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Can We Use ctDNA to Refine Selection of Urothelial Carcinoma Patients for Adjuvant Therapy?

Adjuvant therapy for urothelial carcinoma is a reasonable standard of care consideration for patients after radical cystectomy or nephroureterectomy, for those with lower and upper tract disease, respectively.  Although neoadjuvant cisplatin-combination chemotherapy is still a current standard,1 many patients never receive neoadjuvant therapy. The Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer (POUT) trial results support the use of adjuvant chemotherapy with gemcitabine/cisplatin or gemcitabine/carboplatin, as the primary endpoint of disease free survival (DFS) was positive in favor of adjuvant chemotherapy over surveillance with a HR of 0.45 (95% CI 0.30-0.68, p=0.0001).2  Although overall survival was not the primary endpoint of the trial, the 5-year overall survival was 66% vs. 57%, with a univariable HR 0.68 (95% CI 0.46-1.00, p-0.049).3

Naturally, immunotherapy with anti-PD-1 antibody therapy is another option to consider for patients appropriate for adjuvant therapy.  The CheckMate 274 adjuvant nivolumab trial showed DFS benefit of adjuvant nivolumab over placebo for patients with high-risk muscle invasive urothelial carcinoma of the bladder or upper tract.4  Of the 709 patients randomized to the trial, the primary endpoint of DFS was met by nivolumab with median DFS of 21.0 (95% CI 17.1-33.4) vs. placebo 10.9 (95% CI 8.3-13.9) months, HR 0.70 (95% CI 0.54-0.89), p=0.0006.  The population with PD-L1 expression > or = 1% had a median DFS that was not reached (95% CI 22.0-NE) vs. 10.8 (95% CI 5.7-21.2) months, HR 0.53 (95% CI 0.34-0.84), p=0.0004.  The AMBASSADOR trial recently demonstrated the advantage of pembrolizumab over surveillance for a similar patient population of muscle invasive urothelial carcinoma patients.  Specifically, median DFS was 29.0 months (95% CI 2.18-NE) with pembrolizumab and 14.0 months (95% CI 9.7-20.2) with observation (HR 0.69 [95% CI 0.55-0.87], p=0.0013).5  Neither of these trials are mature enough to demonstrate overall survival benefit, and that data will eventually be very nice to see.

For patients who didn’t receive neoadjuvant chemotherapy, it is worth the debate of whether one should be using cisplatin-based combination chemotherapy or an anti-PD-1 antibody for adjuvant therapy.  However, for those patients who received neoadjuvant cisplatin-based chemotherapy and didn’t have downstaging of disease to pT1 or less are a patient population with a high chance of relapse and an overall poor prognosis.  Those patients are very appropriate for adjuvant immunotherapy.

That said, it is clear that not every patient with high-risk features relapses.  One of the problems with adjuvant therapy is the potential for overtreatment of patients who may actually lack micrometastases.  Current selection methods for trial eligibility take into account prior treatment, histopathologic findings, and some use PD-L1 immunohistochemistry results to attempt to identify patients who may benefit the most from nivolumab.  There is promise for the use of circulating tumor DNA (ctDNA) to better risk stratify and select patients for trials and treatment in the future.  The existing data for ctDNA use is actually quite impressive already.  Specifically, the prognostic value is useful both before and after radical cystectomy, and it appears to outperform pathologic downstaging in predicting treatment efficacy.6  In one study, the assessment of ctDNA after radical cystectomy identified metastatic relapse with 94% sensitivity and 98% specificity.  A recent systemic review of the literature, including prospective studies of neoadjuvant and/or adjuvant chemotherapy and/or immunotherapy treated with radical cystectomy included 6 papers and confirmed the prognostic role of ctDNA after cystectomy.7  Springboarding from this to ongoing and future trial design is the data from a subgroup analysis of the negative phase III IMvigor010 trial that revealed the ctDNA-positive patients treated with atezolizumab had improved disease-free survival.  Additionally, ctDNA clearance after 2 cycles of adjuvant atezolizumab was associated with both improved disease-free and overall survival.

The above data helps support the ongoing hypotheses that patients with high-risk features who are lacking ctDNA may not require adjuvant therapy, while those with detectable ctDNA after radical cystectomy may be patients apt to benefit from adjuvant treatments and even potential adjuvant treatment intensification.  However, prospective therapeutic trials must be performed to confirm these assumptions.  The goal of sparing toxicity from adjuvant therapy using ctDNA selection may still leave some patients at risk of relapse.  On the flip side of adjuvant therapy, is the likelihood that not all patients who receive adjuvant therapy are cured.  Could these patients have biologically treatment-resistant disease that was possibly not going to be cured in the adjuvant setting and potentially never going to be cured?  To add fuel to this stance, with outstanding complete response rates to front-line metastatic urothelial carcinoma treatment with combination enfortumab vedotin with pembrolizumab,8 one also wonders whether it is worth forgoing adjuvant therapy.  There is only one way to know…perform the clinical trials with refined patient selection using ctDNA in the eligibility requirements.  At the current time, the below trials are prospectively determining prognostic and potentially predictive potential for adjuvant treatments using ctDNA technologies.  Let’s accrue patients to them and find out whether we can apply this technology for improved patient selection in the future.

ctDNA Detection-Directed Trials

  • TOMBOLA – Phase II trial of adjuvant atezolizumab at biochemical relapse following radical cystectomy (NCT04138628)
  • IMvigor011 – Randomized phase III trial of adjuvant atezolizumab vs. placebo in patients with high-risk muscle invasive bladder cancer who are ctDNA positive following cystectomy (NCT04660344)
  • MODERN – Randomized phase II-III ctDNA positive receive adjuvant nivolumab plus relatilimab vs. nivolumab while ctDNA negative receive adjuvant nivolumab vs. surveillance (NCT05987241)
  • Randomized phase III trial of adjuvant gemcitabine/cisplatin with ctDNA positive disease vs. at time of radiographic relapse (NCT06257017)
  • ORACLE - Novel Guardant ctDNA assay for patients with various solid tumors following neoadjuvant chemotherapy (Cohort 1 – muscle invasive urothelial carcinoma; cohort 11 – high grade, stage II, III, or limited stage IV treated with curative intent renal cell carcinoma) (NCT05059444)

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Grossman H, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349:859-66.
  2. Birtle A, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet 2020; 395:1268-77.
  3. Birtle AJ, et al. Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial. J Clin Oncol 2024; Epub February 13, 2024.
  4. Bajorin DF, et al. CheckMate 274: Adjuvant Nivolumab May Improve Disease-Free Survival in Patients With Muscle-Invasive Urothelial Carcinoma. J Clin Oncol 39, 2021 (suppl 6, abstr 391).
  5. Apolo A, et al. AMBASSADOR Alliance A031501: Phase III randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma (MIUC) vs observation. J Clin Oncol 42, 2024 (suppl 4; abstr LBA531)
  6. Lindskrog SV, et al. Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up. Clin Cancer Res 2023; 29:4797-807.
  7. Crupi E, et al. Circulating tumor DNA as a Predictive and Prognostic Biomarker in the Perioperative Treatment of Muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol Oncol 2024; 7:44-52.
  8. Powles T, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med 2024; 390:875-88.