Concurrent Chemo, Immunotherapy Offers Viable Option in Metastatic Bladder Cancer

Administration of simultaneous chemotherapy and immunotherapy might be a safe, viable option for some patients with metastatic bladder cancer, according to recent research published in European Urology.

In particular, patients whose tumors have certain genetic mutations may respond especially well to this combination approach.

While chemotherapy and Yervoy (ipilimumab) are both common monotherapies for this patient population, it was unknown if they could be given together, given that chemotherapy's side effect of weakening the immune system might inhibit immunotherapy.

A phase 2 trial, conducted at six cancer centers, showed that not only can these drugs work together for improved outcomes, but they can do so without additional or worse side effects compared to when each agent given alone.

“We showed that chemotherapy did not deplete levels of immune cells in the blood … having obvious counterproductive effects with immunotherapy,” study author Matthew Galsky, M.D., professor of medicine at the Icahn School of Medicine at Mount Sinai and director of genitourinary medical oncology at the Tisch Cancer Institute, said in an interview with CURE.

“We also found that patients with tumors that had mutations in a group of genes involved in repairing DNA damage were most likely to respond to treatment.”

Patients with certain types of mutations in DNA damage response (DDR) genes tended to have better responses with the combination regimen. Additional larger studies are needed to validate these findings; however, if they have similar results, health care providers will have a novel biomarker for improved outcomes, thus moving them one step closer to enable precision medicine.

“The findings do not immediately alter the management of metastatic bladder (urothelial) cancer, but rather represent a potential conceptual advance,” Galsky said, noting that this study provides preliminary evidence to support the activity and safety of combination approaches. He added that this evidence suggests the two drugs work together, and provides background to investigate a biomarker that could help to identify patients who might have a higher chance of benefitting from the combination.

Galsky noted there are a few potential reasons why the duo worked: First, chemotherapy may kill cancer cells, which would lead to the release of antigen, which acts like an internal vaccination. “We did feel that giving chemotherapy might be required to exploit some of the beneficial effects of immune checkpoint blockade in non-melanoma cancers as chemotherapy might kill cancer cells in a way that makes cancers more visible to the immune system, sort of like an internal vaccine,” Galsky said.

Next, chemotherapy cold deplete some of the pro-tumorigenic subsets of immune cells. And the third possible explanation is that chemotherapy and immunotherapy may work together because some patients respond to each treatment type, and since the two are not cross-reactive, it could increase the likelihood that some will respond.

“However, we were also cognizant of the fact that because chemotherapy can transient deplete white blood cells, there might be counterproductive effects of giving these treatments concurrently,” Galsky added.

Current combinations rely on standard-of-care chemotherapy, but that may soon be changing. Other ongoing trials are currently investigating chemotherapy plus PD-1 or PD-L1 blockades versus chemotherapy or checkpoint blockades alone — all of which continue to generate excitement for the advancement of treating this disease.

“The optimal chemotherapy regimens to combine with immune checkpoint blockades are still understudied,” Galsky said. “We only started to scratch the surface of this topic in some ancillary studies in our trial but have designed a current trial to explore this notion.”