Renal cell carcinoma represents a significant cancer burden worldwide, with nearly 340,000 new cases diagnosed annually.¹ Many patients are incurable at diagnosis with approximately 30% presenting with metastatic disease² and up to 40% subsequently developing metastatic disease following initial treatment for localised disease.³ Several histological subtypes have been described – these include clear cell carcinoma (approximately 70-80% of cases), papillary carcinoma (10-15%) and chromophobe carcinoma (3-5%).

Targeted therapies 

Traditionally, cytokine-based immunotherapy was the main stay of treatment in metastatic renal cell carcinoma (mRCC) because cytotoxic chemotherapies are generally ineffective in this cancer type. These include interferon-alpha (IFNα) and interleukin-2 (IL-2).⁴ Significant toxicities related to these agents coupled with their modest response rates limited their use in clinical practice.

Over the past decade, significant progress has been made in terms of understanding the molecular biology of renal cell carcinoma, especially within the clear cell subtype. This led to development of several novel targeted therapies targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways. These treatment modalities demonstrated improvements in both progression-free survival (PFS) and objective response rates (ORR) in patients with mRCC compared to cytokines.^5,6

Although their introduction represented a major breakthrough in the treatment of mRCC, the majority of patients treated with these agents have limited survival and hence development of agents that can induce long-lasting responses associated with improvements in overall survival and less toxicity is overdue.

The advent of immunotherapy

The use of immunotherapy has gained popularity in the field of oncology over the past several years as understanding of the mechanisms relating to T cell-antigen recognition and function evolve. Novel immunotherapeutic agents have been developed, and the most advanced of these are the immune checkpoint inhibitors. 

Given that cytokine-based immunotherapy previously demonstrated activity in mRCC, there has been much interest in use of new generation immunotherapies in this setting. There are several ongoing clinical trials comparing the standard of care, VEGF-targeted therapies to novel immunotherapies.

Checkpoint inhibitors

Immune checkpoint receptors limit the proliferation and activity of T-cells and other immune cells through signalling pathways. In recent years, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 (PD-1) have been two inhibitory checkpoint receptors that have been extensively studied in the context of cancer biology and immunotherapy. 

When bound to their ligands, CTLA-4 and PD-1 dampen immune responses and hence ability to clear tumour cells. PD-1 has two known ligands, namely PD-L1 and PD-L2. PD-L1 is expressed on antigen presenting cells (APCs) and tumour cells. It is responsible for the immunosuppressive effects of PD-1. PD-L2 also inhibits T-cell activation but to a lesser extent. Studies have shown that blockage of checkpoint inhibitors strengthens the T-cell response and this can lead to enhanced anti-tumour activity.⁷

Anti PDL-1 antibodies

Nivolumab

Nivolumab is a humanised monoclonal IgG4 antibody specific for PD-1. It is the first checkpoint inhibitor to show a survival benefit in patients with mRCC. Following favourable results from early clinical trials, a phase 2 trial of nivolumab in mRCC was initiated in 2011. In this study, patients with mRCC previously treated with agents targeting VEGF pathway were randomly assigned (ratio of 1:1:1) to nivolumab 0.3, 2, or 10mg/kg intravenously every three weeks until disease progression or unacceptable toxicity. 

A total of 168 patients were enrolled in the study and the primary objective was to evaluate dose-response relationship measured by PFS. The median PFS was 2.7, 4.0, and 4.2 months respectively according to above doses and respective ORRs were 20%, 22% and 20%. Median overall survival (OS) was 18.2, 25.5 and 24.7 months respectively.⁸ The most common adverse effect was fatigue. This study demonstrated that nivolumab has anti-tumour activity in mRCC with favourable response rates and a manageable safety profile. 

Checkmate 025, a phase 3 randomised study comparing nivolumab with everolimus (mTOR inhibitor) in patients with mRCC who had received previous treatment followed the above-described study. A total of 821 patients with advanced clear cell renal cell carcinoma who had received one or two regimes of antiangiogenic therapy were randomised (1:1 ratio) to receive 3mg/kg nivolumab intravenously every two weeks or everolimus 10mg orally once daily until disease progression or unacceptable toxicity. 

The primary endpoint was OS and secondary endpoints were ORR and safety. The median OS was 25.0 with nivolumab versus 19.6 months with everolimus. Nivolumab demonstrated better ORRs of 25% compared to 5% with everolimus.⁹

Similarly to the study described above, the most common adverse event was fatigue in the nivolumab arm while anaemia was common in the everolimus arm. This study was stopped following a pre-specified interim analysis that determined that the primary endpoint had been reached. 

From this study, it was concluded that previously treated patients with mRCC had improved OS and tolerable adverse events when treated with nivolumab compared to everolimus. Following publication of these results, the US Food and Drug Administration Agency (FDA) approved the use of nivolumab for patients who were previously treated with anti-angiogenic therapy.

Anti PD-L1 antibodies

Atezolizumab

Atezolizumab is a humanised monoclonal antibody containing an engineered Fc-domain that targets PD-L1, one of the PD-1 ligands. Its role is currently being investigated in patients with several malignancies including mRCC. In a phase 1 study, 70 patients with mRCC – either clear cell RCC (90%) or non-clear cell RCC (10%) – were treated with atezolizumab every three weeks for up to one year. The purpose of this study was to determine safety and clinical activity of atezolizumab in mRCC. 

Dose escalation was performed up to 1,200mg. The majority of patients in the study had received prior treatment, including 57% who had received two or more lines of treatment. The ORR for patients with clear cell RCC was 15%, and median PFS was 5.6 months.¹⁰ The toxicity profile of this agent was similar to that previously reported with the PD-1 inhibitors with no major adverse events reported.

Anti CTLA 4 antibodies

Ipilimumab

Ipilimumab is a monoclonal antibody against CTLA-4 and was the first checkpoint inhibitor to be studied extensively in clinical trials. Ipilimumab was evaluated in the treatment of advanced renal cell carcinoma during its early clinical development. A phase 2 trial that enrolled 61 patients treated in two dosing cohorts (high or low) for up to one year showed that it was associated with significant toxicity among patients who showed some responses.¹¹

Due to a better adverse-event profile together with improved efficacy of the PD-1 inhibitors, the use of ipilimumab as monotherapy in RCC has not been developed further and instead its role in combination with other checkpoint inhibitors is being evaluated

Combination therapies

Given the dynamic nature of the immune response and the need to improve on outcomes observed with single agent immunotherapies, there is a rationale to support the use of combination immunotherapy strategies to maximise clinical benefit. This was clearly demonstrated in the Checkmate 067 in metastatic malignant melanoma, which compared nivolumab and ipilimumab with ipilimumab alone or nivolumab alone, and showed an unprecedented 58% response rate for the combination.¹²

Combining immunotherapies is a novel approach in renal cell carcinoma and is the subject of a number of ongoing clinical trials. Checkmate 016 is a large phase 1 study that evaluated the use of nivolumab with ipilimumab at differing doses in patients with mRCC (nivolumab 3mg/kg + ipilimumab 1mg/kg every three weeks x 4 versus nivolumab 1mg/kg + ipilimumab 3mg/kg every three weeks x 4 followed by continuous nivolumab 3mg/kg every two weeks.¹³ Analysis of an expansion cohort of the ipilimumab 1mg/kg plus nivolumab 3mg/kg and ipilimumab 3mg/kg plus nivolumab 1mg/kg arms (47 patients in each group) showed ORRs of 38% and 43%, respectively. 

In addition to testing ipilimumab plus nivolumab, Checkmate 016 also investigated nivolumab at 2mg/kg or 5mg/kg every 21 days in combination with either pazopanib or sunitinib (VEGF inhibitors) at standard doses. The combination was active but with increasing toxicity as treatment-related grade 3 and grade 4 adverse events were observed in over 70% of patients enrolled in the study. The ORR for sunitinib was 52% versus 45% in the pazopanib arm suggesting that this combination warrants further investigation. 

This led to the development of Checkmate 214, a multinational, phase 3 trial comparing combination ipilimumab and nivolumab with sunitinib as first-line treatment for metastatic RCC with doses ipilimumab at 1mg/kg and nivolumab 3mg/kg every three weeks for four treatments, followed by maintenance nivolumab 3mg/kg every two weeks. The primary endpoint for this trial is overall survival and results are awaited.¹⁴

Atezolizumab was evaluated in combination with bevacizumab, a VEGF monoclonal antibody in a phase 1b study (atezolizumab 20mg/kg and bevacizumab 15mg/kg every three weeks), which included 13 patients with RCC in the first-line setting. Treatment was well tolerated and the ORR was 40%, including one complete remission.¹⁵ A phase 2 randomised trial of atezolizumab plus bevacizumab versus atezolizumab versus sunitinib has completed enrolment, and a phase 3 trial of the combination versus sunitinib is currently accruing patients. The primary end point is PFS.^16,17

Pembrolizumab has been tested in a combination with axitinib in an ongoing phase 1b study.¹⁸ The maximum tolerated dose was determined to be axitinib 5mg twice daily and pembrolizumab 2mg/kg every three weeks. 

Objective responses were seen in 55% of patients. In addition, the combination of pembrolizumab and pazopanib is being investigated in an ongoing phase 1/2 study, of note the combination has been reported to cause significant hepatotoxicity, with 65% of patients developing grade 3 or higher liver dysfunction. At the time of presentation of preliminary data in 2015, an ORR of 40% was reported.¹⁹

Conclusion

Incorporation of immunotherapy into the management of mRCC is an exciting and encouraging prospect. The emergence of new immunotherapeutic options will add value in the management of this challenging malignancy. However, more research is needed in order to fully understand their optimal place in the current sequence of therapies for mRCC so that we can make further progress in improving outcomes for our patients with mRCC. 

With future emerging data from ongoing clinical trials, it is hoped that we will soon have answers on how best to integrate these therapies into current treatment paradigms for mRCC, which patients are most likely to benefit as well as the role of combination treatment strategies, particularly in the first-line setting.

References

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