(UroToday.com) The 2022 ASCO annual meeting featured an oral abstract session on kidney and bladder cancer, including a discussant presentation by Dr. Shilpa Gupta discussing whether there is a role for VEGF-TKIs in bladder cancer. For this presentation, Dr. Gupta discussed “Cabozantinib in combination with atezolizumab in urothelial carcinoma: Results from Cohorts 3, 4, 5 of the COSMIC-021 study” by Dr. Monty Pal, and “A randomized, double blind, phase II clinical trial of maintenance cabozantinib following chemotherapy for metastatic urothelial carcinoma: Final analysis of the ATLANTIS cabozantinib comparison” by Dr. Robert Jones. Dr. Gupta notes that the current treatment options for metastatic urothelial cancer in June 2022 includes first-line therapy being platinum-based chemotherapy. As it stands, the only role that immunotherapy has in the first line setting is for those that are platinum-ineligible (pembrolizumab, atezolizumab). Thus, immunotherapy is best used (avelumab) in the maintenance setting among those that have not had progressive disease on first-line platinum-based chemotherapy based on the phase 3 JAVELIN Bladder 100 trial.1 A summary of the current landscape is as follows:
Dr. Gupta notes that the role of the VEGF pathway in urothelial carcinoma is
- Mediation of angiogenesis and stimulation of mitogenic activity
- Serum and tissue VEGF levels correlate with disease stage, grade, disease recurrence, and progression
- HGF/c-Met induces epithelial-mesenchymal transition (EMT) and progression in bladder cancer
- VEGF is a potent immunosuppressive factor in both innate and adaptive anti-tumor immunity
Unfortunately, early trials of older VEGF/TKIs in metastatic urothelial carcinoma (pre-IO era) suffered from high toxicity rate and poor efficacy, however potentially paving the way for next generation VEGF-TKIs and IO combinations.
The first abstract discussed by Dr. Gupta was the ATLANTIS trial. This was a biomarker driven study, specially patients that were not DRD or AR biomarker positive were eligible for randomization to the cabozantinib arm:
Dr. Gupta notes that 54 patients may have gone on to the cabozantinib if they were not selected for the DRD or AR biomarker arm, thus potentially introducing selection bias. The PFS assumption in the placebo group for this trial was 6 months based on results of the LaMB trial and was hypothesized to be 9 months in the cabozantinib arm. Secondary to the pandemic, the statistical plan for this trial was modified due a hold on recruitment, as well as avelumab being approved for maintenance therapy. Because of this, the power went from 90% to 72.3%, dropping the sample size (from 140 to 61) and thus making this an underpowered study. Dr. Gupta notes that the PFS benefit of avelumab versus placebo was 3.7 months, thus a PFS estimate of 9 months with cabozantinib is quite a high bar to achieve.
Duration of treatment in this trial was encouraging (13 twenty-eight day cycles), however, the response rate is low (3.3 % for cabozantinib versus 6.5% for placebo). Furthermore, cabozantinib was tolerable, and there was no treatment discontinuation for treatment-related adverse events. Dr. Gupta emphasized that biomarker analysis will be key for treatment selection. She notes that the author’s conclusions for this trial are appropriate, as follows:
- Though underpowered, this study does not support further investigation of cabozantinib alone as a maintenance therapy after platinum-based chemotherapy in unselected patients with advanced urothelial cancer
- Negative patient selection for DRD and androgen receptor biomarkers may bias interpretation
- Placebo is no longer an acceptable control arm in this indication
- Future trials should consider combining novel agents with maintenance immunotherapy
Dr. Gupta concluded her discussion of the ATLANTIS trial with the following key takeways and opportunities:
- The trial did the right and ethical thing to stop recruitment once avelumab was approved as maintenance therapy
- Single-agent cabozantinib does not warrant further study in metastatic urothelial carcinoma
- Biomarker analysis from this trial will be crucial to inform patient selection in future anti-angiogenesis therapy trial designs
- There may be rationale to combine cabozantinib with avelumab in the maintenance setting with an avelumab control arm
Dr. Gupta then discussed the COSMIC-021 trial, which noted encouraging disease control rates for cabozantinib + atezolizumab for cisplatin ineligible patients in cohort 3 (ORR 20%) and cohort 4 (ORR 30%), with low rates of progressive disease. However, she notes that the duration of response in cisplatin-ineligible patients is lower than historically reported for atezolizumab (IMvigor 2102 – not reached; median follow-up of 11.7 months):
Again, amongst patients having received immune-checkpoint inhibitors (cohort 5), there was a modest objective response rate of 10%, with an encouraging disease control rate (61%). Dr. Gupta wonders: Does prior anti-PD-1 versus anti-PD-L1 therapy matter? Additionally, it is important to note the shortcomings of traditional imaging and an ORR endpoint. Tumor necrosis/lack of tumor progression may be associated with improvement in outcomes with targeted therapy/immunotherapy.
Dr. Gupta concluded her discussion of the COSMIC-021 trial with the following key takeways and opportunities:
- The study provides hypothesis generating data with cabozantinib-atezolizumab combination in treatment naïve and prior platinum and IO treated metastatic urothelial carcinoma patients
- Biomarker analysis from this trial will be crucial to inform future combination trials
- While the objective response rates were modest, the rates of progressive disease were low and disease control rates were encouraging, making this an attractive option for the maintenance setting in metastatic urothelial patients who do not progress after platinum chemotherapy
- We need to reconsider the value/need of ORR as an efficacy endpoint with targeted therapies and IO
- We need to move away from traditional RECIST criteria, and incorporate iRECIST and molecular imaging
Dr. Gupta notes that we await the results of the MAINCAV phase 3 randomized trial of maintenance cabozantinib and avelumab versus maintenance avelumab after first-line platinum-based chemotherapy in patients with metastatic urothelial carcinoma:
Dr. Gupta concluded her discussant presentation with the following conclusions and future directions:
- There is an unmet need to exploit new targets and advance drug development in urothelial carcinoma, and these trials provide hypothesis generating data and inform future phase 3 trial development
- Single-agent VEGF inhibitors do not appear to have meaningful efficacy but show promising activity and disease control when used with immunotherapy
- Immunomodulatory VEGF inhibitors have the potential to overcome resistance to immunotherapy and enhance efficacy
- Robust biomarker and radiomics efforts are critical to optimize precision immunotherapy and targeted therapy for patients with urothelial carcinoma
Presented by: Shilpa Gupta, MD, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.
References:
- Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020 Sept 24;383(13):1218-1230.
- Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 2016;387(10031):1909-1920.