Updated results from a large clinical trial confirm that, for some patients with bladder cancer that can be removed with surgery, receiving immunotherapy immediately afterwards is an effective treatment.
In 2021, initial results from the same trial led the FDA to approve the immune checkpoint inhibitor nivolumab (Opdivo) as a postsurgical (adjuvant) treatment for patients with high-risk bladder cancer.
That approval was based on data showing that, compared with treatment with a placebo, administering nivolumab for 1 year after surgery doubled the amount of time patients lived without their disease recurring in or near the bladder or elsewhere in the body, a measure called disease-free survival (DFS).1
The updated results, presented on February 17 at the 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, included approximately 3 years of follow-up. These results showed that patients who received nivolumab had a median DFS of 22 months, compared with approximately 11 months for those who received a placebo.2
The picture looked even better for patients whose tumors express a protein called PD-L1, which interacts with another protein targeted by nivolumab. That group of patients had a median DFS of more than 52 months.
In the trial, nivolumab was given for a maximum of 1 year, said Matthew Galsky, MD, Professor, Hematology and Medical Oncology; Director, Genitourinary Medical Oncology; and Co-Director, Center of Excellence for Bladder Cancer, and Associate Director, Translational Research, The Tisch Cancer Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, who presented the updated results at the ASCO symposium.
“If you’re just suppressing cancer with a treatment, then potentially, once treatment stops, the cancer starts to grow again,” he said. The long-term survival free of disease seen in some of the study participants “might indicate that [immunotherapy] is actually eradicating the cancer in some patients.”
A Lingering Risk for Recurrence
Bladder cancer that has invaded the bladder muscle or nearby lymph nodes can potentially be cured by surgical removal of the bladder and lymph nodes. But, in more than half of patients who have this type of surgery, called radical cystectomy, cancer cells have already spread (metastasized) elsewhere in the body.
These deposits of metastatic cancer “are too small to be seen on [an imaging] scan,” said Dr Galsky. “But over time those cancer cells grow and divide. And we want to try and avoid that, if possible,” he explained.
The main strategy that clinical trials have tested to prevent bladder cancer from recurring, either at or near the original tumor or at distant locations, has been adjuvant therapy: chemotherapy or immunotherapy drugs given after surgery.
Chemotherapy regimens based on the drug cisplatin are known to shrink tumors in patients with bladder cancer that has metastasized at the time it is diagnosed, explained Andrea B. Apolo, MD, Senior Investigator and Head, Bladder Cancer Section, Genitourinary Malignancies Branch; and Director, Bladder Cancer and Genitourinary Tumors Multidisciplinary Clinic, National Cancer Institute (NCI) Center for Cancer Research, Bethesda, MD. So, these regimens are often used in bladder cancer that can be surgically removed, either before surgery (neoadjuvant therapy) or afterward, as adjuvant therapy.
But many people cannot tolerate cisplatin, Dr Apolo added. “And a lot of people prefer not to get chemotherapy because of the side effects,” she said.
Researchers have been searching for other adjuvant therapy options. A previous clinical trial tested a different immunotherapy called atezolizumab (Tecentriq) as an adjuvant therapy, but it did not improve DFS.3
So for many years, explained Dr Galsky, most patients, following surgery for bladder cancer, underwent observation instead of adjuvant therapy. Observation is following patients with frequent imaging to try to catch a recurrence as early as possible.
But when a previous study found that nivolumab could shrink tumors in patients with more advanced bladder cancer, researchers decided to test the drug as an adjuvant treatment in patients without detectable metastases.4
Preventing Disease Recurrence for Years
The CheckMate 274 trial, which was funded by Bristol Myers Squibb and Ono Pharmaceutical, enrolled more than 700 patients with high-risk, muscle-invasive bladder cancer who had undergone extensive surgery. Participants were eligible if they had received neoadjuvant cisplatin-based chemotherapy but not if they had received any adjuvant treatment.
The researchers randomized participants to receive up to 1 year of treatment with either nivolumab or a placebo. At the time of the ASCO presentation, patients had been followed for a minimum of 31 months.
The incidence of side effects observed during the longer follow-up period was approximately the same as that seen during the initial 6 months of treatment. Approximately 18% of patients who received nivolumab had at least 1 serious side effect, compared with 7% of those who received the placebo. Three of the 353 patients who received nivolumab died of side effects attributed to the drug.
Overall, after a median follow-up of 36 months, patients who received nivolumab lived approximately twice as long without their disease progressing than those who received a placebo.
At the time of the initial publication, there was some evidence that patients whose tumors expressed PD-L1 were benefitting more from nivolumab than those whose tumors lacked PD-L1. But it was too early to calculate their median DFS.
With the longer follow up, the researchers found that patients whose tumors expressed PD-L1 lived more than twice as long without their disease progressing than the group as a whole.
“These results were impressive but not necessarily unexpected, given what we know about that protein and how [it] might relate to sensitivity to [nivolumab],” Dr Galsky said.
However, he added, “for all patients in the study, there was a benefit from [receiving] immunotherapy.” Under the FDA’s approval, nivolumab can be used for anyone with high-risk bladder cancer, regardless of whether their tumors express PD-L1.
Pinpointing Who Needs Adjuvant Therapy
CheckMate 274 participants will continue to be followed to see if those who received nivolumab live longer, a measure called overall survival (OS).
The OS data will matter, explained Dr Apolo. “We know we overtreat a lot of patients with adjuvant therapy,” she said. That is, many people who receive it may have been cured with surgery alone. “But we don’t know yet how to pinpoint who those people are.”
If it turns out that there is no OS improvement from adjuvant immunotherapy, it would make more sense to wait until a cancer recurs or metastasizes to give it, she explained.
A planned NCI-supported trial will soon be looking at whether blood tests for circulating tumor DNA could predict which high-risk patients having surgery for bladder cancer actually need adjuvant therapy and who could safely skip it, Dr Galsky said.
Although CheckMate 274 did not find that treatment with nivolumab decreased participants’ overall quality of life, those who received the drug did experience more side effects and the treatment caused several deaths. “So, if we can identify patients who absolutely don’t need treatment, that certainly makes sense,” said Dr Galsky.
Other immunotherapy drugs are also being tested as adjuvant treatments for patients with high-risk bladder cancer, Dr Apolo said. For example, NCI researchers recently finished treating participants in a trial called AMBASSADOR, which is comparing pembrolizumab (Keytruda) with observation after surgery.5
In the future, researchers are also interested in testing whether administering nivolumab both before and after surgery can reduce the risk for recurrence even further, Dr Galsky explained. A recent study found that giving pembrolizumab both before and after surgery reduced the risk for recurrence for some patients with melanoma, an aggressive type of skin cancer.6
“We’ll see if we see the same thing with bladder cancer,” Dr Galsky said.
- Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384:2102-2114. Erratum in: N Engl J Med. 2021;385:864.
- Galsky MD, Witjes AA, Gschwend JE, et al. Extended follow-up results from the CheckMate 274 trial. J Clin Oncol. 2023;41(6 suppl):LBA443. Epub ahead of print.
- Bellmunt J, Hussain M, Gschwend JE, et al; for the IMvigor010 Study Group. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22:525-537.
- Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18:312-322.
- National Cancer Institute. Testing MK-3475 (pembrolizumab) after surgery for localized muscle-invasive bladder cancer and locally advanced urothelial cancer. www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCT03244384&r=1. Accessed March 21, 2023.
- Phillips C. Immunotherapy before surgery appears effective for some with melanoma. October 12, 2022. www.cancer.gov/news-events/cancer-currents-blog/2022/melanoma-immunotherapy-before-surgery. Accessed March 21, 2023.