Neoadjuvant Nivolumab/Chemotherapy Safe and Effective in Muscle-Invasive Bladder Cancer

Shilpa Gupta, MD

Shilpa Gupta, MD

Nivolumab (Opdivo) in combination with gemcitabine and cisplatin in the neoadjuvant setting led to a pathologic nonmuscle-invasive rate of 66% and a pathologic complete response of 49% as treatment of patients with muscle-invasive bladder cancer who underwent a cystectomy in thephase II BLASST-1 clinical trial. The results were presented at the 2020 Genitourinary Cancers Symposium.

“The downstaging rates we saw were 66%,” said Shilpa Gupta, MD, who presented the data at the meeting. “Our study was powered for 55% to have deemed it a success, and we saw 66%, so this is exciting.”

This combination appeared safe with no added adverse events (AEs) or deaths with the addition of nivolumab to the chemotherapy regimen. There were also no delays to cystectomy.

Most of the treatment-related AEs were associated with chemotherapy, and were mostly grade 1/2 anemia (24%), neutropenia (48%), and thrombocytopenia (31%). Grade 1/2 fatigue was reported by 60% of patients, while grade 1/2 nausea was reported by 70% of patients. Increased alanine aminotransferase and aspartate aminotransferase levels were observed in 24% of patients with fatigue and nausea. Grade ½ acute kidney injury was observed in 14% of patients. 

In terms of immune-related AEs, rash, hypothyroidism, and Guillain Barre Syndrome were reported in 1 patient each, as well as inflamed lymph nodes in 2 patients who were complete responders and benign onbiopsy.

In an interview withTargeted Oncology, Gupta, associate professor of genitourinary oncology at Cleveland Clinic, discussed the results of the BLASST-1 trial evaluating neoadjuvant nivolumab plus gemcitabine and cisplatin in patients with muscle-invasive bladder cancer undergoing a cystectomy. She highlighted the next steps and key points community oncologists need to know about these data now.

TARGETED ONCOLOGY: Can you provide some background to this clinical trial?

Gupta:This is a bladder cancer signal-seeking trial for neoadjuvant nivolumab, gemcitabine, and cisplatin in muscle-invasive bladder cancer patients undergoing cystectomy. These patients are patients who are eligible to receive cisplatin with a creatinine clearance of 50 or greater as opposed to 60 because that is what the real-world practice is like. We treat them with 4 cycles of the regimen, including nivolumab, which is introduced at day 8 of the cycle, and they undergo cystectomy after 6 weeks.

The primary end point of the study was pathologic downstaging to nonmuscle-invasive disease. We also included T2-4N1 patients. Secondary end points were PFS and safety. Correlative end points included whole genome sequencing and immune profiling, among others.

TARGETED ONCOLOGY: What findings were presented at the meeting?

Gupta:The downstaging rates we saw were 66%. Our study was powered for 55% to have deemed it a success, and we saw 66%, so this is exciting. We saw pathologic complete response rate in 49% of patients, which is pretty significant for this patient population. Patients who had T4aN ≤ 1 disease had a downstaging to pTa, which is pretty remarkable.

TARGETED ONCOLOGY: From a safety perspective, how wass this regimen tolerated?

Gupta:The combination was safe, and there were no additional toxicities from nivolumab added to gemcitabine/cisplatin. Most of the AEs were from chemotherapy and were easily manageable. We did see some immune-related AEs, such as hyperthyroidism and adenitis, but those did not require steroids. There were no delays to cystectomy. All patients underwent cystectomy within 8 weeks.

TARGETED ONCOLOGY: Going forward from these data, what would you say the next steps will be?

Gupta:The next step is to look at this regimen in a randomized phase III setting. We have the ENERGIZE trial (NCT03661320), which is already ongoing comparing gemcitabine/cisplatin versus gemcitabine/cisplatin and nivolumab. There is a third arm of gemcitabine/cisplatin and nivolumab plus an IDO inhibitor. We will have more answers as far as how much the immunotherapy is adding to the chemotherapy in this setting.

TARGETED ONCOLOGY: What is the rationale for adding the IDO inhibitor?

Gupta:The data with the doublet of nivolumab and IDO inhibitor has looked promising in a phase I trial, so we want to explore this in the neoadjuvant setting.

TARGETED ONCOLOGY: Do you see this combination with nivolumab/chemotherapy having efficacy in other bladder cancer settings?

Gupta:Yes. Certainly, the chemotherapy and immunotherapy combinations such as chemotherapy plus atezolizumab (Tecentriq) or pembrolizumab (Keytruda) can be explored in the metastatic setting.

TARGETED ONCOLOGY: What do you hope community oncologists take away from these findings?

Gupta: