Chemotherapy May Be Vital to Long-Term Immunotherapy Efficacy in Bladder Cancer

Parminder Singh, MD

In bladder cancer, combination strategies, particularly the combination of immunotherapy and chemotherapy, are under investigation. Chemotherapy, says Parminder Singh, MD, is going to make a comeback to improve treatment efficacy.

The development of immunotherapy made physicians optimistic about moving away from chemotherapy; however, approximately 1 in 7 patients derive benefit from PD-1/PD-L1 monotherapy. In other disease settings, such as lung cancer, the combination of immunotherapy and chemotherapy is showing a benefit in patients regardless of PD-L1 expression.

“Chemotherapy is going to make a comeback as a sensitizing agent for the immune system and consequent immune therapy. It seems counterintuitive because chemotherapy is considered immuno-suppressive, but it appears that chemotherapy can make the tumor environment ‘hot,’ so that it responds to and is controlled by immunotherapy stimulus” says Singh.

OncLive^®: What is the state of immunotherapy in bladder cancer?

KEYNOTE-045 showed that pembrolizumab (Keytruda) sustained its improvement in overall survival compared with chemotherapy. Is the future headed toward combination approaches or continued use of single-agent therapy?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Singh, hematologist/ oncologist, Mayo Clinic, discussed the potential of immunotherapy, the importance of sequencing to avoid disease progression, and the use of chemotherapy and radiation therapy to reach an unmet need in muscle-invasive disease.Singh: Immune therapy is efficacious for patients with bladder cancer, but there are potential toxicities and interactions with other medications to be aware of. We already have 5 FDA-approved agents based on immune checkpoint pathways. They all have activity as single agents, but we know the activity of these agents is limited to a small group of patients. We want to expand those results to other patients who progress.

What patient population sees the greatest benefit from immunotherapy?

The next step is looking at combinations of immune checkpoint inhibitors in combination with newer immune checkpoint inhibitors or with chemotherapy and/or radiation. Those clinical trials are in development and are soon opening.At this point, patient selection is based on the approval or labeling indications of the drug, where the patient lies in the spectrum of disease, and if they have any alternative options. Pembrolizumab and atezolizumab (Tecentriq) are both approved in first- and second-line treatment. Durvalumab (Imfinzi), nivolumab (Opdivo), and avelumab (Bavencio) are approved for cisplatin-ineligible patients who have progressed on platinum-based chemotherapy.

What needs to be done to increase immunotherapy response rates?

What is 1 unmet need you would like to see addressed?

Is the use of immunotherapy going to surpass the use of chemotherapy?

Can you speak to the importance of clinical trials for this field?

How can a physician frame a clinical trial to make it less intimidating for patients?

Chemotherapy responses are higher. There is a chance of achieving remission with cisplatin-based chemotherapy. Physicians don’t want to take away the patients’ options with newly diagnosed, metastatic disease if they are cisplatin ineligible. At the same time, once a patient progresses on cisplatin, the second-line options are limited, and responses are minimal with chemotherapy. That’s one setting in which we routinely use immunotherapy. Additionally, bladder cancer occurs in older patients and they may not be good candidates for platinum-based chemotherapy. In those situations, immunotherapy is a reasonable first-line option.Clinical trials are working to close the gap of response rates, which range from 1 in 6 to 1 in 7 patients. We are looking at combining 2 different immunotherapies or combining immune-based therapy with chemotherapy or radiation. The National Cancer Institute, in collaboration with multiple cooperative groups, is coming out with a phase III trial that is going to look at immune therapy in combination with radiation and chemotherapy. All of these trials will shed light on the activity of combining different modalities. The biggest needs are in 2 disease settings; one is in the Bacillus Calmette-Guerin—refractory, nonmuscle-invasive space where patients end up getting radical cystectomy for early-stage disease. In this setting, we don’t have good options for bladder salvage. The second setting is muscle-invasive disease in which patients want to preserve their bladder. We want to explore options where giving chemotherapy combined with radiation ends up preserving their bladder. Patients with advanced stage disease, though a limited number of patients, need new medications to control the disease after they progress on immune-based therapy. Immune therapy doesn’t work for everyone, but at the same time it provides an option that is well tolerated. Physicians should always keep chemotherapy in their back pocket to salvage patients who are progressing on frontline immunotherapy. There are many patients in my clinical practice who received frontline immunotherapy, progressed, and were later salvaged with chemotherapy.Physicians in the community should refer their patients for clinical trials at the centers where they’re available. Patients need to be referred to clinical trials for newer drugs and new combinations such as targeted agents for the FGFR3 gene, tyrosine kinase inhibitors, and combination strategies. Unless patients go on these clinical trials, we will not know if these therapeutic strategies will work better for patients with bladder cancer.It’s very important for the patient to understand that clinical trials are the only way we can get access to new drugs. Though a patient may feel that they’re going into an experiment where they may or may not receive the study medication, there are also early-phase trials, ones that are looking for safety and for signals of efficacy, in which all patients receive the study medication. If their conscience doesn’t allow them to go on a phase III randomized trial, early-phase trials are an option to get access to new agents that are not available on the market. These trials help foster physician understanding of new agents and bring them forward in the space.

It’s because of patients who had enrolled in previous clinical trials that we now have so many treatment options. A patient’s contribution is invaluable, and we need to understand and appreciate that, so they can continue to support our efforts.