2024 Top Story in Oncology: Emergence of Neoadjuvant Chemoimmunotherapy for Muscle-Invasive Bladder Cancer

Background

Neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy is established as conventional therapy for patients with muscle-invasive bladder cancer (MIBC).^1,2 Both MVAC/dose-dense (dd) MVAC and GC (gemcitabine–cisplatin) are considered reasonable neoadjuvant chemotherapy regimens, despite the absence of high-level evidence for the equivalence of three to four cycles of GC versus three to four cycles of MVAC/ddMVAC.^3,4 The phase III POUT trial established the value of adjuvant platinum-based chemotherapy (cisplatin or carboplatin + gemcitabine) for high-risk muscle-invasive urothelial carcinoma (MIUC) of the upper tract.⁵ Although adjuvant chemotherapy has no high-level evidence in the MIBC setting, meta-analyses of randomized trials suggest a benefit for adjuvant cisplatin-based chemotherapy in this setting.⁶

Thereafter, the CheckMate 274 phase III randomized trial established a role for adjuvant nivolumab for high-risk MIUC after radical resection.⁷ More recently, the AMBASSADOR phase III trial demonstrated improvement in disease-free survival with adjuvant pembrolizumab in patients with high-risk MIUC.⁸ Although another phase III trial evaluating adjuvant atezolizumab was unsuccessful in showing improved outcomes, tumor-informed circulating tumor DNA (ctDNA) to measure minimal or molecular residual disease emerged as a promising postoperative prognostic and potentially predictive biomarker from an analysis of this trial, and prospective validation is ongoing in the IMvigor011 trial.⁹ More dramatic changes have occurred in the therapeutic landscape of first-line therapy for metastatic UC with the incorporation of PD-1/PD-L1 inhibitors in the enfortumab vedotin (EV)–pembrolizumab, GC–nivolumab, as well as the JAVELIN Bladder 100 switch maintenance avelumab regimens.^10-12

NIAGARA clinical trial

At the ESMO Congress in September 2024, NIAGARA — a phase III, open-label, randomized trial that enrolled cisplatin-eligible patients with MIBC — was presented, which is the first trial to demonstrate improved outcomes with neoadjuvant chemoimmunotherapy.¹³ The inclusion criteria were broader than usual: 1) approximately 20% of patients had an estimated creatine clearance of 40 to less than 60 mL/min, and they received split-dose weekly cisplatin combined with gemcitabine; 2) predominant UC was not required, despite only nearly 20% having a variant histologic component; and 3) although only approximately 5% of patients had N1 clinical stage, those with N1 clinical stage were enrolled. Patients received neoadjuvant GC every 3 weeks for four cycles, followed by radical cystectomy with or without neoadjuvant durvalumab plus adjuvant durvalumab every 4 weeks for eight cycles. Event-free survival (EFS) was the key primary endpoint in conjunction with pathologic complete remission (pCR), a co-primary endpoint. Overall survival was the key secondary endpoint.

A total of 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated EFS rate at 24 months was 67.8% (95% CI, 63.6–71.7) in the durvalumab group and 59.8% (95% CI, 55.4–64.0) in the control group (HR for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56–0.82; P < .001 by stratified log-rank test). EFS improvements were seen regardless of subgroup analyses based on age, sex, race, geographic region, PD-L1 expression, stage, variant histology, and creatine clearance. In the reanalysis of pCR, which included 59 samples omitted from the primary analysis, 37.3% (95% CI, 33.2–41.6) of patients in the durvalumab group and 27.5% (95% CI, 23.8–31.6) of those in the control group exhibited pCR (RR, 1.34; 95% CI, 1.13–1.60). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7–85.2) in the durvalumab group and 75.2% (95% CI, 71.3–78.8) in the comparison group (HR for death, 0.75; 95% CI, 0.59–0.93; P = .01 by stratified log-rank test). Treatment-related severe adverse events (TRAEs) occurred in 40.6% of the patients in the durvalumab group and 40.9% of those in the comparison group. TRAEs leading to death occurred in 0.6% of patients in each group. Radical cystectomy was not compromised by the addition of durvalumab, which occurred at a similar rate: 88.0% in the durvalumab group and 83.2% in the control group.

The future

Ongoing adjuvant therapy clinical trials are evaluating: 1) the role of tumor-informed ctDNA-guided adjuvant therapy — that is, escalating therapy for ctDNA-positive disease (PD-1 inhibitor + novel agent) and de-escalating therapy (surveillance) for ctDNA-negative disease, followed by therapy for molecular ctDNA relapse (IMvigor011, MODERN, and TOMBOLA trials); and 2) combinations of novel PD-1 inhibitor plus novel immunotherapeutic agents — for example, neoantigen coding mRNA therapy (INTerpath-005 trial). Moreover, multiple phase III trials are evaluating the role of other neoadjuvant chemoimmunotherapy regimens as well as EV–pembrolizumab.

The NIAGARA trial provokes multiple clinical questions:

1. Is the adjuvant durvalumab component necessary in patients who achieve pCR (or do not achieve pCR) with chemoimmunotherapy, and can ctDNA be employed to guide this component?

2. Can we discover a predictive biomarker to identify patients likely to benefit from the addition of durvalumab to neoadjuvant chemotherapy?

3. How does the use of neoadjuvant chemoimmunotherapy and perioperative immune checkpoint inhibitor therapy, in general, impact therapy for subsequent metastatic disease?

4. In cisplatin-eligible patients who proceed to upfront radical cystectomy, can we rationally make a case for adjuvant chemoimmunotherapy?

5. Can ddMVAC replace GC in the clinic when offering neoadjuvant chemoimmunotherapy (indeed, a US Intergroup trial is evaluating ddMVAC combined with durvalumab for upper tract UC)?

6. Bladder-preserving chemoradiation combined with PD-1/PD-L1 inhibitors is undergoing investigation in phase III trials; however, this regimen is not being compared with the neoadjuvant chemoimmunotherapy approach followed by radical cystectomy.

7. Finally, can we omit radical cystectomy and offer bladder preservation therapy to selected patients with genomic DNA repair alterations or those who achieve clinical and molecular remission following neoadjuvant chemoimmunotherapy, or do we need substantially better clinical staging and molecular tools (eg, urine tumor DNA, plasma DNA methylation patterns, and plasma DNA fragmentomics) to permit this approach?^14,15

The recent news release in October 2024 reporting early discontinuation of the SunRISe-2 phase III trial investigating the novel combination of TAR-200 plus intravenous cetrelimab versus chemoradiation for MIBC suggests that better patient selection is required to omit definitive local therapy (ie, radical cystectomy or radiation). Finally, robust enrollment in clinical trials should be considered a preferred standard of care to expedite advances and identify curative therapies.