Novel Approaches to the Patient with Bladder Cancer

Educational Objectives

The goal of this program is to improve management of bladder cancer using novel approaches. After hearing and assimilating this program, the clinician will be better able to:

1. Differentiate between classic MVAC and dose-dependent MVAC.
2. Explain the significance of cisplatin ineligibility in the KEYNOTE-052 trial.
3. Cite the benefits of atezolizumab in management of metastatic urothelial cancer based on evidence from IMvigor210.

Summary

Introduction: the role of medical oncologists in the treatment of non-muscle invasive bladder cancer (NMIBC) was limited until the recent approval of pembrolizumab; patients with metastatic urothelial cancer (mUC) are categorized as cisplatin-eligible or cisplatin-ineligible; cisplatin ineligibility is defined as creatinine clearance ≤60 mL/min, New York Heart Association (NYHA) class III congestive heart failure (CHF), grade 2 or higher neuropathy or hearing loss; cisplatin-eligible patients treated with cisplatin-based chemotherapy (gemcitabine or dose-dense [dd] MVAC); cisplatin-ineligible patients are tested for programmed death-ligand 1 (PD-L1) status; patients with high PD-L1 levels are treated with immunotherapy and those who are PD-L1-negative can be treated with chemotherapy (eg, gemcitabine-carboplatin); with progression of disease, other options include enfortumab vedotin and erdafitinib, approved by the US Food and Drug Administration (FDA), and clinical trials

Chemotherapy: a 2005 trial published in the Journal of Clinical Oncology compared treatment with gemcitabine vs classic MVAC; data showed response rate (RR) was 49% in gemcitabine arm and 46% in MVAC; survival was prolonged in >10% of patients in cisplatin-based chemotherapy arm; another trial compared ddMVAC with classic MVAC; survival for cisplatin-eligible patients was better in ddMVAC arm; one trial compared carboplatin-based treatments gemcitabine-carboplatin and M-CAVI in patients who were not cisplatin-eligible; 5-yr survival was 50% in each arm

Immunotherapy: treatment landscape in mUC changed after the advent of immunotherapy; 5 immunotherapy agents are approved in second-line setting

KEYNOTE-045 study: enrolled patients with mUC with measurable disease after receiving platinum-based treatment; patients were randomized between single-agent pembrolizumab aministered at 200 mg q3wk vs paclitaxel, docetaxel, or vinflunine; vinflunine was offered to patients outside US since it was not approved by FDA; primary end-point of trial was overall survival (OS) and progression-free survival (PFS) in patients with high PD-L1 status (combined proportion score [CPS] ≥10%); demonstrated improved survival benefit; PFS was not different; outcome of the study was positive; patients who responded to immunotherapy (responders) showed response ≤3 mo; RR was not different; CPS ≥10% was not a good predictor of response; patients with visceral disease experienced improved survival; toxicities were higher in chemotherapy arm (49%) compared with pembrolizumab (15%); atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab are approved in this patient population

IMvigor211 trial: a randomized trial comparing atezolizumab with paclitaxel, docetaxel, and vinflunine after platinum-based treatment; patients were stratified based on immune cell (IC) scoring for PD-L1 status; end-points were PFS and OS; no improvement in OS for atezolizumab; surprisingly, outcome of trial was negative; intent-to-treat OS in atezolizumab and chemotherapy arms was 8.6 mo and 8 mo, respectively; RR in intent-to-treat analysis was similar at 13.4% each; high expressors of PD-L1 were prevalent in 23% vs 21.6% patients in atezolizumab and chemotherapy arms respectively; later atezolizumab received accelerated approval in this cisplatin-ineligible setting

KEYNOTE-052 trial: cisplatin-ineligible patients were enrolled; cisplatin ineligibility was defined by creatinine clearance <60 mL/min, ECOG performance status of 2, grade 2 or higher neuropathy or hearing loss, NYHA class III CHF; all patients were treated with flat dose of pembrolizumab; primary endpoint of objective response was achieved in 24% of patients; disease control rate was observed in 47% patients; PFS was 2 mo and was not encouraging; 6-mo survival was 67%

IMvigor210 trial: this study of atezolizumab had 2 cohorts; one cohort included cisplatin-ineligible patients in the front-line setting; primary end-point was objective response; overall RR of this study was 23%; OS was higher at 15.9 mo in all cohorts; patients with IC scores of 2 or 3 demonstrated shorter survival despite higher RR; patients with IC scores of 0 or 1 reported longer survival but lower RR; this study demonstrated that atezolizumab had beneficial role in front-line setting with some caveats

Antibody-drug conjugate (ADC): enfortumab vedotin is the most recently accelerated approval for mUC; ADC has 2 components, antibody and payload; payload in enfortumab is tubulin inhibitor monomethyl auristatin E (MMAE); in original studies MMAE was shown to be toxic by itself; when conjugated with antibody, it targets cancer cell; once internalized, these molecules are lysed, and releases cytotoxic payload; this cytotoxicity results in apoptosis; EV-201 was a phase 2 pivotal single-arm study of enfortumab vedotin; patients who were treated with PD-L1 or PD-1 antibodies and platinum-based chemotherapy were enrolled; primary endpoint was objective response rate; secondary endpoints included PFS and duration of response (DOR); patients were tested for target for antibody (Nectin-4) before treatment; Nectin-4 was expressed in most mUC patients and is no longer assessed; RR in 125 mUC patients was 44%; shrinkage of tumor was reported in 84% patients; median survival was 11.7 mo; however, many toxicities were reported; the study was discontinued because of sensory neuropathies and deaths from interstitial lung disease

FGFR inhibition: phase 2 study conducted in patients with mUC treated with prior treatment and immunotherapy; FGFR alteration was required prior to enrollment; patients were treated with erdatifinib, an FGFR inhibitor; primary endpoint was objective RR while PFS, OS, and DOR were secondary endpoints; RR was 40% in patients with FGFR alteration; best response was noted in FGFR3 mutation (49%); median survival was 13.8 mo and PFS was 5.5 mo; hyperphosphatemia was common toxicity; high toxicity noted on trial was central serous retinopathy, which can result in retinal detachment on macula and create visual field defects; these toxicities improved on discontinuation of treatment; surgical interventions were rarely required

Combination approaches: various approaches are being explored in mUC

Combination of immunotherapy and chemotherapy: has shown promising results in small-cell lung cancer

Combination of ADC and immunotherapy: in front-line setting; phase 3 study IMvigor130 compared atezolizumab with or without platinum-based chemotherapy and single-agent atezolizumab; patients had metastatic disease, were treatment-naive, ECOG performance status 2 or higher, and eligible for platinum-based therapy; >1200 patients were enrolled and randomized 1:1:1; there were 2 primary endpoints, PFS and OS; findings with final PFS analysis and interim OS analysis were reported; significant improvement in PFS was reported; subset analysis of monotherapy arm, chemotherapy, and atezolizumab was conducted; patients with IC scores of 0 or 1 reported improved outcomes with chemotherapy; in patients with IC scores of 2 or 3, it is reasonable to use atezolizumab; FDA advisory of 2018 recommends chemotherapy in patients who have negative PD-L1 status, while carboplatin and immunotherapy sequence in patients who have positive PD-L1 status

Sequential chemotherapy and immunotherapy: was tested in Hoosier Oncology Group trial; patients received pembrolizumab or placebo after chemotherapy in the trial; primary endpoint was PFS; RR was 22% in pembrolizumab arm compared with 12% in placebo arm; PFS was significantly improved in pembrolizumab arm

Ongoing clinical trials: current phase 3 trial for avelumab in switch maintenance setting reported meeting survival endpoints; findings of combination of pembrolizumab and ADC were reported at 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium; rationale for ADC and immunotherapy includes release of antigen with payload and activation of immune response; data were reported in 45 patients; RR was 73% and complete response (CR) was reported in 15% patients; 93% of patients had some response; PD-L1 status was not predictive of response; median OS was not reported, however, 12-mo survival was achieved in 81% patients; median PFS was 12.3 mo

Non-muscle invasive bladder cancer (NMIBC): KEYNOTE-57 was a phase 2 trial conducted in bacille Calmette-Guerin (BCG)-refractory patients with NMIBC; BCG refractoriness — defined as growth in cancer after treatment with ≥5 of 6 cycles of initial BCG, and 2 of 3 maintenance doses or 2 of 6 second regimen; patients were treated with pembrolizumab ≤24 mo and response was assessed by periodic cystoscopies; primary endpoints were CR rate and disease-free survival; the study had 2 cohorts, including patients with and without carcinoma in-situ (CIS); approval for pembrolizumab was based on favorable results in CIS cohort; RR was 40% in patients who were adequately treated with BCG for a median of 12 cycles; no patient developed muscle-invasive disease after 24 mo of treatment; median duration of CR was 12.7 mo; CR was observed for >6 mo in 75% patients and >9 mo in 53% patients; pembrolizumab was well tolerated

Readings

Balar AV et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017; 389:67-76; doi: http://dx.doi.org/10.1016/S0140-6736(16)32455-2; Balar AV et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017; 18:1483-92; doi: http://dx.doi.org/10.1016/S1470-2045(17)30616-2; Bellmunt J et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. NEJM. 2017;376;1015-1026; doi: 10.1056/NEJMoa1613683; Loriot Y et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. NEJM. 2019;381;338-348; doi: 10.1056/NEJMoa1817323; Maase HV et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23:4602-4608; doi: 10.1200/JCO.2005.07.757; Powles T et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391;748-57; doi: http://dx.doi.org/10.1016/S0140-6736(17)33297-X.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Sadeghi is a speaker for Johnson & Johnson Services Inc, Tempus, and Pfizer Inc. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Sadeghi was recorded at the Scripps Cancer Center’s 40th Annual Conference: Hematology and Oncology 2020, held in San Diego, CA, on February 15, 2020, and presented by Scripps Health, Department of CME. For information on future CME activities from this presenter, please visit www.scripps.org. Audio Digest thanks the speakers and meeting presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

UR450901

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.