Novel Immunotherapies in Perioperative Setting in Muscle-Invasive Bladder Cancer May Transform Clinical Practice

An estimated 82,290 new cases of bladder cancer will be diagnosed in the United States in 2023.¹ The disease is typically divided into 3 groups for the collective purpose of treatment management: muscle-invasive bladder cancer (MIBC), non–muscle-invasive bladder cancer, and metastatic disease. MIBC accounts for approximately 25% of newly diagnosed cases of bladder cancer.² Although the overall 5-year relative survival rate for patients with bladder cancer is 77.9%, the survival rates decrease as disease spreads. Patients with localized tumors, which do not spread outside the bladder wall, have a survival rate of 70.9%, whereas tumors spreading beyond the bladder to nearby lymph nodes or organs in a regional fashion decrease the survival rate to 39.2%.¹

Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy improves survival compared with surgery alone.² In addition, neoadjuvant chemotherapy has a higher quality of evidence and, therefore, is preferred over adjuvant chemotherapy. Systemic treatment options for perioperative therapy have historically been limited to traditional chemotherapy agents. Gemcitabine (Gemzar; Eli Lilly and Company) plus cisplatin has demonstrated noninferiority compared with methotrexate (Otrexup; Otter Pharmaceuticals), vinblastine (Velban; Bedford Laboratories), doxorubicin (Adriamycin; Pfizer), and cisplatin and is a reasonable, safer alternative based on evidence in advanced or metastatic MIBC.³

Older age and comorbidities are considered in the management of MIBC for all treatment modalities.^4-7 However, oncologic drug shortages in recent years (particularly with cisplatin and methotrexate) have complicated treatment decisions, leading to potential changes in therapy or omissions.⁸ Perioperative immunotherapy alone or in combination with cisplatin-based chemotherapy has the potential to provide additional treatment options for patients with MIBC.

Only 1 immunotherapy agent is currently FDA approved as adjuvant therapy in MIBC. Nivolumab (Opdivo; Bristol Myers Squibb) is approved for the adjuvant treatment of adult patients with urothelial carcinoma at high risk of recurrence after undergoing radical resection.⁹ Studies in the perioperative setting of 2 additional immunotherapy agents and an antibody-drug conjugate may reveal significant survival benefits and transform clinical practice. The goal of this review is to highlight perioperative immunotherapy treatment options in the setting of MIBC, which are being explored to optimize curative outcomes, improve resectability, and prevent progression.

Neoadjuvant Atezolizumab

The multicenter, single-arm, phase 2 ABACUS study (NCT02662309) analyzed the clinical efficacy of neoadjuvant atezolizumab (Tecentriq; Genentech, Inc) followed by radical cystectomy in 95 patients with MIBC who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy as initial treatment. Patients in the trial received atezolizumab 1200 mg once every 3 weeks for 2 cycles. Radical cystectomy with lymph node dissection was scheduled 4 to 8 weeks following enrollment. Seventy-five percent of patients had an ECOG performance status of 0; 74% had T2 disease, 18% had T3 disease, and 8% had T4 disease. Moreover, 15% of patients previously had non–muscle invasive disease, 12% previously received intra-vesical BCG, and 41% were PD-L1 positive (defined as expression levels ≥ 5% via immunohistochemistry).¹⁰

The primary end point of pathological complete response rate (defined as pT0N0M0) in 87 evaluable patients who underwent radical cystectomy was 31% (95% CI, 21%-41%) in the overall population and 37% (95% CI, 22%-55%) in patients with PD-L1–positive disease. With a median follow-up of 25 months for all 95 patients, the secondary end points of 2-year disease-free survival (DFS) rate and 2-year overall survival (OS) rate were 68% (95% CI, 58%-76%) and 77% (95% CI, 68%-85%), respectively. Patients who achieved pathologic complete response at time of surgery had an improved 2-year DFS rate of 85% (95% CI, 65%-94%). Statistically significant findings that correlated with poor DFS included higher T stage (T3-T4) at baseline (HR, 2.4; 95% CI, 1.0-5.6; P = .045), higher T stage at cystectomy (HR, 13; 95% CI, 3.7-4.3; P < .001), and node-positive disease at time of surgery (HR, 6.6; 95% CI, 2.4-18; P < .001).¹⁰

The incidence of grade 3 or greater adverse events (AEs) during neoadjuvant therapy was 11%, including transaminitis (3%), fatigue (1%), decreased appetite (1%), and pyrexia (1%). Only 1 cycle of neoadjuvant atezolizumab was administered to 21% of patients, with 9% of discontinuations attributable to treat-ment-related AEs. During the postoperative period, 14% of patients had atezolizumab-related AEs, with notable grade 3 or greater AEs such as adrenal insufficiency and transaminitis occurring in 1% of patients.¹¹

Neoadjuvant atezolizumab has also been evaluated in patients with MIBC who were eligible for cisplatin. A multicenter, single-arm, phase 2 study (NCT02989584) enrolled 44 patients with MIBC who were eligible for radical cystectomy and neoadjuvant cisplatin-based chemotherapy. Patients received four 21-day cycles of atezolizumab 1200 mg every 3 weeks on day 8, gemcitabine 1000 mg/m² on days 1 and 8, and cisplatin at either full dose (70 mg/m2 on day 1) or split dose (35 mg/m² on days 1 and 8 if impaired renal function). Patients received a lead-in dose of atezolizumab prior to the 4 cycles of chemotherapy and an additional dose of atezolizumab after chemotherapy completion, for a total of 6 doses of atezolizumab. Radical cystectomy with lymph node dissection was recommended approximately 4 to 8 weeks after the last dose of chemotherapy.¹²

Of the 44 patients enrolled, 39 were included in the efficacy evaluation. Notably, 79.5% of evaluable patients had T2 disease, 17.9% had T3 disease, and 2.6% had T4a disease. However, only 5.1% of patients had previously received intravesical BCG. Further, 10.3% of patients had PD-L1–positive tumors (defined as expression levels ≥ 5% via immunohistochemistry), and 15.4% of patients received split-dose cisplatin because they had decreased renal function.¹²

The primary end point of pathologic downstaging (defined as < pT2N0M0) was achieved in 69.2% of evaluable patients (95% CI, 55.0%-79.0%). The pathologic complete response rate (defined as pT0N0M0) was 41.0%. With a median follow-up of 23.6 months, the median DFS and median OS were not reached at time of data cutoff. No association was found between PD-L1 status and rate of pathologic downstaging, although it should be noted that the sample size for PD-L1–positive patients was small (only 4 patients). In all 44 enrolled patients, the incidence of grade 3 or greater AEs was 59%, with the most commonly reported being neutropenia (36.4%), lymphopenia (15.9%), and anemia (11.4%).¹²

Perioperative Pembrolizumab

Early clinical data suggest that neoadjuvant pembrolizumab (Keytruda; Merck Sharp & Dohme LLC) is efficacious in MIBC. A multicenter, single-arm, phase 2 study (NCT02690558) analyzed the clinical activity of pembrolizumab in combination with gemcitabine and split-dose cisplatin in 39 patients with MIBC. After a protocol amendment, patients received pembrolizumab 200 mg on day 1, gemcitabine 1000 mg/m2 on days 1 and 8, and split-dose cisplatin 35 mg/m2 on days 1 and 8 of each 21-day cycle for 4 cycles. Radical cystectomy with lymph node dissection was then performed within 4 to 8 weeks of neoadjuvant therapy, if feasible.¹³

Of the 39 patients enrolled, 72% had T2 disease, 23% had T3 disease, and 5% had T4a disease. Eighteen percent of patients previously had non–muscle invasive disease, and 13% previously received intravesical BCG. Eighteen of 33 patients had available baseline tumor tissue that was positive for PD-L1, defined as a modified proportion score of 10 or greater (analogous to the accepted cutoff of a combined positive score of ≥ 10).¹³

The primary end point of pathologic downstaging (defined as < pT2N0M0) was achieved in 56% of patients (95% CI, 40%-72%). The pathologic complete response rate (defined as pT0N0M0) was 36% (95% CI, 21%-53%). With a median follow-up of 15.7 months, 21% of patients had relapsed. The 1-year DFS rate was 75%, and the 1-year OS rate was 91%. Median DFS and median OS were not reached at time of data analysis.¹³

Patients who achieved pathologic downstaging demonstrated longer DFS compared with patients who could not be downstaged (HR, 0.13; 95% CI, 0.03-0.59; P = .009). For the 33 patients with available baseline tumor tissue, the rate of pathological downstaging was not significantly different between patients who were PD-L1 positive or PD-L1 negative (67% vs 47%, respectively; P = .25). The incidence of grade 3 or greater AEs was 74.4%, with the most commonly reported being neutropenia (41.0%), thrombocytopenia (33.3%), and lymphopenia (15.4%).¹³

Additional large studies are under way evaluating the perioperative use of pembrolizumab with or without an antibody-drug conjugate in patients with MIBC. The phase 3 KEYNOTE-866 trial (NCT03924856) is analyzing the clinical efficacy and safety of pembrolizumab vs placebo in combination with neoadjuvant chemotherapy in cisplatin-eligible patients with MIBC. The phase 3 KEYNOTE-905/EV-303 trial (NCT03924895) is evaluating the clinical efficacy and safety of perioperative pembrolizumab monotherapy vs perioperative pembrolizumab with enfortumab vedotin-ejfv (Padcev; Astellas Pharma US, Inc) vs radical cystectomy and pelvic lymph node dissection alone in cisplatin-ineligible patients with MIBC.¹⁴

The multinational, randomized, double-blind, placebo-controlled KEYNOTE-866 trial is expecting to recruit 870 patients with MIBC eligible for cisplatin-based chemotherapy and will randomly assign them 1:1 to receive neoadjuvant gemcitabine 1000 mg/m² on days 1 and 8 and cisplatin 70 mg/m² on day 1, with or without pembrolizumab 200 mg on day 1, every 21 days for 4 cycles. No later than 6 weeks after neoadjuvant treatment, patients will undergo radical cystectomy and pelvic lymph node dissection, followed by either pembrolizumab 200 mg or placebo once every 3 weeks for 13 cycles.¹⁴

KEYNOTE-905/EV-303 is a multinational, randomized, open-label, parallel-group trial evaluating the clinical efficacy and safety of perioperative pembrolizumab with or without enfortumab vedotin in patients with MIBC who are ineligible for or decline cisplatin. Approximately 836 patients will be randomly assigned 1:1:1 to neoadjuvant pembrolizumab 200 mg once every 3 weeks for 3 cycles, followed by surgery, followed by adjuvant pembrolizumab once every 3 weeks for 14 cycles; neoadjuvant enfortumab vedotin 1.25 mg/kg on days 1 and 8 plus pembrolizumab 200 mg on day 1 of each 21-day cycle for 3 cycles, followed by surgery, followed by adjuvant enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 of each 21-day cycle for 6 cycles, followed by 8 additional cycles of pembrolizumab alone; or radical cystectomy and pelvic lymph node dissection alone, followed by observation.¹⁴

The primary end points evaluated in KEYNOTE-866 and KEYNOTE-905/EV-303 are pathologiccomplete response (defined as pT0N0M0) andevent-free survival, respectively. Key secondary end points are OS, DFS, pathologic downstaging(defined as < pT2N0M0), and safety and tolerabilityof treatment.¹⁴

Adjuvant Nivolumab

The randomized, double-blind, multicenter, phase 3 CheckMate 274 study (NCT02632409) of 709 patients with MIBC at high risk of recurrence assessed the efficacy of nivolumab as adjuvant therapy. Eligible patients who had undergone radical cystectomy with or without neoadjuvant cisplatin-based chemotherapy were randomly assigned 1:1 to receive either adjuvant nivolumab 240 mg or placebo every 2 weeks for up to 1 year.¹⁵

Patient stratification was based on 3 factors: PD-L1 expression level (≥ 1%, < 1%, or undetermined) via immunohistochemistry, pathologic nodal status (N+ vs N0 or Nx with < 10 nodes removed or N0 with ≥ 10 nodes removed), and whether the patient had received neoadjuvant cisplatin-based chemotherapy prior to this study. Approximately 39.8% of all patients had PD-L1 expression of 1% or greater, and approximately 43.4% of patients had previous neoadjuvant cisplatin-based chemotherapy.¹⁵

In the nivolumab arm, 3.4% of patients had N3 nodal status compared with 5.6% in the placebo arm. DFS in the intention-to-treat (ITT) population and DFS in the subgroup of patients with PD-L1 expression of 1% or greater were the 2 primary end points of the study. The secondary end points were survival free from recurrence outside the urothelial tract, OS, and disease-specific survival.¹⁵

Significantly more patients in the overall ITT population and the subgroup of patients with PD-L1 expression of 1% or greater achieved sustained remission with nivolumab compared with placebo. With a median follow-up of approximately 20 months, the median DFS in the ITT population was 20.8 months (95% CI, 16.5-27.6) in the nivolumab group vs 10.8 months (95% CI, 8.3-13.9) in the placebo group. The primary end point of DFS improvement at 6 months in the ITT population was met, with 74.9% of patients in the nivolumab group being alive and disease free compared with 60.3% of patients in the placebo group (HR, 0.70; 98.22% CI, 0.55-0.90; P < .001). DFS improvement at 6 months was also achieved in the subgroup of patients with PD-L1 expression of 1% or greater, with 74.5% of patients in the nivolumab group vs 55.7% of patients in the placebo group being alive and disease free (HR, 0.55; 98.72% CI, 0.35-0.85;P < .001).¹⁵

The secondary end points were also met, with 77.0% of the nivolumab group and 62.7% of the placebo group being alive and free from recurrence outside the urothelial tract at 6 months (HR, 0.72; 95% CI, 0.59-0.89). Notably, the median non–urothelial tract recur-rence-free survival in the ITT population was 22.9 months (95% CI, 19.2-33.4) with nivolumab and 13.7 months (95% CI, 8.4-20.3) with placebo. In patients with PD-L1 expression of 1% or greater, 75.3% of patients in the nivolumab arm vs 56.7% of patients in the placebo arm were alive and free from recurrence outside the urothelial tract (HR, 0.55; 95% CI, 0.39-0.79).¹⁵

It is crucial to mention that 53.3% of patients in the nivolumab group and 56.3% of patients in the placebo group discontinued treatment. Disease recurrence was the leading cause for therapy discontinuation in 25.6% of patients in the nivolumab arm and 42.2% of patients in the placebo arm.¹⁵

The incidence of treatment-related grade 3 or greater AEs in this study was higher in the nivolumab group vs the placebo group (17.9% vs 7.2%, respectively). The most prevalent grade 3 or greater therapy-related AEs in the nivolumab group were increases in serum lipase and amylase levels (5.1% and 3.7%, respectively), followed by diarrhea, colitis, and pneumonitis (0.9% for each). In the nivolumab group, there were 2 treatment-related fatalities due to pneumonitis and one death due to bowel perforation, despite treatment with glucocorticoids.¹⁵

It is important to note that not all immune checkpoint inhibitors are recom-mended as adjuvant therapy. The phase 3 IMvigor010 study (NCT02450331) randomly assigned 1:1 a total of 809 patients with MIBC to either adjuvant atezolizumab 1200 mg once every 3 weeks for up to 16 cycles or observation alone and found no significant survival benefit with adjuvant atezolizumab versus observation (median DFS, 19.4 months vs 16.6 months, respectively; HR, 0.89; 95% CI, 0.74-1.08; P = .24).¹⁶

Conclusion

Perioperative systemic treatment of MIBC requires careful consideration to achieve optimal long-term outcomes and maintain a good quality of life. Prognosis varies significantly in this patient population, and an unmet medical need exists because only select patients are eligible to receive neoadjuvant or adjuvant cisplatin-based treatment.New treatment options with immunotherapy and an antibody-drug conjugate have been or are currently being investigated and have shown tolerable toxicity profiles for a large proportion of patients. In the near future, novel therapies in the perioperative setting may transform clinical practice, particularly for patients with preexisting comorbidities.

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About the Authors

Jessie Modlin, PharmD, BCOP, is a clinical oncology pharmacist at St Luke’s Cancer Institute in Boise, Idaho.

Khanh Huynh, PharmD, BCACP, APh, is a staff pharmacist at Sharp Grossmont Hospital in La Mesa, California, and a staff pharmacist at University of California San Diego Specialty Pharmacy.

Whitney Fakolade, PharmD, RPh, is a clinical pharmacist at Price Care Pharmacy in Downey, California.

Kevin Pang, PharmD, is the founder of a clinical-stage authoring group and regular Pharmacy Times Oncology Edition contributor.