Practical Considerations For the Use of Switch Maintenance Therapy: Avelumab First-Line Maintenance in Locally Advanced or Metastatic Urothelial Carcinoma Journal Club - Christopher Wallis & Zachary Klaassen

June 1, 2021

Christopher Wallis and Zachary Klaassen provide insights into the Cancer Treatment Reviews publication Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice. In the context of metastatic urothelial carcinoma, avelumab has previously been assessed in a large phase 1b study, using avelumab as salvage therapy in the poor-risk population. However, its use in switch maintenance therapy was assessed recently in the JAVELIN Bladder 100 trial.

In the JAVELIN Bladder 100 phase 3 trial, avelumab administered as 1L maintenance with best supportive care (BSC) significantly prolonged overall survival vs BSC alone in patients with locally advanced or metastatic urothelial carcinoma that had not progressed with 1L platinum-containing chemotherapy. In this Journal Club, Drs. Wallis and Klaassen highlight this review article which summarizes the data supporting these developments and discusses practical considerations for administering avelumab maintenance in clinical practice, including patient selection, and treatment management.


Christopher J.D. Wallis, MD, Ph.D., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Read the Full Video Transcript

Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we are discussing a recently published paper, entitled Avelumab First-Line Maintenance in Locally Advanced or Metastatic Urothelial Carcinoma: Applying Clinical Trial Findings to Clinical Practice. Here is the citation for this recent publication. As you can see from the author list, these are many of the thought leaders in systemic therapy for bladder cancer.

By way of background, bladder cancer is both common and contributes significantly to morbidity and mortality, both as a genitourinary malignancy, but also more broadly in the cancer populations. While only about 5% of patients with bladder cancer initially present with metastatic disease, between a third, and a half of patients with localized disease will progress to metastatic disease following their local therapy. For patients who are eligible, first-line treatment of advanced urothelial carcinoma, whether metastatic or locally advanced and unresectable, is combination-based platinum chemotherapy. With this approach, disease progression is, however, common, and the median overall survival is typically less than a year and a half, with medians, depending on the study, ranging between 9 and 14 months.

Immune checkpoint inhibition has shown benefit in the second-line therapy of advanced bladder cancer. However, as we can see from the studies included on the right side of this slide, many patients are ineligible for second-line therapy due to a high symptom burden, either from their disease or the toxicity of therapy. And as a result, only approximately 1 in 3 patients are actually able to receive second-line treatment at the time of progression.

Just by way of a few examples, there are obviously more studies.  Pembrolizumab and atezolizumab have a proven benefit for cis-ineligible patients who have PD-L1+ disease, and despite the initial promise, subsequent data showed that this benefit was not found in those who did not have PD-L1+ disease, and such the indication has now been restricted based on biomarker testing.

There is a rationale for the combination of chemotherapy and immunotherapy in metastatic bladder cancer, in particular, chemotherapy may potentiate the IO response through depletion of immunosuppressive cells, increased antigen presentation, neoantigen release, increased CD8+ T cell tumor infiltration, increased natural killer activation, and upregulation of PD-L1 expression. You can see these mechanisms highlighted in this figure taken from the paper we are discussing today.

When we consider the combination of chemotherapy and immunotherapy, there are obviously two approaches. We can combine this concurrently, or we can sequence these approaches. Stepping outside of bladder cancer for a moment to other tumor types, combination chemoimmunotherapy has shown benefit. However, when this has been assessed in bladder cancer, we have not seen benefits. There are two trials here, both IMvigor130 and KEYNOTE-361, which failed to show overall survival (OS) benefits for the combination of chemotherapy and immuno-oncology (IO) approaches. Other tumor types have also shown benefit with the idea of combinations using switch maintenance therapy with an alternate regime, following initial induction chemotherapy. This uses the maintenance immunotherapy to target residual disease, increase the depth of resistance, and prolong the benefits of the initial chemotherapy. Notably, by switching the treatment approach, we avoid issues of cross-resistance, cumulative toxicity, and potentially increased cost.

In the context of metastatic urothelial carcinoma, avelumab has previously been assessed. This is an anti-PD-L1 antibody with dual functionality, targeting adaptive effector T-cells, as well as the innate immune effector natural killer cells. The initial benefit of this approach was demonstrated in a large phase 1b study, using avelumab as salvage therapy in the poor-risk population.

However, its use in switch maintenance therapy was assessed recently in the JAVELIN Bladder 100 trial. This trial enrolled patients with histologically-confirmed unresectable locally advanced or metastatic urothelial carcinoma who had measurable disease per RECIST criteria and did not have disease progression following four to six cycles of gem/cis or gem/carbo induction chemotherapy. They had to be within 4 to 10 weeks following their last cycle of chemotherapy. Notably, patients who received adjuvant or neoadjuvant chemotherapy were excluded if this was received in the last 12 months, as well, patients were excluded if they had contraindications to the use of, or previous use of, immune checkpoint inhibitors.

As you can see here through this study schema, these patients, prior to enrollment, received their standard first-line chemotherapy, and those who had a complete response, partial response, or stable disease following a treatment free-interval were then randomized to best supportive care alone or best supportive care plus avelumab. The primary endpoint here is overall survival, and randomization was stratified according to the best response to first-line chemotherapy in the metastatic site, whether visceral or non-visceral disease. Sub-analyses were undertaken, considering all randomized patients in the PD-L1+ population, as well as a number of secondary endpoints.

Assessing overall survival, this trial was actually stopped at the time of interim analysis based on evidence of improvements in overall survival. And so you can see on the top panel here, the results in the intention-to-treat population, which demonstrated an improvement of nearly 7 months in median overall survival, with a stratified hazard ratio for death is 0.69. And in the PD-L1+ population, again, we see a significant improvement, here with an even larger hazard ratio of 0.56, and unable to calculate the improvement in median overall survival, as this was not reached in the avelumab group.

When we look at subgroup analyses, we see a consistent benefit across all assessed subgroups, including age, sex, performance status, race or ethnicity, first-line chemotherapy regime, the best response to first-line chemotherapy, site of metastasis, renal function, and PD-L1 status. Notably, we see that this benefit of overall survival is demonstrated despite the fact that subsequent PD-1 or PD-L1 inhibitor use is relatively common in the best part of the care control arm. And so, this emphasizes the importance of starting this IO therapy early in the disease process as switch maintenance, as opposed to using it as second-line salvage therapy.

Now I will hand it over to Zach to take us through some practical considerations for the use of switch maintenance therapy.

Zachary Klaassen: Thanks, Chris. Over the next couple of slides, we will talk about a few of the nuances of this trial and how this may relate to everyday practice. The first point is that cisplatin-eligible and cisplatin-ineligible patients were included in this trial, cisplatin plus gemcitabine had a 52% in the avelumab arm, carboplatin plus gemcitabine included 42% of the patients in the avelumab arm, and 6% of patients included a combination of both at some point in their treatment. We see that when comparing avelumab versus the control, both of these regimens had statistically significant benefits for avelumab, so cisplatin plus gemcitabine, with a hazard ratio of 0.69 and a 95% confidence interval of 0.51 to 0.94, and also for carboplatin plus gemcitabine, with a hazard ratio of 0.66 and a 95% confidence interval of 0.47 to 0.91.

Second, looking at the duration of primary chemotherapy, generally, patients in the metastatic setting will receive four to six cycles of first-line chemotherapy. The JAVELIN Bladder 100 trial supported avelumab maintenance for these patients. Looking specifically at the number of cycles, those patients that received four cycles, a hazard ratio of 0.69 and 95% confidence interval of 0.48 to 1.00. With the five cycles, there was a small sample size, so there was no statistical significance, however, with six cycles, a hazard ratio of 0.66 and a 95% confidence interval for significance at 0.47 to 0.92.

Moving to response to prior chemotherapy, JAVELIN Bladder 100 showed an OS benefit for those with objective response or stable disease with the first-line chemo. We see the hazard ratio for objective response was 0.69, with a 95% confidence interval of 0.53 to 0.89. Importantly, for stable disease, not quite statistically significant, but a signal towards a benefit for avelumab, a hazard ratio of 0.70 and a 95% confidence interval of 0.46 to 1.05.

Looking at older patients, the avelumab arm had a median age of 68 years, with 63% of the patients greater than or equal to 65-years-of-age. And when we look at the avelumab versus the control arm in patients less than 65 years, again, not statistically significant, but a signal towards significance for avelumab, at a hazard ratio of 0.79 and a 95% confidence interval of 0.55 to 1.15. However, in patients older than 65-years-of-age, there was a significant benefit for avelumab maintenance, with a hazard ratio of 0.63 and a 95% confidence interval of 0.47 to 0.83.

Moving on to renal impairment, this is important. This is a comorbid population, and as we know, treating these patients, many will have a baseline chronic kidney dysfunction, and JAVELIN Bladder 100 allowed the inclusion of patients with a creatinine clearance of greater than 30 mL/min, and this included 48% of patients in the avelumab arm with creatinine clearance of less than 60 mL/min. And so, looking at the efficacy, avelumab versus control, for those of the creatinine clearance greater than 60 mL/min, a hazard ratio of 0.68, 95% confidence interval of 0.50 to 0.92, and also a statistically significant benefit for avelumab in those with a creatinine clearance of less than 60 mL/min, with a hazard ratio of 0.68 and a 95% confidence interval of 0.50 to 0.94.

When looking at the Bajorin risk group items, including visceral metastasis and performance status, we see that in this trial, that 55% of the patients had visceral metastasis, and there was a nearly significant, but not quite, hazard ratio of 0.82 and a 95% confidence interval of 0.62 to 1.09, favoring avelumab. And when we look at ECOG performance status, 61% of the patients in the trial had ECOG 0 and 39% had ECOG 1. For patients with ECOG 0, a significant hazard ratio of 0.64 and a 95% confidence interval of 0.48 to 0.86, compared to ECOG 1, a hazard ratio of 0.74, and a 95% confidence interval of 0.54 to 1.03.

Looking at PD-L1 status in JAVELIN Bladder 100, there was PD-L1+ among 51% of patients, a PD-L1- in 39%, and an unknown status in 10%. And certainly, we see here, based on these hazard ratios for comparing avelumab maintenance versus a control, a significant benefit for PD-L1+ patients, hazard ratio of 0.56, and a 95% confidence interval of 0.40 to 0.79. And as you can see below with these hazard ratios for PD-L1- and unknown PD-L1 status, there was no statistical benefit for these patients.

Several points about the practical administration of avelumab. The trial found that there were infusion-related reactions of any grade in 10% of patients, in greater than or equal to 3 grade, reactions in 1% of patients. And so they recommended pre-medication with oral antihistamine and acetaminophen for the first four doses of avelumab. Second, avelumab maintenance was administered until disease progression or unacceptable toxicity, and they found that there was no evidence to support a fixed duration of avelumab treatment. We found that in this trial, the median duration of avelumab was 24.9 weeks, and you can see here the range from 2.0 up to almost 160 weeks of treatment.

Certainly, some patients will progress on avelumab maintenance, and at that point, there are several options that the authors listed in their review, including erdafitinib for FGFR3 or FGFR2 mutations or fusions. Secondly, they could also receive enfortumab vedotin, taxane chemotherapy, vinflunine for patients in Europe, or they could be rechallenged with platinum-containing chemotherapy.  More importantly, they could be enrolled in a subsequent clinical trial.

In JAVELIN Bladder 100, there were 148 patients that discontinued avelumab maintenance, and additional therapy was received in several of these patients, including 40% on other drug therapies or multiple therapies, 6% received an anti-PD-1/PD-L1, and 3% received a fibroblast growth factor receptor inhibitor.

Looking at the safety and tolerability of avelumab, not surprisingly, 98% of patients had any grade treatment-related adverse events, 47.4% had a grade greater than or equal to 3 adverse events. Treatment-related adverse events leading to death included 1.2% of patients. And moving down the table, you can see that events leading to avelumab disruption or interruption were 40.7%. In terms of grade 3 or greater adverse events, we can see that the most common ones were increased lipase level, and increase in amylase level, 2.9%, and 2.0% respectively. So otherwise, the majority of these adverse events can be managed with frequent checking of lab results.

The table looks at the survival estimates with approved and non-approved immune checkpoint inhibitors treatment strategies in advanced and metastatic urothelial carcinoma. This figure actually really puts into context the important benefit of the avelumab maintenance therapy after first-line platinum-containing therapy. So if we look here, from the timeline on the left, these are different scenarios of patients getting systemic therapy. On the right is the estimated median overall survival from the start of first-line therapy. So, at the top we see JAVELIN Bladder 100, we can see four to six cycles, about 3 weeks of first-line chemotherapy, then they had a 4 to 10-week treatment-free interval, and subsequently, a median overall survival benefit with avelumab maintenance of 21.4 months. So taking this all together, this is 26.5 months median overall survival from the start of first-line therapy.

Certainly, the other scenarios are not quite as impressive. We see below that immune checkpoint inhibitor as second-line therapy after first-line platinum-containing chemotherapy, 16 to 18 months, immune checkpoint inhibitor in combination with first-line platinum-containing chemotherapy, OS of about 16 to 17 months, and then fourth, the immune checkpoint inhibitor as first-line monotherapy for cisplatin-ineligible patients with a PD-L1+ tumor, 12.3 to 18.5 months, and finally, immune checkpoint inhibitor plus immune checkpoint inhibitors first-line therapy, for instance with durvalumab plus tremelimumab, with a median overall survival of 15.1 months. So this puts into context the impressive benefit that these patients are receiving based on the avelumab first-line maintenance therapy.

So, in conclusion, there is level 1 evidence to support the use of avelumab as a standard of care for first-line maintenance treatment of advanced urothelial carcinoma that has not progressed with platinum-containing therapy. Impressively, avelumab first-line maintenance has already been approved in the US, the European Union, Canada, Japan, Australia, Brazil, and Israel. An avelumab maintenance regimen can be easily incorporated into standard clinical practice for a wide range of patients that we are faced with in this challenging disease.

Thank you very much. We hope you enjoyed this UroToday Journal Club discussion of avelumab first-line maintenance therapy for urothelial carcinoma.
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