Introduction:

BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) represents a high-risk form of urothelial carcinoma (UC).  Previous reports implicate upregulation of the PD-1/PD-L1 immune checkpoint pathway as a resistance mechanism to intravesical BCG therapy and improved preclinical tumor control is demonstrated when immune checkpoint therapy is added to radiation therapy.  Recent FDA approval of systemic PD-1/PD-L1 immune checkpoint inhibitor (CPI) monotherapy represents a new option for BCG-unresponsive NMIBC patients (pts) with carcinoma in-situ (CIS) who face cystectomy as their primary standard alternative.  Despite initial complete responses (CR) to CPI therapy, durable CRs at 12 months are rare indicating a need for novel therapy approaches.  In metastatic UC, increased objective response rates have been observed with combination immunotherapy approaches.  Inspired by the 2015 NCI-sponsored NMIBC Clinical Trials Planning Meeting, the ADAPT-BLADDER trial aims to investigate the safety and efficacy of novel combination immunotherapy approaches in NMIBC pts particularly those incorporating CPI therapy regimens.

Methods:

A multi-arm, multi-stage design was utilized.  The phase 1 portion enrolled BCG-unresponsive NMIBC patients according to consensus criteria.  Pts were assigned to Durvalumab (D); Durvalumab + BCG (D+BCG); or Durvalumab + external beam radiation therapy (D+EBRT).  Durvalumab was administered as 1120 mg iv on day 1 of each 3-week cycle for a maximum of 8 cycles.  TICE BCG 50 mg was administered intravesically weekly x 6 weeks with maintenance therapy per the treating urologist’s discretion.  EBRT was administered to the whole bladder in 3 separate 6 Gy fractions on days 1, 3, 5 of cycle 1 only.  Post-treatment disease evaluations included cystoscopy, urine cytology and for-cause biopsies at 3 months; cystoscopy, urine cytology and mandatory bladder biopsy at 6 months; and long-term disease evaluations per the treating urologist’s discretion.  The primary endpoint of the phase 1 portion was to establish the recommended phase 2 dose (RP2D) of each combination regimen.

Results:

Between 12/2017-2/2020, 28 pts enrolled (3 – D, 13 – D+BCG, 12 – D+EBRT) from 6 sites.  Demographics included: median age 74 years; 82% male; CIS (15 pts), high-grade (HG) Ta/T1 (9 pts), and HG Ta/T1 + CIS (4 pts); median prior BCG regimens 2 (1-7).   Treatment related grade 3/4 events included: hyperglycemia, elevated lipase, elevated transaminases, and rash (1 pt each).  Dose-limiting toxicity (grade 3 elevated transaminases) occurred in 1 D+EBRT pt.  D 1120 mg iv every 21 days combined with full-dose BCG weekly x 6 or EBRT 6 Gy x 3 were the RP2Ds.  Complete response rates at 3- and 6-months were 33% (95% CI: 0.8, 90.6%) / 0% in D, 83% (95% CI: 51.6, 97.9%) / 71% (95% CI: 29.0, 96.3%) in D+BCG, and 55% (95% CI: 23.4, 83.3%) / 33% (95% CI: 4.3, 77.7%) in D+EBRT cohorts.  Translational biomarker analyses will be presented at the meeting.

Conclusion:

Durvalumab in combination with intravesical BCG therapy or EBRT can be safely administered to NMIBC patients.  Complete response rates in the treated BCG-unresponsive NMIBC population are promising with no unexpected adverse events observed.  Longer-term follow up to assess the true frequency of durable responses at 12-months and beyond as well as validation of predictive biomarkers associated with durable responses is warranted.  The multi-arm, multi-stage ADAPT-BLADDER study presents an attractive trial design to optimize assessment of future novel immunotherapy combination strategies in NMIBC patients.

Funding: R01CA235681, AstraZeneca