Immune Checkpoint Inhibitors in Bladder Cancer: Refining Their Role

Publication
Article
Targeted Therapies in OncologyApril 2, 2023
Volume 12
Issue 6
Pages: 28

Emerging data demonstrate the potential of these drugs to optimize survival, preserve quality of life, and even spare patients a radical cystectomy.

Daniel M. Geynisman, MD 

Chief Division of Genitourinary Medical Oncology 

Associate Professor 

Department of Hematology/Oncology 

Fox Chase Cancer Center 

Temple Health 

Philadelphia, PA

Daniel M. Geynisman, MD

Chief Division of Genitourinary Medical Oncology

Associate Professor

Department of Hematology/Oncology

Fox Chase Cancer Center

Temple Health

Philadelphia, PA

The standard treatment for muscle-invasive and metastatic bladder cancer is cisplatin-based chemotherapy.1 Because outcomes are grim for patients who are poor candidates for platinum chemotherapy or who progress after frontline platinum chemotherapy, the approval of immune checkpoint inhibitors (ICIs) was a major milestone for these patients.

Since 2016, the FDA has approved 5 ICIs for bladder cancer in various settings, including first-line, maintenance, and second-line treatment, which “have shown clinical benefits with a significant impact on [overall survival] and a durable tumor control in first-line therapy or upon relapse after standard treatments.”2

This article highlights select trial findings on ICIs in muscle-invasive, non–muscle-invasive, and metastatic bladder cancerpresented at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU).

Matthew Galsky, MD  

Professor of Medicine 

(Hematology and Medical Oncology) 

Director Genitourinary Medical Oncology 

Codirector 

Center of Excellence for Bladder Cancer 

Associate Director for Translational Research 

The Tisch Cancer Institute 

Mount Sinai 

New York, NY

Matthew Galsky, MD

Professor of Medicine

(Hematology and Medical Oncology)

Director Genitourinary Medical Oncology

Codirector

Center of Excellence for Bladder Cancer

Associate Director for Translational Research

The Tisch Cancer Institute

Mount Sinai

New York, NY

Muscle-Invasive Disease

Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy or chemoradiation is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Neoadjuvant chemotherapy results in pathologic complete responses (pCRs) in approximately 30% to 40% of patients with MIBC,3 but—paradoxically—pCR can only be determinedafter the bladder has already been surgically removed. Additionally, both chemoradiation and cystectomy are associated with significant impacts on quality of
life and mortality risks. One study reported a mortality rate within 90 days of cystectomy of 5.4% in patients aged 70 to 79 years and 9.2% in those 80 years or older.4 Moreover, patients who are cisplatin ineligible due to renal dysfunction, impaired performance status, or comorbidities need alternatives to improve their outcomes.

Findings from multiple trials presented at ASCO GU demonstrate how ICIs are being evaluated to help fill the unmet needs of patients with MIBC.


RETAIN

Investigatorsin the phase 2 RETAIN trial (NCT02710734) evaluated a risk-adapted approach based on biomarker selection and clinical staging to avoid cystectomy or chemoradiation. It was the first attempt at a molecularly guided strategy to bladder sparing, and the adaptive design will be tested again in the RETAIN-2 trial(NCT04506554) evaluating the risk-enabled therapy after neoadjuvant immunochemotherapy.

“RETAIN is aunique trial that focuses on localized MIBC. We designed a noninferiority trial looking at being able to combine clinical staging with molecular alterations known to predict for pCR—ATM,RB1, FANCC, orERCC2—to help select patients for active surveillance after chemotherapy,” Daniel M. Geynisman, MD, said in an interview with Targeted Therapies in Oncology™. Geynisman is chief of the Division of Genitourinary Medical Oncology and an associate professor in the Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.


Over 33 months, patients were enrolled at 4 academic centers in the intention-to-treat (ITT) cohort, which ultimately resulted in 71 patients with a median age of 70 years, Geynisman said. The investigators identified a relevant mutation in 33 (46%) patients in the ITT population, and 26 (37%) of
them began predefined active surveillance. Investigators compared the outcomes for these 26 patients with MIBC who showed no evidence of cancer following chemotherapy and were spared a cystectomy (active surveillance group) with those of 45 patients who received standard-of-care chemotherapy followed by a cystectomy (control group). The end point of the trial was 2-year metastasis-free survival (MFS).

“The 2-year MFS [rate]...was 72% for the ITT patients (lower-bound exact 1-sided 95% CI, 62%),” the investigators wrote. “On post hoc analysis, the 2-year MFS [rate] was 65% in the [active surveillance] group (CI, 44%-83%) and 76% (CI, 60%-87%) in the remaining patients (P = .42).”5

"Although we did not meet the lower bound of 95% confidence interval of 64% needed to call the risk-adapted approach noninferior, it was quite close at 62%,and a number of patients on active surveillance have been able to benefit,” Geynisman said. “Of the 26 patients with mutations who went on to active surveillance, almost half were alive, metastasis free, and with their bladder intact. These patients did not have metastatic disease, nor did they need surgery to remove their bladder or chemoradiation. That is a significant win for those patients.”

As a result, Geynisman noted, “along with a recently presented [Hoosier Cancer Research Network] trial, [2 ongoing trials] are building on this. The RETAIN-2 trial combines chemotherapy with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin with the immunotherapy drug nivolumab [Opdivo] in the neoadjuvant setting in a very similar approach. The trial will evaluate [whether] immunotherapy will improve the 2-year MFS rate and decrease the rate of disease recurrence.

The ongoing Alliance [for Clinical Trials in Oncology] A031701 trial [NCT03609216] will use a slightly different mutation panel to select patients.

“The overall goal of both these trials is to more appropriately select patients for bladder-sparing management.”


CheckMate 274

CheckMate 274 (NCT02632409) is a phase 3, multicenter, double-blind, randomized, controlled trial that evaluated the role of adjuvant nivolumab treatment in patients with high-risk muscle-invasive urothelial carcinoma (UC) after radical surgery. The primary end points were disease-
free survival (DFS) in the ITT population and in patients with a PD-L1 expression level of 1% or more.

Investigators randomly assigned 353 patients to receive nivolumab (PD-L1≥1%, n= 140) and 356 patients to receive placebo (PD-L1≥1%, n= 142). At 6 months,the anti–PD-1 antibody nivolumab demonstrated significantly higher DFS rates in the ITT population vs placebo (74.9% vs 60.3%, respectively; HR for disease recurrence or death, 0.70; 98.22% CI, 0.55-0.90;P< .001) and in patients with a PD-L1 expression level of 1% or more vs placebo(74.5% and 55.7%, respectively; HR, 0.55; 98.72% CI, 0.35 to 0.85;P< .001).6

Matthew Galsky, MD, presented extended follow-up results from the CheckMate 274 trial at ASCO GU. Galsky is a professor of medicine (hematology and medical oncology), director ofgenitourinary medical
oncology, codirector of the Center of Excellence for Bladder Cancer, and associate director for translational researchat The Tisch Cancer Institute at Mount Sinai in New York, New York.

Galsky said that with a median follow-up of 36.1 months, median DFS in the ITT cohort was 22 months with nivolumab vs 10.9 months with placebo, and 52.6 months vs 8.4 months, respectively, in patients with PD-L1expression of 1% or greater. Non–urothelial tract recurrence-free survival and distant-MFS
benefits also were observed in patients treated with nivolumab in both populations. Treatment-related adverse events were consistent with those of the primary CheckMate 274 analysis.7

“These results show that ICIs continue to fill in the unmet need for patients with muscle-invasive urothelial cancer of the bladder who have a high risk of recurrence after surgery,” Galsky said during an interview with Targeted Therapies in Oncology. “One notable [advantage] is the sustained benefits of
nivolumab at the 3-year follow-up—even despite the 12-month duration of adjuvant treatment.” Galsky added that “the next step for CheckMate 274 involves translational research to evaluate the relationship between tumor microenvironments and responses to ICI blockade in the adjuvant setting.”

HCRNGU16-257

Galsky and colleagues also presented findings of nivolumab in combination with gemcitabine and cisplatin from the selective bladder-sparing phase 2 HCRN GU16-257 trial (NCT03558087) examining whether transurethral resection of bladder tumorplus systemic therapy might definitively treat a subset of patients with MIBC.

The study evaluated the role of neoadjuvant nivolumab in avoiding radical cystectomy in cisplatin-eligible patients with a clinicalCR (cCR). The coprimary end points of the study were to determine the cCRrate with gemcitabine, cisplatin,andnivolumab and to determine the ability of cCR as a biomarker (for which follow-up is not yet mature).


Patients received 4 cycles of gemcitabine, cisplatin, and nivolumab, followed by clinical restaging. Those who achieved a cCR were eligible to proceed without cystectomy and receive nivolumab every 2 weeks for 8 weeks, followed by surveillance. Proceeding to surgery was recommended for patients who did not achieve a cCR.

Galsky said that of the 76 patients enrolled, 33 (43%) achieved cCR butone of those patients opted to have surgery. A bladder-intact MFS of at least 2 years was achieved in most patients with a cCR.8

“We were able to use a[stringently defined cCR] along with a standardized clinical response reassessment to identify patients who would have a favorable outcome and spare them a cystectomy,” Galsky said. “Our findings may help other clinicians apply a more personalized approach to the
management of [patients with MIBC].”


Non–Muscle-Invasive Disease


Standard treatment for high-risk non-MIBC (NMIBC) is transurethral bladder resection followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy to eradicate any residual disease. Unfortunately, as many as 50% of patients become unresponsive to BCG or experience recurrence
within 12 months, with PD-1 pathway activation implicated in BCG resistance.12 Radical cystectomy is usually recommended for these patients.

A significant unmet need exists for safe, effective bladder-sparing treatments in patients with high-risk NMIBC, and this need was explored at ASCO GU.

KEYNOTE-057

The single-arm, multicohort phase 2 KEYNOTE-057 trial (NCT02625961) was designed to investigate the safety and efficacy of pembrolizumab monotherapy in patients withhigh-risk NMIBC who are unresponsive to BCG and ineligible for or choose not to undergo radical cystectomy. Pembrolizumab received approval for the treatment of carcinoma in situ (CIS) with or without papillary tumors based on results from cohort A.13

At ASCO GU, lead author Andrea Necchi, MD, presented long-awaited data from cohort B (papillary tumors without CIS). Necchi is an associate professor of oncology at Vita-Salute San Raffaele University and chief of the Genitourinary Medical Oncology Division at San Raffaele Research Hospital at IRCCS San Raffaele Hospital and Scientific Institute inMilan,Italy.

Cohort B was designed to address the unmet needs of patients with BCG-unresponsive high-risk NMBIC who are ineligible for or decline to undergo cystectomy. These patients have few approved treatment
options and are often excluded from clinical trials.


Patients in cohort B (n= 132) received pembrolizumab for a median of 9.5 cycles (range, 1.0-35.0). At 12 months, 43.5% of patients remained disease free of high-risk NMBIC; the median DFS duration was 7.7 months, the progression-free survival rate was 88.2%, and the OS rate was 96.2%. These results suggest that pembrolizumab monotherapy also may be beneficial for patients with non-CIS papillary high-risk NMIBC unresponsive to BCG who are ineligible to undergo orwhodecline radical cystectomy.14

Metastatic Disease


In the metastatic setting, UC is a highly aggressive malignancy with a 5-year survival rate of approximately 5%.15 Cisplatin-based chemotherapy is also a first-line treatment standard in the metastatic setting; however, approximately 60% of patients are ineligible due to performance status or
comorbidities.16,17 ICIs are now a standard of care in mUC for patients who are ineligible for cisplatin-based therapy, and the drugswere the focus of multiple presentations at ASCO GU.

IMvigor130

Similar to pembrolizumab, atezolizumab (Tecentriq) is a humanized IgG1 monoclonal antibody that inhibits binding of PD-L1 to receptors of PD-1. Atezolizumab has demonstrated efficacy and a manageable safety profile in multiple types of cancer, including locally advanced UC or mUC.18

The final OS results comparing arm A (atezolizumab+platinum/gemcitabine) with arm C (placebo+platinum/gemcitabine) as first-line treatment for patients with locally advanced UC or mUC from the randomized phase 3 IMvigor130 study (NCT02807636) were presented at ASCO GU by Enrique Grande, MD,head of oncology at MD Anderson Cancer Center Madrid in Spainand anauthor on the study.


Patients were randomly assigned 1:1:1 to arms A, B (atezolizumab alone), or C. Patients in arms A and C received cisplatin or carboplatin per investigator choice. Despite a trend toward improved OS in arm A vs C(median OS, 16.1 vs 13.4 months, respectively), the OS benefit was not statistically significant in ITT patients with mUC as of the data cutoff of August 31, 2022.19

However, consistent with those of prior exploratory analyses, data from the subgroup of patients treated with cisplatin trended toward improved OS vs those who received carboplatin.19 Similar results were also reported in patients who received cisplatin regardless of PD-L1 status (TABLE).19

In the ITT population, the disease control rate was 65% in arm A and 60% in arm C, and “no new safety signals were seen.”19 Regarding the hypothesis-generating data from the study that the choice of chemotherapy backbone might matter, Grande concluded that “further mechanistic investigations are
warranted.”

Another presentation of the IMvigor130 study data focused on the final OS analysis of atezolizumab monotherapy vs chemotherapy in untreated patients with locally advanced UC or mUC. With the same cutoff date, atezolizumab monotherapy did not result in significant improvement in OS. Median OS was 15.2 months (95% CI, 13.1-17.7) in the atezolizumab arm vs 13.3 months (95% CI, 11.9-15.6) in the chemotherapy arm.20

The 12-and 24-month OS rates with atezolizumab were 57.9% and 34.5%, respectively, compared with 54.6% and 32.3% with chemotherapy. Of note, the data suggest a potential benefit for first-line atezolizumab monotherapy vs chemotherapy in cisplatin-ineligible patients with high PD-L1 expression (IC2/3). In this subgroup, the median OS was 18.6 months (95% CI, 14.0-49.4) with atezolizumab vs 10.0 months (95% CI, 7.4-18.1) with chemotherapy.20

In the ITT population, atezolizumab monotherapy demonstrated better tolerability vs chemotherapy. Discontinuation resulting from treatment-related adverse events andadverse events was less common with atezolizumab(61% and 9%, respectively) than with chemotherapy (96% and 34%).20

Overall,results from the IMvigor130 study did not demonstrate a clear survival benefit for chemo-immunotherapy over chemotherapy.19,20

Conclusions and Implications for Practice


The emerging data for ICIsin bladder cancer are exciting and demonstrate the potential to change the therapeutic landscape for all patients with this disease. In high-risk NMIBC, ICIs in combination with BCG could reduce progression to MIBC and recurrent high-risk disease,thereby lessening the need for early cystectomy andimprovingpatient outcomes.14

In the MIBC setting, the response rates to anti–PD-1/L1 therapies in combination with chemotherapy appear to indicate pCR.6,11 The extended results of the CheckMate 274 trial show DFS benefit in the adjuvant setting with nivolumab with or without prior neoadjuvant therapy in patients who demonstrate high-risk pathological features for recurrence.6 Additionally, biomarker analysis can be included to help predict patients who might benefit from bladder-sparing management. As Geynisman emphasized, “The future direction in bladder cancer is to more appropriately select patients for bladder-sparing management.”

Moreover, up to 50% of patients with mUC are platinum ineligible or decline chemotherapy in the first-line setting.17 ICI monotherapy has provided these patients with an option to receive systemic therapy with a manageable toxicity profile, with some patients achieving durable responses.2


A number of promising trials and management strategies for bladder cancer were presented at ASCO GU, but meaningful end points, OS outcomes, and pathologic response rates remain critical to determining the best treatment option for patients with this disease.

References
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