Brittany Lovely

Clinical outcomes, including delay to recurrence, were not significantly improved for patients with bacillus Calmette-Guérin-unresponsive non–muscle invasive bladder cancer undergoing treatment with a combination of the recombinant pox-viral vector vaccine Panvac and bacillus Calmette-Guérin (BCG).

Results of the phase 2 study (NCT02015104) were presented at the 2021 American Urologic Association Annual Meeting.

Patients with high-grade NMIBC who did not respond to 1 or more induction courses of intravesical BCG were randomized to receive BCG (n = 15) or BCG plus Panvac (n = 15). The 12-month recurrence-free survival (RFS) rate was 42.9% (95% CI, 22.9%-80.0%) for those who received BCG alone compared with 44.4% (95% CI, 24.8%-79.9%) for those who received the combination (

The median time to recurrence was 11.7 months vs 9.9 months, respectively (

 = .77). The RFS rate for entire population was 43.3% (95% CI, 27.9%-66.8%).

The 12-month progression-free survival rates were 79.6% (95% CI, 56.9%-100%) and 78.6% (95% CI, 59.8%-100%) for patients treated with BCG alone and BCG plus Panvac, respectively.

Four patients from the BCG alone arm and 5 patients from the combination arm sought radical cystectomy following treatment.

In terms of baseline histologic characteristics, 14 patients had Ta, 7 had T1, 6 patients had carcinoma in situ alone, 2 had carcinoma in situ with Ta, and 1 had carcinoma in situ with T1. Additionally, 33% of patients (n = 10/30) had at least 2 prior induction courses of BCG.

The vaccine is designed to enhance the presentation of CEA and MUC-1, which are overexpressed in certain cancers, and activate cytotoxic T-lymphocyte response. The therapy consists of a recombinant vaccinia viral vector, a modified vaccinia Ankara-Bavarian Nordic, and a recombinant fowlpox vector. It is administered via a vaccinia priming dose, followed by multiple boosting doses of the fowlpox vector.

Participants enrolled to the phase 2 trial received BCG in 6 weekly injections; those in the Panvac arm received the vaccine in 5 injections over 15 weeks.

In the inclusion criteria for the study, investigators noted that all subclassifications for BCG failure would be considered for inclusion into the study, including BCG-refractory, -resistant, and -relapsing.

Investigators noted in the abstract that the trial was “unique” stating, “It originated prior to the definition of BCG-unresponsive disease and at least a third of the patients on this trial were already BCG unresponsive upon enrollment and received more BCG.”

In a guidance for developing drugs and biologics for treatment, the FDA defined BCG-unresponsive disease as having at least 1 of the following characteristics: persistent or recurrent carcinoma in situ with or without recurrent Ta/T1 disease within 12 months of the completion of adequate BCG therapy, recurrent high-grade Ta/T1 disease within 6 months of the completion of adequate BCG therapy, and/or T1 high-grade disease at the first evaluation after a BCG induction course.

Further, the FDA defined adequate BCG is defined as at least 5 of 6 doses of an induction course plus at least 2 of 3 doses of maintenance therapy, or at least 5 of 6 doses of an induction course plus at least 2 of 6 doses of a second induction course.

“Unlike [ongoing] trials, this trial had a comparison group of BCG alone and, despite the heavy pretreatment in up to a third of patients, the RFS in both arms was still comparable to what has been seen in current BCG unresponsive trials,” the investigators concluded.

The abstract was presented by Ragheed Saoud, MD, a urologist at Northwell Health in Riverside, New York.

1. Saoud R, Telfer S, Marfur M, et al. Clinical outcomes of a randomized, prospective, phase II study to determine the efficacy of bacillus Calmette-Guerin (BCG) given in combination with Panvac versus BCG given alone in adults with high grade BCG-refractory non-muscle invasive bladder cancer. 

. 2021;206(suppl3):e302. doi:10.1097/JU.0000000000002001.14

2. CEA-MUC-1-TRICOM vaccine CV301. National Cancer Institute. Accessed September 13, 2021. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/cea-muc-1-tricom-vaccine-cv301

3. Study of bacillus Calmette-Guerin (BCG) combined with Panvac versus BCG alone in adults with high grade non-muscle invasive bladder cancer who failed at least 1 course of BCG. ClinicalTrials.gov. Updated January 22, 2020. Accessed September 13, 2021. https://clinicaltrials.gov/ct2/show/NCT02015104

4. BCG-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. FDA. 2018. Accessed September 13, 2021. https://www.fda.gov/media/101468/download

Articles

The 12-month recurrence-free survival rate was 42.9% for those who received BCG alone compared with 44.4% for those who received the combination.

Combination Panvac-BCG does not significantly improve outcomes in non–muscle invasive bladder cancer

Two-year follow-up data for the nadofaragene firadenovec shared during the 2021 American Urologic Association Annual Meeting showed that the novel intravesical gene therapy maintained its efficacy in patients with bacillus Calmette-Guérin (BCG) unresponsive non–muscle invasive bladder cancer (NMIBC).

Long-term findings from 2 cohorts of a phase 3 study (NCT02773849) were shared at the meeting. Investigators reported that among 103 patients with carcinoma in situ (CIS) with or without Ta/T1, 20 patients (19.4%) remained free from high-grade recurrence. Further, of the 55 patients who achieved a complete response (CR) at 3 months following their first dose of nadofaragene firadenovec, 20 (36.4%) remained disease free at 24 months.

In the cohort of patients with high-grade Ta/T1 without CIS (n = 48), 16 patients (33.3%) did experience disease recurrence and 16 (47.5%) of the 35 patients who achieved a complete response at 3 months did not experience high-grade recurrence at 24 months.

As of the September 2020 data cutoff, 62.1% (n = 64/103) of patients with CIS with or without Ta/T1 remained on study. The rate was similar in the high-grade Ta/T1 cohort (68.8%; n = 33/48).

“Nadofaragene [firadenovec] represents a potential novel treatment option for patients with high-grade BCG-unresponsive NMIBC,” said Anne K. Schuckman, MD, in a presentation of the data for the first cohort of patients. She added that the therapy holds the potential to “advance the current treatment paradigm” for these patients. Schuckman is an assistant professor at the Keck School of Medicine at the University of Southern California (USC), and director of urologic oncology at the Los Angeles County + USC Medical Center.

Yair Lotan, MD, who presented the results of the high-grade Ta/T1 cohort, concurred, adding that “[nadofaragene firadenovec] demonstrates sustained durability of response.”

Lotan is a professor of urology and holds the Helen J. and Robert S. Strauss Professorship in Urology at UT Southwestern Medical Center. He is also chief of urologic oncology and the Jane and John Justin Distinguished Chair in Urology as well as the medical director of the urologic clinic at UT Southwestern and Parkland Health and Hospital System.

The multicenter, open-label study enrolled 157 patients with high-grade BCG-unresponsive NMIBC to 2 cohorts: those with CIS with or without Ta/T1 (n = 107) and high-grade Ta/T1 without CIS (n = 50); 103 and 48 patients were included in the efficacy analysis, respectively.

Nadofaragene firadenovec was administered as a single intravesical 75-mL dose of (3 × 1011 viral particles/mL) over 1 hour and was given once every 3 months for up to 4 doses, with additional dosing permitted at investigator’s discretion. The intravesical delivery of the agent prolongs the exposure of the bladder to the human recombinant interferon α-2b (INFα-2b).4 In preclinical studies, IFNα-2b production resulted in tumor regression, presenting a potential avenue for treatment of patients whose tumors do not respond or recur after BCG.

BCG-unresponsive disease was defined as persistent high-grade T1 recurrence occurring within 12 months of BCG initiation, relapse with CIS after initial CR less than or equal to 12 months after last BCG treatment, or relapse with high-grade Ta/T1 NMIBC after last BCG treatment.

Baseline characteristics differed slightly between the 2 cohorts.

Patients in the CIS cohort had a median age of 72 years, 89% of patients were men, and 99% received 2 or more prior courses of BCG prior to enrollment. Specifically, 42% of patients received 2 courses and 57% received 3 or more courses of BCG. In terms of disease stage at study entry, 76% had CIS only, 20% had Ta plus CIS, and 5% had T1 plus CIS. The median time from initial diagnosis of bladder cancer was 20 months.

Those in the Ta/T1 cohort had a median age of 71 years, 68% of individuals were men, and 90% of patients received 2 or more prior BCG courses; 56% received 2 courses and 34% received 3 or more courses. The time from initial diagnosis of bladder cancer was 15 months and 70% of patients had Ta disease and 30% had T1 disease.

At 12 months, protocol mandated a 5-site biopsy, which includes the dome, trigone, right and left lateral walls, and the posterior wall. The primary end point was CR in patients with CIS with or without high-grade Ta/T1 papillary disease.

The trial met its primary end point of CR within 12 months. Specifically, 53.4% (95% CI, 43.3%-63.3%) of patients in the CIS cohort (n = 103) had a CR, all of which occurred at 3 months. The median duration of CR was 9.69 months (95% CI, 9.17-not estimable [NE]); 25 patients (24.3%; 95% CI, 16.4%-33.7%) were free from high-grade recurrence at 12 months.

Twelve-month data for the high-grade Ta/T1 cohort (n = 48) trended slightly higher with 72.9% (95% CI, 58.2%-84.7%) of patients achieving a CR at 3 months and 21 patients (43.8%; 95% CI, 29.5%-58.8%) were recurrence free at 12 months. The median duration of CR was 12.35 months (95% CI, 6.67-NE).

In terms of patients who proceeded to cystectomy at 24 months of the 20 patients in the CIS cohort who had a durable CR at 24 months, 50% went on to cystectomy; for those who did not achieve a CR (n = 48), 23 underwent cystectomy by 24 months. Of the 48 patients who did not achieve a CR, 40 had high-grade recurrence, 7 did not meet the sponsor definition of CR at 3 months, and 1 patient discontinued treatment.

Overall, the cystectomy-free survival rate for this cohort was 64.6% (95% CI, 54.1%-73.3%). Further, the overall survival (OS) rate was 94.4% (95% CI, 87.0%-97.6%).

For the patients in the high-grade Ta/T1 cohort, of those who were high-grade recurrence free at 24 months (n = 16), 7 had cystectomy by 24 months. For those patients who were not high-grade recurrence free at 3 months (n = 13), 4 proceeded to cystectomy by 24 months. The cystectomy-free survival rate was 69.8% (95% CI, 53.4%-80.9%) and the OS rate was 93.2% (95% CI, 80.4%-97.8%).

Finally, in terms of safety, both investigators reported that most drug-related adverse effects (AEs) were transient and localized with a median duration of 2 or fewer days. Additionally, most drug-related AEs were grade 1/2 and no grade 4 or 5 AEs were reported in either cohort.

The most common AEs observed in the CIS cohort were discharge around the catheter (24%), fatigue (23%), bladder spasm (18%), micturition urgency (17%), chills (12%), dysuria (10%), and pyrexia (10%).1 The rates for these AEs in the Ta/T1 cohort were 26%, 12%, 14%, 14%, 10%, 16%, and 10%, respectively.

Two patients in this cohort discontinued because of drug-related AEs in the CIS cohort and 1 patient discontinued treatment in the Ta/T1 cohort.

1. Shuckman AK, Lotan Y, Boorjian SA, Cilwa KE, Dinney CPN. Efficacy of intravesical nadofaragene firadenovec for patients with carcinoma in situ (CIS), BCG-unresponsive non-muscle invasive bladder cancer (NMIBC): longer-term follow-up from the phase III trial. 

. 2021;206(suppl 3):e296. doi:10.1097/JU.0000000000002001.01

2. Lotan Y, Shuckman AK, Boorjian SA, Cilwa KE, Dinney CPN. Phase III trial of intravesical nadofaragene firadenovec in patients with high-grade, BCG-unresponsive, non-muscle invasive bladder cancer: two year follow-up in the Ta/T1 cohort. 

. 2021;206(suppl 3):e296. doi:10.1097/JU.0000000000002001.02

3. Instiladrin in patients with bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC). ClinicalTrials.gov. Updated September 10, 2021. Accessed September 11, 2021. https://clinicaltrials.gov/ct2/show/NCT02773849

4. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. 

. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4

5. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd-IFNα/Syn3 for patients with high-grade, bacillus Calmette-Guerin-refractory or relapsed non-muscle-invasive bladder cancer: a phase II randomized study. 

. 2017;35(30):3410-3416. Published cor-rection in 

Long-term findings from 2 cohorts of a phase 3 study showed sustained efficacy with the novel intravesical gene therapy in patients with BCG-unresponsive non–muscle invasive bladder cancer. 

2-year update shows nadofaragene firadenovec maintained efficacy in NMIBC

Investigators may have found an efficacy biomarker for nadofaragene firadenovec in patients with bacillus Calmette-Guérun (BCG)–unresponsive non-muscle invasive bladder cancer (NMIBC), a population in which the novel agent has already demonstrated strong clinical activity.

Specifically, investigators conducted a secondary analysis of a phase 3 study (NCT02773849),

 hypothesizing that anti-adenoviral antibody levels and fold change metrics could be novel predictors of durable response to nadofaragene firadenovec. Based on response to the intravesical gene therapy, patients with peak titer levels that were greater than 800 and peak fold changes greater than 8 were determined to be favorable for response. Patients who did not meet both criteria were designated as unfavorable.

At month 12 following the first treatment with nadofaragene firadenovec, 47 patients were responsive to treatment and a total of 44 patients were nonresponders. On-treatment peak titer levels greater than 800 were reached in 89.4% of responders compared with 59.1% of nonresponders (

 = .001). Regarding peak fold change, 51.1% of responders had a peak fold change of at least 8 compared with 27.3% of nonresponders (

Further, the combination of markers was noted in 46.8% and 18.2% of responders and nonresponders, respectively (

“[Peak titer levels] were associated with the highest sensitivity, accuracy, and negative predictive value,” said Anirban P. Mitra, MD, PhD, a urologic oncology fellow at The University of Texas MD Anderson Cancer Center in Houston. “In addition, when we looked at peak fold changes with a cutoff of 8 this was also able to significantly distinguish between responders and nonresponders such that we then classified patients as ‘favorable’ if they had a combination of peak titer greater than 800 and a peak fold change greater than 8.”

Mita added that the marker combination was associated with the highest sensitivity and positive predictive value.

To conduct this analysis, investigators performed anti-adenoviral antibody assessment using a quantitative ELISA 1 to 24 hours prior to treatment at baseline and before each dose at 3, 6, 9, and 12 months or at the study-withdrawal visit. The assay assessed for both raw titers as well as fold change, which was calculated as the ratio of on-treatment antibody levels compared with baseline levels. The final treatment response was assessed at the trial’s primary end point of 12 months following the first dose or at the time of high-grade recurrence.

Patients enrolled to the trial received a single intravesical 75-mL dose of nadofaragene firadenovec (3 × 1011 viral particles/mL) over 1 hour.

 The replication-deficient recombinant adenovirus is designed to deliver interferon–α-2b (INFα-2b) to the bladder epithelium. The therapy mimics viral infection, resulting in IFNα-2b production and subsequent tumor regression offering a novel treatment for patients whose tumors do not respond or recur after BCG.

In the absence of high-grade recurrence, patients received repeat dosing via catheter at 3 months, 6 months, 9 months, and 12 months; additional dosing was permitted at investigator’s discretion. The primary end point was complete response at any time. A total of 157 patients were enrolled and treated in the study and nonresponders 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).

The optimal titer threshold was determined based on the assessment of peak titers and peak fold change. For both responders and nonresponders, peak titers were achieved for most patients approximately 6 months after initiation of treatment; peak fold changes were also observed to occur by month 6. Therefore, investigators selected the optimal antibody titer level threshold to be 200 at baseline and 800 post treatment when maximizing the area under the receiver operating characteristic curve.

Mitra noted that baseline level (200) was not associated with a difference between responders and nonresponders; “however, a posttreatment cutoff of 800 was able to significantly distinguish between responders and nonresponders at 3 months and importantly also at peak titer levels.”

Most crossovers between low- and high-titer subgroups occurred in the first 6 months of treatment. After this time point the highest proportion of responders continued to have posttreatment titers greater than 800, further supporting the use of peak titers as a marker to predict durable response.

Finally, Mita presented an exploratory analysis of baseline titers levels as predictive markers for posttreatment titer level. Despite not being associated with durable response, low baseline titers were associated with low posttreatment titers (≤ 800). High posttreatment titers levels (>800) were significantly associated with patients who had high baseline titer levels.

Specifically, for those with high posttreatment levels, the median baseline antibody level at 3 months was 400 (interquartile range [IQR], 200-1600) compared with 200 (IQR, 125-400) for those with low posttreatment titers (

For those who had high posttreatment titers at peak, the median baseline antibody level was 400 (IQR, 200-800) vs 200 (IQR, 1-400) for those with low posttreatment titers (

1. Mitra AP, Narayan VM, Boorjian SA, et al. Anti-adenoviral antibody levels predict nadofaragene firadenovec response in BCG-unresponsive NMIBC: 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, bacillus Calmette-Guerin-refractory or relapsed non-muscle-invasive bladder cancer: a phase II randomized study. 

. 2017;35(30):3410-3416. Published correction in J Clin Oncol. 2019;37(24):2187.

3. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. 

Antibody titers and fold changes may prove to be a prognostic marker for the efficacy of nadofaragene firadenovec.

Nadofaragene Firadenovec efficacy biomarker emerges in BCG-unresponsive NMIBC

Induction immunotherapy followed by chemoimmunotherapy did not significantly improve outcomes versus chemotherapy alone in the frontline setting for patients with metastatic urothelial carcinoma (mUC), according to findings presented at the 2020 ESMO Congress.

In a phase 2 study, treatment-naïve patients who were ineligible for cisplatin-based chemotherapy were randomized to 2 cycles of induction avelumab (Bavencio) followed by 6 cycles of avelumab plus gemcitabine/carboplatin followed by avelumab maintenance therapy (n = 42) or standard of care (SOC) gemcitabine/carboplatin alone (n = 43). The overall response rates were 57.1% (24/42) in the avelumab arm and 53.5% (23/43) in SOC arm (

 = .73). Specifically, 45.2% and 11.9% of patients in the avelumab arm experienced partial and complete responses, respectively, compared with 44.2% and 9.3% in the SOC arm.1,2

The median PFS was 6.9 months in the avelumab arm versus 7.4 months in the SOC arm (

 = .1356). Further, the median OS benefit was 10.5 months versus 13.2 months (

“The main objective of obtaining a 45% response rate was achieved in the avelumab treatment arm, however a similar response rate was unexpectantly observed in the chemotherapy treatment arm,” Begoña P. Valderrama, MD, of the Hospital Universitario Virgen del Rocío, in Sevilla, Spain, said during a presentation of the data at ESMO. “Induction immunotherapy alone before chemotherapy and immunotherapy is not an adequate strategy. The previous hypothesis that immunotherapy before chemotherapy might optimize chemotherapy response was not proven.”

Higher rates of disease progression and death were observed in the avelumab arm. Thirteen patients (31%) progressed or died prior to the first response assessment, and 6 of the deaths occurred in the first month. Only 4 patients progressed or died in the SOC arm.

 No adverse prognostic factor imbalance was observed in these patients, Valderrama explained.

In terms of safety, treatment related adverse-events (AEs) grade 3 or higher were reported in 70.7% and 65.1% of patients, respectively. In the avelumab arm, 41.5% grade 3 AEs were associated with avelumab. “No new unexpected toxicities were found beyond the ones that were already know with each of the agents given alone,” Valderrama said.

In a planned post-hoc analysis censoring all patients who died in the first 30 days (n = 6), the PFS data demonstrated similar results in both arms: 7.4 months in both the avelumab and placebo arms 

 = .7755). Further, at 15 months follow-up a superior percentual benefit in OS was observed in patients who received avelumab plus chemotherapy followed by avelumab maintenance. OS survival rates for avelumab versus placebo were 51.25% (95% CI, 33.64%-66.41%) and 38.96% (95% CI, 21.84%-55.76%), respectively.

 The follow-up data are still immature, but are consistent with the findings seen in the Javelin Bladder 100 maintenance study (NCT02603432), Valderrama said.

Avelumab retains its position as the preferred regimen for patients who are cisplatin ineligible as maintenance therapy following gemcitabine and carboplatin. On June 30, 2020, the FDA approved the agent as maintenance treatment for patients with locally advanced or mUC that has not progressed with first-line platinum-based chemotherapy. The approval added to the 2017 indication in mUC for patients who have disease progression during or following platinum-containing chemotherapy, or experience disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Valderrama BP. Phase II multicenter, randomized study to evaluate efficacy and safety of avelumab with gemcitabine/carboplatin (CG) vs CG alone in patients with unresectable or metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin-based therapy. Abstract presented at: 2020 European Society for Clinical Oncology Virtual Congress.; September 18-21, 2020; virtual. LBA27. https://cslide.ctimeetingtech.com/esmo2020/attendee/confcal_1/session

Gust KM. What’s the future of IO in urothelial carcinoma? How to combine or sequence the old and the new? Discussion presented at: 2020 European Society for Clinical Oncology Virtual Congress.; September 18-21, 2020; virtual. Presentation ID 5007. https://cslide.ctimeetingtech.com/esmo2020/attendee/confcal_1/session

FDA approves avelumab for urothelial carcinoma maintenance treatment. News release. FDA. Updated July 1, 2020. Accessed September 18, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment

The addition of avelumab to standard first-line gemcitabine/carboplatin did not improve outcomes in patients with metastatic urothelial carcinoma. 

Brittany Lovely

Articles

Combination Panvac-BCG does not significantly improve outcomes in non–muscle invasive bladder cancer

2-year update shows nadofaragene firadenovec maintained efficacy in NMIBC

Nadofaragene Firadenovec efficacy biomarker emerges in BCG-unresponsive NMIBC

Upfront immunotherapy regimen falls short in bladder cancer