Dear Readers,
In this issue, we highlight recently presented and published trials from ESMO 2024 Annual Meetings. In the future, please reach out to us directly in order to highlight any specific clinical trials at pkagarwal@uchicago.edu or cns9006@med.cornell.edu and/or at BLC@iospress.com.
Sincerely,
Piyush K. Agarwal, MD
Associate Editor, Bladder Cancer
Director, Bladder Cancer Program
The University of Chicago
Chicago, Illinois
Cora N. Sternberg, MD, FACP
Associate Editor, Bladder Cancer
Clinical Director, Englander Institute for Precision Medicine
Weill Cornell Medicine
New York, New York
Study Title: A Phase 3 Trial of Neoadjuvant Durvalumab plus Chemotherapy Followed by Radical Cystectomy and Adjuvant Durvalumab in Muscle-Invasive Bladder Cancer (NIAGARA)
Clinicaltrials.gov identifier: NCT03732677
Sponsor: AstraZeneca
Enrollment: 1063 patients
Rationale: Although neoadjuvant chemotherapy delivered before radical cystectomy provides a survival advantage over radical cystectomy alone, the benefit is small and up to 50% of patients will recur with disease within 3 years. Given that the use of adjuvant immunotherapy has improved disease-free survival in patients with higher risk for recurrence after radical cystectomy for Muscle-Invasive Bladder Cancer (MIBC) based on two phase 3 clinical trials, CheckMate 274 (Nivolumab) and AMBASSADOR Alliance A031501 trial (Pembrolizumab), this trial was conceived to see if the use of standard neoadjuvant chemotherapy combined with immunotherapy both prior to and after radical cystectomy could enhance outcomes.
Study Design: This is a phase 3, open-label, randomized trial of patients with muscle-invasive bladder cancer (MIBC) eligible for cisplatin-based chemotherapy (cT2-T4aN0/1M0) and assigned to either neoadjuvant gemcitabine-cisplatin followed by radical cystectomy (RC) alone or neoadjuvant durvalumab, an anti PDL-1 inhibitor (for 4 cycles) plus gemcitabine-cisplatin, followed by radical cystectomy (RC) and adjuvant durvalumab (for up to 8 cycles).
Endpoints: There were dual primary endpoints. The first primary endpoint was event-free survival (EFS) defined as the time from randomization to the first occurrence of any of the following: disease progression preventing RC, recurrence after RC, failure to undergo RC, or death from any cause. The second primary endpoint was pathologic complete response rate (pCR). The secondary endpoints included overall survival (OS), time to disease recurrence or death, safety and tolerability. The 5% alpha (2-sided) was allocated between the two primary endpoints. The study was considered positive if either of the dual primary endpoints was met.
Results: Overall, 1530 patients were enrolled, and 1063 patients were eventually randomized: 533 patients to the durvalumab arm and 530 patients to the standard of care arm. Most patients had urothelial cancer but 14% in the durvalumab arm and 17% in the comparator arm had urothelial cancer with variant histologic subtypes. Overall, 85% of randomized patients underwent RC and 70% of patients in the durvalumab arm received adjuvant durvalumab. On an intent to treat (ITT) analysis, the addition of durvalumab to neoadjuvant chemotherapy significantly improved EFS as compared to neoadjuvant chemotherapy alone (2-year EFS of 67.8% vs. 59.8% (HR 0.68 (95% CI: 0.56–0.82, p < 0.0001)). The EFS benefit was consistent across various patient subgroups except for patients with clinical lymph node metastases at baseline which was attributed to the small sample size of this subgroup. The second primary endpoint of pCR was statistically significant in favor of the durvalumab arm on a re-analysis (37.3% vs. 27.5%, p = 0.0005). Regarding the secondary endpoint of OS, 2-year survival was improved in the durvalumab arm (82.2% vs. 75.2% (HR 0.75 (95% CI: 0.59–0.93, p = 0.016)). Safety and tolerability were comparable in both arms. Grade 3/4 adverse events possibly related to treatment occurred in 41% of patients in both arms and consisted primarily of anemia, urinary tract infection, and neutropenia. Nausea was overall the most common adverse event. Death occurred in 5% of patients in the durvalumab arm and in 6% of patients in the comparator arm.
Comments: The trial supports a possible new standard in MIBC patients who are cisplatin-eligible that consists of perioperative immunotherapy added to neoadjuvant chemotherapy with cisplatin and gemcitabine. Interestingly, adverse events were very similar in both arms and the use of durvalumab did not impact ability of patients to receive surgery. Nonetheless, and perhaps controversial: Contemporary results from the Vesper trial of neoadjuvant chemotherapy with ddMVAC (Pfister C et al., JCO 2023) are very similar without the need for adjuvant immunotherapy in everyone. This can be given later in case immunotherapy is required.
Reference: Presented by Thomas B. Powles at the ESMO 2024 Annual Meeting, Barcelona, Spain. Powles T et al., N Engl J Med 2024 Sep 15. doi: 10.1056/NEJMoa2408154. Online ahead of print.
Study Title: Phase III Randomized Adjuvant Study of Pembrolizumab in Muscle Invasive and Locally Advanced Urothelial Carcinoma (AMBASSADOR) Versus Observation
Clinicaltrials.gov identifier: NCT03244384
Sponsor: National Cancer Institute (Alliance A031501)
Enrollment: 702
Rationale: Two phase 3 randomized trials had conflicting results in terms of the efficacy of adjuvant immunotherapy in patients with high-risk muscle-invasive urothelial carcinoma. The IMvigor010 trial, randomly assigned patients with postoperative muscle-invasive urothelial carcinoma (MIUC) to adjuvant atezolizumab or observation, did not show a treatment benefit with respect to the primary end point of disease-free survival (DFS). The median DFS was 19.4 months with atezolizumab and 16.6 months with observation (HR for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.08). However, the CheckMate 274 trial, compared adjuvant nivolumab with placebo and showed a treatment benefit with respect to the co-primary end points of DFS among all the patients (ITT population) and among patients with PD-L1 expression level of 1% or more, with a median DFS of 20.8 months with nivolumab vs. 10.8 months with placebo (HR for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90) and a more pronounced DFS benefit in the population with a PD-L1 expression of 1% or more (HR, 0.55; 98.72% CI, 0.35 to 0.85). The OS data from the CheckMate 274 trial are still immature.
Study Design: Open-label, randomized, phase III trial of muscle-invasive urothelial cancer (MIUC) of the bladder, upper tract, or urethra following radical surgery (radical cystectomy, nephroureterectomy, and urethrectomy respectively) with either: 1) ≥pT2 and/or pN + or positive margins at surgery following NAC OR 2) ≥pT3 and/or pN + or positive margins at surgery without NAC (cisplatin-ineligible patients or patients who refused NAC). Patients enrolled up to 16 weeks after surgery and randomized 1:1 to either pembrolizumab (200 mg IV every 3 weeks) or observation. Stratification factors included pathologic stage, centrally tested PD-L1 status, and receipt of prior NAC.
Endpoints: The primary endpoints were both DFS and overall survival (OS). The secondary endpoints included evaluation of DFS by PD-L1 status, evaluation of OS by PD-L1 status, and safety.
Results: A total of 702 patients were randomized; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. Patients with bladder cancer comprised 75.4% of the population in the pembro arm and 75.6% in the observation arm. The median duration of follow-up for DFS was 44.8 months. The median DFS was 29.6 months (95% confidence interval [CI], 20.0 to 40.7) with pembrolizumab (pembro) and 14.2 months (95% CI, 11.0 to 20.2) with observation (HR for disease progression or death, 0.73; 95% CI, 0.59 to 0.90; two-sided P = 0.003). If we look at DFS by PDL-1 status, PDL-1 positive CPS > 10 was 36.9 months with pembro vs. 21 months on observation HR (95% CI) 0.81 (0.61–1.08) and for PDL-1 < 10 the DFS was 22.1 months with pembro compared to 9 months with observation HR 0.71 (95%CI, 0.53–0.95). Grade 3 or higher adverse events (regardless of attribution) occurred in 50.7% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group. The HR (95% CI) was 0.73 (0.59–0.90) p = 0.0027.
Comments: Adjuvant pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs observation for patients with high risk MIUC after radical surgery. Subgroup analysis showed DFS benefit with pembro vs observation irrespective of PDL-1 expression and lymph node status. Metastatic recurrences were more common in patients on observation vs pembro. Common sites of metastasis included lymph nodes, lung, bone and liver. Based on the doubling of the median DFS and manageable toxicity, this trial supports adjuvant pembro as a therapeutic option in patients with high risk MIUC. Of note, 22 patients in the pembro group (15.1%) reported subsequent treatment with a checkpoint inhibitor as compared with 83 patients (52.2%) in the observation group. There was a very high number of patients in the observation arm who were given adjuvant nivolumab based on the CheckMate 274 trial and Nivolumab approval.
Reference: Presented by Andrea Apolo at the ESMO 2024 Annual Meeting, Barcelona, Spain. and Apolo AB et al. N Engl J Med. .2024 Sep 15. doi: 10.1056/NEJMoa2401726. Online ahead of print.
Study Title: Phase 2b Clinical Study Evaluating Efficacy and Safety of TAR-200 in Combination With Cetrelimab, TAR-200 Alone, or Cetrelimab Alone in Participants With High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Intravesical Bacillus Calmette-Guérin (BCG) Who Are Ineligible for or Elected Not to Undergo Radical Cystectomy – Updated Results from the SunRISe-1 study
Clinicaltrials.gov identifier: NCT04640623
Sponsor: Janssen Research & Development, LLC
Enrollment: 200
Rationale: BCG unresponsive high-risk non-muscle invasive bladder (BCG UR HR NMIBC) cancer was a disease state with limited options but now there are three US FDA approved agents with several new drugs in development. TAR-200 is an intravesical delivery device leading to sustained release of gemcitabine which has demonstrated excellent results as a single agent. In the SunRISe-1 study, patients were randomized in this phase 2b study into three cohorts: TAR-200 + CET (anti-PD-1) (Cohort 1 [C1]), TAR-200 alone (C2), or CET alone (C3) in patients with BCG UR HR NMIBC ineligible for/refusing radical cystectomy.
Study Design: Patients with BCG unresponsive CIS +/- HG papillary disease (Ta or T1) who received their last dose of adequate BCG within 12 months of CIS diagnosis and with acceptable performance status (ECOG 0-2) were enrolled into one of the 3 cohorts.
Endpoints: The primary endpoint was overall complete response (CR) rate in the CIS population. Secondary endpoints included duration of response (DOR), overall survival, safety, and tolerability. Assessments: local cystoscopy, centrally assessed urine cytology Q12W, centrally assessed biopsy at weeks 24/48.
Results: Centrally confirmed CR rates in C1, C2, and C3 were 68%, 84%, and 46%, respectively. Low discontinuation (d/c) rates due to treatment-related adverse events (TRAEs) were seen with TAR-200 (C2, 6%) and CET (C3, 7%) alone, with higher rates in the combination (C1, TAR-200 26% or CET 23%). No treatment-related deaths occurred.
Comments: TAR-200 monotherapy is highly effective, with the highest single agent CR rate of 84% in patients with BCG-UR high-risk NMIBC, based on published data, without the need for re-induction. Responses to TAR-200 monotherapy are highly durable; 82% of patients remain in response after a median follow-up of 9.2 months. TAR-200 monotherapy was well tolerated, with few grade >= 3 treatment related adverse events or treatment related adverse events leading to discontinuation. Cetrelimab monotherapy provided a CR rate comparable to other anti-PD-(L)1 agents .SunRISe-1 results indicate a more favorable risk benefit profile for TAR-200 monotherapy compared with TAR-200 + cetrelimab or cetrelimab monotherapy in BCG-UR high risk NMIBC. Results from SunRISe-1 Cohort 2 supports further study of TAR-200 monotherapy in patients with BCG-UR high-risk NMIBC and a cohort 4 is now actively enrolling to evaluate high risk papillary-only NMIBC.
Reference: Presented by Van der Heijden et al. at the ESMO 2024 Annual Meeting, Barcelona, Spain
Study Title: A Phase 2 Multi-Cohort, Open-Label, Multi-Center Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin (RC48-ADC) Alone or in Combination With Pembrolizumab in Subjects With Locally-Advanced Unresectable or Metastatic Urothelial Carcinoma That Expresses HER2
Clinicaltrials.gov identifier: NCT04879329
Sponsor: Seagen Inc.
Enrollment: 20 for Cohort C (planned enrollment = 332)
Rationale: Vedotin-based antibody drug conjugates (ADCs) have changed the landscape of previously untreated la/mUC.. Enfortumab vedotin and pembrolizumab has been an extremely effective combination in locally advanced unresectable or metastatic urothelial carcinoma (la/mUC). Novel biomarker-informed treatments may improve outcomes further.
Up to 50% of tumors express HER2 (Immunohistochemistry (IHC) ≥ 1+) making HER-2 an attractive target. Disitamab vedotin (DV; RC48-ADC) is an investigational ADC comprising a fully humanized HER2-directed monoclonal antibody, disitamab, conjugated to the to a toxic payload, monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker..
DV can mediate immunogenic cell death following the release of MMAE within target tumor cells, providing the rationale to combine DV with immune checkpoint inhibitors.
DV also elicits antitumor activity through the bystander effect, wherein intracellular MMAE released from DV can diffuse across cell membranes and cause apoptosis in adjacent cells. DV combined with PD-1 inhibitors, such as toripalimab, has previously demonstrated promising antitumor activity with a manageable safety profile in patients with la/mUC.
Study Design: This is a phase 2, single-arm, multicohort, open-label multicenter international trial. Cohort C enrolled treatment-naïve patients with HER2-expressing la/mUC with HER2 expression defined ≥ 1 + staining on IHC. Planned enrollment for part 1 was 20 patients to receive DV IV every 2 weeks and pembrolizumab IV every 6 weeks.
Endpoints: The primary endpoint was confirmed ORR (cORR) per blinded independent central review (BICR). Secondary endpoints included investigator-assessed (INV) cORR, overall survival, duration of response, progression-free survival, and safety.
Results: The preliminary data from Cohort C were presented at ESMO 2024. At data cutoff, all 20 patients received DV and P and 9 patients (45) remained on treatment. Median age was 75. Seven patients (35%) were cisplatin-ineligible and six patients (30%) were HER2-high (IHC 3 + or IHC 2+/amplified). Twelve patients (60%) had primary bladder cancer, 14 patients (70%) had visceral metastases, and 5 patients had lymph node-only disease. Overall, performance status was good (ECOG 0-1) and after median duration of exposure of 18.1 weeks for DV and 18.0 weeks for P, efficacy was evaluable in 18 patients but only the secondary outcome evaluated. INV-cORR was 61.1% (95% CI, 35.7–82.7; CR: 16.7%; PR: 44.4%) in all pts and 76.9% (95% CI, 46.2–95.0; CR: 23.1%; PR: 53.8%) in HER2-low pts (IHC 1 + or IHC2+/non-amplified). DCR was 94.4% (95% CI, 72.7–99.9) in all pts and 92.3% (95% CI, 64.0–99.8) in HER2-low pts. TRAEs occurred in 20 (100%) pts, the most common being fatigue (DV, 50%; P, 40%) and diarrhea (DV, 45%).
Comments: Disitamab vedotin plus pembrolizumab (DV + P) demonstrated encouraging preliminary activity in treatment-naive patients with HER2-expressing la/mUC. Responses to DV + P were observed in both patients with HER2-positive and HER2-low la/mUC. DV + P had a manageable safety profile. Other cohorts are randomizing patients to DV vs. DV + P or DV + P vs. platinum-based chemotherapy. It will be interesting to see how effective this combination might be in EV + P pre-treated patients or how it would compare to EV + P in a first line setting for la/mUC. The efficacy and safety of first line DV + P compared with chemotherapy are being evaluated in a phase 3 study (SGNDV-001; NCT05911295) in the North America, Latin America, Europe, Australia, and Asia.
Reference: Presented by Matthew D. Galsky at the ESMO 2024 Annual Meeting, Barcelona, Spain
