Expert Examines Current and Future Strategies for Bladder Cancer Subtype

In addition to discussing the genomic correlation between certain genes and response to neoadjuvant chemoimmunotherapy in muscle-invasive bladder cancer (MIBC), Shilpa Gupta, MD, highlighted ongoing research in the adjuvant and neoadjuvant settings and bladder sparing regimens.

Shilpa Gupta, MD

Case Comprehensive Cancer Center

Gupta, a genitourinary oncologist from Case Comprehensive Cancer Center, spoke with CancerNetwork^® during the 2023 Genitourinary Cancer Symposium, detailing findings from a genomic analysis of the phase 2 BLASST-1 trial (NCT03294304) which assessed the correlation between response and genes and oncogenic signaling pathways, as well as somatic hotspot mutations in a group of 10 patients with MIBC who were treated with neoadjuvant chemoimmunotherapy.¹

In particular, she indicated that ERCC2, ARID1A, DSP, HMCN1, ERBB2, ERBB3, STAG2, BRCA2, and VHL were present only in those who responded to treatment. Conversely, ERCC4, PALB2, CDKN2A, and CSMD3 were only present in nonresponders.

What are the current treatment options for muscle-invasive bladder cancer?

The current standard [of care] for muscle-invasive bladder cancer is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. Since our patient population has a median age of 71 [years], many patients may not be fit for cystectomy.

If they have tumors that are smaller—there is no hydronephrosis and no widespread carcinoma in-situ—tri-modality therapy with maximal [transurethral resection of bladder tumor] TURBT [plus] concurrent chemotherapy and radiation is another valid option. In the past, this used to be reserved for patients who were unfit for surgery or older and not able to tolerate the surgery well but nowadays, a lot of younger patients are also interested in preserving their bladders.

They ask us about this option up front. For patients who are not eligible to receive cisplatin-based chemotherapy due to chronic kidney disease, hearing loss, heart failure, neuropathy, or just poor physical performance status, ideally, up-front cystectomy is the [best] option. [However], if they are overall in poor shape then, again, surgery may not be the best option.

What current research efforts are underway to help improve survival in this space?

Immunotherapy has changed the way we treat locally advanced and metastatic urothelial cancer after platinum-based chemotherapy. Once we established that, this is a very good option for patients in the metastatic setting. There were efforts to try to move this into the muscle-invasive setting, as well.

For example, there are a variety of studies that have looked at immunotherapy as a single agent or in combination with cisplatin-based chemotherapy prior to surgery. The BLASST-1, which combined nivolumab [Opdivo] with gemcitabine and cisplatin, looked at pathologic downstaging.2

In 21 patients who were enrolled, we saw a 66% of pathologic downstaging rate and a 50% pathologic complete response rate if we include CIS [carcinoma in situ]. A lot of other people have also combined pembrolizumab [Keytruda], durvalumab [Imfinzi], and avelumab [Bavencio] with chemotherapy and shown that the pathologic complete responses are in the range of 35% to 38%.

In the era of immunotherapy, the big question is whether event-free survival is a more valid end point. In terms of pathologic downstaging, we are not seeing a huge improvement compared with historical chemotherapy alone. A lot of phase 3 trials are going on in this setting. A couple of them have completed enrollment.

For example, [one trial is] exploring durvalumab with chemotherapy vs chemotherapy alone, and the phase 3 ENERGIZE trial [NCT03661320; is examining] nivolumab and chemotherapy vs chemotherapy alone have completed accrual. We should see results in the coming years. That’s the story of perioperative care.

In the adjuvant setting, 2 phase 3 trials have explored the use of immunotherapy in high-risk patients—for example, patients who got neoadjuvant cisplatin-based chemotherapy and still have residual pT2 or higher disease, node-positive disease, or patients who are not candidates for chemotherapy and have pT3 or higher disease.

Patients were [randomly assigned] to immunotherapy or the control arm, for example, atezolizumab [Tecentriq] vs observation in the phase 3 IMvigor010 trial [NCT02450331]. In the phase 3 CheckMate 274 trial [NCT02632409], it was nivolumab vs placebo. The IMvigor010 study was negative and there was no benefit with atezolizumab [in terms of] disease-free survival or overall survival.

In the CheckMate 274 trial, there was an improvement in disease-free survival of about 12 months in all comers. It was even more pronounced in patients whose tumors had high PD-L1. We have not seen an overall survival signal yet [but these data] got nivolumab approved in the setting for high-risk patients.3

Are there any current barriers to access multidisciplinary care in bladder cancer?

[There are] some barriers to multidisciplinary care. We try our best to [utilize] multidisciplinary care. [We try to] see patients on the same day or around the same day when possible. For patients to make an informed decision, anybody with muscle-invasive bladder cancer needs to be evaluated by urologists who are diagnosing them, but also medical oncologists and radiation oncologists so that a clear plan can be formulated for the patient and they can make an informed decision.

There’s a lot of interest in hearing about different treatment options. There are also several trials that are looking at the option of a bladder sparing regimen in patients who have a great response to neoadjuvant chemotherapy. There are also trials looking at combining immunotherapy with concurrent chemoradiation therapy. More and more trials are incorporating novel agents in the neoadjuvant spaces too.

Having access to information for these trials and options in general with multidisciplinary care is something that we need to incorporate at institutions. The other barrier is gender and other disparities based on socioeconomic factors [and race]. That needs to be addressed because we know that patients with bladder cancer who are African American do much worse than those who are not.

These barriers need to be addressed at a more global level.

Can you review the trial you presented at ASCO GU?

We previously presented the clinical data [for this trial] at the 2020 Genitourinary Cancers Symposium. [At this year’s meeting], we presented the genomic data from the DNA sequencing [analysis] for our patients who enrolled in the BLASST-1 trial. We found that the median tumor mutational burden matched closely with [The Cancer Genome Atlas] TCGA results.

We also identified mutations in ERCC2, ARID1A, ERBB2, ERBB3, BRCA2, and VHL that were exclusively present in responders—those who had pathologic downstaging—vs ERCC4, PALB2, C3KN2A, and CSMD3 [which] were exclusively present in nonresponders.

This is hypothesis generating for how we can understand biomarkers of response and resistance. We also found some somatic hotspot mutations in 10 patients [including] FGFR3, PIKCA, KDM6A, TP53, and other genes.

Lastly, we looked at oncogenic signaling pathways and found those in 20 patients—for example, genomic integrity, RTK signaling, and transcription factor. The RTK signaling and transcription factor were primarily enriched in responders only.

These findings are providing insight into how we can tease out what immunotherapy is adding to chemotherapy. There has already been work done on biomarkers of response to cisplatin-based chemotherapy. We wanted to tease that out.

We’re also on a bigger level comparing the genomic analysis from this chemoimmunotherapy combination trial to patients who enrolled in the phase 2 PURE-01 trial [NCT02736266] who got pembrolizumab [Keytruda] alone, and patients who got chemotherapy alone in another neoadjuvant chemotherapy cohort as a part of our Department of Defense grant.

The idea is to understand how biomarkers play a role in response and resistance and can potentially help us select patients better.

References

1. Gupta S, Makarov V, Sonpavde GP, et al. Genomic analysis from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in patients with MIBC undergoing cystectomy. J Clin Oncol. 2023;41(suppl 6):559. doi:10.1200/JCO.2023.41.6_suppl.559
2. Gupta S, Gibb E, Sonpavde GP, et al. Biomarker analysis and updated clinical follow-up from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in patients with muscle-invasive bladder cancer (MIBC) undergoing cystectomy. J Clin Oncol. 2022;40(suppl 6):528. doi:10.1200/JCO.2022.40.6_suppl.528
3. FDA approves nivolumab for adjuvant treatment of urothelial carcinoma. News release. FDA. August 19, 2021. Accessed February 22, 2023. https://bit.ly/3koaGMg