The field of metastatic renal cell carcinoma (mRCC) has been dominated by targeted therapies during the past decade. Inhibitors of the vascular endothelial growth factor receptor (VEGFR) or mammalian target of rapamycin (mTOR) entered the clinic and triggered a grand search for the ultimate sequence. With more and more data emerging, it became clear that continuous treatment was a cornerstone in mRCC, but an optimal sequence could not be recommended. Compared with historical controls, targeted agents increased the overall survival (OS) expectation to 30 months in mRCC [1,2], but long-term survival is restricted to approximately 10% of patients who achieve a median OS of 55 months [3▪]. Objective response rates (ORRs) remain within the range of 24–31% with VEGFR inhibitors (VEGFRi), but less than 1% achieve a complete response (CR) . It became clear that further improvement in survival will require novel mechanisms of action, instead of developing inhibitors with higher specifity for the same target .
The discovery of immune checkpoints has generated a completely new approach in cancer treatment. In principle, the T-cell's PD-1 axis is used to curb immune response and thereby prevent autoimmune disease as a vital necessity in the human body. Tumours utilize this mechanism by expression of programmed death ligand-1 (PD-L1) or PD-L2, which binds to PD-1 on the T-cell surface and thereby halts the cytotoxic T-cell response. A similar interaction between T-cell and antigen-presenting cell is used for activating T-cells, as a first step of the host's immune response (Fig. 1).
Inhibitors of programmed death-1 (PD-1) or its ligand (PD-L1 or 2) were shown to reverse tumour-induced cytotoxic T-cell blockade . Furthermore, blockade of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) was associated with T-cell activation, leading to clinical response . The clinical relevance of PD-L1 activity was shown in analyses of its expression in RCC. In localized disease, PD-L1 expression and the detection of tumour infiltrating lymphocytes (TILs) were associated with a poor clinical outcome in RCC [6▪,7].
Each tumour utilizes a distinct mechanism, which evades immune surveillance. Hence, identification of the underlying immune modulation will lead to an individual approach of immune therapy in patients [8▪▪]. Therefore, most current studies mandate tumour biopsies in order to define predictive marker for these therapies.
Data generated so far come from phase I or phase II clinical studies. It became obvious that these novel agents were able to induce a high rate of ORR, but assessment of tumour response may have to follow modified criteria. Basically, enlargement of tumour may be seen prior to tumour shrinkage, which has led to the development of modified tumour response criteria for immunotherapies.
However, the ORR of 20–22% with single-agent PD-1 inhibition in previously treated patients has raised awareness for this novel class of agents and has spurred clinical development of combinational therapies in order to boost clinical activity in mRCC [9▪▪,10]. Current research focuses on combinations in mRCC, as well as single-agent application in mRCC.
SINGLE AGENT ACTIVITY OF T-CELL CHECKPOINT INHIBITORS
With the introduction of T-cell checkpoint inhibitors in clinical development, a new approach to early clinical studies was born. Phase I studies were enlarged and included baskets of different tumour entities in order to spur clinical development by assessing safety and efficacy separately. Such an approach was chosen for the development of BMS-936559, MPDL3280A and nivolumab. Phase I studies consisted of 140–296 patients with different cancers enrolled in each study, including a fraction of patients with mRCC (Table 1) [11–13].
No clear dose–response relationship could be established in these clinical studies, which is why for future development of nivolumab in mRCC, a pick the winner randomized phase II design was chosen to explore this relationship [9▪▪]. This study was thought to detect an increasing duration of median progression-free survival (PFS) with higher doses of nivolumab (0.3 vs. 2 vs. 10 mg/kg). Surprisingly, the study failed to show a dose–response relationship. Median PFS was 2.7, 4.0 and 4.2 months (P = 0.9) and ORR 20, 22 and 20% (P = 1.0) in each group, respectively. Because response assessment during treatment with immunotherapies is prone to bias, modified criteria for tumour assessment were also tested as an exploratory endpoint in that study. According to modified response criteria, PFS was 4.3, 5.4 and 6.9 months and showed a trend for significance (P = 0.6), respectively, indicating a potential relevance of modified response criteria in the field of immunotherapies.
Objective responses remained durable in most cases, with 75, 50 and 45% ongoing responders in the 0.3, 2 and 10 mg/kg treatment groups, respectively. More surprisingly, a difference was detected among treatment groups, with 18.2, 25.5 and 24.7 months median OS, respectively. Hazard ratios favoured the 2 mg/kg (hazard ratio 0.8) and 10 mg/kg (hazard ratio 0.9) compared with the 0.3 mg/kg dose. On the basis of the safety, efficacy and OS data, a dose of 3 mg/kg was chosen for future development.
The latest trial shows the difficulties to select the appropriate dose for drug development with immunotherapies. Once objective response occurs, it may be long-lasting in patients. However, the role of disease stabilization needs further exploration in the context of checkpoint inhibitors, because stable disease may be durable as well in mRCC. The currently ongoing pivotal phase III trial comparing nivolumab with everolimus after failure of a VEGFRi in mRCC is thought to report later this year. Given the higher number of patients and the direct comparison, it may elucidate the role of ORR on OS with PD-1 inhibition in mRCC.
DUAL T-CELL CHECKPOINT INHIBITION IN METASTATIC RENAL CELL CARCINOMA
On the basis of the encouraging results of single-agent checkpoint inhibitors, combined approaches were sought in mRCC. CTLA-4 inhibition was known to prime T-cells and a previous single arm study showed objective responses as a single agent in mRCC [14▪]. The induction of T-cell activity, followed by the modulation of the cytotoxic T-cell response through a PD-1 inhibitor, was thought to spur efficacy in mRCC. A recent study in malignant melanoma confirmed this hypothesis and showed rapid and deep responses for this combination, at the costs of toxicity [15▪]. However, the early and deep tumour shrinkage detected in melanoma is used as a proof-of-concept study for dual checkpoint inhibition, per se. This led to the development of similar approaches in mRCC.
A large phase I study explored the role of different combination partners for nivolumab in mRCC. One cohort of this study explored the efficacy and safety of PD-1 and CTLA-4 inhibition in mRCC with a nivolumab/ipilimumab combination . Two doses of ipilimumab (1 and 3 mg/kg) and nivolumab (3 and 1 mg/kg) were arbitrary chosen and explored for future development. Interestingly, objective response was similar among both groups (43 and 48%, respectively), but toxicity was excessive with the 3 mg/kg ipilimumab dose, mainly consisting of ipilimumab-associated adverse events. Hence, the dose of ipilimumab 1 mg/kg and nivolumab 3 mg/kg was chosen for subsequent studies, which is in contrary to the combinational dose chosen for future development in melanoma (ipilimumab 3 mg/kg and nivolumab 1 mg/kg).
The current clinical development includes a phase III trial, which tests the combination of ipilimumab/nivolumab in first-line against sunitinib (NCT02231749). Whether the dose picked for further development is optimal remains illusive. On the basis of the increase in toxicity seen with these combinations, a formal dose-defining study would have great value to the field. Given the data from the single-agent nivolumab trial, a lower dose may yield similar responses, while decreasing a fair amount of immune-related adverse events.
Furthermore, additional checkpoints were identified and are explored in future clinical trials, rendering a more complex picture of immunotherapies, thereby opening a window of opportunity to individualize treatment immunotherapies.
COMBINATION OF CHECKPOINT INHIBITION WITH TARGETED THERAPIES
A distinct approach tested the combination of targeted therapies with checkpoint inhibitors in early clinical trials. Current second-line options consist of everolimus or axitinib in the treatment algorithm of mRCC. Treatment efficacy broadly remains within the scope of 4–5 months for everolimus, axitinib or single-agent nivolumab [9▪▪,17,18]. Improvement of clinical efficacy is thought to be achieved through the combination of targeted therapies and checkpoint inhibitors. A recent phase I study therefore explored the combination of nivolumab with either pazopanib or sunitinib in order to improve second-line options . All patients failed either sunitinib or pazopanib and received the remaining VEGFRi in combination with nivolumab as subsequent therapy. The study implemented a two-stage design. The first stage included exclusively patients with prior therapy, whereas in the second stage, treatment-naive patients were enrolled.
The objective response rate remained high for both cohorts of patients. The combination of pazopanib and nivolumab achieved an ORR of 45% in previously treated patients. The treatment with sunitinib and nivolumab included patients with prior failure of pazopanib and treatment-naive patients and therefore achieved an ORR of 52%. Durable responses were achieved in three out of nine and 10 out of 17 patients, respectively. However, hepatic toxicity was prohibitive, which led to discontinuation of the pazopanib cohort after stage 1. Thirty-six percent in the sunitinib arm and 25% in the pazopanib arm discontinued therapy because of toxicity.
Overall, the efficacy detected for the combination of nivolumab with a VEGFRi was encouraging, but overlapping toxicity profiles may render this approach prohibitive. Axitinib is a distinct VEGFRi, which literally lacks hepatic toxicity and therefore may be an ideal candidate for such a combination. A current phase I/II clinical study is ongoing (NCT02133742). Certainly, VEGFRi may not be used interchangeably in this context. From current data, differences for VEGFRi ability to modify the immune environment have been reported.
Bevacizumab is another targeted agent, lacking hepatic toxicity, and therefore a promising candidate for combinational therapy. MPDL3280A and bevacizumab were explored in a phase I trial, indicating its potential clinical use . A total of 10 patients were exposed to the combination, and four out of 10 achieved an objective response, while four out of 10 patients remained stable for at least 6 months. Interestingly, only one patient progressed without any benefit from treatment. A current large, randomized phase II study tests the role of MPDL3280A as a single agent or in combination with bevacizumab in comparison to sunitinib, in order to define the role of this novel combination in mRCC (NCT01984242).
PREDICTIVE MARKERS FOR CHECKPOINT INHIBITION
On the basis of the precise mechanism of action of antibodies against immune checkpoints, the development of companion diagnostics seemed encouraging. A predictive value of PD-L1 expression for ORR was seen in most studies, indicating a superior response in PD-L1 positive mRCC [8▪▪,9▪▪,21]. Whether PD-L1 positivity is a necessity for dual checkpoint blockade or a combination with VEGFRi remains illusive and is a crucial question, which might be answered within ongoing studies.
However, a great variation was seen among tests used and cut-offs implied for positivity. Furthermore, PD-L1 expression may be obtained from the tumour cells, stroma or infiltrating immune cells [8▪▪]. Clearly, a standardized approach is needed in order to succeed with a clear-cut marker for the current generation of inhibitors.
The current clinical development of T-cell checkpoint inhibitors in the field of cancer is encouraging. Novel trials have been launched in chromosomal instable cancers, including mRCC. Compared with the current targeted therapies available, single agent PD-1/PD-L1 inhibitors remain very well tolerated with only a fraction of grade 3/4 toxicity seen with VEGFRi. The main advantage of checkpoint inhibitors is the induction of durable responses in mRCC. On the basis of the number of additional T-cell checkpoints available for pharmacological intervention, novel classes of checkpoint inhibitors will develop in the future. Given the encouraging clinical activity and the good tolerability of the current inhibitors, combinational approaches are likely to become a key component of future immune therapies (Table 2). Ongoing studies explore these novel concepts and are not limited to checkpoint inhibitors. These trials may have the potential to further improve clinical outcome in mRCC by induction of durable responses.
Financial support and sponsorship
Conflicts of interest
I have received honoraria from Bayer, BMS, GSK, Novartis and Pfizer.
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
1. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369:722–731.
2. Eichelberg C, Vervenne WL, De Santis M, et al. SWITCH: a randomized sequential open-label study to evaluate efficacy and safety of sorafenib (SO) followed by sunitinib (SU) versus sunitinib followed by sorafenib in the treatment of metastatic RCC. Eur Urol 2015; [Epub ahead of print]. doi: 10.1016/j.eururo.2015.04.017.
3▪. Grünwald V, McKay RR, Krajewski KM, et al. Depth of remission is a prognostic factor for survival in patients with metastatic renal cell carcinoma. Eur Urol 2015; 67:952–958.
This study defines the prognostic role of deep tumour repsonse in mRCC.
4. Grünwald V, Merseburger AS. The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors: is there more to come? Eur J Cancer 2013; 49:2504–2511.
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6▪. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 2004; 101:17174–17179.
A pivotal finding of the study is the unfavourable prognosis of PD-L1 positive mRCC.
7. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res 2007; 13:1757–1761.
8▪▪. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 2014; 20:5064–5074.
This is among the first articles exploring the relationship of PD-L1 topography in different tumour types. It provides relevant insights on how to define PD-L1 positivity and its colocalization to immune cells. It is a current milestone for all who are dealing with the issue of biomarker development of PD-L1.
9▪▪. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol 2015; 33:1430–1437.
It is a key for PD-1 inhibition in mRCC. It provides insights into the role of dose and tumour response to nivolumab in mRCC, while maintaining tolerability.
10. Topalian SL, Sznol M, Brahmer JR, et al. Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: survival and long-term safety in a phase I trial. J Clin Oncol 2013; 31: (suppl; abstr 3002).
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This is the reference trial for single-agent ipilimumab activity in mRCC.
15▪. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369:122–133.
This is the proof of concept for dual checkpoint inhibition and provides first clinical evidence for this approach.
16. Hammers H, Plimack ER, Infante JR, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol 32 2014; 5s: (suppl; abstr 4504).
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18. Motzer RJ, Escudier B, Tomszak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013; 14:552–562.
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21. McDermott DF, Sznol M, Sosman JA, et al. Immune correlates and long term follow up of a phase Ia study of mpdl3280a, an engineered pd-l1 antibody, in patients with metastatic renal cell carcinoma (MRCC). Ann Oncol 2014; 25: (suppl_4): iv280-iv304. 10.1093/annonc/mdu337.