Skip to main content

22-10-2020 | Oncology | News | Article

Neoadjuvant dual immune-checkpoint blockade shows promise in UC

Author: Laura Cowen

medwireNews: Cisplatin-ineligible patients with locally advanced or high-risk urothelial carcinoma (UC) could benefit from neoadjuvant treatment with a PD-1/PD-L1 inhibitor in combination with a CTLA-4 inhibitor, show two phase 1 studies published in Nature Medicine.

The first study, by Jianjun Gao and colleagues from The University of Texas MD Anderson Cancer Center in Houston, USA, included 28 patients (median age 71 years, 71% men) who were treated with two cycles of the PD-L1 inhibitor durvalumab 1500 mg/kg and the CTLA-4 inhibitor tremelimumab 75 mg/kg every 4 weeks before cystectomy.

All of the patients were cisplatin-ineligible and had localized disease with high-risk features, including bulky tumors, variant histology, lymphovascular invasion, hydronephrosis, and/or high-grade upper urinary tract disease; 43% had T3 disease and 11% had T4 disease.

The primary study endpoint was safety, and the researchers found that 21% of patients experienced an immune-related adverse event (irAE) of grade 3 or worse, which was below the prespecified limit of 30%. This included four patients with asymptomatic laboratory abnormalities and two with hepatitis and/or colitis. There were no treatment-related deaths.

Of the 24 patients who ultimately underwent surgery, 37.5% had a pathologic complete response (pCR), while the overall downstaging (p≤T1N0) rate was 58.3%.

Gao and co-authors point out that the pCR rate was “particularly encouraging in the 12 patients with large T3/T4 tumors,” at 42%, with a downstaging rate of 75%.

They add that this suggests “an added clinical benefit” compared with single-agent immune-checkpoint inhibition, where pCR rates in this subgroup of patients have previously been reported at 17%.

At 1-year, 88.8% of patients were alive and 82.8% were relapse-free.

In a statement to the press, Gao said that the study “provides early evidence that neoadjuvant treatment with combination checkpoint inhibitors is feasible in a group of patients who are in need of additional treatment options.”

In the second study (NABUCCO), 24 cisplatin-ineligible patients with stage III UC were treated with the CTLA-4 inhibitor ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus the PD-1 inhibitor nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43, followed by resection.

Of these, 58% had node-negative (cT3-4aN0) disease at baseline and 42% had baseline lymph node metastases (cT2-4aN1–3).

Michiel van der Heijden (Netherlands Cancer Institute, Amsterdam) and co-investigators report that all but one (96%) of the patients met the primary endpoint of undergoing resection within 12 weeks of initiating treatment. The patient who did not meet this goal had a 4-week delay due to immune-related hemolysis.

Just over half (55%) of patients experienced a grade 3 or 4 irAE, with the rate falling to 41% when clinically insignificant laboratory abnormalities (mainly lipase elevation) were excluded.

The pCR rate in this study was 46%, while the proportion with no remaining invasive disease (p≤TisN0/TaN0) was 58%.

The researchers note that 50% of the 14 patients with no baseline lymph node metastases had a pCR, compared with 40% of the 10 patients with clinically suspected baseline lymph node metastases.

Based on their findings, van der Heijden et al conclude that “ipilimumab plus nivolumab is feasible and highly active as preoperative treatment in UC.”

They add: “The therapeutic efficacy in this cohort, with poor prognosis and high unmet clinical need, warrants further development through randomized trials.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2020 Springer Healthcare Ltd, part of the Springer Nature Group

Nat Med 2020; doi:10.1038/s41591-020-1086-y
Nat Med 2020; doi:10.1038/s41591-020-1085-z