Clinical Benefit and Safety of Avelumab/BSC Upheld With Long-Term Data From JAVELIN Bladder 100

Jeanny B. Aragon-Ching, MD

Since results from JAVELIN Bladder 100 (NCT02603432) were reported in 2020, avelumab (Bavencio) used in combination with best supportive care (BSC) for patients with metastatic urothelial cancer (mUC) has become the golden standard for second-line treatment after failure on frontline chemotherapy, and in the maintenance setting of mUC.

At 2 medical meetings this year, results were presented that solidify avelumab’s ability to improve overall survival (OS) and progression-free survival (PFS) in this patient population, according to Jeanny B. Aragon-Ching, MD.

“The updated analysis for the long-term survival and the patients who have received treatment for more than a year has impact in the standard of care treatment paradigm. This resonates with our current standard of care and states that a third of patients still benefit from treatment from prolonged avelumab maintenance therapy,” Jeanny B. Aragon-Ching, MD, the clinical program director of Genitourinary Cancers at the Inova Schar Cancer Institute, and associate professor of Medical Education at the University of Virginia told Targeted Oncology™, in an interview.

Results from the long-term analysis of JAVELIN Bladder 100 were presented during the American Society of Clinical Oncology (ASCO) Annual Meeting. It showed that avelumab in combination with BSC continued to demonstrate an OS advantage over BSC alone. In 700 treated patients, the median OS in the combination arm was 23.8 months (19.9-28.8 months) compared with 15.0 months (13.5-18.2 months) in the BSC-only arm (HR, 0.76; 95% CI, 0.631-0.915; P = .0036). The median PFS by investigator assessment was 5.5 months (4.2-7.2 months) in the avelumab/BSC arm vs 2.1 months (1.9-3.0 months) in the BSC-only arm (HR, 0.54; 95% CI, 0.457-0.645; P < .0001). OS and PFS advantage were also shown with avelumab/BSC in the PD-L1-positive patient population.¹

At the 2022 European Society of Medical Oncology (ESMO) Congress, Aragon-Ching presented findings from a subgroup analysis of the JAVELIN Bladder 100 trial, which assessed treatment with avelumab maintenance for 12 months or more. The findings showed that the safety profile of avelumab was consistent with shorter follow-up. Specifically, grade ≥ 3 treatment-related adverse events occurred in 19.5% of patients, and grade ≥ 3 immune-related AEs occurred in 7.6%.²

In the interview, Aragon-Ching, discussed recent updates from the JAVELIN Bladder 100 trial. She also discussed ongoing research involving the novel agent EV-103 in patients with mUC.

TARGETED ONCOLOGY: Can you talk about avelumab and how it is used in practice today?

Aragon-Ching: Avelumab it is an immunotherapy drug. The current indications are in bladder cancer, and that is for second-line therapy of metastatic urothelial cancer who have failed prior first-line therapy with chemotherapy. The other big indication for avelumab is in the maintenance phase of bladder cancer and that is after they receive chemotherapy in the first line and they've achieved either a complete response, a partial response, or stable disease. They then go on to maintenance immunotherapy with avelumab, and they continue with the treatment until progression, or until there's excessive toxicity.

What was the rationale for combining avelumab with best supportive care to treat advanced UC?

The reason why best supportive care was used in this trial is because for the longest time, and that is prior to the JAVELIN Bladder 100 trial, our standard of care before was chemotherapy. Once chemotherapy is done, after 4 to 6 cycles of treatment, we stop, and best supportive care encompasses no active anti-neoplastic treatment. But if there was a need for pain medications because they have pain from the cancer, they get pain medicines. For instance, other supportive care treatments include the same blood transfusions if they have anemia or if they have any other non-antineoplastic treatment that they need to care for their cancer. That is because if they are not on any active treatment, if they do start progressing, and they have symptoms, symptom management is important.

JAVELIN Bladder 100 was trying to answer the question, should we change our practice of giving chemotherapy only up to 4 to 6 cycles of therapy, and then stop and wait until progression? In the past, that is when we start using second-line immunotherapy agents, and of course, JAVELIN Bladder 100 changed the standard of care treatment. Now, if patients do achieve good response, or even stable disease, they are able to go on to maintain this avelumab treatment.

Can you give a recap of what was observed in the primary analysis of the study? What are the key findings from the subgroup analysis?

The primary analysis of JAVELIN bBadder 100 did show improvement in overall survival in both the intent-to-treat population of patients as well as the PD-L1-postive population of patients. The subgroup analysis presented at ESMO 2022 looks at the patient population who received avelumab maintenance for more than 1-year. We were trying to find out if there are particular characteristics of these patients that we can see through longer-term maintenance with avelumab.

What we found was that the characteristics are pretty much similar to the main group of patients who receive overall avelumab therapy, which is about 350 patients. What we also found is, with a median follow-up time of about 38 months, about 33.7% of patients were able to receive avelumab maintenance for 1 year or more. We also found that their long-term overall survival is not reached, but the 95% confidence intervals spans over 50 months to not estimable. In addition, the progression-free survival was good at about a median average of about 26.7 months. There were no additional safety signals seen. Although I would say with prolonged avelumab maintenance, we do still see some treatment-related adverse events. It's still very important to follow these patients through the grade 3 or more immune-related adverse events, which occurred in about 4.2% of patients. There is a need to continue following these patients, even beyond a year of avelumab maintenance treatment.

How can these findings be applied in the field or in future research?

I think the message here is that JAVELIN Bladder 100 changed the landscape of treatment for metastatic urothelial cancer patients. I would say for most patients, and for all patients who are otherwise eligible to receive chemotherapy, either gemcitabine/cisplatin or gemcitabine/carboplatin, they should receive chemotherapy followed by avelumab maintenance if they achieve any kind of response or stable disease. That is the best way to improve their overall survival. In fact, it is the best way to improve progression-free survival.

What is your key takeaway from this subgroup analysis?

The updated analysis for the long-term survival, and the patients who have received through treatment for more than a year, has impact in the standard of care treatment paradigm. This resonates with our current standard of care and states that a third of patients still benefit from treatment from prolonged avelumab maintenance therapy.

What were some other exciting trends in this space?

A lot of the other abstracts that are being looked at now include EV-103, which is looking at upfront treatment with EV-103, and pembrolizumab [Keytruda]. This is a very well-defined population of patients, the cisplatin-ineligible cohort. That's very interesting to see the responses are 64.5% in that combination cohort, but there is also a well-defined side effect profile that people need to be aware of. That is 1 of the exciting trends in metastatic urothelial cancer right now.

_REFERENCES:

_{1. Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Long-term follow-up results from the JAVELIN Bladder 100 trial. J Clin Oncol. 2020; 40(6):487-487. doi:10.1200/JCO.2022.40.6_suppl.487}

_{2. Barthelemy P, Thibault C, Voog E, et al. 1757P - Preliminary results from AVENANCE, an ongoing, noninterventional real-world, ambispective study of avelumab first-line (1L) maintenance treatment in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2022; 33 (suppl_7): S785-S807. doi:10.1016/annonc/annonc1080}