KEY TAKEAWAYS
- The phase 2 study aimed to assess if mFast-SeqS aneuploidy scores after one pembrolizumab cycle predict treatment benefits.
- The primary endpoint was to measure baseline aneuploidy scores, and the secondary endpoint was an extended PFS.
- One-third of patients with a low baseline score did not respond, and their aneuploidy scores significantly increased post-treatment compared to responders.
Currently, pembrolizumab is the standard second-line treatment for metastatic urothelial cancer. However, its effectiveness varies among patients, and it carries the risk of significant side effects. Hence, there is an urgent need for reliable biomarkers to identify patients who are likely to benefit from pembrolizumab therapy.
An earlier study demonstrated that a high aneuploidy score (Z-score ≥ 5) in cell-free DNA (cfDNA) at baseline, measured using the modified fast aneuploidy screening test-sequencing system (mFast-SeqS), was associated with a poor response to pembrolizumab. Conversely, a low aneuploidy score (Z-score < 5) at baseline did not predict treatment response.
This study explored whether mFast-SeqS aneuploidy scores in cell-free DNA (cfDNA) can differentiate between patients who will benefit from pembrolizumab therapy and those who will not, early in the treatment course (after the first cycle).
The mFast-SeqS method was used to evaluate aneuploidy in blood samples from 74 patients with metastatic urothelial cancer (mUC) at baseline and after the first cycle of pembrolizumab. Responders were identified as patients exhibiting stable disease (SD) or partial/complete response (PR, CR) per RECIST v1.1 and who sustained treatment for more than 6 months from pembrolizumab initiation. Non-responders, in contrast, needed to meet these specified criteria.
A total of 60 patients out of 74 provided paired samples. At baseline, 25% (n=15) exhibited a high aneuploidy score, while 75% (n=45) had a low score. Among the high baseline score group, 13% (n=2) were responders, and 87% (n=13) were non-responders. Responders demonstrated a significant decrease in aneuploidy score post one cycle of pembrolizumab (p=0.005), regardless of their baseline score. For patients with a low baseline score, 47% were non-responders, and they experienced a noteworthy increase in aneuploidy score post cycle 1 compared to responders (p=0.039).
Early assessment of aneuploidy scores using mFast-SeqS could help identify mUC patients unlikely to benefit from second-line pembrolizumab treatment (after 1 cycle), enabling timely treatment modifications and potentially minimizing unnecessary toxicity.
Source: https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.4584
Clinical Trial: https://www.clinicaltrials.gov/study/NCT03263039
Youssra Salhi, Maud Rijnders, Pauline Mendelaar, Vania de Weert, Corine Beaufort, R Head, Hans M. Westgeest, Jens Voortman, Maureen J.B. Aarts, John W.M. Martens, Astrid Aplonia Maria Van Der Veldt, Ronald De Wit, Saskia M Wilting, Debbie Robbrecht DOI 10.1200/JCO.2023.41.16_suppl.4584, J Clin Oncol 41, 2023 (suppl 16; abstr 4584).
