Adjuvant Nivolumab Approved in Europe for Select High-Risk Muscle-Invasive Urothelial Carcinoma

The European Commission has approved nivolumab (Opdivo) for use in the adjuvant treatment of adult patients with muscle-invasive urothelial carcinoma and a PD-L1 expression of 1% or higher on tumor cells, who are at a high risk of recurrence following radical resection.¹

The regulatory decision is supported by data from the phase 3 CheckMate-274 trial (NCT02632409), in which the immunotherapy resulted in a 47% reduction in the risk of disease recurrence or death vs placebo in patients with a PD-L1 expression of 1% or higher. The median disease-free survival (DFS) was not yet reached in the investigative arm vs 8.41 months with placebo (HR, 0.53; 95% CI, 0.38-0.75; P = .0005).

“For years, patients with muscle-invasive urothelial carcinoma have lived with the unfortunate reality that, despite being diagnosed early enough to have their cancer removed, around half will face disease recurrence, with few safe and effective treatment options available to help prevent this cycle,” Fred Witjes, MD, professor of oncological urology at Radboud Institute for Molecular Life Sciences, stated in a press release. “With the approval of nivolumab, clinicians will now have an immunotherapy treatment option to offer certain patients after surgery that, in the CheckMate-274 clinical trial, significantly reduce the risk of disease recurrence or death. This approval has the potential to transform the way we treat muscle-invasive urothelial carcinoma for appropriate patients in the European Union.”

The multicenter, double-blind, phase 3 trial enrolled those who had radical surgery within 120 days prior to randomization, with or without neoadjuvant cisplatin-based chemotherapy. Patients needed to have pathological evidence of urothelial carcinoma with a high risk of recurrence.² They also must have been free of disease within 4 weeks prior to randomization, an ECOG performance status of 0 or 1, and acceptable tumor tissue for biomarker analysis.

Study participants were randomized 1:1 to receive nivolumab at 240 mg or placebo given every 2 weeks for up to 1 year or until disease recurrence or trial discontinuation. Patients were stratified based on PD-L1 expression (≥1% vs <1% or indeterminate), pathological nodal status (N+ vs B0 or NX with <10 nodes removed vs N0 with ≥10 nodes removed) and use of neoadjuvant cisplatin-based combination treatment (yes vs no).

The 2 primary end points of the trial were DFS in the intention-to-treat (ITT) population and in the subset of patients with a PD-L1 expression level of 1% or higher on tumor cells. Secondary end points comprised survival free from recurrence outside of the urothelial tract, overall survival, and disease-specific survival in both populations.

Exploratory end points included distant metastasis–free survival (DMFS), safety, toxicity profile, and health-related quality of life.

A total of 709 patients underwent randomization on the trial; 353 patients were randomized to receive the immunotherapy and 356 were randomized to placebo. Moreover, within the population of patients with a PD-L1 expression level of 1% or higher, 140 received nivolumab and 142 received placebo.

In the ITT population, 47.3% and 47.2% of those in the investigative and control arms, respectively, had resected lymph nodes with urothelial carcinoma invasion. Moreover, 43.3% and 43.5% of patients, respectively, had previously received neoadjuvant cisplatin-based chemotherapy. The patient characteristics at baseline were noted to be well balanced between the 2 treatment arms in both populations.

The median follow-up was 20.9 months (range. 0.1-48.3) in those who received nivolumab, and 19.5 months (range, 0.0-50.0) in those who received placebo. In the ITT population, the median DFS was 20.8 months (95% CI, 16.5-27.6) with the immunotherapy and 10.8 months (95% CI, 8.3-13.9) with placebo. A higher percentage of patients were alive and free of disease at 6 months in the nivolumab arm vs the placebo arm, at 74.9% and 60.3%, respectively (HR, 0.70; 98.22% CI, 0.55-0.90; P < .001).

In the population of patients with a PD-L1 expression level of 1% or higher, 74.5% of those in the nivolumab arm were alive and free of disease at 6 months vs 55.7% of those in the placebo arm (HR, 0.55; 98.72% CI, 0.35-0.85; P < .001).

Additional data published in the New England Journal of Medicine indicated that within the ITT population, the median survival free of recurrence outside the urothelial tract was 22.9 months (95% CI, 19.2-33.4) in those who received nivolumab vs 13.7 months (95% CI, 8.4-20.3) in those who received placebo.

At 6 months, the percentage of patients who were alive and free of recurrence outside the urothelial tract was 77.0% and 62.7% with nivolumab and placebo, respectively (HR, 0.72; 95% CI, 0.59-0.89). In the population of patients with a PD-L1 expression level of 1% or higher, 75.3% of those who received the immunotherapy and 56.7% of those who were given placebo were alive and free of recurrence outside of the urothelial tract at 6 months (HR, 0.55; 95% CI, 0.39-0.79).

DMFS was also noted to be longer with nivolumab vs placebo in both patient populations. In the ITT population, the median DMFS with the immunotherapy was 40.5 months (95% CI, 22.4–not estimable [NE]) vs 29.5 months (95% CI, 16.7-NE) with placebo. Moreover, 82.5% and 69.8% of patients in the investigative and control arms, respectively, were alive and free of distant metastasis at 6 months (HR, 0.75; 95% CI, 0.59-0.94). In the population of patients with PD-L1 expression level of 1% or higher, 78.7% of those in the nivolumab arm were alive and free from distant metastasis at 6 months vs 65.7% of patients in the placebo arm (HR, 0.61; 95% CI, 0.42-0.90).

Regarding safety, nivolumab was found to be generally well tolerated, with a toxicity profile that proved to be consistent with what has previously been reported with the agent in those with solid tumors.

The most common treatment-related adverse effects (TRAEs) of any grade in the immunotherapy arm included pruritus (23.1%), fatigue (17.4%), and diarrhea (16.8%). The TRAEs that were grade 3 or higher and were most frequently experienced with nivolumab included elevated serum levels of lipase (5.1%) and amylase (3.7%), as well as diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%).

The toxicity profile of nivolumab was comparable in the population of patients who had a PD-L1 expression level of 1% or higher on tumor cells.

“We are driven by the goal of advancing new treatment options that can help change the outlook for patients with cancer, whether they are diagnosed at an earlier stage or with metastatic disease,” Dana Walker, MD, MSCE, vice president and development program lead of genitourinary cancers at Bristol Myers Squibb, added in the press release. “This approval for [nivolumab] gives us the opportunity to introduce a new post-surgery standard of care for certain patients with urothelial cancer, building on our legacy as the first company to bring immune checkpoint inhibitors to patients in the European Union in the adjuvant settings of melanoma and esophageal cancers.”

Previously, in August 2021, the FDA approved nivolumab for use in the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence following radical resection, irrespective of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status based on earlier data from CheckMate-274.³

References

1. Bristol Myers Squibb receives European Commission approval for Opdivo (nivolumab) as adjuvant treatment for patients with radically resected, high-risk muscle-invasive urothelial carcinoma with tumor cell PD-L1 expression ≥1%. News release. Bristol Myers Squibb; April 5, 2022. Accessed April 5, 2022. https://bit.ly/3LD22RQ
2. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114. doi:10.1056/NEJMoa2034442
3. US Food and Drug Administration approves Opdivo (nivolumab) for the adjuvant treatment of patients with high-risk urothelial carcinoma. News release. Bristol Myers Squibb; August 20, 2021. Accessed April 5, 2022. https://bit.ly/3mevpR8