First Study of Immunotherapy/Chemo Combo Fails to Show Significant Benefit in Urothelial Cancer

The addition of the immunotherapy Yervoy (ipilimumab) to cisplatin and gemcitabine did not significantly improve overall survival (OS) for patients with metastatic urothelial cancer, according to findings from a new phase 2 study. These results were presented at the 2016 Genitourinary Cancers Symposium, a meeting of hundreds of oncologists and other oncology professionals in San Francisco in mid-January.

In the single-arm study, which was the first to explore the combination of a CTLA-4 inhibitor with chemotherapy in urothelial cancer, the median OS was 14.6 months. The one-year OS rate was 59 percent, which did not meet the primary endpoint of the study. The objective response rate (ORR) with the combination was 64 percent.

“Response rate and survival were similar to historical controls, and the primary endpoint was not met,” said lead investigator Matthew Galsky, director of Genitourinary Medical Oncology at the Tisch Cancer Institute at Mount Sinai. “We set a high bar for the improvement in one-year overall survival of 20 percent compared with historical controls. We felt that we would really need to see something robust to warrant moving this regimen forward."

In the phase 2 study, 36 patients with metastatic urothelial carcinoma received induction therapy for two cycles with gemcitabine and cisplatin followed by the doublet plus Yervoy for four cycles. The primary endpoint of the study was the one-year OS rate. To be significant, the lower bound of the 90 percent confidence interval needed to exceed 60 percent, which is equivalent to a one-year OS rate of 80 percent. The secondary endpoints of the study focused on ORR, progression-free survival and safety.

Across both stages of the study, gemcitabine was administered at 1000 mg/m² on days 1 and 8 and cisplatin was given at 70 mg/m² on day 1 of each 21-day cycle. Yervoy was administered at 10 mg/kg on day 1 of each cycle. Following treatment with the triplet, patients with stable disease or better went on to receive maintenance Yervoy at 10 mg/kg every three months.

The median age of patients was 60 years and the majority were males (81 percent). The primary tumor site was the bladder (78 percent), with 20 percent having renal pelvic disease. Nearly a third of the patients (30%) had a Karnofsky performance status of 80 percent and 58 percent had visceral metastasis. Prior treatments included systemic chemotherapy (15 percent) and surgical removal of the primary tumor (53 percent).Across the full study, the complete response (CR) rate was 14 percent. Overall, 17 percent of patients experienced an improvement in response with the addition of Yervoy following induction therapy. There was one CR following induction therapy and four CRs with the addition of Yervoy. “It’s unclear, of course, if this is related to [Yervoy] or to additional chemotherapy,” noted Galsky.

The partial response rate was 50 percent, across both treatment phases. These responses were primarily achieved during induction therapy (53 percent), some of which converted to CRs. The stable disease rate was 31 percent. After the predefined six cycles of treatment, 15 patients had stable disease or better and were eligible for maintenance therapy.

Patients received a median of five cycles of gemcitabine plus cisplatin and 3 cycles of Yervoy. Disease progression was the most common cause of treatment discontinuation.

At least one grade 3/4 adverse event (AE) was experienced by 72 percent of patients. Potentially immune-related grade 3/4 AEs included diarrhea (8 percent), colitis (6 percent), rash (6 percent), adrenal insufficiency (3 percent), hypopituitarism (3 percent), and hyperthyroidism (3 percent).

The most commonly occurring grade 3/4 AEs in the trial were neutropenia (36 percent), anemia (28 percent), thrombocytopenia (19 percent) and diarrhea (9 percent). The most frequently reported grade 1/2 AEs were fatigue (64 percent), nausea (64 percent), anemia (36 percent), diarrhea (36 percent), anorexia (31 percent), rash (28 percent), vomiting (28 percent), alopecia (28 percent), neuropathy (25 percent) and thrombocytopenia (25 percent).

“The majority of adverse events were grade 1 and 2 in severity. The majority of grade 3 and 4 events were hematologic. We did observe non-hematologic toxicities consistent with immune-mediated toxicity,” said Galsky. “Based on the character, severity, and frequency of the adverse events, the side effect profile was consistent with additive toxicity rather than synergistic toxicity.”

In an exploratory analysis of immune cells, a significant depletion was not seen in circulating regulatory T cells or myeloid-derived suppressor cells following induction chemotherapy. Additionally, induction therapy did not appear to impact CD4 and CD8 levels, based on peripheral blood measurements. After the addition of Yervoy, there was an expected expansion in CD4 and CD8 cells, noted Galsky.

“We did see pharmacodynamic effects consistent with the mechanism of [Yervoy], despite administration of concurrent cytotoxic chemotherapy,” he said. “This does potentially bode well for upcoming trials combining cytotoxic chemotherapy with PD-1 and PD-L1 blockade.”

There are currently several trials assessing immune checkpoint inhibitors in combination or as monotherapy for patients with urothelial cancer. As combination therapy, a phase 2 study is exploring the PD-1 inhibitor Keytruda (pembrolizumab) with concurrent radiation and gemcitabine (NCT02621151) and a phase 1 study plans to explore Keytruda with gemcitabine or docetaxel (NCT02437370).

The PD-L1 inhibitors atezolizumab and avelumab are currently being assessed primarily as monotherapy for patients with urothelial cancer. Atezolizumab is being compared with observation as an adjuvant therapy following cystectomy for patients with bladder cancer in the phase 3 IMvigor-010 study (NCT02450331).

Galsky MD, Hahn NM, Albany C, et al. Phase II trial of gemcitabine + cisplatin + ipilimumab in patients with metastatic urothelial cancer. J Clin Oncol. 2016; 34 (suppl 2S; abstr 357).