Nadofaragene Firadenovec Efficacy Biomarker Appears in Non-BCG-Responding NMIBC
Researchers may have found a biomarker of efficacy for nadofaragene firadenovec in patients with bacillus Calmette-Guérun (BCG) – non-invasive muscle bladder cancer (NMIBC), a population in which the new agent has already demonstrated strong clinical activity.
Specifically, investigators conducted a secondary analysis of a phase 3 study (NCT02773849),1 hypothesizing that anti-adenoviral antibody levels and factor change measurements could be new predictors of a sustained response to nadofaragene firadenovec. Based on the response to intravesical gene therapy, it was determined that patients with peak titer levels greater than 800 and peak factor changes greater than 8 favored the response. Patients who did not meet both criteria were rated as unfavorable.
By month 12 after the first treatment with nadofaragene firadenovec, 47 patients were responders to treatment and a total of 44 patients were non-responders. Peak titer during treatment greater than 800 were achieved in 89.4% of responders versus 59.1% of non-responders (P = .001). For maximum change factor, 51.1% of responders had a maximum change factor of at least 8, compared to 27.3% of non-responders (P = .020).
In addition, the combination of markers was noted in 46.8% and 18.2% of responders and non-responders, respectively (P = .004).1
“[Peak titer levels] were associated with the highest sensitivity, precision and negative predictive value, ”said Anirban P. Mitra, MD, PhD, urologic oncology researcher at the MD Anderson Cancer Center at the University of Texas at Houston. “In addition, when we looked at the peak fold changes with a cutoff of 8, it also significantly distinguished between responders and non-responders so that we then classified the patients as ‘favorable’. ‘they had a combination of peak titer greater than 800 and maximum fold change greater than 8.
Mita added that the combination of markers was associated with the highest sensitivity and positive predictive value.
To perform this analysis, the investigators performed an assessment of anti-adenoviral antibodies using a quantitative ELISA 1 to 24 hours before treatment at baseline and before each dose at 3, 6, 9 and 12 months or at the study withdrawal visit. The test assessed both the raw titers as well as the factor change, which was calculated as the ratio of antibody levels during treatment to baseline levels. The final response to treatment was assessed as the primary endpoint of the trial, either 12 months after the first dose or at the time of high-grade recurrence.1
Patients included in the trial received a single intravesical dose of 75 mL of nadofaragene firadenovec (3 × 1011 virus particles / mL) for 1 hour.1 The replication-deficient recombinant adenovirus is designed to deliver interferon-α-2b (INFα-2b) to the epithelium of the bladder. The therapy mimics viral infection, resulting in production of IFNα-2b and subsequent tumor regression, offering a novel treatment for patients whose tumors do not respond or recur after BCG.2.3
In the absence of high-grade recurrence, patients received repeated catheter doses at 3 months, 6 months, 9 months and 12 months; an additional dose was permitted at the discretion of the investigator. The primary endpoint was complete response at all times. A total of 157 patients were enrolled and treated in the study and non-responders were reported at 6 months (n = 21), 9 months (n = 8) and 12 months (n = 15).
The efficacy population included 151 patients and a complete response was observed in 59.6% of patients at 3 months. The duration of response or high-grade recurrence-free survival was 7.31 months (range, 5.68-11.93).3
The optimal titer threshold was determined based on the evaluation of the peak titers and the change in peak factor. For responders and non-responders, peak titers were reached for most patients about 6 months after the start of treatment; Peak fold changes were also observed at month 6. Therefore, the researchers selected the optimal antibody titer threshold of 200 at baseline and 800 after treatment when maximizing the area under the operating characteristic curve of the receptor.1
Mitra noted that the baseline (200) was not associated with a difference between responders and non-responders; “However, a post-treatment cut-off of 800 made it possible to make a significant distinction between responders and non-responders at 3 months and especially at peak titer levels.”
Most crosses between the low and high titer subgroups occurred within the first 6 months of treatment. After this point in time, the highest proportion of responders continued to have post-treatment titers above 800, further supporting the use of peak titers as a marker to predict a sustainable response.
Finally, Mita presented an exploratory analysis of baseline titer levels as predictive markers of post-treatment titer level. Although not associated with a durable response, low baseline titers were associated with low posttreatment titers (≤ 800). High titers after treatment (> 800) were significantly associated with patients who had high baseline titers.
Specifically, for those with elevated levels of post-treatment, the median baseline antibody level at 3 months was 400 (interquartile range [IQR], 200-1600) versus 200 (IQR, 125-400) for those with low post-processing titers (P <.001>
For those with high post-treatment titers at the peak, the median baseline antibody level was 400 (IQR, 200-800) versus 200 (IQR, 1-400) for those with low post-treatment titers (P <.001>
1. Mitra AP, Narayan VM, Boorjian SA, et al. Anti-adenoviral antibody levels predict response to nadofaragene firadenovec in BCG-insensitive NMIBCs: results from a phase 3 trial. J Uro. 2021; 206 (suppl 3): e119-e120. doi: 10.1097 / JU.0000000000001977.02
2. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd-IFNα / Syn3 for patients with high-grade, Calmette-Guérin refractory or relapsed, non-muscle invasive bladder cancer: a randomized phase II study. J Clin Oncol. 2017; 35 (30): 3410-3416. Correction published in J Clin Oncol. 2019; 37 (24): 2187.
3. Boorjian SA, Alemozaffar M, Konety BR, et al. Nadofaragene firadenovec intravesical gene therapy for non-muscle invasive bladder cancer not responding to BCG: a single arm, open, repeated dose clinical trial. Lancet Oncol. 2021; 22 (1): 107-117. doi: 10.1016 / S1470-2045 (20) 30540-4