Immunotherapy Just After Chemo May Allow Some Patients with Bladder Cancer to Maintain Health Benefits

When Christopher Schade noticed blood in his urine in 2010, he found himself at the beginning of a long and challenging road.

A urologist found a tumor in his bladder, and Schade, now 66, received a diagnosis of urothelial cancer, the most common form of bladder cancer. The doctor removed the tumor and inserted chemotherapy into Schade’s bladder in the recovery room.

During a follow-up CT scan a year later, doctors saw no problems with Schade’s bladder, but found enlarged lymph nodes in his abdomen and neck area that turned out to be cancerous, likely spread from the bladder cancer. This time, Schade was treated with systemic platinum-based chemotherapy.

A stiff neck sent Schade back to the doctor in 2015, and that, too, was diagnosed as a recurrence of cancer in his lymph nodes. Offered chemotherapy or a clinical trial with two immunotherapies, Schade recalled his treatment in 2011, which he described as “not a pleasant experience.” He was working in the garage door business then, and chemotherapy’s side effects, which included the loss of his hair and physical strength, interfered.

“I struggled to make it into work and function normally,” he says. So, in 2015, Schade chose the clinical trial, receiving a combination of Imfinzi (durvalumab) and tremelimumab for one year. Fortunately, the immunotherapy worked, shrinking his tumors, with side effects that included treatable pancreatitis and pneumonitis, both conditions caused by inflammation triggered by the immune-activating effect of the drugs.

Imfinzi is one of five immunotherapies approved by the Food and Drug Administration (FDA) for treatment in cases where bladder cancer progresses after chemotherapy. All the drugs are checkpoint inhibitors, meaning they interfere with the activity of proteins cancer uses to keep the immune system quiet so that it won’t attack. The treatment allows the body to more effectively recognize and fight the disease.

Similar to the others in its class, Imfinzi was approved in 2017 to treat patients with locally advanced (inoperable) or metastatic bladder cancer experiencing disease progression after responding to initial, or first-line, treatment with a platinum-based chemotherapy.
In addition, a couple of these drugs are available to patients with recurrent advanced or metastatic disease who cannot receive chemotherapy. But now, some patients have the opportunity to receive immunotherapy sooner, while they are still experiencing disease control from chemotherapy, as a means of prolonging their response.

Bavencio (avelumab), also approved in 2017 to treat disease progression or recurrence after chemotherapy, received the green light in June for use as a maintenance treatment, to be administered to patients with stable or improved disease immediately after first-line platinum-based chemotherapy for bladder cancer that, at initial diagnosis, was locally advanced or metastatic. This means that, after the completion of chemotherapy, eligible patients will no longer have to wait until their cancer returns to be considered for immunotherapy in order to lengthen or extend remission.

Metastatic bladder cancer is a challenging disease to treat, says Dr. Petros Grivas, a medical oncologist at UW Medicine in Seattle, an associate professor at the University of Washington and lead researcher of the JAVELIN Bladder 100 phase 3 trial that led to Bavencio’s approval by the FDA for this maintenance use. The prognosis for those whose disease is metastatic when first diagnosed is poor, and giving patients immunotherapy treatment earlier, when their cancer has responded to chemotherapy and not yet progressed, was shown to prolong overall survival, meaning the time from the start of treatment until death, and to delay disease progression.

Treating Metastatic Bladder Cancer

The most common first-line treatment for metastatic bladder cancer is chemotherapy that combines a platinum agent — cisplatin or, if the patient cannot tolerate it, carboplatin — with gemcitabine, a chemotherapy that doesn’t contain platinum, Grivas says. For many types of solid tumors, including bladder cancer, this type of treatment is given for a set number of cycles, typically four to six, rather than indefinitely, as the treatment doesn’t cure cancer that has spread to distant locations in the body and can cause side effects.

After receiving up to six cycles of treatment, a patient with metastatic bladder cancer continues to see the doctor for follow-up visits to monitor for cancer progression. “Unfortunately, the vast majority of patients will develop progression of their cancer, usually within a period of months,” says Dr. Matthew Galsky, a medical oncologist at the Icahn School of Medicine at Mount Sinai in New York City. “It was always sort of a strange approach to stop treatment in the context of a metastatic cancer,” he says, “but we didn’t have anything better that would offer a favorable risk-benefit profile. Giving a treatment holiday seemed to be the best approach.”

Now, patients who have stable or improved disease after completing chemotherapy can potentially receive Bavencio to maintain those health benefits.

The JAVELIN Bladder 100 trial data showed a significant overall survival benefit for patients who received Bavencio immediately following chemotherapy compared with those who did not. The median overall survival for those who received Bavencio plus best supportive care was 21.4 months, compared with 14.3 months for those in the group that received best supportive care alone. “The study showed a very significant difference in terms of overall survival, as well as progression-free survival,” meaning the time from the start of treatment until disease worsened, Grivas says. It is expected that the results will change the standard of care for this population of patients. “It’s really exciting news for patients and their families,” Grivas says.

Under previous treatment guidelines, about 25% to 55% of patients received another therapy if their disease progressed after initial chemotherapy. A patient might not receive treatment if their cancer was progressing too quickly or they were not fit enough for treatment, Grivas says. Making Bavencio available as a maintenance treatment will allow more patients to receive immunotherapy.

About 70% to 80% of patients finishing first-line chemotherapy have a disease that is stable or improved, he says, and the majority of them will be eligible to receive immunotherapy. Exceptions include those who have active autoimmune disease or immunosuppression.

Newer Strategies to Improve Treatment

The use of Bavencio as a maintenance treatment exemplifies an important strategy in improving care for metastatic bladder cancer: moving FDA-approved drugs to an earlier therapy phase so they can have a larger impact, Galsky says.

There are two other key approaches, he adds. One involves identifying combination regimens capable of overcoming resistance to immunotherapies given alone. The other is using biomarkers — genetic alterations specific to patients or their cancers — to better identify who should receive which treatment. Based on analyses of the number of mutations in a patient’s tumor and whether the mass expresses the immune-dampening protein PD-L1, “there is some resurgence of interest in trying to better identify subgroups of patients who might do quite well with (checkpoint inhibitors) alone,” Galsky says.

Not surprisingly, the five immunotherapies already approved to treat disease that flares up after chemotherapy are attractive candidates to move to an earlier treatment setting, Galsky says. In addition to JAVELIN Bladder 100, Galsky led a second trial testing that concept. The randomized phase 2 study compared the immunotherapy Keytruda (pembrolizumab) given as maintenance versus placebo after first-line chemotherapy. This strategy is called switch maintenance therapy because, when initial treatment ends, the patient is switched to a different treatment for maintenance therapy, as is done with Bavencio.

The trial met its main goal of showing better progression-free survival, as well as higher response rates, with Keytruda. While it did not show a significant overall survival benefit, which was a secondary goal, “that’s probably mostly related to the smaller sample size and the fact that the study was underpowered to show a survival improvement,” Galsky says. His study also allowed patients with cancer that progressed on the placebo to instead get Keytruda, known as “crossover,” which may have diminished the observable overall survival benefit.

In some cancer types, such as lung cancer, chemotherapy may work better in combination with immunotherapy than it does alone in some patients, Grivas says, but that hasn’t been the case with metastatic bladder cancer. In that disease, he says, chemotherapy can help shrink or control the tumor, potentially allowing the immunotherapy to work better afterward. “These are all theoretical concepts,” Grivas says. “I don’t think we have a good answer for why the back-to-back approach seems to work better, so far, compared to the combination approach.”

One clinical trial, IMvigor130, did test chemotherapy in combination with immunotherapy to treat bladder cancer. Patients received platinum-based chemotherapy with or without the immunotherapy Tecentriq (atezolizumab) as a first-line treatment.

The study showed prolonged progression-free survival but on interim analysis did not show a significant overall survival benefit, Grivas says. He is watching for longer-term follow-up results from this and several other trials testing chemotherapy/immunotherapy combinations, including CheckMate901, which is investigating the immunotherapies Opdivo (nivolumab) and Yervoy (ipilimumab) with or without chemotherapy.

Biomarkers To Guide Immunotherapy

The immunotherapies approved to treat metastatic bladder cancer that worsens or comes back after chemotherapy, including Bavencio, target the PD-L1 and PD-1 signaling pathways, chains of chemical reactions that send messages to cells from their environment that suppress the immune response to tumors. Targeting these pathways stops the proteins PD-L1 and PD-1 from binding together and may boost the body’s immune response against cancer cells.

About half the patients in the JAVELIN Bladder 100 trial had a high level of expression of PD-L1 in their tumor, and they experienced a greater degree of overall survival benefit. However, an overall survival benefit also was seen to a smaller degree that was not statistically significant in patients with PD-L1-negative tumors, Grivas says. Because of that, he says, every patient completing platinum-based chemotherapy who has stable or improved disease should be considered for Bavencio maintenance treatment, as long as they don’t have any uncommon contraindications.

Even though patients both with and without PD-L1 expression in their tumors should be offered Bavencio maintenance, “biomarkers are the holy grail,” Grivas says, and many studies are looking at gene alterations that might help define which patients are best suited for immune checkpoint inhibitor therapy. Across the five immunotherapies approved for metastatic bladder cancer, “most of the studies suggest that PD-L1 expression has some ability to enrich for responses, but that hasn’t necessarily informed practice in most clinical disease states of bladder cancer because of the lack of great alternative treatment options,” Galsky says.

That said, the JAVELIN Bladder 100 researchers are working to identify data on different biomarkers in the tumor tissues that were examined in their trial, and they hope to present that data soon.

Combining Biomarkers

Carefully selecting patients for a specific checkpoint inhibitor is important, as these drugs have side effects, including a high cost that might not be entirely covered by health insurance. “It is extremely important to develop clinically useful biomarkers to guide treatment decisions,” says Dr. Sangeeta Goswami, an assistant professor of genitourinary oncology at The University of Texas MD Anderson Cancer Center in Houston. Using initial biopsy samples to identify a tumor’s genetic and immune attributes can help determine if a patient is a good candidate for a specific treatment, she says.

The rates of overall response to immunotherapies for bladder cancer, meaning the proportion of tumors that shrink or stay stable when treated, range from 17% to 25%, Goswami says. “One of the major questions is why the majority of patients aren’t responding to single-agent immune checkpoint therapy,” she says. According to Goswami, it’s important to start looking at combinations of a tumor’s genetic and immunological attributes to help predict response.

Warren Buiekema, seen here at the Ishnala Supper Club in Wisconsin, had thyroid problems as a side effect of immunotherapy for bladder cancer.

One promising biomarker is mutational burden, or a tumor’s number of genetic mutations, which research shows is potentially associated with a higher response rate to immunotherapy. IMvigor130 has also shown that when patients have both high tumor mutational burden and high PD-L1 expression, they experience improved progression-free survival compared with patients who have only one of the biomarkers, or neither of them. A proportion of patients who participated in the IMvigor130 study had this combination and markedly better outcomes with checkpoint inhibitors alone versus chemotherapy, Galsky says.

Patients in the IMvigor130 trial received Tecentriq plus chemotherapy, Tecentriq alone or chemotherapy alone as a first-line treatment for metastatic bladder cancer. “A combination of those two biomarkers is emerging as a potentially powerful way to predict which patients would be best suited for immune checkpoint blockade, but further validation of that is required,” Galsky says.

To further parse which patients respond to immunotherapy for metastatic bladder cancer, Goswami and her colleagues used genetic sequencing data to find that patients who responded to treatment with checkpoint inhibitors in two previously conducted phase 2 trials were more likely to have the ARID1A gene mutation. This mutation is present in about 25% of patients with metastatic bladder cancer, 35% of those with endometrial cancer and 50% of those with ovarian cancer, she says.

Goswami also observed that patients whose tumors had a higher expression of CXCL13, a protein involved in antibody-producing B cell immune activation, experienced improved overall survival. She hypothesized that since both biomarkers are important on their own, combining them could increase their ability to predict better treatment response. Using data from the same two trials, CheckMate 275 and IMvigor 21, she found that patients with both mutations experienced improved overall survival compared with those who had either biomarker individually or the absence of both.

Given that a minority of patients respond to immunotherapy, targeting the right patient, when possible, is important. “Increasing the response rate will change the landscape of treatment for these patients,” Goswami says.

Immunotherapy Side Effects

While side effects occur with immunotherapy, they aren’t different in the maintenance setting compared with other settings. The Bavencio side effects in the JAVELIN Bladder 100 trial were similar to those already known to be associated with immunotherapy, Grivas says, and no new safety issues were found during the trial.

The most common serious side effects observed in the trial, which occurred more frequently in the group that took Bavencio, were urinary tract infection, anemia, the presence of blood in urine, fatigue and back pain. No severe side effects or deaths were reported. Diarrhea and rash are also fairly common side effects of checkpoint inhibitors.

“These are drugs that will be used when patients progress anyway,” Galsky notes, so individuals who take maintenance immunotherapy may simply experience side effects a few months earlier than they would have otherwise.

Warren Buikema, now 73, experienced some side effects after he received immunotherapy for progressive bladder cancer in 2018.

He initially received a diagnosis in 2016 after experiencing burning with urination. His first treatments consisted of surgery to remove the tumor and insertion of Bacillus Calmette-Guérin (BCG), a type of immunotherapy for earlier-stage cancer, into the bladder.

During a regular follow-up, the doctor found lesions in Buikema’s bladder that weren’t healing and eventually became cancerous. In 2018, Buikema entered a clinical trial, receiving a combination of chemotherapy and the immunotherapy Opdivo (nivolumab). To avoid further cancerous lesions, Buikema had his bladder surgically removed in 2019.

Likely as a result of the immunotherapy, Buikema was told, he experienced thyroid problems leading to the need for thyroid replacement medication. While the immunotherapy treatment left him feeling foggy and disconnected for a short time following its administration, he says, that side effect wasn’t bad.

Despite the possibility of side effects, Galsky believes that immunotherapy maintenance treatment in patients with advanced or metastatic bladder cancer is a true breakthrough and worth strong consideration by patients and their doctors.

“In general, the results seem favorable enough to change practice, in my opinion,” he says of Bavencio maintenance. “This is the largest degree of benefit in terms of overall survival that we’ve seen in a randomized phase 3 trial for metastatic urothelial cancer.” “This is a very exciting time in the bladder cancer area, because we’ve been doing chemotherapy for the last 30 to 40 years,” Goswami adds. “We now have so many options. We have to make it more personalized to see how we sequence therapy and how we know what biomarkers to use for treatment.”