Survival after neoadjuvant/induction combination immunotherapy vs combination platinum‐based chemotherapy for locally advanced (Stage III) urothelial cancer

Abstract

Despite treatment with cisplatin-based chemotherapy and surgical resection, clinical outcomes of patients with locally advanced urothelial carcinoma (UC) remain poor.We compared neoadjuvant/induction platinum-based combination chemotherapy (NAIC) with combination immune checkpoint inhibition (cICI). We identified 602 patients who attended our outpatient bladder cancer clinic in 2018 to 2019.Patients were included if they received NAIC or cICI for cT3-4aN0M0 or cT1-4aN1-3M0 UC. NAIC consisted of cisplatin-based chemotherapy or gemcitabine-carboplatin in case of cisplatin-ineligibility. A subset of patients (cisplatin-ineligibility or refusal of NAIC) received ipilimumab plus nivolumab in the NABUCCO-trial (NCT03387761). Treatments were compared using the log-rank test and propensity score-weighted Cox regression models. We included 107 Stage III UC patients treated with NAIC (n = 83) or cICI (n = 24). NAIC was discontinued in 11 patients due to progression (n = 6; 7%) or toxicity (n = 5; 6%), while cICI was discontinued in 6 patients (25%) after 2 cycles due to toxicity (P = .205). After NAIC, patients had surgical resection (n = 50; 60%), chemoradiation (n = 26; 30%), or no consolidating treatment due to progression (n = 5; 6%) or toxicity (n = 2; 2%). After cICI, all patients underwent resection. After resection (n = 74), complete pathological response (ypT0N0) was achieved in 11 (22%) NAIC-patients and 11 (46%) cICIpatients (P = .056). Median (IQR) follow-up was 26 (20-32) months. cICI was associated with superior progression-free survival (P = .003) and overall survival (P = .003) compared to NAIC. Our study showed superior survival in Stage III UC patients pretreated with cICI if compared to NAIC. Our findings provide a strong rationale for validation of cICI for locally advanced UC in a comparative phase-3 trial.

Perioperative Chemoimmunotherapy With Durvalumab for Muscle-Invasive Urothelial Carcinoma: Primary Analysis of the Single-Arm Phase II Trial SAKK 06/17

“…Some have rather short follow-up, while others have been very recently updated. [33][34][35] Trial comparison is obviously difficult in view of different patient populations included (clinical T stage and N stage, cisplatin eligible v ineligible, and geographic region) but overall pCR and pathologic response <ypT2 appear similar in all studies, including ours, with rates of 30%-40% and 55%-65%, respectively. An interesting comparison can be done with the results from the perioperative VESPER trial that compared the cisplatin-based and immunotherapyfree regimens of GC and ddMVAC demonstrating a benefit for the use of ddMVAC with a pCR rate of 42% and an EFS at 2 years of approximately 77%.…”

Recent developments in perioperative combination therapy in muscle-invasive bladder cancer

“…Still, these results offer ground for comparative studies with standard of care chemotherapy. A retrospective cohort study comparing a contemporary platinum-based NAC cohort to the NABUCCO cohort suggested a benefit in OS in favour of combination ICI [31]. As of writing, there are two ongoing phase II trials studying perioperative anti-CTLA-4/PD-(L)1 combinations.…”

Reply to: Comments on “Neoadjuvant/induction combination immunotherapy vs combination platinum‐based chemotherapy for locally advanced (Stage III) urothelial cancer”

“…We thank Dr Takahashi for the comments on our study. 1 We would like to take the opportunity to address these and to clarify our position on the role of preoperative platinum-based chemotherapy (NAIC) or combination immune checkpoint inhibition (cICI) and cystectomy in patients with locally advanced urothelial carcinoma (cT3-4aN0M0 or cTanyN+M0 UC).…”

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Dear editor,We thank Dr Takahashi for the comments on our study. 1 We would like to take the opportunity to address these and to clarify our position on the role of preoperative platinum-based chemotherapy (NAIC) or combination immune checkpoint inhibition (cICI) and cystectomy in patients with locally advanced urothelial carcinoma (cT3-4aN0M0 or cTanyN+M0 UC).The commenter argues that cystectomy is not indicated for patients with cTanyN+M0 UC-that is, for patients in the induction setting. However, our treatment of patients in the induction setting conforms to the clinical guidelines of the National Comprehensive Cancer Network, which recommend cystectomy in patients with response to systemic treatment.

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“…In fact, comorbidity status was not different between patients treated with NAIC and cICI in our analysis and patients ≥80 years were included in both treatment groups. 1 Finally, the commenter suggests conducting a phase II trial rather than a phase III trial. Our data would support any prospective, comparative trial design.…”