A Double Whammy to Treat Bladder Cancer

IMMUNOTHERAPY HAS RECENTLY ASSUMED an important role across a spectrum of cancer types, including genitourinary malignancies in general and, specifically, bladder cancer. Immune system boosters known as checkpoint inhibitors are emerging as a meaningful new treatment strategy, although chemotherapy remains a major player in the advanced-disease setting.

CHEMOTHERAPY

Guru P. Sonpavde, M.D., bladder cancer director at Dana- Farber Cancer Institute in Boston, offered an overview of the treatment landscape for urothelial carcinoma — the most common type of bladder cancer — during a presentation at the 2018 OncLive® State of the Science Summit™ on Genitourinary Cancers.

Platinum-based chemotherapy regimens improve survival for those with advanced urothelial carcinoma. In particular, it makes sense to give such chemotherapy before removing the bladder — known as radical cystectomy — in high-risk, locally advanced or muscleinvasive bladder carcinoma, Sonpavde said. In these disease stages, the cancer has spread outside the organ where it started, he explained. By shrinking the cancer, chemotherapy makes surgery less extensive and more likely to result in the removal of the whole tumor.

The phase 3 SWOG 8710 trial tested this idea. During a 12-week period, investigators gave a chemotherapy regimen of three cycles of presurgical methotrexate, Velban (vinblastine), doxorubicin and cisplatin (a drug containing platinum) to patients with muscle-invasive bladder cancer. Findings showed that the median overall survival with the combination was 77 months versus 46 months in the cystectomy-alone group.

It’s less clear whether platinum-based chemotherapy is effective if given after surgery. “How good is adjuvant (post-surgical) chemotherapy? Unfortunately, we do not have good adjuvant trials for bladder cancer postradical cystectomy. These patients are frequently not in good condition to receive adjuvant chemotherapy,” Sonpavde said.

Although there are no ongoing post-surgical trials, studies that look back at patient medical records and analyses of results from multiple completed studies support adjuvant chemotherapy. For example, the POUT study, a phase 3 randomized trial of adjuvant chemotherapy versus surveillance in upper tract urothelial cancer, was stopped early because it achieved a measure of success: The disease-free survival endpoint was met, with patients who took chemotherapy 1 ½ times more likely to remain free of disease than those in the surveillance group. At a two-year follow-up, 51 percent of patients under surveillance had achieved disease-free survival, compared with 70 percent in the chemotherapy group.

Not surprisingly, the biggest unmet need in the bladder cancer space involves the treatment of patients who are not eligible for platinum-based chemotherapies, Sonpavde said. People with these malignancies can develop renal insufficiency because of urinary obstruction, making them ineligible for platinum therapy or requiring significantly reduced doses. For these patients, who tend to have poorer survival outcomes than those who can take platinum, immunotherapy may be an option.

In addition, some patients are not able to undergo radical cystectomy, or they refuse it. Historically, these patients have had just the tumor surgically removed and were then offered radiation therapy, Sonpavde said. They might also receive chemotherapy along with radiation, such as a regimen of 5-fluorouracil plus mitomycin C in patients with locally advanced bladder cancer. However, little data exist on recurrence after this treatment, he noted. Radiation plus cisplatin has been offered to carefully selected patients, usually without the development of hydronephrosis — kidney swelling caused by the inability to drain urine — he said; survival of up to five years has been observed for those who don’t experience hydronephrosis.

Special, less-often-discussed therapy situations include recurrence after one year following platinum therapy given before or after surgery. Ordinarily, if recurrence happens when patients are more than one year out from pre- or postsurgical platinum therapy, platinum is given again. “Some retrospective data do suggest that, if you repeat platinumbased therapy in patients who are more than one year out from preoperative cisplatin chemotherapy, you might get similar outcomes compared with patients who got first-line chemotherapy with cisplatin who had not had previous preoperative cisplatin,” Sonpavde said.

IMMUNOTHERAPY

Patients less than one year out from preoperative platinum therapy receive a different second-line therapy. The taxane family of chemotherapy drugs has been used after cisplatin-based chemotherapy in patients in the United States, adding a median survival of seven to nine months, Sonpavde said.

Presently, immunotherapy’s role is to fill the gaps: It is used for those whose cancer has progressed despite chemotherapy or patients who can’t take platinumbased chemotherapy, the preferred choice for initial, or first-line, treatment.

“This is the era of immunotherapy,” Sonpavde said. “There is a lot of push and pull in the immune system, and there are (cell-signaling) pathways that are inhibiting the immune system (in patients with bladder cancer.)”

A sign that immunotherapy can reverse this problem: Urothelial carcinoma has a high frequency of random genetic mutations — the fourth highest of all cancers, behind melanoma, squamous cell carcinoma of the lung, and lung adenocarcinoma, Sonpavde noted. This is meaningful because immunotherapies known as checkpoint inhibitors tend to work best in cancers that express a plethora of mutations.

Two checkpoint inhibitors have been approved as first-line drugs for patients with advanced urothelial cancer, but those drugs and three others have revolutionized treatment even more in second-line therapy, given when a cancer has progressed after initial treatment, Sonpavde said.

Checkpoint inhibitors work by disabling proteins such as PD-1 and PD-L1, which keep the immune system in check so it doesn’t become overly aggressive. With those checkpoints out of commission, the immune system can work harder to recognize and fight cancer.

Sonpavde highlighted data from the phase 3 KEYNOTE- 045 study, which included patients with advanced urothelial cancer that had progressed or recurred after treatment with platinum-based chemotherapy. Updated findings in the second-line treatment of patients with bladder cancer were presented at the 2018 Genitourinary Cancers Symposium.

In initially published results, patients who took chemotherapy experienced a median overall survival rate of 7.4 months, whereas those who took the checkpoint inhibitor Keytruda (pembrolizumab) had an overall survival of 10.3 months. There was no difference in progression-free survival between the two groups.

Although Keytruda is not the sole approved PD-1 inhibitor in the post-platinum setting, it is the only one that improved overall survival in a phase 3 trial.

Which patients, among those deemed eligible, are most likely to benefit from the drug is still a partially unanswered question. More biomarkers are needed to identify those expected to respond, although doctors can rely on certain clues.

Most important, a cancer’s expression of PD-L1 can predict response to immunotherapy, and Sonpavde noted that the protein’s prevalence in a tumor is correlated with stage and grade — the higher the stage of disease, the higher the expression. If a patient’s muscle-invasive bladder cancer expresses a lot of the protein, it’s a good sign that immunotherapy will be effective. Alternatively, doctors know that if patients with non-muscle-invasive bladder cancer are receiving a different type of immunotherapy — bacillus Calmette- Guerin vaccine — PD-L1 expression is associated with poor outcomes.

But Keynote-045’s results made it obvious that PD-L1 is not the only marker for response to Keytruda, Sonpavde said. Even though high levels of PD-L1 in a cancer are associated with good response to immunotherapy, he said, “all subgroups seemed to benefit from pembrolizumab, regardless of PD-L1 expression.”

Are there any other known predictors of response? Sonpavde mentioned one: After treatment with Keytruda in muscle-invasive bladder cancer, an increased infiltration of cluster of differentiation (CD) 8-positive T cells can signal that a patient will respond well to the treatment.

Time until response does not take as long as some believe, according to Sonpavde. “There is a dogma out there that immunotherapy yields very delayed responses, but that was not the case” in Keynote-045, he said. “The median time to response was the same with chemotherapy and pembrolizumab, at about 2.1 months.” The duration of response with Keytruda in the trial was impressive, he added.

Currently, Imfinzi (durvalumab) and Opdivo (nivolumab) — both of which are approved in the secondline setting, in addition to Bavencio (avelumab) — and the combination of Opdivo and Yervoy (ipilimumab) are all being investigated in phase 3 trials for the first-line treatment of advanced urothelial carcinoma.

“Given the availability of first-line pembrolizumab and atezolizumab (Tecentriq) for cisplatin-ineligible patients, the selection of patients for these inhibitors versus carboplatin-based chemotherapy and the optimal sequencing of these strategies requires investigation,” Sonpavde concluded.

About four months after Sonpavde’s talk, more evidence emerged to guide first-line treatment with immunotherapy. In May, the Food and Drug Administration (FDA) instructed doctors not to give single-agent checkpoint inhibitors as initial treatments to patients whose urothelial carcinoma expresses little PD-L1 and who are eligible for platinum-based chemotherapy.

The FDA warning was based on an assessment of data from the phase 3 KEYNOTE-361 study and the phase 3 IMvigor130 study, which showed that patients in this population who took immunotherapy alone had decreased survival compared with those taking chemotherapy. The trials are exploring Keytruda and Tecentriq, respectively, with or without chemotherapy compared with chemotherapy or immunotherapy alone.

“This is not surprising, as chemotherapy is very active in this setting,” Andrea Apolo, M.D., chief of the bladder cancer section in the genitourinary malignancies branch at the National Cancer Institute, tweeted following the announcement.

Looking ahead and beyond immunotherapy, the pipeline is filling rapidly with emerging agents in a variety of drug classes, such as enfortumab vedotin, FGFR3 inhibitors, neoantigen peptide vaccines, pan-HER inhibitors and mTOR inhibitors.