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Expert Critique

FROM THE ASCO Reading Room

I. Alex Bowman, MD Assistant Professor, Division of Hematology/Oncology University of Texas Southwestern Medical Center

Here, Galsky and colleagues report the results of a phase II trial combining chemotherapy and immunotherapy with the anti-CTLA-4 monoclonal antibody ipilimumab for first-line treatment of metastatic urothelial cancer. The study, initiated in 2010, predates the introduction of anti-PD-1/PD-L1 monoclonal antibodies, which have dramatically changed the treatment paradigm of urothelial cancer. In this trial, they report a 69% overall response rate and 61% 1-year survival rate among 36 patients treated with a combination of ipilimumab and gemcitabine/cisplatin, a standard chemotherapy-doublet for the treatment of metastatic urothelial cancer. The combination appears to be well tolerated, without evidence of synergistic toxicity. Of note, grade 3 or higher diarrhea occurred in 11% of patients, although the dose of ipilimumab used in this trial was high (10 mg/m2). They also found that DNA damage repair mutations in tumor tissue were associated with a favorable response to the combination, as they are to platinum-based chemotherapy or immunotherapy alone. Although ipilimumab is not currently approved for use in urothelial cancer, a number of PD-1/PD-L1-based immunotherapy combinations (either with chemotherapy, anti-CTLA-4 antibodies, or other immunomodulatory agents) are currently under study and it is likely that we will see combination therapy in the near future.

Full Critique

Combining chemotherapy and immune checkpoint blockade in patients with metastatic urothelial cancer is safe and effective, particularly for patients with high expression of a biomarker of a particular mutation.

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have rapidly become a standard treatment for patients with metastatic bladder (urothelial) cancer. Currently, at least three large ongoing international randomized trials have been designed to compare chemotherapy plus PD-1/PD-L1 blockade with chemotherapy alone versus PD-1/PD-L1 blockade alone.

"Given that chemotherapy and PD-1/PD-L1 blockade represent the two main pillars of systemic therapy for metastatic bladder (urothelial) cancer, there was much enthusiasm for those phase III studies and they actually moved forward without phase II testing," Matthew Galsky, MD, of Icahn School of Medicine at Mount Sinai in New York City, told ASCO Reading Room. "Our study provides preliminary evidence to support the activity of such combination approaches, and preliminary evidence to support the safety of such approaches.

"Evidence suggests that concurrent chemotherapy does not have a clear counterproductive effect on the immune system. We also provide preliminary evidence for a biomarker to identify patients who might benefit most from the combination approach."

When Galsky and colleagues designed the study in 2010, the only immune checkpoint inhibitor approved by the FDA was the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitor ipilimumab, which was approved in melanoma. "We would not have guessed that immune checkpoint blockade would revolutionize the treatment of advanced solid tumors, with approvals across a large number of tumor types, including bladder urothelial cancer," said Galsky.

"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."

He noted that because chemotherapy can transiently deplete white blood cells, there might be counterproductive effects of giving these treatments concurrently.

The researchers designed a that enrolled 36 patients with metastatic urothelial cancer who had not previously received chemotherapy. The patients received two cycles of standard chemotherapy with gemcitabine and cisplatin followed by four cycles of chemotherapy plus ipilimumab.

The objective response rate was 69%, and the 1-year overall survival rate was 61%. The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations.

Grade 3 or higher adverse events occurred in 81% of patients, with the majority of events being hematologic. The side effects were consistent with what has been observed independently with chemotherapy and with ipilimumab, Galsky said.

On exploratory analysis, there were no significant changes in the composition and frequency of circulating immune cells after chemotherapy alone. However, there was a significant expansion of circulating CD4 cells with the addition of ipilimumab, which correlated with improved survival.

"We found that the combination of standard chemotherapy plus ipilimumab was safe in patients with metastatic urothelial cancer. We showed that chemotherapy did not deplete levels of immune cells in the blood -- it did not have obvious counterproductive effects with immunotherapy. We also found that patients with tumors that had mutations in a group of genes involved in repairing DNA damage were the most likely to respond to treatment."

The relationship between DNA damage response and repair gene mutations and response to immunotherapy is rapidly evolving, he explained. are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma, and of immune checkpoint blockade response.

"There has been much less work on biomarkers predicting patients who might respond particularly well to the combination of chemotherapy and immunotherapy, although we believe that some of these biomarkers, such as DNA damage response mutations, might be the same as those predicting response to the individual components."

Galsky and colleagues have now initiated two new trials: one of patients with early bladder cancer, and the other assessing different chemotherapy combinations with immunotherapy.

"There is a longstanding observation that a subset of patients with muscle-invasive bladder cancer might be treated effectively with chemotherapy alone without having to have their bladders removed. However, this approach has not advanced for a number of reasons, and removal of the bladder -- cystectomy -- remains a standard approach. We are seeking to determine if the combination of chemotherapy and PD-1 blockade might allow some patients with muscle-invasive bladder cancer to be definitively treated with this regimen without requiring removal of their bladders."

The study will prospectively validate the biomarkers identified to determine if they might predict which patients are most well suited for this strategy.

The optimal chemotherapy regimens to combine with immune checkpoint blockade are still understudied, Galsky noted. Currently, combination regimens are largely driven by the chemotherapy regimens that are already standard of care for the treatment of the particular cancers, but those regimens might not be optimized to exploit the immunomodulatory effects of chemotherapy.

He said that oxaliplatin might work best in terms of causing cancer cells to die in a way that is most apparent to the immune system: "We will perform a small randomized study of PD-1 blockade given in combination with a chemotherapy regimen that includes oxaliplatin versus a chemotherapy regimen that does not include oxaliplatin in patients with metastatic urothelial cancer to determine if the oxaliplatin-containing regimen has better immunomodulatory effects."

The ongoing phase III studies "provide the perfect opportunity to validate our preliminary observations utilizing a class of immune checkpoint inhibitors that are arguably more effective as single agents in bladder urothelial cancer than the CTLA4 blockade we used. PD-1/PD-L1 inhibitors are poised to impact standard of care."