(UroToday.com) Dr. Shilpa Gupta provided an excellent talk discussing ways to optimize survival for patients with muscle invasive bladder cancer. She reviewed the current state of MIBC and where we are aiming to go.
In between where we are now and where we would ideally like to be are the things we can do.
She began with an overview of the current state of MIBC management, which I summarize below.
SWOG 8710 and BA06 EORTC 30894 trials established that neoadjuvant chemotherapy (NAC) improves survival in cisplatin-eligible NMIBC. Regimens utilized were MVAC and CMV.
Meta-analyses have demonstrated a 5-year OS benefit of 8% with NAC. Both dose-dense MVAC and gem/cis are standard options.
However, despite surgery and NAC, there remains a high risk of recurrence – and not all patients get NAC. 50% of patients are ineligible pre-operatively and 30% refuse NAC.
Historically, there have been limited options for cisplatin-ineligible patients.
On the other hand, adjuvant therapy is meant to improve DFS and OS in patients at high risk. In the EORTC 30994, where they compared immediate vs deferred chemotherapy (investigator’s choice of MVAC, ddMVAC, GC) in patients with pT3-4 or N+ bladder cancer following cystectomy, they found a survival benefit favoring adjuvant therapy (6.74 years vs. 4.60 years – but p = 0.13, so not significant). It was underpowered due to issue with accrual. But a subsequent meta-analysis demonstrated a 6% absolute improvement in OS with adjuvant chemotherapy at 5 years.
Incorporating adjuvant IO in these high risk patients is the next rational step. There are 3 trials of interest, two of which have report (some) results.
1. IMvigor010 – no DFS or OS benefit with adjuvant atezolizumab.
2. CheckMate-274 – adjuvant nivolumab demonstrated DFS benefit (22 months vs. 10.9 months), but OS results are still pending. Importantly, in patients with high PD-L1, the results were more pronounced.
3. AMBASSADOR – these results are still pending. It may end up being the tie-breaker.
She did touch on the results of the POUT trial, which specifically looked at adjuvant therapy for UTUC s/p surgical resection with nephroureterectomy. There was a significant 5-year DFS benefit with adjuvant therapy (HR 0.45). But, it is a rarer disease and may not be able to translated exactly to MIBC. And unfortunately, the above adjuvant IO trials didn’t show benefit in their UTUC subsets – but they represented a small proportion of the study cohort.
Moving onto trimodality therapy, she notes the following:
- It is a valid option for bladder preservation for MIBC patients as an alternative to RC
- Absence of trials comparing TMT to RC – but in cohort analyses and meta-analyses, long-term survival appears to be similar
- 5-year DFS can approach 80-85% in well selected patients
- Neoadjuvant chemotherapy prior to TMT is being explored
In summary, any patient with MIBC should be evaluated in a multidisciplinary setting – with input from Med-Onc, Rad-Onc and Urologic Oncology. She put up a proposed paradigm for management at this time:
At this time, she began to talk about the emerging role of immunotherapy, novel therapies and biomarkers.
First, she addressed the role of chemotherapy/IO combinations in the neoadjuvant setting. Based on published data, it would appear that the Neoadjuvant combination is effective in cis-eligible patients.
But, neoadjuvant single-agent IO and enfortumab vedotin (EV) are also effective and safe in these patients.
Indeed, the pCR rates are comparable to NAC alone. EV-103 Cohort H demonstrated that EV for cisplatin-ineligible MIBC patients was safe, had a pCR 36.4% and pathologic response in 50% of patients – and as such, should be considered strongly for these patients.
Based on the above, she asked the question – do we really need to add chemotherapy to IO, when IO alone seems to have good response? Likely not.
Below are some of the ongoing neoadjuvant IO trials for MIBC:
What will these trial tell us?
We WILL learn the following:
- Is pCR and event-free survival (EFS) better with IO / GC combo than GC alone?
- Is pCR/EFS better with EV-pembro than GC?
- Is pCR/EFS with IO, EV-pembro better than upfront surgery in cis-ineligible MIBC patients?
We WILL NOT learn the following:
- Would EFS with IO+/-antibody drug conjugate (ADC) still be better if control arm allowed adjuvant nivo?
- Is adjuvant IO+/-EV needing in patients achieving pCR?
- Could patients with N1+ predominant variant histology have benefit from treatment?
- What is driving the benefit (in neoadjuvant, adjuvant setting or both)?
She next began to touch on biomarkers.
Circulating tumor DNA (ctDNA) has been demonstrated to highly prognostic in MIBC, both in the neoadjuvant chemotherapy and neoadjuvant atezolizumab (ABACUS trial) setting. In IMvigor010, patients who were ctDNA positive had improved DFS and OS with atezolizumab vs observation. This has now led to 2 prospective trials that ctDNA guided adjuvant IO therapy – Imvigor011 (ayezolizumab) and MODERN (nivolumab).
Similarly, there is a push towards using biomarkers to guide bladder preservation. She highlighted the trials below that use chemotherapy:
Dr. Geynisman presented on the RETAIN trial later in the session.
She then briefly discussed IO therapy in the TMT setting. These are still early and have not been reported out. She herself is leading a study about the role of an ADC (Sacituzumab Govitecan) and adaptive radiation for bladder preservation:
Currently, there are no validated biomarkers to determine therapy.
She finally did bring up an interesting proposition. Historically, we have been testing new drugs in the late-stage setting of metastatic urothelial carcinoma – and if it shows effect, moving it up to the neoadjuvant and adjuvant setting. However, this takes time to see response and therefore takes time to bring new treatments to the forefront. In contrast, the I-SPY2 trial approach for breast cancer trials many new drugs in the neoadjuvant setting – and if there is a good response (as shown by surgical pathology), then it can be rapidly launched in the later stage settings.
She ended with her conclusion slide, below. We have progressed from the pre-IO era to the current IO, novel therapy era – but there is still a lot of work to go to get to precision medicine and to close the gap in access to novel treatments globally (as many patients still aren’t able to access currently approved therapies).
Presented by: Shilpa Gupta, MD, Cleveland Clinic Taussig Cancer Institute
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Associate Professor of Urology, University of California, Davis @tchandra_uromd on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.