More Analyses Explore Benefit of Frontline Maintenance Avelumab Plus BSC in Advanced UC

Joaquim Bellmunt, MD, PhD

Prolonged overall survival (OS) has been observed with avelumab (Bavencio) maintenance in combination with best supportive care (BSC) vs BSC alone in patients with advanced urothelial carcinoma (UC) treated in the frontline setting that has not progressed with 1L platinum-containing chemotherapy.

The OS results are from a long-term analysis of the JAVELIN Bladder 100 trial (NCT02603432). In the study, 700 patients were randomized 1:1 to either avelumab maintenance plus BSC or BSC alone. In addition to OS, the primary end point of the study, progression-free survival (PFS), and safety were assessed as secondary outcomes.

Following the primary analysis of the JAVELIN Bladder 100 trial, which showed an 8-month improvement in OS with the addition of avelumab maintenance to BSC, the FDA granted approval to avelumab for the maintenance treatment of patients with locally advanced or metastatic UC that has not progressed with first-line platinum-containing chemotherapy.

Patients continued to be followed for a median of ≥ 38 months during the long-term analysis. The results showed that avelumab maintenance added to BSC achieved a median OS of 23.8 months (95% CI, 19.9-28.8) compared with 15.0 (95% CI, 13.5-18.2) in the BSC-only arm (HR, 0.76; 95% CI, 0.631-0.915; P =0.0036. In the PD-L1 positive subgroup of patients with advanced UC, the median OS with the addition of avelumab maintenance was 30.9 months (95% CI, 24.0-39.8) vs 18.5 months (95% CI, 14.1-24.2) with BSC alone (HR, 0.69; 95% CI, 0.521-0.901; P =0.0064).

In an interview with Targeted Oncology™, Joaquim Bellmunt, MD, PhD, associate professor, Medicine, Harvard Medical School and director, Bladder Cancer Program, Beth Israel Deaconess Medical Center, further discussed the long-term OS data for first-line maintenance avelumab in mUC and sub-analyses of the JAVELIN Bladder 100 trial being read out at the upcoming 2022 American Society of Medical Oncology (ASCO) Annual Meeting.

TARGETED ONCOLOGY: As a recap, what was observed in the primary analysis of the JAVELIN Bladder 100 trial?

Bellmunt: The primary analysis of survival showed that the median overall survival in the patients who receive avelumab maintenance was 21.4. And in the best supportive care arm, it was 14.3 months. That means a 7-month improvement in median overall survival with a hazard ratio of 0.69.

The first analysis was done in October 2019. And the analysis presented at AUA was after at least 2 years of follow-up with a data cutoff of June 2021. So, with that, we see that the long-term follow-up of this trial is confirming the results that were already published in the New England Journal in 2020.

How was the long-term analysis of the JAVELIN Bladder 100 trial carried out?

This trial was designed in patients with metastatic bladder cancer that were receiving treatment with platinum gemcitabine or carboplatin/gemcitabine and if the patients didn't progress, meaning if the patients were able to obtain partial response, stable disease, or complete response, then the patients were randomized to receive maintenance avelumab plus best supportive care.

With this recent analysis, what we have seen is that the median overall survival in the avelumab maintenance is 23.8 months, and in the best supportive care arm it is like 15.0 months, meaning an 8-month difference in the median. The hazard ratio is more or less the same at 0.76, and the benefit has been seen across different subgroup of patients. Independent of patients responding or not responding, all patients benefited from receiving avelumab maintenance.

The benefit was seen in survival and was also seen in progression-free survival. So, in this updated analysis, the PFS in the overall population of patients receiving avelumab was 5.5 months, it was 2.1 months in patients receiving best supportive care. So, a substantial PFS prolongation was seen in these patients receiving avelumab maintenance.

Another analysis being presented during AUA is around subsequent therapy the patients received because obviously, we know that a particular therapy sometimes impacts overall survival. And what we saw in the analysis was that in patients that were assigned receive avelumab maintenance, 11.4% of patients received subsequent therapy with a PD-1 or PD-L1 inhibitor while in the best supportive care 53% of patients received a PD-1/PD-L1 inhibitor. This means that giving maintenance avelumab sooner provides a survival advantage.

What did longer follow-up teach you about frontline maintenance avelumab treatment in this patient population?

We now know that the percentage of patients who are alive in this trial or at years is 49.8% in the avelumab maintenance population versus 38.4% in the best supportive care arm. We haven't seen unexpected adverse events, so it confirms the safety of this type of approach when using switch maintenance to manage patients who do not progress to chemotherapy in the first line.

These results support the recommendation of avelumab first-line maintenance as a standard of care in urothelial cancer, patients with metastatic disease receiving chemotherapy with platinum-based therapy, carboplatin, or cisplatin, and those who are not progressing. So, this is a new standard of care when managing metastatic bladder cancer patients.

So, now the concept of avelumab maintenance as the standard of care has been included in all the guidelines.

What other type of sub analysis will be important from this study?

Upcoming at the ASCO 2022 Annual Meeting, we are going to update additional data on what's the role of second-line therapies if the patient will receive chemotherapy as rescue therapy because this is something that we don't know presently.

What do we do after the patient has received chemotherapy, followed by maintenance avelumab and they progress? Some guidelines say the next step is enfortumab vedotin, and in fact, there is very limited data on that. In the analysis that is going to be presented at ASCO, we are going to see the results of a patient receiving rechallenge with chemotherapy because those patients have already responded to first-line chemotherapy, or at least they have not progressed. The patients have a holiday period where they receive avelumab maintenance and then when they progress, some patients can receive again platinum-based therapy. And this is something that we don't know, all these data need to be collected. So, what's the outcome in these patients, either it's good to receive subsequent chemotherapy, or maybe there is a chance to give a targeted therapy, but we presently don't know.

We know that the blood cancer landscape is changing so quickly, we are waiting for new trials in the first line combining immunotherapy with an antibody-drug conjugate that may be changing the future in the way that we treat first-line metastatic patients. As more data are being analyzed from these trials, we will be able to design the best strategy in terms of how to sequence therapy in patients with bladder cancer in order to provide improved survival while preserving the quality of life. That's a very important thing.

_REFERENCE:

_{Avelumab first-line maintenance for advanced urothelial carcinoma: long-term follow-up results from the JAVELIN Bladder 100 trial. J Urol. 2022;207(5):e183. doi: 10.1097/JU.0000000000002536.02}