Immunotherapy for GU Ca: A primer for urologists

April 18, 2017

This article discusses the current status and potential future developments in immunotherapy for genitourinary malignancies with insights from urologic oncology specialists Hyung L. Kim, MD, and Daniel P. Petrylak, MD.

Immunotherapy for genitourinary malignancies is not new, as high-dose interleukin-2 (IL-2 [Proleukin]) for metastatic renal cell carcinoma (mRCC) and intravesical bacillus Calmette-Guérin for high-grade bladder cancer have been used since the 1990s. However, the modern era of immunotherapy for bladder, renal, and prostate cancer began in 2010 with the approval of sipuleucel-T (Provenge), the autologous, dendritic cell-based vaccine for treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), and it is a rapidly evolving landscape.

Since then, multiple checkpoint inhibitors (CPIs) have been approved for mRCC and metastatic urothelial carcinoma (UC), and numerous trials of immunotherapy for prostate cancer, UC, and RCC are ongoing.

This article discusses the current status and potential future developments in immunotherapy for genitourinary malignancies with insights from urologic oncology specialists Hyung L. Kim, MD, and Daniel P. Petrylak, MD.

Mechanism of action

Sipuleucel-T, which is the first therapeutic cancer vaccine approved by the FDA, stimulates an anti-tumor T-cell response using the patient’s own antigen-presenting cells that are removed, activated, and educated against tumor antigen ex vivo, and then reinfused.

Rather than inducing an immune response, CPIs release inhibitory mechanisms and restore the body’s natural T-cell-mediated antitumor response. The T-cell-mediated immune response is regulated by a system involving stimulatory and inhibitory molecules. The inhibitory molecules, which are known as immune checkpoints, regulate activation of cytotoxic lymphocytes and their effector function to maintain self-tolerance and minimize damage to normal collateral tissue during an immune response. The development of CPI immunotherapy for cancer was initiated by the finding that some tumors highly express immune checkpoint molecules.

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The two CPIs currently approved for treatment of genitourinary cancers, nivolumab (Opdivo) and atezolizumab (Tecentriq), are monoclonal antibodies targeting the programmed death receptor-1 (PD-1) protein that is expressed on T cells or its ligand, programmed death-ligand 1 (PD-L1). Nivolumab, which targets PD-1, was approved in 2015 for patients with mRCC who progressed on prior anti-angiogenic therapy with an anti-VEGFR TKI agent. In February 2017, nivolumab received FDA approval for use as second-line therapy for patients with locally advanced or metastatic UC.

Atezolizumab is an anti-PD-L1 antibody that was approved in 2016 for use as second-line therapy in patients with locally advanced or metastatic UC. A February 2017 article published online in the New England Journal of Medicine reported positive results from the randomized, phase III KEYNOTE-045 clinical trial that investigated the anti-PD-1 antibody pembrolizumab (Keytruda) as second-line therapy in patients with platinum-refractory advanced UC. Compared with the control, which was standard of care treatment using the investigator’s choice of chemotherapy, pembrolizumab significantly improved median overall survival and was associated with a lower rate of treatment-related adverse events. The objective response rate was also significantly higher with pembrolizumab and the responses were more durable.

Next: "CPIs have produced some very exciting results"

 

Dr. Kim“Compared with vaccines that work by pressing the accelerator on the immune system, the CPIs work by releasing the brakes on the immune system. CPIs have produced some very exciting results in terms of improving overall survival and producing durable responses in patients with advanced renal and bladder cancer,” said Dr. Kim, co-medical director of the Urologic Oncology Center, Cedars-Sinai, Los Angeles.

“Not only can the CPIs shrink the tumor, but it has been suggested that immunotherapy can alter the long-term growth kinetics. In other words, tumor growth may occur at a slower rate, and that too can translate into improved survival.”

Read: Bladder cancer test shows high sensitivity

Dr. Kim also pointed out some unique pharmacodynamics characteristics of the immunotherapies. For example, improved survival with sipuleucel-T is not accompanied by a PSA response, and early imaging in patients with UC or RCC treated with a CPI may show the tumor size is increased.

“However, the change may not be a sign of tumor progression. Instead, it may represent a pseudoresponse in which immune cells have infiltrated the tumor,” Dr. Kim explained.

In addition, whereas the effect of chemotherapy persists only as long as the drug is in the body, the anti-tumor effect of immunotherapy may continue after the treatment is stopped, mediated by the activity of memory T cells.

Safety

The modern immunotherapy agents have a different and better safety profile than that of chemotherapy and with IL-2.

Dr. Petrylak“Interleukin-2 has good clinical activity as treatment for mRCC in selected patients, particularly those with pulmonary metastases, but it can be fairly toxic with the potential to cause shock and hypotension,” said Dr. Petrylak, professor of medicine and urology, Yale School of Medicine, New Haven, CT.

Among the immunotherapy agents approved for genitourinary malignancies, sipuleucel-T is probably the best tolerated. Its most common adverse events are chills, fatigue, fever, back pain, nausea, joint ache, and headache.

The adverse events most commonly associated with CPIs arise from activation of the host immune system and include immune-mediated colitis, dermatitis, hepatotoxicity, hypophysitis, and hypothyroidism. With prompt recognition and timely management using immunosuppression and temporary dose modification or treatment interruption, the severity of these toxicities can be limited, and they are usually reversible.

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“It is important to monitor patients for the immune-related adverse events, but it is interesting that some studies of immunotherapy found that development of autoimmune toxicity corresponded with a better anti-tumor response,” Dr. Kim said.

Adverse events associated with the CPIs targeting the PD-1/PD-L1 axis appear to be less severe than those occurring with anti-CTLA-4 antibodies.

Next: Future directions

 

Future directions

Immunotherapy for the genitourinary cancers is a very active area of research. For prostate cancer, the investigational pipeline of immunotherapies includes other therapeutic vaccines, and CPIs are also being studied in clinical trials.

The relative lag in development of CPI treatment for prostate cancer may be explained in part by an early finding that PD-L1 was not highly expressed on CRPC specimens. Therefore, it was reasoned that antibodies targeting the PD-1/PD-L1 axis would not be effective, said Dr. Petrylak.

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In an early pilot study investigating nivolumab as treatment for mCRPC, there were no objective responses observed among the 17 enrolled patients who were all heavily pretreated.

The commercially available CTLA-4 antibody, ipilimumab (Yervoy), was also investigated as treatment for mCRPC in two phase III trials, one enrolling patients prior to docetaxel (Taxotere) and the other after docetaxel failure, but no survival benefit was seen. In a post hoc analysis in the post-docetaxel chemotherapy trial, however, improved survival was seen with ipilimumab versus placebo in men who had boney, non-visceral metastases.

Benefit was also observed in men with enzalutamide (XTANDI)-resistant mCRPC in a study investigating pembrolizumab, which is an anti-PD-1 antibody like nivolumab. Upregulation of PD-L1 expression by enzalutamide is one possible explanation for the antitumor activity that was observed with pembrolizumab, Dr. Petrylak said.

Ongoing trials for mCRPC are investigating CPIs as single agents and in combination with available treatments (eg, radium 223 [Xofigo] or enzalutamide). There are also trials evaluating sipuleucel-T combined with approved drugs (eg, abiraterone acetate [Zytiga], enzalutamide, radium 223) or with a CPI.

Similarly, studies are evaluating a CPI combined with agents from another therapeutic class (eg, chemotherapy, investigational molecules targeting pathways regulating immunotherapy resistance, targeted small molecules) as treatment for UC and RCC.

“Studies of combination approaches using immunotherapy for UC and RCC include those exploring what appears to be an interesting interplay between angiogenesis and immunotherapy,” Dr. Petrylak said.

Combinations of CPIs that target different checkpoint axes are also being investigated for mRCC and prostate cancer.

“The combination of ipilimumab and nivolumab is already approved for the treatment of metastatic melanoma,” Dr. Kim said.

Read: Role of molecular biomarkers in localized prostate cancer

CPIs targeting novel checkpoints, such as lymphocyte activation gene-3, are also in clinical trials for UC and RCC.

In addition, ongoing research with the available immunotherapies for genitourinary malignancies is examining genomic and other potential predictors for response.

Next: Sequencing and earlier use

 

Sequencing and earlier use

Other studies are investigating optimal sequencing of immunotherapy and other treatments.

The question of the preferred sequence of agents for treatment of patients with minimally or asymptomatic mCRPC was addressed by a consensus panel of members of the Society for Immunotherapy of Cancer, of which Dr. Petrylak was a member. Based on a review of the available evidence, nearly all (90%) of the panel members recommended using sipuleucel-T before an androgen receptor-targeted agent. They were unanimous in recommending the of sipuleucel-T or an androgen receptor-targeted agent prior to radium and chemotherapy.

A role for immunotherapy earlier in the disease course is also an area of research interest.

“As second-line treatment for bladder cancer, immunotherapy has survival benefits compared with chemotherapy. Now, ongoing trials are comparing these two categories as front-line therapy,” said Dr. Petrylak.

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There is good rationale for investigating earlier use of immunotherapy, as available evidence shows that it tends to be more effective when the tumor burden is lower. This phenomenon may be explained by the fact that the tumor itself causes immune suppression, Dr. Kim said.

“We have entered into an exciting time when there is a whole new class of therapies available for patients who develop metastatic disease,” he said. “The next step will be testing them as neoadjuvant and adjuvant therapies for patients with high-risk localized disease, and the studies of neoadjuvant treatment will need to determine whether preoperative use of immunotherapy creates any safety issues for subsequent surgery.”

Dr. Kim noted that while immunotherapy for genitourinary cancers is currently in the realm of medical oncologists, urologists should be familiar with these agents and stay tuned for results from clinical trials investigating them as earlier intervention.

 

Disclosures: Dr. Kim holds a patent on a novel approach for checkpoint inhibition. Dr. Petrylak has received consultant fees from Bayer, Bellicum, Dendreon, Sanofi, Johnson & Johnson, Exelixis, Ferring, Millenium, Medivation, Pfizer, and Roche Laboratories. He has received grant support from Oncogenix, Progenics, Johnson & Johnson, Merck, Millineum, Dendreon, Sanofi, Agensys, Eli Lilly, and Roche Laboratories, and has an ownership interest/investment in Bellicum and Tyme Technologies.

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