ASCO 2022: Expanding Horizons in Localized Bladder Cancer

(UroToday.com) In this presentation, Dr. Van Der Heijden summarized the presentations from abstracts 4506-4508. He first focused on abstracts 4507 and 4508, which examined the role of immunotherapy in non-muscle invasive bladder cancer (NMIBC). Before delving into the data, he summarized his perspective on goals for novel therapies in BCG-refractory NMIBC, specifically that these treatments should result in a high rate of durable response, leading to substantial delays in cystectomy and low rates of progression to muscle-invasive disease. To formally codify these goals, a review paper was published in 2016 laying out a framework for NMIBC trials.1 This paper proposed a clinically meaningful initial complete response rate of 50% at 6 months and 30% at 12 months. Though not technically meeting these criteria, pembrolizumab has become a widely adapted standard of care in high-risk NMIBC based on the KEYNOTE-057 study that demonstrated a 19% one year complete response rate.2

 

After this context, Dr. Van Der Heijden first discussed the QUILT 3032 protocol of an IL-15 superagonist (N-803) in combination with BCG for BCG-unresponsive NMIBC.

 

ASCO 2022_Michiel Simon Van Der Heijden_RCC_0 

The results from this study in each cohort were rather good, with a 71% initial complete response rate and 12 month complete response rate of 45% in Cohort A. In Cohort B, 57% of patients were disease free at 12 months.

He then went on to discuss the TRUCE-02 study of combination immunotherapy and chemotherapy in high-risk NMIBC. The schema of this study is shown below.

ASCO 2022_Michiel Simon Van Der Heijden_RCC_1 

With a relatively short follow-up of 9 months, the complete response rate was 55%. Notably, the alopecia rate in this study was 82%. Certain translational results (AR and TCF7L2 mutation as well as alteration in homologous recombination repair genes) and their association with response are hypothesis-generating.

 

Regarding these two presentations overall, Dr. Van Der Heijden concluded that the QUILT 3032 data are promising but require phase 3 trial validation. TRUCE-02 on the other hand did not clearly lay out a case for the addition of chemotherapy to immunotherapy in NMIBC, especially since BCG was not a requirement and many patients suffering from alopecia.

 

ASCO 2022_Michiel Simon Van Der Heijden_RCC_2 

Finally, Dr. Van Der Heijden discussed results profiling cell-free methylated DNA as a biomarker to predict response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Unfortunately in this disease context, despite the benefit of neoadjuvant chemotherapy, overall outcomes are still unfavorable. Ideally, biomarkers would exist to help stratify patients for initial neoadjuvant therapy, and the same or different biomarker could then be retested after a period of therapy to suggest intensification, ongoing treatment, or treatment switch.

 

ASCO 2022_Michiel Simon Van Der Heijden_RCC_3 

 

Groups including that of the presenter have studied plasma genomic markers as putative biomarkers to accomplish the above-illustrated schema. For example, clearance of circulating tumor DNA after two cycles of chemotherapy is associated with a favorable response to neoadjuvant treatment.

 

Dr. Van Der Heijden summarized the cell-free methylated DNA analysis from the SWOG S1314 study. First he showed the schema of the trial, which compared two different neoadjuvant chemotherapy regiments for MIBC, and allowed for tumor and blood collections.

ASCO 2022_Michiel Simon Van Der Heijden_RCC_4 

 

The authors of that presentation developed a score based on methylation of selected genomic loci to stratify patients by their known responses. The accuracy of this score did not seem to change with treatment, which seems somewhat confusing as it is known that clearance of circulating tumor DNA is associated with response to therapy.

 

ASCO 2022_Michiel Simon Van Der Heijden_RCC_5 

Of further interest was the finding that cell-free methylated DNA score was not correlated with cell-free methylated DNA that mapped to bladder cells based on previously published methylation profiles. This raises the question of the source of the cell-free methylated DNA being analyzed, but may just reflect tumor-specific changes in bladder cell methylation.

 

Dr. Van Der Heijden concluded his talk by emphasizing that biomarkers to optimize therapy initiation and switches are critical to improving patient outcomes in localized bladder cancer. Cell-free methylated DNA is a promising approach but needs further validation before becoming mainstream.

 

Presented by: Michiel Simon Van Der Heijden, MD, PhD, Netherlands Cancer Institute

Written by: Alok K. Tewari, MD, PhD, medical oncologist at the Dana-Farber Cancer Institute, @aloktewar on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.

References:
1. Ashish Kamat, Richard Sylvester, Andreas Bohle, et al. “Definitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group.” J Clin Oncol. 2016;34(16):1935-1944.

2. Arjun Balar, Ashish Kamat, Girish Kulkarni, et al. “Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study.” Lancet. 2021;22(7):919-930.