Updated CheckMate 274 Data Reaffirm Benefit of Adjuvant Nivolumab in Muscle-Invasive Urothelial Carcinoma

Following the FDA approval of nivolumab (Opdivo) for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection in August 2021, long-term follow-up of the phase 3 CheckMate 274 trial (NCT02632409) reaffirmed the benefit of adjuvant immunotherapy in this patient population, according to Matthew Galsky, MD.¹

Extended follow-up data presented at the 2023 Genitourinary Cancers Symposium showed that at a median follow-up of 36.1 months (range, 0.0-75.3) in the intention-to-treat (ITT) population, nivolumab provided a median disease-free survival (DFS) of 22.0 months (95% CI, 18.8-36.9) vs 10.9 months (95% CI, 8.3-15.2) with placebo (HR, 0.71; 95% CI, 0.58-0.86).² Moreover, in patients with PD-L1 expression of at least 1%, the median DFS was 52.6 months (95% CI, 25.8-not estimable) for nivolumab vs 8.4 months (95% CI, 5.6-17.9) for placebo (HR, 0.52; 95% CI, 0.37-0.72).

“[These data further] support the use of adjuvant immune checkpoint blockade as an important component of our treatment [for] patients with muscle-invasive urothelial cancer,” said Galsky, who is a professor of Medicine (Hematology and Medical Oncology), director of Genitourinary Medical Oncology, and co-director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute, New York, New York, in an interview with OncLive®.

In the interview, Galsky, who is also the associate director for Translational Research at The Tisch Cancer Institute, discussed the key long-term findings and the clinical implications of the updated data from CheckMate 274, as well as other exciting research efforts underway in urothelial cancer.

OncLive^®: What were the key objectives of the Checkmate 274 trial?

Galsky: Checkmate 274 was a study of adjuvant nivolumab vs placebo in patients with muscle-invasive urothelial cancer at high risk for recurrence after radical surgery. High risk of recurrence was defined by pathological stage, so [the study included] patients who had neoadjuvant chemotherapy and had pathological T2 or higher urothelial cancer in their surgical specimen, or those who didn’t have neoadjuvant chemotherapy and had pathological T3 or higher disease in their surgical specimen but were cisplatin ineligible.

[Previously,] we [did not have] data to guide treatment in those 2 contexts in terms of post-operative systemic treatment to mitigate the risk of recurrence, so the trial was designed to meet that unmet need.

What were the previously reported findings that led to the FDA approval of adjuvant nivolumab in high-risk urothelial carcinoma?

Checkmate 274 led to the approval of adjuvant nivolumab in the United States and elsewhere in the world for the treatment of patients with muscle-invasive urothelial cancer at high-risk for recurrence after radical surgery. That [approval] was based on the initial results of the study, which were presented with a minimum follow-up of 5.9 months.

The co-primary end points were presented at the [time of the] initial report, [and they included] DFS in the ITT population and DFS in those with tumors [that had] PD-L1 expression greater than or equal to 1%. That primary analysis showed an improvement in DFS in both of those populations, meeting the co-primary end points.

What were the key long-term efficacy findings presented at the 2023 Genitourinary Cancers Symposium?

We now have minimum follow-up from the Checkmate 274 trial of 31.6 months. The report of this extended follow-up includes the co-primary endpoints of DFS in all randomized patients and in the subset of patients with tumor PD-L1 expression greater than or equal to 1%.

Secondary end points included non–urothelial tract recurrence-free survival, [which] are recurrences within the pelvis but outside of the urothelial or urinary tract. Exploratory end points included distant metastases–free survival, and a new end point that hadn’t been [previously] reported for this cohort: progression-free survival 2 [PFS2]. The [latter] end point is measured from the time of randomization to the time of progression on subsequent next-line therapy. For instance, a patient who is randomized to placebo develops recurrent disease, starts immune checkpoint blockade for metastatic recurrence, and then progresses. [PFS2] is measured from that time point.

With extended follow-up, all those end points were reported in both the ITT population and in the subset of patients with tumor PD-L1 expression greater than or equal to 1%. All those end points showed a benefit in favor of nivolumab. With this extended follow-up, the effect size has remained remarkably consistent across every single one of those end points.

Were there any new safety signals observed with extended follow-up?

With longer follow-up, no new safety signals were observed. Grade 3 or higher [treatment-related] adverse effects [occurred in] 18% of patients in the [nivolumab] arm compared with 7% [of those] in the placebo arm. The safety profile of nivolumab, in this context, was very similar to what has been seen across all clinical disease states.

Are there any next steps planned for this research or future avenues for investigation that these data open up?

This trial establishes adjuvant immune checkpoint blockade as a standard treatment for urothelial cancer. There are a number of ongoing investigations related to this study and building on this study.

What’s still coming from Checkmate 274? There is a robust translational research effort related to [the trial] to try and better understand which tumor microenvironment is predisposed to a benefit from immune checkpoint blockade in the adjuvant setting. There are also the survival data from the study, which is a secondary end point and an event-driven end point, so we haven’t seen that [information] yet.

Then, there is future research seeking to refine the use of adjuvant immune checkpoint blockade. There are now at least 2 randomized studies seeking to integrate circulating tumor DNA to define which patients might benefit from immune checkpoint blockade and perhaps which patients can be safely observed after surgery.

What is your take-home message regarding this research?

With much longer follow-up from this dataset, we’re seeing incredibly stable effects for adjuvant nivolumab vs placebo across all the end points of the study; the consistency is remarkable. Across all primary, secondary, and exploratory end points in the ITT population, the effect size is consistently in the 0.7 range for hazard ratios. In patients with tumor PD-L1 expression greater than or equal to 1%, the hazard ratios across all those end points are consistently in the 0.5 range.

Were there any other research efforts presented during the meeting that you would like to highlight?

The other data being presented at the 2023 Genitourinary Cancers Symposium that was of interest were 2 studies seeking to determine whether we can shift the [treatment] paradigm [for] patients with muscle-invasive bladder cancer [MIBC]. What I mean by that is whether we can define a population of patients who might be treated curatively with transurethral resection plus systemic therapy alone.

Two studies reported updated results. One study that I’m involved with, the [phase 2] HCRN GU 16-257 trial [NCT03558087], enrolled patients with MIBC who were cisplatin eligible. Patients received 4 cycles of gemcitabine/cisplatin plus nivolumab. After completion of 4 cycles, patients underwent clinical restaging, which included cystoscopy, biopsies, urine cytology, and MRI of the bladder. If all those assessments were normal, they were considered to have a clinical complete response [CR]. If a clinical CR was observed, they were offered the opportunity to receive an additional 4 months of nivolumab and then observation, rather than have a cystectomy or radiation to the bladder. They [were permitted] to have a cystectomy in that setting. If patients didn’t have a clinical CR, cystectomy was recommended.

The study that tested a slight twist on that theme was the [phase 2] RETAIN BLADDER trial [NCT02710734,] which [also’ enrolled patients with MIBC. Patients receive dose-dense MVAC [methotrexate, vinblastine, adriamycin, and cisplatin]. If patients had a clinical CR and their tumors harbored one of a predefined set of alterations in DNA damage response genes, then they were offered the opportunity to proceed with observation.

These 2 data sets together are interesting to compare, and [it is] interesting to think about how this paradigm could be moved forward. Results from HCRN GU 16-257 suggest that clinical CR uniformly assessed and consistently defined does identify a patient population who has a favorable prognosis and could be targeted for a risk-adapted, bladder-sparing approach.

References

1. 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 March 7, 2023. https://news.bms.com/news/
2. Galsky MD, Witjes JA, Gschwend JE, et al. Extended follow-up results from the CheckMate 274 trial. J Clin Oncol. 2023;41(suppl 6):LBA443. doi:10.1200/JCO.2023.41.6_suppl.LBA443