Adjuvant Nivolumab Approaches EU Approval for Select High-Risk Muscle-Invasive Urothelial Carcinoma

Dana Walker, MD, MSCE

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of nivolumab (Opdivo) for use as an adjuvant treatment in adult patients with muscle-invasive urothelial carcinoma with a PD-L1 expression of at least 1% on tumor cells, who are at a high risk of recurrence following radical resection.¹

The opinion is supported by data from the phase 3 CheckMate-274 trial (NCT02632409), which showed that the immunotherapy (n = 353) significantly improved median disease-free survival (DFS) vs placebo (n = 356) in the intent-to-treat (ITT) population, at 20.8 months (95% CI, 16.5-27.6) vs 10.8 months (95% CI, 8.3-13.9), respectively.²

At 6 months, 74.9% patients who received nivolumab were alive and free of disease vs 60.3% of those who received placebo (HR, 0.70; 95% CI, 0.55-0.90; P < .001). The percentage of those who were alive and disease-free at 6 months in the subset of patients with a PD-L1 expression of 1% or higher, was also higher with nivolumab (n = 140) vs placebo (n = 142), at 74.5% vs 55.7%, respectively (HR, 0.55; 98.72% CI, 0.35-0.85; P < .001).

“Based on the results of the CheckMate-274 trial, [nivolumab] is the first and only immunotherapy to significantly extend DFS for high-risk patients with muscle-invasive urothelial carcinoma,” Dana Walker, MD, MSCE, vice president, development program lead of genitourinary cancers, at Bristol Myers Squibb, stated in a press release. “The CHMP’s positive recommendation brings us one step closer to providing patients in the European Union a chance to change the course of their disease at an early stage with an effective and tolerable adjuvant immunotherapy option.”

To be eligible for enrollment on the multicenter, double-blind CheckMate-274, patients were required to have undergone radical surgery within 120 days prior to randomization, with or without having received neoadjuvant cisplatin-based chemotherapy. Patients also needed to have pathological evidence of urothelial carcinoma and be determined to have a high risk of recurrence.

Other eligibility criteria included: being free of disease within 4 weeks prior to randomization, having acceptable tumor tissue available for analysis, and having an ECOG performance status of 0 or 1.

Study participants were randomized 1:1 to receive intravenous nivolumab at 240 mg or placebo, given every 2 weeks via a 30-minute infusion. Treatment was given for up to 1 year, or until disease recurrence or trial discontinuation. Investigators permitted dose delays or discontinuations to appropriately manage toxicity.

Patients were stratified based on PD-L1 expression level (1% or higher vs less than 1% or indeterminate), pathological nodal status (N+ vs N0 or NX with less than 10 nodes removed vs N0 with 10 or more nodes removed), and the utilization of neoadjuvant cisplatin-based chemotherapy (yes vs no).

The co-primary end points of the trial were DFS in both the ITT population and the subset of patients who had a PD-L1 expression of 1% or higher on tumor cells. Key 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, and health-related quality of life.

Baseline characteristics were noted to be balanced between the 2 treatment arms in this population, as well as in the subset of patients with a PD-L1 expression of 1% or higher. In the ITT population, 47.3% and 47.2% of patients in the nivolumab and placebo arms, respectively, had resected lymph nodes with urothelial carcinoma invasion, and 43.3% and 43.5% of patients, respectively, previously received neoadjuvant cisplatin-based chemotherapy.

Among those who were given nivolumab, the median follow-up was 20.9 months (range, 0.1-48.3) vs 19.5 months (range, 0-50.0) in those who received placebo. Among those in the ITT population, 53.3% of patients who received the immunotherapy and 56.3% of those who were given placebo discontinued treatment. The most common reason for discontinuation was disease recurrence, which occurred in 25.6% of those in the investigative arm and 42.2% of those in the control arm.

Additional data from a subgroup analysis showed that those who received nivolumab had a higher probability of DFS than those who were given placebo, irrespective of nodal status, PD-L1 status, or prior neoadjuvant cisplatin-based chemotherapy.

In the ITT population, the median survival free from recurrence outside of the urothelial tract in the nivolumab and placebo arms, respectively, was 22.9 months (95% CI, 19.2-33.4) and 13.7 months (95% CI, 8.4-20.3). Moreover, the percentages of these patients who were alive and free of this recurrence at 6 months were 77.0% and 62.7%, respectively (HR, 0.72; 95% CI, 0.59-0.89).

In the subset of patients with a PD-L1 expression of 1% or higher, the percentage of patients who received nivolumab and who were alive and free from recurrence outside the urothelial tract was 75.3% vs 56.7% of those who received placebo (HR, 0.55; 95% CI, 0.39-0.79).

Nivolumab also extended DMFS vs placebo in both 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 from distant metastasis at 6 months (HR, 0.75; 95% CI, 0.59-0.94). In the PD-L1–positive subset, 78.7% of those who received nivolumab and 65.7% of those given placebo were alive and free from distant metastasis at 6 months (HR, 0.61; 95% CI, 0.42-0.90).

A total of 351 patients and 348 patients in the nivolumab and placebo arms, respectively, had received at least 1 dose of treatment, and the median duration of exposure in these 2 arms was 8.8 months (range, 0-12.5) and 8.2 months (range, 0-12.6), respectively.

Any-cause adverse effects (AEs) were experienced by 98.9% and 95.4% of those in the investigative and control arms, respectively; grade 3 or higher effects were experienced by 42.7% and 36.8% of patients, respectively. Treatment-related toxicities were reported in 77.5% of those who received the immunotherapy vs 55.% of those given placebo; grade 3 or higher treatment-related toxicities were experienced by 17.9% and 7.2% of patients, respectively.

In the nivolumab arm, the most frequent any-grade treatment-related AEs (TRAEs) included pruritus (23.1%), fatigue (17.4%), and diarrhea (16.8%). The most frequent TRAEs that were grade 3 or higher in severity in this arm included elevated serum levels of lipase (5.1%) and amylase (3.7%), diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%).

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 after undergoing radical resection, irrespective of previous neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.³ The decision was based on earlier findings from CheckMate-274.

References

1. Bristol Myers Squibb receives positive CHMP opinion recommending 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; February 25, 2022. Accessed February 25, 2022. https://bit.ly/36IPpFR
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 February 25, 2022. https://bit.ly/3mevpR8