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Emerging Salvage Therapy
After Progression on Immune Checkpoint Inhibitors, What Is Next?

Released: June 20, 2018

Expiration: June 19, 2019

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More than one half of all patients with advanced urothelial cancer are considered platinum ineligible. In the past, these patients may have received palliative chemotherapy or may have gone directly to hospice if they could not tolerate chemotherapy. Today, FDA-approved immune checkpoint inhibitors (ICIs) pembrolizumab and atezolizumab are options for platinum-ineligible patients with urothelial cancer. It is important for clinicians to recognize that there are now first-line alternatives to chemotherapy for patients with metastatic disease or poor performance status or who otherwise may not have been able to receive treatment in the past.

Although gemcitabine and carboplatin have often been used as primary therapy for cisplatin-ineligible patients with bladder cancer, the median OS is only approximately 9 months with this combination, and few CRs are seen. In our clinic today, we generally use pembrolizumab or atezolizumab for first-line treatment of bladder cancer in nearly all patients who are ineligible for cisplatin-based therapy, except for those with previous history of autoimmune disease. I prefer ICIs to gemcitabine/carboplatin in this setting based on better efficacy and tolerability and because not all of these patients can tolerate alternative chemotherapy regimens that do not include cisplatin. In fact, there are now studies showing that even some patients with autoimmune disorders can be safely treated with ICIs. I usually reserve chemotherapy or clinical trial enrollment as second line options for cisplatin-ineligible patients.

When Should You Switch From Immunotherapy to Chemotherapy?
For patients who receive an ICI as first-line therapy, the question then becomes what to do at progression. In some tumor types, immunotherapy can be continued beyond progression instead of switching to second-line chemotherapy. In bladder cancer, it is important to determine whether a patient who is progressing is symptomatic or not. In the past, with few options for second line therapy, we treated with immunotherapy past progression and saw some secondary responses. However, now that additional options are available in clinical trials, it is important to determine whether a patient truly is progressing, is symptomatic, and consequently needs a new therapy; if so, they may be eligible for ongoing clinical trials for new salvage treatments. On the other hand, if they have pseudoprogression with little or no symptoms of disease, this likely indicates an immune response to immunotherapies.

Approaches for Emerging Salvage Therapy 
There are 2 main types of therapy options currently being investigated in clinical trials for salvage therapies for bladder cancer. One type involves building on cytotoxic agents. The ongoing phase III RANGE study is a randomized trial of second-line ramucirumab (a VEGFR2 antibody) plus docetaxel vs docetaxel plus placebo in patients with urothelial carcinoma who failed platinum chemotherapy. Approximately 10% of the patients in this study were treated with previous checkpoint inhibition therapy. Initial results showed that investigator-assessed PFS was significantly longer with ramucirumab plus docetaxel compared with docetaxel alone: 4.07 months vs 2.76 months, respectively (HR: 0.76; P = .0118). OS results are not yet mature, and additional results from the RANGE study should be available in 2019.

The other type of therapy being studied in advanced bladder cancer is antibody–drug conjugates (ADCs). One example of an ADC is enfortumab vedotin, a monoclonal antibody that targets nectin-4, which is linked to the cytotoxic agent monomethyl auristatin E. Interim results from the EV-101 trial after chemotherapy and a phase I trial after immune checkpoint inhibition resulted in breakthrough therapy designation by the FDA in March 2018 for the treatment of patients with locally advanced or metastatic urothelial cancer who have progressed after ICIs. The pivotal phase II EV-201 trial with enfortumab vedotin is ongoing and enrolling patients with advanced bladder cancer who have received immune checkpoint inhibition. Other ADCs being evaluated as second-line therapy include sacituzumab govitecan (IMMU 132), which consists of the cytotoxic agent SN-38 fused to a Trop-2 receptor antibody. Unfortunately, because of the widespread expression of Trop-2, there is concern that there could be significant toxicity associated with this ADC.

A Tool to Help Guide Treatment Decisions for Bladder Cancer
To see how 5 experts are using ICIs for patients with bladder cancer, please refer to CCO’s Interactive Treatment Decision Tool. This tool can help you select individualized treatment options based on your patient’s specific disease characteristics and overall fitness by offering recommendations from 5 expert faculty for the specific case scenarios you provide. Use this tool, along with several other online CCO activities and commentaries, to optimize the care of your patients with bladder cancer.

How will you start using these new approaches to treat your patients with advanced and metastatic bladder cancer? Share your thoughts in the comment box below.

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In your current practice, what are you most often recommending for your patients with bladder cancer who progress after/on ICIs?
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