Urological Cancer Treatment Landscape to be Transformed by the Approval of Immune Checkpoint Inhibitors
Written By Adam Bradbury, Associate Analyst for GBI Research
Urological cancers afflict the male and female urinary tract and the male reproductive organs, and include malignancies such as bladder, kidney and prostate cancer. These indications can reduce quality of life by causing urinary incontinence, erectile dysfunction and hematuria, as well as resulting in considerable mortality.
Prostate cancer has a high five-year survival rate of 99%, but kidney and bladder cancer have lower rates of 74% and 77% respectively. Survival rates depend on several factors, including the stage of the cancer when it is first diagnosed – metastatic kidney and bladder cancer can have five-year survival rates as low as 8% and 10% respectively. There is therefore a greater unmet need in bladder and kidney cancer than in prostate cancer.
The prevalence of urological cancers is anticipated to rise in developed countries, due to populations becoming increasingly elderly and obese, which are risk factors for these cancers. Prostate cancer has by far the highest prevalence of any urological cancer, followed by bladder cancer, which has a slightly higher prevalence than kidney cancer.
Urological cancers share many common pathophysiological components, key proteins and frequent genetic mutations, within the processes of tumor initiation, invasion, angiogenesis and metastasis (Nishida et al., 2006; Wittekind and Neid, 2005). They also share common aberrant pathways, such as the PI3K/Akt/mTOR pathway.
Co-option of the immune system through immune checkpoints is another area of overlap between urological cancers, and has been targeted in the treatment of these indications in recent years. Immune checkpoints refer to many inhibitory pathways within the immune system that are crucial for maintaining self-tolerance and modulating the duration and strength of physiological immune responses (Pardoll, 2012). Tumors co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells. Clinical studies have demonstrated that PD-1- and CTLA-4-targeting immune checkpoint inhibitors have shown anti-tumor activity in bladder, kidney and prostate cancer.
The treatment landscape for oncology has traditionally been dominated by small molecule chemotherapies that act on non-specific targets, and therefore affect both malignant and healthy cells. However, in recent years there has been a strong trend of focusing on targeted biologic therapies that act on molecular components of the underlying disease pathophysiology, with the hope that they will offer less toxic and more efficacious treatments. Although this trend is observed across many therapy areas, it has been most prominent within oncology. As with oncology as a whole, urological cancer treatments have many unmet needs in terms of both safety and efficacy, which could be met by the approval of targeted therapies.
Immune checkpoint inhibitors are targeted drugs that prevent cancer cells from turning off T cells by blocking ligand–receptor interactions that initiate immune checkpoints. This allows T cells to infiltrate a tumor and stop it from growing through immune-system-mediated destruction (West, 2015). Marketed immune checkpoint inhibitors include mAbs such as Opdivo (nivolumab) and Keytruda (pembrolizumab), which target PD-L1, and Yervoy (ipilimumab), which targets CTLA-4. These drugs are currently only marketed for certain cancer types (including bladder cancer, melanoma, kidney cancer, lung cancer and Hodgkin’s lymphoma) but are being trialed across a range of other cancer indications. Tecentriq (atezolizumab) and Opdivo (nivolumab) are the two currently approved immune checkpoint inhibitors within uro-oncology, and are marketed for bladder and kidney cancer respectively.
Over the past five years immune checkpoint inhibitor trials have reported strong clinical data in many tumor types across oncology, including melanoma, kidney cancer, colorectal cancer, and non-small cell lung cancer. Promisingly for this class of treatment, radiation therapy has been shown in trials to sensitize tumors to immune checkpoint inhibitors. Radiation induces chemokines that attract effector T cells to the tumor, and vascular adhesion molecules that facilitate T-cell infiltration, in a process which has been named 'immunogenic modulation' (Esposito et al., 2015).
Until the 2016 approval of the PD-L1 inhibitor Tecentriq, small molecule chemotherapy agents, which inhibit DNA synthesis/repair or microtubule formation, were the only products used in bladder cancer’s limited treatment regimens. Tecentriq was specifically approved for the treatment of patients with a type of bladder cancer (urothelial carcinoma) that has progressed after platinum-based chemotherapy, although a recent Phase II study also found it effective in the first-line treatment setting (McKee, 2016).
Other immune checkpoint inhibitors such as durvalumab and avelumab are expected to gain approval for bladder cancer, and this treatment group’s uptake is predicted to be high due to the relatively high toxicity associated with chemotherapy agents and the typically poor performance status of many elderly patients, which necessitates the use of less-toxic targeted therapies.
In contrast, the treatment landscape for kidney cancer already contains many targeted therapies, including angiogenesis inhibitors such as Sutent (sunitinib malate) and Votrient (pazopanib hydrochloride), and cancer immunotherapies such as the immune checkpoint inhibitor Opdivo. Opdivo gained FDA approval in November 2015, for metastatic kidney cancer patients who have received a prior angiogenesis inhibitor therapy.
A significant survival advantage was found when Opdivo was compared to everolimus in metastatic renal cell carcinoma patients who had received prior anti-angiogenic therapy, and the effectiveness of single-agent Opdivo has been found to persist in the long term, with a third of the patients treated surviving for at least four years (Motzer et al., 2016).
The list of cancers that may be susceptible to the checkpoint inhibitor class of immunotherapy drugs is rapidly expanding. In recent years Opdivo has been approved for melanoma, Hodgkin’s lymphoma and squamous non-small cell lung cancer, and it is likely to be approved for further oncology indications during the forecast period. Increasing clinician familiarity will see Opdivo’s uptake and usage expand, translating into strong revenues.
There are several immune checkpoint inhibitors in the late-stage (Phase III or later) pipeline for urological cancers. Of these, durvalumab and avelumab are predicted to gain FDA approval in the next five years. No substantial checkpoint inhibitor approvals are expected for prostate cancer – the most prevalent urological cancer – during the forecast period.
Overall, despite only occupying a small fraction of the uro-oncology pipeline, immune checkpoint inhibitors are anticipated to transform both the kidney and bladder treatment landscapes, where there are, at present, only a limited set of treatment options. This in turn is anticipated to lead to this class of therapy occupying a growing share of both the market and the pipeline.
References
Esposito A, et al. (2015). Immune checkpoint inhibitors with radiotherapy and locoregional treatment: synergism and potential clinical implications. Current Opinions in Oncology; 27: 445–451.
McKee S (2016). Data backs first-line use of Roche’s Tecentriq. Pharma Times. Available from: http://www.pharmatimes.com/news/data_backs_first-line_use_of_roches_tecentriq_1034830 [Accessed October 7, 2016].
Motzer RJ, et al. (2016). CheckMate 025 phase III trial: Outcomes by key baseline factors and prior therapy for nivolumab (NIVO) versus everolimus (EVE) in advanced renal cell carcinoma (RCC). American Society of Clinical Oncology; 34: 498.
Nishida N, et al. (2006). Angiogenesis in Cancer. Vascular Health and Risk Management; 2: 213–219.
Pardoll DM (2012). The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer; 12: 252–264.
West H (2015). Immune checkpoint inhibitors. JAMA Oncology; 1: 115.
Wittekind C and Neid M (2005). Cancer invasion and metastasis. Oncology; 69: 14–16.