Check, Please! Checkpoint Inhibitors Show Promise in Bladder Cancer

Treated in a clinical trial for his bladder cancer, DAVE DIMICK had a complete response to the immunotherapy Imfinzi. PHOTO BY ADENA STEVENS

Treated in a clinical trial for his bladder cancer, DAVE DIMICK had a complete response to the immunotherapy Imfinzi. - PHOTO BY ADENA STEVENS

Four months after Dave Dimick entered a clinical trial for the immunotherapy drug Imfinzi (durvalumab) in 2015, his doctors told him he’d had a “complete response.” He figured it was good news from the smiles on their faces, but he was afraid to ask for more details, because ever since he had been diagnosed with stage 4 bladder cancer two years earlier, he had heard nothing but bad news. Prior to the trial, his cancer had spread to his lymph nodes, and two chemotherapy regimens had failed to keep the disease in check.

“I Googled ‘complete response’ and learned that it meant I was in remission,” Dimick recalls. He stayed on Imfinzi for a year, receiving the drug by infusion once every two weeks. His only side effect was joint pain, which was treated with anti-inflammatory agents. Although remissions are not always permanent, every imaging scan taken since Dimick stopped taking the drug has shown no trace of his cancer. “I’m one of the lucky ones,” says Dimick, 61, who lives in Hasbrouck Heights, New Jersey, and works in the fencing business. “I haven’t felt this good in four years.”

Imfinzi was approved by the Food and Drug Administration in May 2017 for patients with advanced or metastatic bladder cancer whose disease has progressed despite platinum-based chemotherapy. It’s one of five new drugs approved to treat bladder cancer since 2016 — all of which work by blocking “checkpoints,” such as the naturally occurring proteins PD-1 and PD-L1, that normally rein in the immune system and prevent it from recognizing and attacking cancer. Before 2016, there hadn’t been a new treatment approved for bladder cancer in 30 years.

Initially approved to treat some types of melanoma and lung cancer, checkpoint inhibitors look promising in a number of cancer types. The rapid expansion of the number of these drugs available to patients with metastatic bladder cancer has revolutionized the treatment of the disease, oncologists report. “Before, we could offer chemotherapy, which was hard for patients to tolerate, and for many, the cancer ultimately returned,” says Elizabeth Plimack, M.D., chief of the Division of Genitourinary Medical Oncology at Fox Chase Cancer Center in Philadelphia.

“Now, we have a wealth of immunotherapy treatments. When they work, the quality of the response can last for months or years.”

The other immunotherapy drugs approved over the past year and a half are Tecentriq (atezolizumab), Bavencio (avelumab), Keytruda (pembrolizumab) and Opdivo (nivolumab). All work by inhibiting PD-1 or PD-L1, and all are approved for the treatment of patients who previously received chemotherapy. Keytruda and Tecentriq are also approved for patients who are not eligible for chemotherapy.

CRAIG BROWN's bladder cancer has gone into remission on the immunotherapy Tecentriq, without side effects. PHOTO BY MIKE PETERS

CRAIG BROWN's bladder cancer has gone into remission on the immunotherapy Tecentriq, without side effects. — PHOTO BY MIKE PETERS

The side effects reported in the trials of these drugs included fatigue, nausea, itching, kidney injury and pneumonia, and a small percentage of patients developed immune disorders like thyroid disease, diabetes and hepatitis.Craig Brown is happy to report that he has not experienced any noticeable side effects while taking Tecentriq.

Diagnosed at age 61 with stage 4 bladder cancer that had spread to his ribs, Brown enrolled in a clinical trial of the drug after undergoing six months of chemotherapy. After three immunotherapy treatments, his bladder tumor disappeared, and he’s now in remission. He continues to get the drug every three weeks, along with scans every 12 weeks. He is among about one-quarter to one-third of eligible patients with cancer who respond to immunotherapy.

“There are no side effects at all,” says Brown, an accountant who lives in North Caldwell, New Jersey. “That makes it possible for me to do everything I always used to do,” such as boating and spending time with his family, he says. “I’m extremely grateful.”

In bladder cancer, Keytruda stands out among immunotherapies because it was the first of the new crop to be granted a full approval by the FDA, rather than an accelerated approval, says Dean Bajorin, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. Bajorin was one of the investigators in the large phase 3 studies that compared Keytruda with chemotherapy and led to the drug’s full approval. The other drugs were given the green light after smaller phase 2 studies, but will need to undergo larger, randomized trials in order to gain final full approval.

The results of the phase 3 Keytruda studies were impressive. In patients whose cancer had previously progressed despite chemotherapy, Keytruda reduced the risk of death by 27 percent. Survival at 18 months was 36 percent for patients receiving Keytruda versus 20 percent for those treated with additional chemotherapy; median overall survival for those patients was 10.3 months with Keytruda versus 7.4 months with chemotherapy. “That trial showed unequivocal superior response rates and tolerance of therapy,” Bajorin says. “In another trial, which enrolled patients who were not eligible for standard chemotherapy, Keytruda achieved an objective response rate of 29 percent. Those results are also encouraging.”

Although the other four approvals were granted based on similarly impressive results from small trials, recent data from a larger trial of Tecentriq have raised some questions about whether all five medicines will prove equally effective over the long run. In May, a phase 3 trial comparing Tecentriq with chemotherapy failed to show an improvement in overall survival. Analysis of the trial data is ongoing, with full data expected later this year.

CHOOSING THE BEST COURSE OF TREATMENT

Even though the menu of immunotherapy options for bladder cancer patients has expanded over the past year, oncologists still recommend chemotherapy as the firstline treatment for patients with metastatic disease who are otherwise healthy enough to tolerate it. In the meantime, studies are being conducted to determine whether immunotherapy should be used as a firstline treatment. For instance, a planned phase 2 study will consider pre-surgical treatment with durvalumab and tremelimumab for patients who aren’t eligible for cisplatin.

Standard treatment with chemotherapy involves choosing from among a few regimens, including cisplatin plus gemcitabine; cisplatin and gemcitabine plus paclitaxel; and MVAC (methotrexate, vinblastine, doxorubicin and cisplatin). In more recent years, a protocol called dose-dense MVAC has gained popularity, because it can be administered in two-week cycles versus three- or four-week cycles for classic chemotherapy treatments. A recent trial of 166 patients comparing dose-dense-MVAC with two older regimens found similar efficacy, but the rate of toxic side effects was 32 percent with the newer dosing schedule versus 55 percent for classic MVAC.

For patients with localized disease, surgery is also an option. Early-stage disease, or “non-muscle invasive” bladder cancer, can sometimes be treated by removing the tumor without needing to remove the bladder, but if the cancer has invaded the muscle, chemotherapy and removing the entire bladder and nearby lymph nodes may be required. A newer technique involves reconstructing the bladder with a “neobladder,” a piece of intestine that’s connected to the urethra, allowing for normal urination.

When surgery and chemotherapy aren’t effective enough, the cancer can spread to other parts of the body. This is when the new immunotherapy options come into play. Choosing the right drug, however, can be challenging. Measuring bladder tumors for high PD-L1 expression is a way of helping to predict the likelihood that a patient will respond to a PD-1 inhibitor, and there are diagnostic tests available to do just that.

But oncologists are divided on the question of whether tumoral PD-L1 levels should be measured in patients at all. In one early trial of Keytruda in bladder cancer, 38 percent of patients with high PD-L1 responded well to the drug. Similarly, the overall response rate in an early Imfinzi trial was 31 percent, while the response rate in patients with high PD-L1 levels was 46 percent.

The monkey wrench, Bajorin says, is that some patients in the trials had complete responses even though their tumors had no PD-L1 expression. PD-L1 testing, he says, “is not ready for prime time. We do not think it should be employed for clinical decision-making because of its inaccuracy in predicting clinical response.”

One big advantage of immuno-oncology treatments, oncologists agree, is that they don’t produce the harsh side effects that are common with chemotherapy drugs, such as vomiting and hair loss. For that reason, many patients are asking to skip chemotherapy as a firstline treatment altogether and go straight to one of the newly approved immune-boosting drugs.

That presents a challenge, because it was not clear whether there was a survival benefit with immuno-oncology drugs compared with chemotherapy in second-line treatment until the results of the Keytruda trial came in, says Joaquim Bellmunt, M.D., Ph.D., associate professor at Harvard Medical School and director of the bladder cancer center at Dana-Farber Cancer Institute. Some disappointment came when the Keytruda and Tecentriq trials arrived at opposite conclusions on survival.

“Why one trial is positive and the other is negative is a big question,” Bellmunt says. Ongoing analyses are trying to determine whether trial design and patient selection are the reasons behind this lack of benefit for Tecentriq in the phase 3 trial. Another possibility is that drugs that block PD-1 versus PD-L1 may have different levels of effectiveness.

EYEING COMBINATION STRATEGIES

That’s not the only area of research when it comes to the best use of the newer treatments for bladder cancer. Several trials are underway, not only comparing immuno-oncology treatments with chemotherapy for firstline treatment, but also testing whether giving the two treatments together might be more effective than either by itself. Combining Keytruda with chemotherapy is already approved for treating lung cancer, for example, and the drug is now being combined with gemcitabine and cisplatin in a trial of bladder cancer patients who have not undergone previous systemic chemotherapy.

A trial of Imfinzi combined with radiation therapy in bladder cancer patients is being planned, and a similar study will be conducted that combines Keytruda and radiotherapy. In addition, that and another upcoming trial are combining Imfinzi with tremelimumab, an experimental immunotherapy that blocks a different checkpoint called CTLA-4. This combination recently produced disappointing results in a lung cancer trial, failing to improve progression-free survival when compared with chemotherapy, but oncologists who treat patients with bladder cancer still hold out hope for such immuno-oncology cocktails. “We’re looking to improve outcomes by combining immunotherapeutic agents,” Bellmunt says.

One closely watched trial combines Keytruda with the targeted drug epacadostat, an experimental compound that blocks an enzyme called IDO1. The enzyme suppresses the immune system by blocking the activation of certain T cells, which in turn allows tumor growth. A small trial presented at a meeting in June showed that, in 40 patients, the Keytruda/epacadostat combination produced an objective response rate of 35 percent. The study is ongoing, and a phase 3 trial is also planned.

“There’s a keen interest in combining checkpoint inhibitors with something else to help the immune system work better,” Plimack says. Combination approaches could help two categories of patients: those who haven’t yet been treated with immunotherapy, and those who have but who have become resistant to it. Imfinzi is now being tested in combination with several different types of drugs, including Lynparza (olaparib), which inhibits a tumor-promoting enzyme called PARP, and AZD4547, an experimental compound that inhibits the activity of fibroblast growth factor receptor (FGFR) proteins that would otherwise help drive bladder cancer.

TARGETING THE FUTURE

Treatments that disable FGFR, PARP and IDO1 are examples of targeted drugs, an approach that continues to generate interest. These drugs tamp down the effects of damaging genetic mutations in tumors. FGFR3 mutations are a focus because they are found in 75 percent of early-stage bladder tumors and 20 percent of muscle-invasive cases. Among the FGFR3 inhibitors that have recently entered clinical trials are LY3076226 and B-701, the latter of which is being tested in combination with Keytruda.

An emerging target called nectin-4 is also being investigated. Nectin-4 is a protein that’s found in high concentrations in 65 percent of bladder tumors. The experimental agent enfortumab vedotin is an antibody connected to a toxic compound that seeks out nectin-4 and destroys tumor cells that contain the protein. In an early trial in 71 bladder cancer patients, the drug produced a 41 percent objective response rate, and three patients went into remission. A phase 2 trial started this year.

In addition, data presented in September demonstrated that adding the targeted drug Cyramza (ramucirumab) to the chemotherapy docetaxel in patients with previously treated metastatic bladder cancer delayed median time to disease progression by over a month.

Despite the promise of targeted treatments, however, many oncologists predict it is immunotherapy that will find an ever-expanding role in the treatment of bladder cancer. Trials are already underway to answer a pressing question: Could checkpoint inhibitors prevent early-stage bladder tumors from spreading?

“Normally, bladder cancer that’s limited to the surface of the bladder can be treated” with surgery or topical drugs, Plimack says. “But when persistent tumors keep coming back, those patients are at risk for having the cancer grow and spread. So, addressing the cancer early is attractive. We hope checkpoint inhibitors will allow these patients to remain cancer-free with their bladders intact.”

Michael Molnar’s disease is more advanced than that, and he is grateful to be benefiting from a combination of targeted and immunotherapy approaches.

A patient with bladder cancer from the Lehigh Valley, in Pennsylvania, Molnar was out of options when he entered the trial for Keytruda plus epacadostat in the fall of 2016. He had been diagnosed with bladder cancer in 2014 that was later found to have spread to his lymph nodes. After treatments administered within the bladder failed to eradicate the cancer, the decision was made to remove the bladder, and then Molnar underwent chemotherapy, which initially worked. But nine months after his treatment, the cancer returned.

Molnar receives Keytruda by infusion once every three weeks, and takes epacadostat in pill form twice a day. After just one treatment with the combination, Molnar’s tumors shrank by 50 percent. Two of the three tumors he started with have disappeared, and the third is tiny. Molnar expects to stay in the trial through at least 2018. The side effects of the two drugs are so minor, he says, “it’s like taking vitamins.” Molnar, 53, who works in the cable communications business, is able to walk and swim for exercise. “This has given me my life back,” he says.