Rashid Sayyid: Hello everyone, this is Rashid Sayyid. I'm a Urological Oncology Fellow at the University of Toronto. And along with Zach Klaassen, Assistant Professor and Program Director at Augusta University, we'll be discussing the recently published update from the JAVELIN Bladder 100 Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma, the results from the JAVELIN Bladder 100 trial after at least two years of follow up.

This paper was recently published in the Journal of Clinical Oncology with Dr. Thomas Powles as the first author.

So we're just going to start with giving an overall recap, the study design of the JAVELIN Bladder 100. Many of you will be familiar with this, but we'll take a second and go through the different eligibility criteria, and different nuances of the study designed. So this study was a randomized controlled trial that included patients with unresectable, locally advanced or metastatic urothelial carcinoma.

All patients had to have had no evidence of disease progression on standard first-line chemotherapy. Meaning, these patients either had a complete response, a partial response, or stable disease, with standard first-line chemotherapy, which was 46 cycles of cis/gem or carboplatin and gemcitabine. Patients had to wait for four to 10 weeks, and then 700 patients were randomized in a one-to-one fashion to the experimental arm of avelumab plus standard of care. And they were either randomized as well to best supportive care alone, with 350 patients in each arm. Patients were continued on the treatment arm until they had evidence of progressive disease, unacceptable toxicity, or withdrawal.

The primary endpoint of the study was overall survival, and the primary analysis population was all randomized patients and the PD-L1 positive population as well. Secondary endpoints included progression-free survival per RECIST criteria, and safety as well.

So the initial report, which was published in 2020 in the New England Journal of Medicine, showed at a median follow-up within about 19 months that avelumab plus best supportive care versus best supportive care alone, prolonged the median overall survival from 14.3 to 21.4 months, with a hazard rate of 0.69, 95% confidence interval that was below one with the P of 0.001.

So the primary endpoint again, was overall survival, as mentioned, assessed from random assignment in the overall and PD-L1 positive populations. Where secondary endpoints, as we mentioned, include progression-free survival, objective response, which was investigator-assessed for the RECIST 1.1 criteria, and safety as well.

Given that the trial had met its primary objective in the initial analysis, all updated analyses were considered exploratory. Efficacy endpoints were assessed using the intention to treat principle. And then safety outcomes were assessed in all patients who received at least one dose of avelumab. As a standard survival analysis using Kaplan-Meier curves, were used to estimate time-to-event outcomes, meaning, overall survival, progression-free survival. And hazard ratios and restricted mean survival times were used to estimate the treatment effect and time-to-event endpoints. And stratified odds ratios for objective response, which is a binary outcome as opposed to the time-to-event outcomes previously mentioned, were calculated using the Mantel-Haenszel method.

At this point, I'll turn it over to Zach, to delve further into the results and discussion of this study.

Zach Klaassen: Thanks so much, Rashid. That was a great introduction and set the table for this updated analysis.

So this is the baseline characteristics. As you can see here, this is stratified by avelumab plus best standard of care, versus best standard of care alone. We can see that these treatment groups were well-balanced, and median age was late 60s. The majority of patients, roughly three quarters, were male, and the majority of patients, roughly two thirds, were White. And we can see that the majority of these patients, more than 50% were randomized in Europe. But the second most common location being Asia, at 20 to 21%.

As you'd expect in a clinical trial, most patients, more than 60%, had excellent performance status. ECOG zero. Roughly 50% had positive PD-L1 baseline status. And the most common chemotherapy regimen for first-line chemotherapy was gemcitabine plus cisplatin, more than 50%, but the second most common regimen being gem plus carbo, at roughly 34% to 42%.

Majority of patients had partial response at just under 50%, with about one quarter having complete response, and roughly 50% of patients had visceral metastases. And interestingly, for upper urothelial carcinoma trial, roughly one third to one quarter of patients had upper tract disease, where the remaining had lower or bladder urethra, prostate gland, urothelial carcinoma.

This is the Kaplan-Meier estimated overall survival in the overall population with the extended follow-up. We can see here that avelumab plus BSC was in blue, whereas the control group alone was in red. The median overall survival for avelumab was 23.8 months, compared to 15.0 in the best standard of care alone arm. With a stratified hazard ratio favoring the avelumab arm of 0.76. 95% confidence interval 0.63 to 0.91, which was statistically significant.

This is the forest plot of the overall subgroup analysis. We can see that there's many subgroups that the trialists looked at, and we can see generally, that for the most part, the subgroups favored avelumab plus best standard of care, with the hazard ratios to the left of one, favoring the avelumab arm.

This is one of the key secondary findings was Kaplan-Meier estimate of overall survival in the PD-L1 positive population. Similar colored scheme, avelumab plus best standard of care in blue, best standard of care alone in red.

And we could see that the avelumab arm in this PD-L1 positive population had a median overall survival of 30.9 months, compared to 18.5 months best standard of care alone. With a stratified hazard ratio favoring avelumab plus best standard of care of 0.769, and a 95% confidence interval of 0.52 to 0.90, which was statistically significant.

Switching outcomes to investigator-assessed progression-free survival in the overall population. The median rPFS was 5.5 months in the avelumab arm, compared to 2.1 months in the best standard of care alone arm. With a hazard ratio favoring avelumab of 0.54. 95% confidence interval of 0.46 to 0.64. And we can see here, an early and consistent splitting of the curves favoring the avelumab arm for rPFS.

This is investigator-assessed PFS in the PD-L1 positive population. Median time to PFS was 7.5 months in the avelumab arm, compared to 2.8 months in the best standard of care alone arm. With a stratified hazard ratio, again favoring avelumab, of 0.46. 95% confidence interval of 0.36 to 0.59 favoring the avelumab arm for PFS in the PD-L1 positive population.

So these next two tables look at subsequent anti-cancer drug therapy by treatment arm and reasons for discontinuation. And we can see here that impressively, 12.3% of patients were still undergoing avelumab, in the avelumab plus best standard of care alone arm, compared to only 2.9% of patients in the best standard of care alone arm.

In terms of the percentage of discontinued to receive subsequent drug therapy, 52.9% in the avelumab arm, compared to 72% in the best standard of care alone arm. We can see the majority of patients in the best standard of care alone arm underwent a PD-L1 or PD-1 inhibitor at 53.1%. We can see that discontinued and did not receive subsequent therapy was 34.9% of patients in the avelumab arm, compared to 25.1% in the best standard of care alone arm.

And we look at patients who discontinued therapy because of progressive disease. Those that underwent a subsequent therapy with 75.6% of patients in the avelumab arm, compared to 81.8% of patients in the best standard of care alone arm, which was most commonly PD-1 or PD-L1, 60% of patients in the best standard of care alone arm compared to 12.9% in avelumab arm.

This looks in a little bit more detail, again, broken down by avelumab plus best standard of care versus best standard of care alone. But also, looking at it specifically in these arms, patients that received subsequent therapy and those that did not receive subsequent therapy. So the reason for discontinuation, as you would expect, was progressive disease, 85.4% avelumab, patients that received subsequent therapy, compared to 41.8 in the avelumab arm that did not receive subsequent therapy, compared to 89.3% of patients in the BSC alone arm that received subsequent therapy, compared to 56.8 that did not receive subsequent therapy in the best standard of care alone arm.

When we jump down here to geographic region, as we mentioned earlier, Europe had the most patients, compared to Asia, which was second. And we don't see any variation specific across geographic regions when it comes to either arm, or those that received or did not receive subsequent therapy.

So by way of discussion, longer term results from JAVELIN Bladder 100 continue to show prolonged overall survival and progression-free survival with avelumab first-line maintenance plus best standard of care, versus best standard of care alone, in the overall population and across various subgroups.

Of note, this is the only Phase III trial to report significant improvement overall survival in the first-line setting in patients with advanced urothelial carcinoma since trials that established the efficacy of platinum containing chemotherapy.

Secondly, overall survival was prolonged with avelumab, despite 72% of patients in the control arm receiving subsequent anti-cancer drug therapy, including PD-1, PD-L1 inhibitors at 53.1%.

These results confirm the long-term safety profile of avelumab first-line maintenance with 19.5% of patients receiving more than two years of treatment, and low overall rate of discontinuation because of treatment related adverse events at 10.2%.

So in conclusion, longer term results from JAVELIN Bladder 100 further support the recommendation of avelumab first-line maintenance as standard of care for patients with advanced urothelial carcinoma, that has not progressed with first-line platinum containing chemotherapy with level one evidence.

We thank you very much for your attention. We hope you enjoyed this Journal Club discussion of the JAVELIN Bladder 100 trial recently published in the Journal of Clinical Oncology.