ctDNA Detection May Predict Neoadjuvant Immunotherapy Response in MIBC

Assessment of circulating tumor DNA (ctDNA) in the blood plasma with the RaDaR assay may help to identify response to treatment with neoadjuvant immunotherapy in patients with muscle-invasive bladder cancer (MIBC), thereby mitigating the need for aggressive cystectomy, according to a press release on data from the phase 1b/2a NABUCCO trial (NCT03387761).¹

In the phase 1b/2a NABUCCO trial, investigators found that ipilimumab plus durvalumab should be given at high doses to patients with stage III urothelial cancer and that absence of ctDNA in blood may predict progression-free survival.

Investigators of the trial reported that the RaDaR assay’s detection of an absence of ctDNA in plasma correlated with patient responses to treatment with neoadjuvant nivolumab (Opdivo) and ipilimumab (Yervoy). The absence of ctDNA in the blood plasma correlated with both pathological complete responses (pCR; odds ratio [OR]; 45.0; 95% CI, 4.86-416.46) and progression-free survival (HR, 10.4; 95% CI, 2.86-37.50).

However, absence of ctDNA in the urine was associated with pCR but not PFS.

“By determining if a patient has responded well to neoadjuvant treatment, RaDaR provides necessary insights to help oncologists decide whether a patient may be a candidate for bladder-sparing treatment strategies,” Vishal Sikri, president and head of Advanced Diagnostics at NeoGenomics, said in the press release.

The feasibility of neoadjuvant therapy was assessed in cohort 1 of the phase 1b/2a NABUCCO trial, in which patients were treated with 3 mg/kg of ipilimumab plus 1 mg/kg of nivolumab. Patients received 3 mg/kg of ipilimumab plus 1 mg/kg of nivolumab in cohort 2A or 1 mg/kg of ipilimumab plus 3 mg/kg of nivolumab in cohort 2B for 2 cycles with a subsequent 3 mg/kg dose of nivolumab.

The primary end point of the trial was the number of patients who received surgical resection less than 12 weeks following immunotherapy. Secondary end points included pCR rate, estimated grade 3 or higher immune-related adverse effects, perioperative complications, ctDNA in plasma during follow-up, and CT scans 1 and 2 years as follow-up after surgery.

Patients 18 years and older with high-risk, resectable stage III urothelial cancer were eligible for enrollment on the trial. Additional inclusion criteria included having a World Health Organization performance status of 0 or 1, formalin-fixed paraffin-embedded tumor specimens in paraffin blocks from available diagnostic transurethral resection, and a negative pregnancy test within 2 weeks of day 1 of cycle 1 for patients of childbearing potential.

Patients who had active autoimmune disease in the past 2 years, a documented history of severe autoimmune disease, or received prior treatment with CTLA-4 or PD–L1–targeting agents were unable to enroll on the trial. Patients were also unsuitable for enrollment if they had a known history of human immunodeficiency virus, medical conditions requiring treatment with immunosuppressive medications, other malignancies in the last 2 years, or a major surgical procedure within 4 weeks prior to enrollment.

Additional findings indicated that pCRs occurred among 43% (n = 6) of patients in cohort 2A and 7% (n = 1) of those in cohort 2B.² Investigators concluded that ipilimumab and nivolumab should be administered at a high dose in patients with stage III urothelial cancer and that absence of ctDNA in the blood could be predictive of PFS.

“The findings from the NABUCCO trial offer initial evidence in hopefully improving the outlook for these patients [with MIBC]. Importantly, the research shows that the RaDaR assay can be used successfully to guide decision-making and help oncologists personalize patient care based on their risk of recurrence,” Shashikant Kulkarni, chief scientific officer at NeoGenomics, concluded.

References

1. RaDaR^® assay demonstrates clinical potential for helping oncologists determine whether or not muscle-invasive bladder cancer patients undergo radical surgery. News release. NeoGenomics. February 6, 2023. Accessed February 8, 2023. bit.ly/3YdbPVq
2. van Dorp J, Pipinikas C, Suelmann BBM, et al. High- or low-dose preoperative ipilimumab plus nivolumab in stage III urothelial cancer: the phase 1B NABUCCO trial. Nat Med. Published online February 2, 2023. doi:10.1038/s41591-022-02199-y