Imfinzi, Tremelimumab Combo Benefits Advanced Urothelial Cancer Patients, Phase 1 Trial Data Show

Imfinzi, Tremelimumab Combo Benefits Advanced Urothelial Cancer Patients, Phase 1 Trial Data Show

An immunotherapy combining an approved and an investigative treatment —  Imfinzi (durvalumab) and tremelimumab — showed potential to reduce tumor activity and prolong survival as a second-line therapy in patients with metastatic urothelial cancer, a common type of bladder cancer, according to data from an open-label Phase 1 study.

The combined treatment resulted in an objective response rate of 20.8 percent, or 35 of the 168 advanced cancer patients, with responses being durable (lasting between 1.9 and 24.9 months) and early — a median of 1.8  months after a first treatment — according to results reported at the recent American Association for Cancer Research (AACR) annual meeting.

Data from this Phase 1 trial (NCT02261220) were presented in the poster, “Durvalumab + tremelimumab in patients with metastatic urothelial cancer.” Analysis was conducted on results collected through Oct. 20, 2017, with a median follow-up of 11.6 months.

At  six months, the progression-free survival (PFS) rate was 25.4 percent with a median PFS of 1.9 months, and the overall survival rate was 60.9 percent, with a median of 9.5 months.

Durvalumab, sold under the brand name Imfinzi, is a human antibody that specifically binds to PD-L1, impeding its interaction with PD-1 and CD80, two molecules that cancer uses to evade an immune system attack.

Imfinzi is approved by the U.S. Food and Drug Administration as a second-line therapy to treat platinum-chemotherapy resistant metastatic urothelial cancer, a cancer of the urinary system. It is also approved for certain advanced non-small cell lung cancer patients, and is under investigation in other cancers.

Tremelimumab is an investigational human antibody that blocks the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). As such, it helps to activate T-cells, immune system cells with cancer-fighting abilities.

The combination is being developed by AstraZeneca and its subsidiary, MedImmune.

In this Phase 1 trial, patients with platinum-refractory metastatic urothelial cancer received Imfinzi at 20 mg per kilogram of body weight and tremelimumab at 1 mg/kg of body weight for four months, followed by 10 mg/kg of Imfinzi for 12 months.

Enrolled urothelial cancer patients — the trial involved 380 patients with various advanced solid cancers — were divided into three groups: those with PD-L1 expression — and subsequent T-cell suppression — equal or higher than 25 percent (68 patients), those whose PD-L1 expression was less than 25 percent (86 patients), and 14 other patients whose PD-L1 expression was not known. Overexpression of PD-L1 is associated with poorer outcomes.

Overall, treatment was seen to be safe and effective in reducing tumor activity regardless of a person’s PD-L1 status. But those with the highest expression rates — PD-L1 higher than 25 percent — had higher response rates (29.4 percent vs. 15.1 percent) and superior six-month overall survival rates than those with PD-L1 expression levels lower than 25 percent.

The most common treatment-related adverse effects were severe itching, or pruritus (26 percent), fatigue (24 percent), diarrhea (20 percent), rash (14 percent), and higher-than-usual levels of lipase (12 percent), an enzyme that at high levels can be a sign of pancreas damage. One patient died of a pulmonary hemorrhage that was found to be treatment-related.

Trial results in people with advanced non-small cell lung cancer were also reported at the AACR meeting.

“The mature data sets from these Phase I trials help further characterize the overall survival of durvalumab plus tremelimumab combination in 2nd-line nonsquamous nonsmall cell lung cancer and 2nd-line metastatic urothelial carcinoma,” said Sean Bohen, chief medical officer for AstraZeneca, in a press release. “We look forward to exploring whether OS is distinguished from durvalumab monotherapy in our Phase III MYSTIC and DANUBE trials, expected to read out later this year and next year, respectively.”

Imfinzi in combination with tremelimumab, or Imfinzi alone, are being tested against standard-of-care chemotherapy as first-line therapies in non-small cell lung cancer patients in the MYSTIC (NCT02453282) study, and in advanced urothelial cancer patients in DANUBE (NCT02516241).