regulating T-cell activation. In the early stages of T-cell activation, CTLA-4 response triggers inhibition of T-cell proliferation and function [3].

The expression of PD-L1 is common in both ccRCC [4] and non-ccRCC [5]. Moreover, RCC is a highly immunogenic and chemoresistant tumor [6]. To date, efficacy of systemic therapy for mRCC was based on single-agent TKI therapy; this approach yielded important improvements in progression-free survival (PFS), but to a lesser extent in overall survival (OS). Specifically, TKIs that failed to provide durable responses and CRs were exceptional. In consequence, durable responses, CRs and meaningful OS benefit without excessive toxicity, represent an unmet need in mRCC. This unmet need was recently fulfilled with the advent of several single immune-oncology agents or immune-oncology combination approaches. Moreover, the combinatorial approach of immune-oncology agents with various TKIs is under investigation. In addition, recent data provided insights into the combinatorial therapy relying on immune-oncology and anti-VEGF antibody with promising PFS results, despite immature OS outcomes [1▪▪].

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SINGLE-AGENT IMMUNOTHERAPY COMPLETED PHASE 3 TRIALS

Nivolumab

Nivolumab is a PD-1 inhibitor and represents the standard of care in mRCC after first or second-line failure of VEGF targeted agents. It was the first immune-oncology agent approved by the FDA (November 2015) and European Commission (April 2016) for the treatment of patients with advanced or metastatic ccRCC.

Specifically, a phase 3 randomized, open-label, trial (Checkmate 025) was conducted by Motzer et al. [7▪,8] (Supplementary Table 1, http://links.lww.com/COSPC/A18). It compared nivolumab to everolimus in second or third-line setting in 821 patients with advanced ccRRC. The primary endpoint was OS. The latter was significantly improved in nivolumab-treated patients [median OS: 25 vs. 19.6 months; HR 0.73, confidence interval (CI) = 0.57–0.93] was observed.

Secondary endpoints included objective response rate (ORR), PFS, stratified OS according PD-L1 expression and adverse event rates. Here, ORR was higher in nivolumab (25.5 vs. 5%; OR 5.98; CI = 3.68–9.72). After stratification according to PD-L1 expression (≥1 or <1%), OS advantage was observed regardless PD-L1 expression. However, no difference was demonstrated for PFS (median PFS 4.6 vs. 4.4 months HR: 0.88, CI = 0.75–1.03).

Treatment-related adverse events occurred in 79% of nivolumab patients vs. 88% of everolimus patients. Specifically, grade 3 or 4 treatment-related adverse events occurred in 19% nivolumab patients and in 37% everolimus patients. Most common was fatigue with nivolumab and anemia with everolimus.

In post-hoc analyses, the greatest benefit for nivolumab was observed in poor-risk patients followed by intermediate and favorable risk patients in this order (according to Memorial Sloan Kettering Cancer Center for mRCC prognostic risk group). Additional post-hoc analyses showed higher OS benefit, when nivolumab was used after pazopanib failure, relative to sunitinib or IL-2 failure [7▪].

Based on this findings, nivolumab was defined as the new standard of care for patients with advanced RCC after failure of first or second-line TKI-based therapy. This said, cabozantinib (a multitargeted TKI) was also recently compared with everolimus and also demonstrated improved PFS and OS outcomes. In consequence, cabozantinib represents a second or third-line treatment alternative in a setting of advanced RCC [9].

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COMBINATION IMMUNOTHERAPY COMPLETED PHASE 3 TRIALS

Nivolumab and ipilimumab

Ipilimumab is a fully human mAb (IgG1) that blocks CTLA-4 sites. The combination of nivolumab–ipilimumab has shown high degree of efficacy in the context of metastatic lung cancer [10] and metastatic melanoma [11]. Superior results with single-agent nivolumab in multiple metastatic sites including RCC, as well as highly impressive efficacy of combined nivolumab and ipilimumab in metastatic tumor sites other than RCC prompted nivolumab–ipilimumab phase 1/2 trial (CheckMate016) for ccmRCC patients [12].

Subsequently, the nivolumab 3 mg and ipilimumab 1 mg combination, identified in Checkmate 016 [12] phase 1/2 trial served as the basis for the phase 3 CheckMate214 trial [13▪▪] (Supplementary Table 1, http://links.lww.com/COSPC/A18), in which this combination was compared with the standard of first-line sunitinib in 1096 advanced or metastatic ccRCC treatment naïve patients. The three primary endpoints consisted of ORR, PFS and OS in intermediate–poor-risk patients according International Metastatic Renal Cell Carcinoma Database Consortium risk groups. Overall α for treatment effect was set at 0.05, which was divided as follow: 0.001 ORR, 0.009 PFS, 0.04 OS. Additional preplanned analyses were also stratified according to baseline tumor PD-L1 expression.

In the main analyses focusing on intermediate and high-risk patients nivolumab–ipilimumab combination resulted in higher ORR (42 vs. 27%; P < 0.0001) and higher CR rate (9 vs. 1%), relative to sunitinib. In addition, the nivolumab–ipilimumab combination significantly improved OS (median OS: NR vs. 26 months HR: 0.63, CI = 0.44–0.89), compared with sunitinib. However, PFS was not significantly improved (median PFS 11.6 vs. 8.4 months HR: 0.82, CI = 0.64–1.05).

Furthermore, analyses stratified according to PD-L1 expression in intermediate and high-risk patients favored those with PD-L1 at least 1%. Specifically, better ORR (58 vs. 22%; P < 0.0001), higher PFS (median PFS 22.8 vs. 5.9 months; HR 0.48; P < 0.0003) and higher OS (median OS: NR vs. 19.6 months, HR 0.45; P < 0.001) were noted in patients with PD-L1 at least 1% expression.

It is noteworthy that in exploratory analyses focusing on favorable risk patients, PFS and ORR favored sunitinib. Finally, adverse events occurred in 509 on 547 (93% any grade, 46% grades 3 and 4) with nivolumab and ipilimumab and in 521 on 535 (97% any grade, 63% grades 3–5) with sunitinib.

Based on these extremely promising and so far unparalleled results, nivolumab and ipilimumab combination has been defined as the new standard of care for patients with intermediate and high-risk mccRCC patients.

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Atezolizumab and bevacizumab

The combination between atezolizumab, a PD-L1 inhibitor and bevacizumab, a mAb targeting VEGF was tested in 305 mccRCC patients within a phase 2 trial (IMmotion 150) [14]. Encouraging efficacy rates were recorded in PD-L1 expressors treated with the combination of atezolizumab–bevacizumab vs. atezolizumab monotherapy or sunitinib monotherapy. Currently, a phase 3 trial (IMmotion 151) [14] (Supplementary Table 1, http://links.lww.com/COSPC/A18) is comparing atezolizumab and bevacizumab combination vs. sunitinib in 915 treatment naïve mccRCC patients. Here, patients were enrolled regardless MSKCC risk group.

The primary endpoints of the study were PFS in PD-L1 at least 1% expressors and OS in intent-to-treat (ITT) patients. In outcome analyses, the 5% alpha was split between 4% for PFS analyses in PD-L1 at least 1% expressors and 1% for OS analyses in the ITT population. Secondary endpoints included PFS in ITT patients and OS in PD-L1 at least 1% expressors.

Median PFS in PD-L1 at least 1% patients was 11.2 months for atezolizumab–bevacizumab arm vs. 7.7 months for sunitinib arm (HR 0.74; P = 0.02). In ITT analyses, HR was 0.83 (95% CI 0.70–0.97) with median PFS of 11.2 months for atezolizumab–bevacizumab compared with 8.4 months for sunitinib. Data regarding OS are immature. ORRs were 43 and 35% for atezolizumab–bevacizumab vs. sunitinib. Finally, 40% of the atezolizozumab–bevacizumab arm experienced grade 3 or 4 adverse events vs. 54% of the sunitinib arm.

Based on the above results, the combination of atezolizumab–bevacizumab represents an alternative to first-line sunitinib without providing the benefit of OS that was recorded for the nivolumab–ipilimumab combination. However, the atezolizumab and bevacizumab combination potentially provides a more easily manageable treatment option based on its toxicity profile than the nivolumab–ipilimumab combination. Moreover, the use of atezolizumab and bevacizumab represents an option across all disease risk strata, including patients with favorable risk disease as long as PD-L1 expression is greater than 1%. Based on this consideration, PD-L1 testing might be required in first-line treatment consideration.

Currently, multiple PD-L1 expression kits are commercially available. However, one unique PD-L1 specific kit should be identified as a standard for quantifying PD-L1 expression. This recommendation is particularly important in the light of recent data demonstrating important differences in PD-L1 expression rates according the PD-L1 kit that was applied.

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Ongoing phase three immune-oncology-tyrosine kinase inhibitor trials

Currently, three phase 3 immune-oncology-TKI vs. sunitinib or pazopanib trials are ongoing. In addition, one phase 3 trial is comparing immune-oncology-epacadostat combination to sunitinib monotherapy. The endpoints consist of ORR, PFS and OS. Each of those four phase 3 trials is based on corresponding phase 1 trial that provided efficacy and tolerability estimates.

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Pembrolizumab and axitinib

Due to the limited survival benefit of anti-VEGF monotherapy, combination of anti-VEGF with immune-oncology agents has been proposed.

Pembrolizumab is a humanized antibody directed against PD-1 and was the first PD-1 inhibitor approved by the FDA for the treatment of unresectable or metastatic melanoma. In the last few years, its beneficial effect has also been shown in other tumors such as nonsmall-cell lung cancer and esophageal cancer [15,16]. In this trial, pembrolizumab is combined with axitinib, a very potent oral multitargeted tyrosine kinase receptor inhibitor, which selectively inhibits VEGF receptors 1, 2 and 3. Axitinib represented the second-line standard of care prior to the advent of nivolumab and cabozantinib. A phase 1b open-label trial (NCT02133742) evaluating safety, pharmacokinetics and pharmacodynamics of axitinib combined with pembrolizumab in treatment of naïve advanced RCC patients has recently been completed (Table 1) [17]. During the study span, 52 patients were enrolled. Primary endpoint was dose-limiting toxicity, to estimate the maximum tolerated dose and recommend phase 2 dose. Three dose-limiting toxicities were reported: one transient ischemic attack, one grades 2–3 headache and one grade 2 headache, fatigue, asthenia and dehydration. Grade 3 or 4 treatment-related adverse events occurred in 34 (65%) of the patients. Of all, 38 (73%; CI 59.0–84.4%) patients achieved an OR (four complete and 34 partial). The latter represent the higher of all phase 1b/2 trials.

Table 1

Table 1

In conclusion, the pembrolizumab–axitinib combination showed promising antitumor activity and manageable toxicity in patients with treatment-naive advanced RCC. Currently, the phase 3 trial comparing pembrolizumab–axitinib vs. sunitinib (Keynote 426) [17] has completed recruitment of its 840 treatment naïve advanced ccRCC patients. His efficacy data are anxiously awaited based on ORR demonstrated in phase 1 trial. The estimated study completion date is in January 2020 (Table 2).

Table 2

Table 2

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Pembrolizumab and lenvantinib

Lenvantinib is an inhibitor of VEGF receptors 1–3, fibroblast growth factor receptors 1−4, platelet-derived growth factor receptor α, RET and KIT. A phase 2 trial (NCT02501096) [18] evaluated lenvantinib–pembrolizumab ORR after the assessment of the maximum tolerated dose in phase 1b (Table 1). During the study span, 30 mccRCC patients were enrolled (8 phase 1b + 22 phase 2). A total 19 patients (63%) received prior systemic therapy and specifically, 16 (53%) received prior VEGF-targeted therapy. At data cutoff, 17 (57%) patients were still receiving treatment, eight (27%) completed treatment with eventual disease progression, and 5 (17%) discontinued treatment. Overall, ORR was estimated at 63.3%.

In conclusion, the investigators stated that lenvantinib–pembrolizumab combination has promising antitumor activity and manageable toxicity in patients with advanced RCC. A phase 3 trial (NCT02811861) evaluating lenvantinib–pembrolizumab vs. lenvantinib–everolimus vs. sunitinib monotherapy in first-line treatment for mccRCC patients is ongoing [18]. The estimated study completion date is in January 2020 (Table 2).

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Avelumab and axitinib

Avelumab is an IgG1 anti PD-L1 mAb. Unlike other immune-oncology agents, avelumab represents the only antibody among PD-1 and PD-L1 capable of inducing innate immune mechanism against cancer cell by increasing their susceptibility to natural killer cells [19].

In the phase 1 avelumab trial (Javelin Renal 100) [20], 55 treatment naïve advanced ccRCC patients were enrolled to evaluate its safety and efficacy in combination with axitinib (Table 1). Overall, 51 (92.7%) patients experienced avelumab-related adverse events vs. 52 (94.5%) patients experienced axitinib-related adverse events, when combination therapy relying on both agents was used. During the study span, two deaths occurred. One due to disease progression and one was related to treatment toxicity (myocarditis). Here, ORR was 58% (CI 44–71%). Based on these figures, the investigators stated that avelumab–axitinib combination has promising antitumor activity and manageable toxicity in patients with advanced RCC.

Currently, a phase 3 trial (Javelin Renal 101) [21] is evaluating the combination avelumab–axitinib vs. sunitinib in 830 treatment naïve advanced ccRCC patients. The estimated study completion date is in April 2021 (Table 2).

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Pembrolizumab and epacadostat

Epacadostat is an oral inhibitor of indoleamine 2,3-dyoxigenase 1. This enzyme induces immune tolerance by suppressing T-cell activity (Table 1).The epacadostat-pembroluzimab antitumor activity and safety profile has been studied in a Phase 1/2 trial (ECHO-202/KEYNOTE-037) [22]. During the study span, 33 advanced ccRCC patients were enrolled (11 phase 1 + 22 phase 2). All patients received at least one prior antiangiogenic therapy but were unexposed to prior immune-oncology agent-based therapy. Efficacy of the treatment was evaluable in 30 patients. OR was observed in nine of 19 (47%) patients with one or less previous treatment lines: complete in one and partial in nine. Conversely, no OR was observed in patients with more than 1 previous treatment lines. Therapy-related adverse events at least grade 3 occurred in 15% of the patients and two of them discontinued treatment.

In conclusion, the investigators stated that epacadostat-pembrolizumab combination has promising antitumor activity and manageable toxicity in patients with advanced RCC. A phase 3 trial (NCT03260894) evaluating pembrolizumab-epacadostat vs. sunitinib or pazopanib in first-line treatment for locally advanced or mccRCC patients is ongoing. The estimated study completion date is in June 2023 (Table 2).

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Ongoing phase 1 immune-oncology-tyrosine kinase inhibitor trials

Nivolumab and pazopanib or sunitinib

Pazopanib is a multitargeted TKI that focuses on tumor angiogenesis and cell proliferation. Its antiangiogenic properties stem from its effect on intracellular tyrosine kinase of VEGF receptor and platelet-derived growth factor receptor.

Specifically, a phase 1 effectiveness and dose finding trial (Checkmate 016) is examining nivolumab in association with sunitinib or pazopanib in metastatic RCC patients exposed to at least one prior line of systemic therapy. Here, nivolumab–sunitinib or nivolumab–pazopanib showed encouraging safety profile (73% grade 3 or 4 adverse events in sunitinib group vs. 60% grade 3 or 4 adverse events in pazopanib group) and antitumor activity expressed as 45% ORR (all partial responses) after nivolumab–pazopanib and 52% (3% of partial and 48% of CRs) after nivolumab–sunitinib [23] (Table 1). The estimated completion date is June 2018.

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ADJUVANT IMMUNOTHERAPY

The rationale for adjuvant therapy in RCC patients treated with either partial or radical nephrectomy is based on suboptimal survival evidences especially, in intermediate or high-risk individuals. Of those, up to 30% of RCC patients may experience disease recurrence [24]. The latter is directly related to tumor stage and tumor grade. In consequence, ideal candidates for adjuvant immunotherapy consist of individuals with Fuhrman grades 3–4, stage III or N1 disease or a combination of those three variables. Individuals with such disease profile represented the focus of three previous TKI-based trials [25–27]. Of those, all failed to demonstrate an OS benefit. Conversely, one showed disease-free survival benefit of adjuvant sunitinib relative to placebo. Based on the unmet need for documented OS improvement after adjuvant therapy in patients with non-ccmRCC neoadjuvant and adjuvant immune-oncology-based agent trials are ongoing.

Specifically, on the four ongoing phase 3 trials, the PROSPER trial represents a neoadjuvant approach. The remaining three represent adjuvant trials that are based on pathological disease characteristics (Table 3).

Table 3

Table 3

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HIGH-DOSE IL-2 AND VACCINE THERAPY

IL-2 and IFN-α-2a [28] represented initial approaches to immunotherapy in the setting of mRCC. Subcutaneous IFN-α-2a failed to show efficacy. Conversely, high or intermediate-dose IL-2 showed OS benefit on a smaller scale than nivolumab–ipilimumab and atezolizumab–bevacizub trials. Moreover, rate limiting toxicities were reported [29]. In consequence, intermediate or high-dose IL-2 use may only be applied to a marginal proportion of highly select individuals with clear cell histology, pulmonary metastasis and perfect performance status without known comorbidities. Associated responses are comparable with the ones reported in the CheckMate 214 trial; however, the robustness of IL-2 data based on sample size is not comparable with the CheckMate 214 trial. Similarly, the CheckMate 214 trial reports superior tolerability and substantially lower toxicity, relative to the original IL-2 reports. Last but not least, two vaccine trials failed to show an OS benefit in patients with advanced RCC [30,31].

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CONCLUSION

In conclusion, immune-oncology–immune-oncology first-line combination therapy represents the standard of care for intermediate-to-poor risk treatment naïve ccmRCC. Moreover, immune-oncology-anti-VEGF antibody combination represents a treatment option across all risk levels in patient with PD-L1 expression at least 1%. In addition, immune-oncology monotherapy (nivolumab) represents one of two ideal treatment options for second-line ccmRCC patients. Last but not the least, immune-oncology agents showed efficacy in patients with nonclear cell histological subtype, such as papillary and chromophobe mRCC [32]. In the coming months to years, four additional phase 3 studies relying on immune-oncology-TKI or immune-oncology-epacadostat combination will report their efficacy and tolerability data. In consequence, multiple immune-oncology options will be available for specific patient profiles according to phase 3 data.

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Acknowledgements

We would like to thank Dr Feliz Preisser and Dr Elio Mazzone for their assistance with the study.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

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The combination of atezolizumab–bevacizumab represents an alternative to first-line sunitinib without providing the benefit of overall survival that was recorded for the nivolumab–ipilimumab combination.

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Keywords:

adjuvant chemotherapy; immunotherapy; kidney cancer; neoadjuvant chemotherapy

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