Chemo Plus Immunotherapy Shows Promise for Advanced Bladder Cancer

The combination of nivolumab, gemcitabine and cisplatin produces significant pathologic response rates in patients with muscle-invasive bladder cancer (MIBC) in the neoadjuvant setting, according to new data from the phase II Bladder Cancer Signal Seeking Trial (BLASST-1).

Preliminary findings, which also demonstrate the safety of this immunotherapy/chemotherapy approach, recently were presented at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium.

The targeted immunotherapy drug nivolumab is a checkpoint inhibitor that blocks the programmed cell death protein 1/ ligand 1 (PD-1/PD-L1) immune response pathway. Gemcitabine is an antimetabolite. Cisplatin is a DNA crosslinking agent.

“Immunotherapy has really advanced the treatment for metastatic bladder cancer patients,” notes BLASST-1 study chair Shilpa Gupta, MD, a Cleveland Clinic Cancer Center oncologist who initiated the trial to explore the potential synergistic benefits of the nivolumab/gemcitabine/cisplatin combination in the neoadjuvant setting. “We wanted to understand the impact of immunotherapy in combination with chemotherapy for patients with localized disease who had yet to undergo surgery.”

With immunotherapy moving into earlier stages of disease, this trial addressed an unmet need for bladder cancer patients, according to Dr. Gupta. “Standard of care for MIBC is chemotherapy followed by radical cystectomy, but that only results in responses among 30-40% of patients and the majority still have disease recurrence after surgery, despite chemotherapy,” she explains. “We wanted to combine chemotherapy with immunotherapy to see if we could achieve higher responses at surgery.”

Study details

Between February 2018 and June 2019, 41 patients were enrolled at three sites. Their median age was 66, and 63% were male. The majority of patients (90%) had T2N0 disease, followed by T3N0 (7%), and T2-4N1 (3%).

Participants received gemcitabine-cisplatin plus nivolumab, followed by radical cystectomy within eight weeks. Thirty-eight received four cycles of the combination, two received two cycles, and one was treated with a single cycle. Forty patients underwent surgery.

The study’s primary endpoint was pathologic response. “We determined that the study would be a success if we achieved a pathologic downstaging rate of 45% at cystectomy,” says Dr. Gupta, who leads Cleveland Clinic Cancer Center’s Bladder Cancer Program.

Safety as well as progression-free survival at two years were the secondary endpoints. “Safety is key in these patients,” Dr. Gupta emphasizes. “If the addition of an agent results in more toxicities or delayed surgery, then we are doing a disservice to the patient.”

Initial results indicate that the immunotherapy/chemotherapy combination is safe and effective for the treatment of MIBC, with significant pathological responses, manageable toxicities, no delays to surgery and no patient deaths.

“We found that the primary endpoint was exceeded, with pathological downstaging of 66%,” reports Dr. Gupta. “Pathologic complete responses were observed in 49% of patients. Additionally, the combination was found to be safe, with no added toxicities from the immunotherapy. The majority of the hematologic toxicities were seen from chemotherapy” and included grade 3-4 neutropenia and thrombocytopenia.

Harnessing immunotherapy

Immunotherapy has impacted the treatment of a number of cancer types, including metastatic bladder cancer. A growing body of research supports its efficacy and Dr. Gupta believes it will become a backbone in the neoadjuvant treatment setting moving forward.

What still needs to be understood, she says, is how much benefit can be derived from combining immunotherapy with chemotherapy in this patient population. “Does immunotherapy work better alone, or with chemo? This question, along with safety, is being addressed in ongoing randomized trials.

“It is also key that we make sure immunotherapy and chemotherapy combined does not lead to excessive toxicities,” she says. “We did not see that in our single-arm phase II study, which is very reassuring. However, it will be helpful to validate this with data from phase III randomized trials.”

Next steps, ongoing research

Additional findings from the BLASST-1 study will be released as they become available. “The secondary endpoint of progression-free survival at two years will be updated when that milestone is achieved next year,” Dr. Gupta says. “Also, the ongoing correlative work looking at the whole genome sequencing, molecular subtyping and other immunologic biomarkers will be competed in the near future.”

The phase III ENERGIZE trial already is underway and enrolling patients, according to Dr. Gupta, who is the principle investigator for this study at Cleveland Clinic. The randomized trial will evaluate gemcitabine/cisplatin alone versus gemcitabine/cisplatin plus nivolumab with or without BMS-986205, an indoleamine 2, 3-dioxygenase 1 inhibitor, for treatment of advanced bladder cancer. The outcome should further inform the results of the BLASST-1 study, she says.

“Muscle-invasive bladder cancer is a highly aggressive disease and even after surgery, more than 50% of patients recur and eventually develop metastatic disease, which is incurable,” Dr. Gupta notes. “We really need to harness strategies that can downstage more and more patients at the time of surgery to improve their outcomes because their responses at the time of surgery correlate with the long-term survival outcomes. Our goal is to have effective therapies with no added toxicities in this space.”

Dr. Gupta recently received a two-year, $573,850 grant from the Department of Defense to study biomarkers of response and resistance to immunotherapy and to apply machine learning algorithms to generate a comprehensive biomarker. The award will assist her team in the identification of biomarkers to help predict whether MIBC patients will be responsive or resistant to immunotherapy.

To watch a video interview of Dr. Gupta discussing the BLASST-1 trial results, click here.