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Combination immunotherapy, chemotherapy feasible in metastatic bladder cancer
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Combination therapy with immune checkpoint blockade and chemotherapy appeared feasible for some patients with metastatic bladder cancer, study data showed.
“Because chemotherapy and immunotherapy are the two pillars of treatment for metastatic bladder cancer, we sought to better understand how these treatments might be best given together,” Matthew Galsky, MD, director of genitourinary medical oncology and professor of urology, medicine and medical oncology at Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai, said in a press release. “Already the results of this trial have inspired the creation of two more trials that seek to better the treatment of [patients with bladder cancer] by combining chemotherapy with immunotherapy.”
The researchers performed a multicenter, single-arm phase 2 study of 36 chemotherapy-naive patients with metastatic bladder cancer. Galsky and colleagues conducted peripheral blood flow cytometry on all patients, and whole exome sequencing of archival tumor tissue on 28 patients. All patients received two cycles of gemcitabine and cisplatin, followed by another four cycles of gemcitabine and cisplatin plus ipilimumab (Yervoy, Bristol-Myers Squibb).
OS at 1 year served as the main endpoint. Secondary endpoints included safety, objective response rate and PFS.
Patients demonstrated an ORR of 69%, with 17% of patients achieving complete response.
The 1-year OS rate was 61% (lower bound 90% CI, 51%), and median OS was 13.9 months (95% CI, 10.5-23.4). Median PFS was 7.9 months (95% CI, 6.4-9.9).
More than three-quarters of patients (81%) experienced adverse events of grade 3 or higher, most of which were hematologic. The most common grade 3 or worse immune-related adverse event was diarrhea (11%). No treatment-related deaths occurred.
Gemcitabine and cisplatin alone did not appear to produce any significant changes in the composition and frequency of circulating immune cells, according to an exploratory analysis, but the addition of ipilimumab appeared to significantly expand circulating CD4 cells which, in turn, correlated with improved survival.
Researchers also noted response rate appeared significantly higher among patients with deleterious somatic mutations in DNA damage response genes (P = .03). All ten patients with these deleterious mutations achieved a partial or complete response (sensitivity, 47.6%; specificity, 100%; positive predictive value, 100%; negative predictive value, 38.9%).
“Our work is an example of using genomics to enable precision medicine,” Andrew V. Uzilov, PhD, a co-author of the study and director of cancer genomics for Sema4, said in the release. “By looking for loss-of-function mutations in DNA damage repair genes, we may be able to predict who will do well on a combined chemotherapy plus immunotherapy regimen. In our study, we looked at a pool of 55 DNA damage repair genes as predictive biomarkers. We are now exploring further which of these genes, and what types of mutations within them, best predict treatment response, as well as the interplay of DNA damage repair status with other predictors of immunotherapy response.”
The researchers acknowledged that the study was limited by the single-arm design and small sample size. – by Andy Polhamus
Disclosures: Galsky reports advisory roles with AstraZeneca, Bristol-Myers Squibb, Genentech, Merck and Pfizer, as well as research funding from Bristol-Myers Squibb and Merck. The other authors report no relevant financial disclosures.
Perspective
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Chemotherapy alone can exert immunomodulatory effects by releasing tumor antigens and, potentially, by directly modulating immune cellular subsets. This was the basis for testing the combination of ipilimumab and chemotherapy in a small (n = 36) biomarker-driven combination study of standard-of-care gemcitabine and cisplatin plus ipilimumab as first-line therapy. It is one of the first therapies to combine chemotherapy with checkpoint inhibition for patients with bladder cancer.
The safety profile appeared manageable and compatible with known chemotherapy and CTLA toxicity, with minimal overlap and no synergistic adverse events. The study did not meet its primary clinical endpoint of 1-year improvement in OS.
The efficacy of ipilimumab as monotherapy has not been clinically studied in bladder cancer, although tremelimumab (AstraZeneca) has been reported to have single-agent activity in advanced bladder cancer.
The study by Galsky and colleagues was initiated in 2012, prior to the explosion of data on PD-1/PD-L1 inhibitors in bladder cancer and other tumors. There are multiple ongoing clinical trials of chemotherapy plus PD-1/PD-L1 inhibitors in bladder cancer. Also, the dose of ipilimumab given in this study was high at 10 mg/kg. Higher doses yield higher responses at the cost of higher toxicity and decreased tolerability.
The higher dose-dependent toxicity of ipilimumab and the lack of efficacy data make this combination obsolete. Nevertheless, the study contributes to our body of knowledge by demonstrating tolerability, even at the higher dose of ipilimumab.
DNA damage response (DDR) gene alterations are an important factor in platinum sensitivity. The authors explore the effect of these alternations on the activity of the combination. The response rate was significantly higher among patients with deleterious somatic mutations, consistent with data reported with cisplatin chemotherapy in bladder cancer.
Because this was a single-arm study of a combination of cisplatin-based chemotherapy and a CTLA-4 inhibitor, the impact of the DDR alternations on the sensitivity of ipilimumab cannot be deciphered from these data. Additionally, the genes selected and the assay used to detect the DDR gene alteration are not standardized and vary considerably among studies. However, the data support the theory that DDR gene alteration tumors are a more sensitive class of tumors that are more susceptible to available therapies.
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