PD-L1 inhibitor plus chemo improves PFS for metastatic urothelial Ca

August 19, 2019

Treatment combining the immunotherapy atezolizumab (Tecentriq) and platinum-based chemotherapy significantly improved progression-free survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma compared to chemotherapy alone.

Treatment combining the immunotherapy atezolizumab (Tecentriq) and platinum-based chemotherapy significantly improved progression-free survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma compared to chemotherapy alone.

Adding the monoclonal antibody atezolizumab, which binds with programmed death ligand 1 (PD-L1), also appears to improve overall survival in these patients but the data are not yet mature, according to an Aug. 5 Roche press release on atezolizumab’s phase III IMvigor130 study.

IMvigor130 is a multicenter trial of 1,213 patients with metastatic urothelial carcinoma who have not received prior systemic therapy who were randomized to receive atezolizumab plus gemcitabine with either cisplatin or carboplatin; atezolizumab alone; or platinum-based chemotherapy with gemcitabine and either cisplatin or carboplatin plus placebo, according to the release, which does not include specific trial results. Roche will be sharing those with the FDA and other global health authorities, according to the release.

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“The interim analysis is clearly exciting and the approach is valid. This opens up the opportunity for using immunotherapy in a broader group of patients-even those who can tolerate chemotherapy. And if this combination ultimately does turn out to be positive and yield a survival benefit, it could potentially become standard of care in these patients,” said Badrinath Konety, MD, MBA, of the University of Minnesota, Minneapolis.

Atezolizumab is approved in the U.S. alone or in combination with targeted therapies or chemotherapies for certain types of metastatic urothelial cancer, forms of non-small cell and small cell lung cancer, and in PD-L1 positive triple-negative breast cancer. In 2017, atezolizumab failed a phase III trial in advanced bladder cancer when results didn’t show it could prolong patients’ lives. This was after phase II data showed a durable response to the drug.

Dr. Konety, who is not an investigator with Roche, said the news dampened enthusiasm for atezolizumab and other PD-LI inhibitors for advanced bladder cancer at the time. But these new phase III data are again encouraging because they show a clear synergistic benefit of immunotherapy and chemotherapy over standard of care.

“Of course, this is still the interim analysis. We don’t have a final analysis yet,” Dr. Konety said.

Unfortunately, bladder cancer patients treated with platinum-based chemotherapy tend to progress. And once they progress, there are not many options for second-line therapy.

Patients who have metastatic urothelial cancer have a median survival between 13 to 18 months with the standard of care: cisplatin-based chemotherapy. Some bladder cancer patients can’t tolerate cisplatin, which is toxic to the kidneys. So, doctors oftentimes use the less powerful carboplatin to treat these patients.

Next: "Anything we can do to improve response rates and survival is going to be a significant advantage"“That’s where all these immunotherapy agents are being used-in patients who cannot tolerate cisplatin or in those who progress through standard chemotherapy. Overall, prospects are not great for this subset of patients. So, anything we can do to improve response rates and survival is going to be a significant advantage,” Dr. Konety said.

Atezolizumab is among several immunotherapy agents approved for advanced bladder cancer and being studied in various bladder cancer patient types.

“Researchers are working in this space-in advanced disease, in patients who have not had any other treatment. There are trials for patients who cannot tolerate standard chemotherapy and for patients who have failed prior chemotherapy,” Dr. Konety said. “Now, there also are trials starting in patients who have not had surgery. These are not patients with disease that has spread; these are patients with localized disease and the standard of care is neoadjuvant chemotherapy. The studies are exploring the combination of immunotherapy plus chemotherapy in the neoadjuvant setting.”

Urologists will be involved in the use of PD-1 and PD-LI immunotherapy medications in the context of neoadjuvant chemotherapy, before surgery, as well as for non-muscle invasive bladder cancer, particularly because bacillus Calmette-Guerin is in short supply, according to Dr. Konety.

Positive phase III data might signal a paradigm shift for management of non-muscle invasive bladder cancer, he said.

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These immunotherapy drugs tend to be generally well tolerated but are associated with increased inflammation resulting in self-limiting hepatitis, pneumonitis, etc., according to Dr. Konety.

“It’s important for urologists to get comfortable with understanding these drugs because we will be seeing these patients. Especially if patients are getting these drugs before cystectomy in the non-muscle invasive setting, we’re the ones who are going to be doing the cystoscopy and following these patients and monitoring the disease,” he said. “We need to understand how to recognize side effects and understand dosing schedules and things like that.”

Dr. Konety pointed out that while these medications are known to attack PD-1 or PD-L1 receptors, very few tumors express these receptors. It’s not yet clear why but many of these drugs show some response even in patients who don’t have the receptors, he said.

Dr. Konety is a clinical trial investigator for Merck and Bristol-Myers Squibb.