Perioperative chemoimmunotherapy with durvalumab (Durva) in combination with cisplatin/gemcitabine (Cis/Gem) for operable muscle-invasive urothelial carcinoma (MIUC): Preplanned interim analysis of a single-arm phase II trial (SAKK 06/17).

Abstract

499 Background: Cisplatin-based neoadjuvant chemotherapy followed by surgery is the standard of care for patients (pts) with MIUC but relapse rates remain high. Immune checkpoint inhibitors have demonstrated efficacy in advanced urothelial carcinoma (UC). We hypothesize that the integration of the PD-L1 inhibitor durvalumab into perioperative management of MIUC improves outcome. Methods: SAKK 06/17 is an open label single arm phase II study including 61 pts. Operable MIUC cT2-T4a cN0-1 pts without contraindication for Cis were eligible. Four cycles of preoperative Cis/Gem q3w are administered in combination with 4 cycles Durva 1500mg q3w starting at cycle 2. Durva is continued after surgery q4w for 10 cycles. Primary endpoint is event free survival at 2 years. We report a preplanned interim analysis of the secondary endpoints safety, pathological complete remission ypT0 N0 (pCR,) and pathological response rate (PaR, defined as ≤ypT1N0) on the first 30 resected pts. Results: Among 34 eligible pts (27M, 7F; median age 70, range 41-81 years) included from 07/18 – 02/19, 33 pts (97%) had primary bladder cancer and 1 pt had upper tract UC. Clinical T2, T3, T4 and TxN1 stage were present at diagnosis in 68%, 18%, 15% and 15%, respectively. Four cycles of chemo-immunotherapy were completed per protocol in 34 pts (100%). No tumor progression was noted at preoperative restaging. AE related to Durvalumab were G3 in 5 pts (15%) and G4 in 3 pts (9%). Surgery was performed as planned in 30 pts (88%), 3 pts refused surgery and 1 pt had a frozen pelvis. Operation technique was open in 20 pts (67%) and laparoscopic/robot-assisted in 10 pts (33%). Postoperative complications included Clavien-Dindo III in 6 pts (20%) and IV in 2 pts (7%) with infections being most common (5 pts, 17%). pCR was found in 9 pts (30%) and additional 6 pts (20%) had ypT1/ypTis for a PaR of 50%. Conclusions: The combination of Cis/Gem and Durva as neoadjuvant treatment for MIUC is feasible with manageable toxicities and pCR and PaR rates in the expected range. The rate of postoperative complications warrants further close follow up. Clinical trial information: 2017-003565-10.

Neoadjuvant Therapy Using Checkpoint Inhibitors before Radical Cystectomy for Muscle Invasive Bladder Cancer: A Systematic Review

“…An initial search retrieved 254 results, which underwent assessment to identify the eligible publications. Finally, 8 studies (4 papers and 4 abstracts), including 404 patients were included [13][14][15][16][17][18][19][20]. The screening and selection processes are demonstrated in Figure 1.…”

Immune Checkpoint Inhibitors in Urothelial Bladder Cancer: State of the Art and Future Perspectives

“…No tumor progression was recorded at preoperative restaging with a pCR achieved in 30% of patients, and a pathological response rate of 50%. Postoperative complications arose in 27% of cases, and infections were the most common (17%) [46].…”

Improving Anti-PD-1/PD-L1 Therapy for Localized Bladder Cancer

“…Gemcitabine combined with pembrolizumab for cisplatin-ineligible patients yielded results comparable to pembrolizumab alone in NCT02365766, a Phase 1b/II study: 45.2% achieved pCR, whereas 51.6% reached <pT1N0 [ 52 ]. Interim analysis of SAKK06/17 showed pCR in 30% ( n = 9) after treatment with gemcitabine and durvalumab pre- and post-operatively, whereas 20% of patients reached non-muscle invasive disease (pT1/pTis) [ 53 ]. Preclinical studies and interim study reports are encouraging and suggest a synergistic effect of chemotherapy with PD-L1 blockade.…”