Immunotherapy 'Altering the Landscape' for Bladder Cancer

Zosia Chustecka

October 08, 2016

COPENHAGEN — More evidence that immunotherapy with programmed cell death (PD) inhibitors is effective in bladder cancer was presented here today at the 2016 European Society for Medical Oncology (ESMO) Congress.

The results come from two new phase 2 trials. The CheckMate-275 study showed nivolumab (Opdivo, Bristol-Myers Squibb) was active in patients with metastatic bladder cancer who progressed despite first-line platinum-based chemotherapy, while the KEYNOTE-052 study showed pembrolizumab (Keytruda, Merck) was active as first-line therapy in cisplatin-ineligible patients with metastatic or locally advanced bladder cancer.

The companies are expected to use data from these trials to obtain approval for bladder cancer as a new indication for the agents, which are already approved for melanoma and lung cancer.

The first immunotherapy for bladder cancer, atezolizumab (Tecentriq, Genentech), was approved by the US Food and Drug Administration earlier this year. The decision was based on the IMvigor 210 trial for use in patients with locally advanced or metastatic disease that has progressed during or following platinum-containing chemotherapy or within 12 months of receiving neoadjuvant or adjuvant platinum-containing chemotherapy.

It seems that every company is conducting a phase 2 study with its own immunotherapy to get a bladder cancer indication, commented session cochair Bernard Escudier, MD, from the Institut Gustave Roussy, Villejuif, France, but "we need phase 3 trials," he told Medscape Medical News in an interview.

"Everything that we have seen in the past few years shows that immunotherapy is active in bladder cancer — probably more active than chemotherapy, at least overall," he said. All the evidence suggests that immunotherapy is important in bladder cancer, he added, "but it is still important to know which patients will benefit more from one than the other, because we have some patients who benefit a lot from chemotherapy."

In the first instance, he feels a randomized clinical trial of standard chemotherapy vs immunotherapy as first-line treatment in bladder cancer is needed — and is being planned. The next step would be to look at combinations of these therapies.

So far, the PD-L1 biomarker has not proven to be very useful in selecting patients who may respond to immunotherapy, he said, as patients who are PD-L1-negative sometimes respond. There is some suggestion that, for patients who are PD-L1-negative, it would be best to start with a combination of therapies, while in those who are PD-L1-positive, it may be reasonable to begin with immunotherapy as monotherapy, Dr Escudier commented. But he agreed with some of the other speakers that the question of which drugs to use is mainly a clinical decision. For example, in a patient with a high burden of disease, it is probably better to start with chemotherapy to try to shrink the tumor and then add immunotherapy. "This is what we do," Dr Escudier noted.

Immunotherapy Active as First-Line Therapy

KEYNOTE-025 with pembrolizumab was the first study of immunotherapy as first-line therapy. It was conducted in patients metastatic or locally advanced bladder cancer ineligible for cisplatin — which can be up to half of the patient population. And when cisplatin cannot be used, these patients have a median survival of just 9 to 10 months with alternative chemotherapies.

Arjun Balar, MD, assistant professor, NYU Langone Medical Centre, New York, presented a preliminary analysis of the first 100 patients enrolled in the trial at the congress.

The primary endpoint of objective response rate was 24%. Median duration of response has not yet been reached and treatment was well tolerated.

"Pembrolizumab has substantial activity with a favorable safety profile as first-line therapy in cisplatin-ineligible patients with metastatic bladder cancer," Dr Balar concluded.

The biomarker cutpoint to identify patients most likely to respond to the drug was determined to be 10% or greater total PD-L1 expression in immune or tumor cells. Thirty patients had this level of expression, of whom 11 (37%) responded to treatment.

Dr Balar commented that the biomarker cutpoint will need to be validated in the larger study population, but seems to identify patients most likely to respond to pembrolizumab. "Immunotherapy is rapidly redefining our treatment approach for patients facing this dreadful disease," he said.

Also Active as Second-Line Therapy

The nivolumab study was similar to the atezolizumab study in that both showed benefit from using immunotherapy as second-line in patients with metastatic bladder cancer who have progressed despite first-line platinum-based chemotherapy.

Of the 265 patients on nivolumab evaluable for efficacy, the primary endpoint of objective response rate was 19.6% for all patients (and 16.1% in patients with low to no PD-L1 expression). Median duration of response was not reached (median follow-up of 7 months), with responses ongoing in 76.9% of responders. Median progression-free survival was 2 months (confidence interval [CI]: 1.87 - 2.63), and median overall survival was 8.74 months (95% CI: 6.05 - not estimable).

In patients with tumors expressing higher or lower levels of PD-L1 (including those with < 1% PD-L1), the objective response rate was higher than that historically achieved with chemotherapy, reported Matthew Galsky, MD, professor of medicine, Mount Sinai School of Medicine, New York, New York.

Immunotherapy Altering the Landscape

Commenting on the current management of bladder cancer in an ESMO press release, Maria De Santis, MD, associate clinical professor for oncology, Cancer Research Centre, University of Warwick, UK, said: "There are insufficient treatment options for patients ineligible for cisplatin and those progressing on cisplatin-based chemotherapy."

She continued, "This year the first immune checkpoint inhibitor, atezolizumab, was approved for patients with bladder cancer, and CheckMate-275 provides similar results with nivolumab in the second-line setting."

The KEYNOTE-052 results with pembrolizumab "confirms that immunotherapy is also active as first-line therapy in cisplatin-ineligible patients, with a slightly lower response rate than chemotherapy," said Dr De Santis. "However, the duration of response with pembrolizumab seems to exceed that of chemotherapy in historical controls."

"Immune checkpoint inhibitors have started to alter the therapeutic landscape for bladder cancer," she commented. "We expect even more dramatic changes in the coming years with the use of immunotherapy in other clinical stages and as combination therapy."

The CHECKMATE-275 study (nivolumab) was funded by Bristol-Myers Squibb. The KEYNOTE-052 study (pembrolizumab) was funded by Merck. Dr Galsky reports ownership of Dual Therapeutics stock. He has consulted with Genentech, Merck, Novartis, Astellas; received research funding from Bristol-Myers Squibb, Dendreon, Janssen, Novartis, and Merck; and has intellectual properties with Mount Sinai School of Medicine. Dr Escudier has served as a speaker or member of a speakers bureau for Novartis, GlaxoSmithKline, Pfizer, and Bayer HealthCare Pharmaceuticals.

European Society for Medical Oncology (ESMO) Congress. Abstract LBA31_PR (nivolumab) and LBA32_PR (pembrolizumab). Presented October 8, 2016.

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