1.GU14-188: In this Phase II trial, Dr. Hristos Kaimakliotis and colleagues assessed neoadjuvant gemcitabine and pembrolizumab prior to cystectomy in patients with cT2-4aN0M0 urothelial carcinoma. While this trial enrolled both cisplatin eligible and ineligible patients, this report focussed on the ineligible subset.
This study notably demonstrated that the regime was well tolerated with patients receiving a median of the same number of doses as intended. Further, treatment-related adverse events did not preclude cystectomy in any case though disease characteristics precluded surgery in three patients (8%). Pathologic complete response was seen in 14 patients (45%) with downstaging to ≤ ypT1 in 52%.
2. NABUCCO: Given encouraging data in the neoadjuvant use of checkpoint inhibitor monotherapy (pembrolizumab or atezolizumab), this study sought to assess the effect of combination therapy with nivolumab and ipilimumab in patients with cT3-4aN0 or cT2-4aN1-3 bladder cancer who were cisplatin-ineligible.
In data presented at ESMO 2019, the authors found a 46% pathologic complete response rate and ≤ ypT1 rate of 58%. In the presentation at the 2020 ASCO Virtual Meeting, Dr. Van Dijk demonstrated low recurrence rates (two of 24 patients) with one patient developing metastatic disease and dying of bladder cancer. Biomarker stratified analysis demonstrated that patients with a complete response had a significantly higher tumor mutational burden.
Integrating data on neoadjuvant immunotherapy, Dr. Gupta highlighted data from a number of trials as follows:
Further, she highlighted a number of ongoing and yet-to-open trials in this disease space as follows:
She further noted that work into the underlying molecular biology of muscle-invasive bladder cancer has raised the potential for precision medicine. In particular, patients with claudin-low tumors have a higher risk of upstaging and derive less benefit from conventional cytotoxic neoadjuvant chemotherapy. However, they may derive greater benefit from immunotherapeutic approaches.
Dr. Gupta then moved from muscle-invasive bladder cancer to advanced renal cell carcinoma.
3. Neoadjuvant/adjuvant durvalumab +/- tremelimumab in renal cell carcinoma (RCC): Dr. Orenstein presented results of a Phase 1b trial assessing the role of neoadjuvant/adjuvant durvalumab +/- tremelimumab in patients with clinical stage T2b-4 or N1 disease with the primary goal of assessing the safety and feasibility of this perioperative approach.
The authors showed that the use of this neoadjuvant approach was not associated with delays to surgery (median time seven days, range two to 56). While durvalumab monotherapy was well tolerated (cohort 1), the addition of tremelimumab was associated with significant toxicity, and this required study suspension due to high rates of adverse event-related treatment discontinuation.
Dr. Gupta highlighted that other ongoing trials (including PROSPER RCC, EA8143, and PROBE) will assess the role of neoadjuvant immunotherapy in advanced renal cell carcinoma.
4. SWOG S1605: Finally, Dr. Gupta examined the data on checkpoint inhibition using atezolizumab in Bacillus Calmette-Guérin (BCG) refractory nonmuscle-invasive bladder cancer, a study presented by Dr. Peter Black at ASCO 2020. In short, among patients with carcinoma in situ (CIS), complete response was seen in 20 of 74 patients on mandatory biopsy at six months. The complete response was somewhat higher (31 of 74, 42%) at three months.
Dr. Gupta highlighted that 22 patients had to be removed from the efficacy analysis cohort as a result of ineligibility including not meeting FDA definitions of BCG refractory. She further highlighted the many ongoing Phase II and III trials in nonmuscle-invasive bladder cancer.
In conclusion, Dr. Gupta highlighted the importance of the use of data derived in these trials to understand biomarkers of response and resistance as well as the importance of adaptive trial designs to accelerate drug development and approval.
Presented by: Shilpa Gupta, MD, Staff Member, Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
Written by: Christopher J.D. Wallis, MD, PhD, Urologic Oncology Fellow, Vanderbilt University Medical Center, Nashville, Tennessee, Twitter: @WallisCJD, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020