Adjuvant immune checkpoint blockade in urothelial cancer: A new era?

Patients with muscle-invasive urothelial cancer of the bladder and invasive urothelial cancer of the upper urinary tract are at generally at high risk for metastatic recurrence despite curative intent surgery. A series of clinical trials investigating systemic therapies applied in the adjuvant setting have been performed over the past few decades in an attempt to mitigate this risk.¹ Compared with the development of therapeutic approaches in the metastatic setting, the development of therapeutic approaches in the adjuvant setting is potentially more impactful but more complicated. That is, in the metastatic setting, we mainly face the question “Who benefits from treatment?” Whereas in the adjuvant setting, we face both the question “Who needs treatment?” and “Who benefits from treatment?” A large proportion of patients with muscle-invasive urothelial cancer will achieve cure with surgical resection alone. On the other hand, for those patients who harbor micrometastatic disease after surgery, just as in the metastatic setting, not all such cancers will be sensitive to the systemic therapy being applied.

Historically, we have addressed the “Who needs treatment?” question in the adjuvant setting by using pathologic features of the primary tumor and regional lymph nodes to help refine estimates regarding recurrence risk. Such features, in turn, have formed the eligibility criteria for clinical trials. The majority of adjuvant trials in urothelial cancer have enrolled patients with bladder-only primary tumors and have limited enrollment to patients who had not received prior neoadjuvant chemotherapy and had pathologic T3 or higher urothelial cancer or pathologic evidence of regional lymph node involvement. Randomized trials exploring adjuvant cisplatin-based chemotherapy in this context suffered from methodologic flaws and/or closed early due to poor accrual, leaving some doubt regarding the efficacy of this approach despite meta-analyses suggesting a benefit.²

Although trials of adjuvant cisplatin-based chemotherapy in high-risk urothelial cancer continued, for a number of reasons, neoadjuvant cisplatin-based chemotherapy became the standard preferred treatment standard supported by level I evidence.^3,4 Therefore, regardless of one’s interpretation of the studies evaluating adjuvant cisplatin-based chemotherapy, additional unmet need populations at high risk for recurrence after surgery arose not addressed by the prior generation of studies: (1) patients with pT3 or higher and/or pN-positive disease who are considered cisplatin ineligible⁵ and (2) patients with residual ypT3 or higher and/or ypN-positive disease despite having received prior cisplatin-based neoadjuvant chemotherapy. These 2 distinct populations have formed the basis for large phase 3 trials exploring PD-1 and PD-L1 immune checkpoint inhibitors in the adjuvant setting triggered by the safety and efficacy of these therapies in metastatic urothelial cancer.

Three somewhat similarly designed adjuvant trials, with some nuances, have been conducted to test adjuvant PD-1 or PD-L1 blockade. IMvigor010 (NCT02450331) randomized patients with urothelial cancer of the upper tract or bladder at high risk for recurrence (as defined above) after definitive surgery to atezolizumab (Tecentriq) administered for 1 year vs observation.⁶ This was the first in the series of immune checkpoint blockade adjuvant trials to report and it was presented at the 2020 American Society of Clinical Oncology Annual Meeting, though it has not been published. The trial did not meet the primary end point of improvement in disease-free survival with atezolizumab in the intent-to-treat population, nor was there in an improvement in the subset of patients with tumors harboring increased PD-L1 protein expression.

The Checkmate 274 trial (NCT02632409) employed similar eligibility criteria but randomized patients to 1 year of adjuvant nivolumab (Opdivo) vs placebo (rather than observation).⁷ This trial, presented at the 2021 Genitourinary Cancers Symposium, met coprimary end points of an improvement in disease-free survival in the intent-to-treat population (HR, 0.70; 95% CI, 0.54-0.89; P < .001) and in the subset of patients with tumors harboring increased PD-L1 protein expression (HR, 0.53; 95% CI, 0.34-0.84; P < .001). Overall survival, a secondary end point of this study and an event-driven analysis, has not been assessed. A third trial enrolling a similar patient population but randomizing patients to 1 year of adjuvant pembrolizumab (Keytruda) vs observation, dubbed the AMBASSADOR trial (NCT03244384), is still enrolling.

Many questions have arisen regarding the disparate results reported from IMvigor010 and Checkmate 274. Ultimately, these are different drugs explored, employing different PD-L1 biomarkers, in trials that likely enrolled patients with slightly different baseline characteristics and involved some important clinical trial design nuances. For example, the former involving randomization between atezolizumab and observation may have been affected by informed censoring based on the proportion of patients randomized to observation that withdrew early from the study. Checkmate 274 represents the first trial demonstrating an improvement in outcomes with an adjuvant immune checkpoint inhibitor in urothelial cancer, addresses a patient population without previously available systemic therapies to mitigate risk of recurrence, and represents the first big step in a new era of immune checkpoint inhibitor for muscle-invasive urothelial cancer.

Galsky is acting chief, Division of Hematology and Medical Oncology, and professor of medicine at Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York City, New York.

References

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6. Hussain MHA, Powles T, Albers P, et al. IMvigor010: primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma (MIUC). J Clin Oncol. 2020;38(suppl 15):5000. doi:10.1200/jco.2020.38.15_suppl.5000

7. Bajorin DF, Witjes JA, Gschwend J. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC). J Clin Oncol. 2021;339(suppl 6):391. doi:10.1200/JCO.2021.39.6_suppl.391