Checkmate 274: expanding treatment options for muscle-invasive bladder cancer

Urothelial carcinomas comprise a heterogenous group of cancers arising from the urethra, bladder, ureters, or renal pelvis. Bladder cancers are the most common primary site, comprising up to 90–95% of urothelial carcinomas, whereas upper tract primaries can make up 5–10% of cases. Staging of urothelial carcinoma depends on the depth of invasion of the primary tumor, and is classified as non-muscle invasive, muscle-invasive, or metastatic (1). Non-muscle-invasive bladder cancers have historically been treated with local therapies and usually have an excellent prognosis. Muscle-invasive urothelial carcinomas tend to be much more aggressive, are managed with radical surgery, and can have recurrence rates of 50% or more, many of which are metastatic recurrences (2,3).

Given this high recurrence and mortality risk, there has been considerable interest in improving outcomes after radical cystectomy for muscle-invasive bladder cancers (MIBCs). In the early 2000s, the results of a SWOG intergroup study were published, establishing neoadjuvant cisplatin based combination chemotherapy (MVAC) as standard of care in MIBC (4). To this day, neoadjuvant cisplatin based chemotherapy remains the standard of care for MIBC, with new regimens (dose dense MVAC with granulocyte colony stimulating factor support and gemcitabine/cisplatin) being used in an effort to reduce toxicities from conventional MVAC (5,6). Neoadjuvant cisplatin based chemotherapy enables some patients to achieve a pathologic complete response at the time of surgery, and also has approximately 6% absolute overall survival (OS) benefit over a 10-year period (7). Although this defined the standard of care for many years, outcomes for many patients with MIBC remained poor, particularly for those at high risk of recurrence based on remaining pathologic disease at the time of surgery. These patients have significantly worse survival, ranging from 10–40% at five years (8,9).

Standard of care adjuvant therapies for these high risk patients, particularly for those who received neoadjuvant chemotherapy, were lacking. Immunotherapy was starting to be used in the metastatic setting with an improvement in OS, so this was speculated to have a role in the adjuvant setting (10,11). Nivolumab is a programmed cell death protein 1 (PD-1) monoclonal antibody that received accelerated approval for metastatic bladder cancer based on an objective response rate of 19.6% in a phase 2 single arm study (12). CheckMate 274 evaluated the use of adjuvant nivolumab in patients with high risk MIBC after radical cystectomy.

CheckMate 274, originally published in 2021, enrolled patients between April 2016 and December 2020 who had high risk surgically resected urothelial carcinoma (defined as pathologic stage T2–T4/node positive if neoadjuvant chemotherapy was given or T3–T4/node positive if no neoadjuvant chemotherapy was given). Patients were randomized to nivolumab or placebo for up to one year and followed for the primary endpoints of disease-free survival (DFS) in the intention to treat (ITT) and programmed cell death ligand 1 (PDL1) >1 populations. OS was one of the secondary endpoints. Initial results showed a statistically significant improvement in median DFS from 10.8 months to 20.8 months and a 6-month DFS benefit from 60% to 75% in the ITT population (P<0.001). The PDL1 >1 population also showed superior 6-month DFS outcomes with nivolumab compared to placebo at 75% vs. 56%, respectively with hazard ratio (HR) 0.55 [95% confidence interval (CI): 0.39–0.79]. OS was premature at that time.

Expanded efficacy data from CheckMate 274 was published in October 2024 (13). This update reported outcomes at a median follow-up of 36 months, as well as interim OS data with an exploratory analysis of patients with bladder primary tumors. As previously reported, the ITT population had a median DFS of 22 vs. 10.8 months in the nivolumab vs. placebo arms, respectively. In this update, the PDL1 >1 patients showed a median DFS of 52.6 vs. 8.4 months in the nivolumab and placebo arms, respectively. Median OS was 69.5 vs. 50.1 months in the ITT nivolumab and placebo arms, respectively, with HR 0.76 (95% CI: 0.61–0.96). Median OS was not reached for patients with PDL1 >1 for either arm. Additional outcome measures included ITT mNUTRFS [25.9 vs. 13.7 with HR 0.72 (95% CI: 0.59–0.88)], mDMFS [47.1 vs. 28.7 months with HR 0.74 (95% CI: 0.60–0.92)], and mPFS2 (61.2 vs. 47.1 months with HR 0.79 (95% CI: 0.63–0.98)). PDL1 >1 outcomes included mNUTRFS [52 vs. 8.4 months with HR 0.53 (95% CI: 0.38–0.74)], mDMFS [NR vs. 20.7 months with HR 0.58 (95% CI: 0.40–0.84)], and mPFS2 [NR vs. 39.4 months with HR 0.54 (95% CI: 0.37–0.79)]. Results from the MIBC subgroup analysis were also shown, which confirmed a DFS benefit in this population. Specifically, the ITT MIBC population showed a median DFS (mDFS) of 25.6 vs. 8.5 months in the nivolumab vs. placebo arms, respectively, with HR 0.63 (95% CI: 0.51–0.78). Non-urothelial tract recurrence free survival (NUTRFS), distant metastasis free survival (DMFS), and progression free survival 2 (PFS2) also showed statistically significant improvements in this population. The PDL1 >1 MIBC population showed DFS 52.6 vs. 8.3 months in the nivolumab vs. placebo arms, respectively, with HR 0.44 (95% CI: 0.30–0.63). Median NUTRFS, DMFS, and PFS2 also showed statistically significant improvements in this population. Median DFS in the PDL1 <1 population were also reported, and also showed improvement [18.3 vs. 9.7 months in the nivolumab vs. placebo arms, respectively, with HR 0.74 (95% CI: 0.56–0.97)]. The DFS benefit of adjuvant nivolumab in the MIBC subgroup was seen regardless of neoadjuvant chemotherapy use, with HR 0.58 (95% CI: 0.43–0.79) and HR 0.69 (95% CI: 0.50–0.94) with and without neoadjuvant chemotherapy, respectively (14). Overall, the interim analysis showed a 24% reduction in the risk of death for patients treated with nivolumab in the ITT population and a 44% reduction in the risk of death for patients in the PDL1 >1% population. Other secondary analysis also supports an OS benefit for adjuvant nivolumab (15).

The implications of the expanded efficacy data from CheckMate 274 reinforce the results from the initial publication and further establish a role for adjuvant nivolumab in high risk MIBC. This is the first adjuvant immunotherapy trial in high risk muscle invasive urothelial carcinoma to show both a DFS benefit and an OS benefit. In context, adjuvant pembrolizumab in the AMBASSADOR trial showed a DFS benefit compared to observation in the ITT population (29.6 vs. 14 months, respectively). OS was not statistically different at three years (60.8% vs. 61.9% in the pembrolizumab arm vs. placebo arm, respectively). Interestingly, the greater impact of adjuvant immunotherapy in PDL1 >1 patients seen in Checkmate 274 was not seen in AMBASSADOR. PDL1 negative patients had a HR of 0.71, from median DFS of 17 vs. 9 months in the pembrolizumab vs. observation arm. Comparatively, PDL1 >1 patients had a HR of 0.81 from median DFS of 37 vs. 21 months). In other words, PDL1 >1 patients did better overall, but did not derive greater benefit from immunotherapy compared to the observation arm in AMBASSADOR. It is unclear why the two trials showed discongruent results based on PDL1 status, but suggests that PDL1 status may not be a perfect tool to select patients for adjuvant treatments.

There are likely multiple reasons for the fact that adjuvant nivolumab showed OS benefit in Checkmate 274 but adjuvant pembrolizumab did not show OS benefit in AMBASSADOR. First, there were likely differences in study populations. The fact that the comparator arm in Checkmate 274 had a worse DFS than the comparator arm in AMBASSADOR suggests some differences between the study populations, and that perhaps Checkmate 274 had a higher risk cohort that could be more likely to benefit from adjuvant therapy. Notably, patients in Checkmate 274 had a lower rate of neoadjuvant chemotherapy use (approximately 43%) compared to patients in AMBASSADOR (approximately 63%). Additionally, the rate of subsequent immunotherapy in the comparator arm from AMBASSADOR was 50%, while the rate of subsequent immunotherapy in the comparator arm in Checkmate 274 was 26%. This likely also played a role in the difference in OS outcomes between AMBASSADOR and Checkmate 274 with immunotherapy being more readily available for those in the AMBASSADOR trial leading to some unanticipated crossover by patients in the observation group. Interestingly, AMBASSADOR trial failed to show OS benefit despite the fact that the comparator arm also had half the rate of subsequent antibody drug conjugate compared to the pembrolizumab arm, which we now know improves survival in recurrent/metastatic urothelial carcinoma (16). In contrast, IMVIGOR010 failed to show even DFS benefit to adjuvant atezolizumab, regardless of PLD1 expression (HR 1.01 for PDL1 IC2/3 patients and HR 0.81 for PDL1 IC0/1 patients, neither of which met statistical significance) (17). Reasons for the lack of benefit seen in IMVIGOR010 are unclear. It is possible that there are biological differences between anti-PDL1 checkpoint inhibitors (atezolizumab) compared to anti-PD1 checkpoint inhibitors (pembrolizumab and nivolumab) which may have played a role in the difference in outcomes. Additionally, trial design differences such as use of placebo control in Checkmate 274 (vs. observation in AMBASSADOR and IMVIGOR010) may have led to better adherence with randomization as suggested by lower rates of patient drop-out in Checkmate 274 compared to the other studies. The studies also used different PDL1 assays (Dako 28-8 in Checkmate 274, Dako 22C3 in AMBASSADOR, and VENTANA SP142 in IMVIGOR010), which is relevant because these assays were used to stratify patients based on PDL1 status during randomization and also for subgroup analyses based on PDL1 status. These explanations, however, are speculative, and the lack of consistent class effect of adjuvant immunotherapy warrants further investigation.

After the publication of Checkmate 274, the NIAGARA trial evaluated the role of perioperative durvalumab in high risk muscle invasive urothelial cancer (18). This trial randomized patients with MIBC to gemcitabine and cisplatin followed by cystectomy vs. gemcitabine/cisplatin/durvalumab followed by durvalumab maintenance. Primary endpoints were pathologic complete response and event-free survival (EFS). OS was a secondary endpoint. The trial showed a 24-month EFS of 67.8% vs. 59.8% in the durvalumab vs. control arms, respectively (statistically significant). Estimated OS was 82.2% vs. 75.2% in the durvalumab vs. control arm, respectively. This was statistically significant, though at this time, the data is immature and the breakdown of subsequent therapies used on progression is not yet available. The rate of pathologic complete response was 33.8% vs. 25.8% in the durvalumab vs. control arm (which did not meet statistical significance based on prespecified threshold).

A direct prospective comparison between the NIAGARA regimen and the Checkmate 274 regimen has not been performed. Additionally, a full breakdown of the pathologic stage from NIAGARA is not yet available, but 60% of the patients in the comparator arm had at least pT2 disease or greater at the time of cystectomy. These patients would be candidates for adjuvant nivolumab based on the Checkmate 274 data. Therefore, it is unclear whether perioperative immunotherapy is superior to using adjuvant immunotherapy for high risk patients as was done in Checkmate 274. Currently, both the Checkmate 274 and the NIAGARA regimens are category 1 options in the NCCN guidelines.

Taken in summary, CheckMate 274 remains the only phase 3 trial to date to show both DFS and OS benefit to using adjuvant immunotherapy in high risk muscle invasive urothelial cancer. This trial shows a benefit in the ITT population and the PDL1 >1 populations, as well as the MIBC subgroup across all major trial endpoints including DFS, OS, NUTRFS, DMFS, and PFS2. This trial did show a greater impact of nivolumab in the PDL1 >1 patients compared to the ITT population, but this preferential impact is not seen consistently in other MIUC trials involving immunotherapy and Checkmate 274 was not powered for a direct comparison between PDL1 positive and negative patients. A benefit was also seen regardless of neoadjuvant chemotherapy use in the MIBC subgroup, as outlined above. On the basis of this data, adjuvant nivolumab is a compelling and standard of care option for patients who have high risk disease at the time of surgery. Applying this data to the rapidly evolving landscape of MIBC remains a challenge. Enfortumab vedotin with pembrolizumab is now the standard of care front line option for metastatic bladder cancer, and Checkmate 274 had a 26% rate of subsequent immunotherapy in the control arm and the rate of ADC use is not known. Therefore, it is difficult to state whether the OS benefit will hold true today, but certainly the DFS benefit remains. Additionally, the use of perioperative chemoimmunotherapy with gemcitabine, cisplatin, and durvalumab followed by durvalumab maintenance after surgery has become commonplace in MIBC based on the NIAGARA data, and is also a category 1 option in the National Comprehensive Cancer Network (NCCN) guidelines. At this time, we cannot say which approach is superior, but the data overall supports the use of immunotherapy in MIBC.

The next steps in the management of patients with MIBC will be optimizing patient selection when choosing regimens. It remains to be determined which patients benefit the most from perioperative/adjuvant immunotherapy. Some patients can be cured by neoadjuvant chemotherapy and cystectomy alone, and we are likely overtreating these patients. On the other hand, many patients might experience an enhanced disease-free interval and possibly survival as a result of perioperative/adjuvant immunotherapy, and these are the patients we hope to treat. Circulating tumor DNA (ctDNA) has been shown to be highly predictive of disease recurrence in MIBC (19). One study found ctDNA analysis to have a 94% sensitivity and 98% specificity for predicting metastatic recurrence within 5 years of radical cystectomy in patients who received neoadjuvant chemotherapy for MIBC (20). In the NIAGARA trial, clearance of ctDNA after neoadjuvant treatment and surgery was strongly associated with pathologic complete response and significantly superior clinical outcomes, with median DFS not reached going out several years (21). Future trials could therefore clarify whether ctDNA positivity can select the highest risk patients for whom adjuvant therapies are most likely to provide benefit, and also whether ctDNA negativity can identify patients who are effectively cured from their neoadjuvant therapy and surgery and might be spared from adjuvant therapies. This is an active area of investigation. Besides ctDNA, other biomarkers that reflect mutation and gene expression profiles (like interferon gamma signature, CD4 gene expression, tumor mutational burden, transforming growth factor beta gene signature, and others) may also have a role in selecting patients most likely to benefit from adjuvant immunotherapy (22). Advanced imaging techniques may also improve patient selection for perioperative chemoimmunotherapy or adjuvant immunotherapy as suggested by the finding that fluorodeoxyglucose positron emission tomography (FDG PET) scans may better identify occult regional nodal metastasis than conventional CT or MRI imaging, particularly in variant histology subtypes (23). As we continue to explore the optimal management of MIBC, neoadjuvant cisplatin-based chemotherapy followed by adjuvant nivolumab in select patients a la Checkmate 274 regimen, and now also the NIAGARA regimen, define the current standard of care.

Acknowledgments

None.

Footnote

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