Maintenance avelumab for metastatic urothelial cancer: a new standard of care

ABSTRACT

The Javelin Bladder 100 trial was the first trial to establish the role of switch maintenance therapy in patients with metastatic urothelial cancer using avelumab, a PD-L1 inhibitor, for patients who achieve complete response, partial response, or stable disease to standard chemotherapy of 4–6 cycles with gemcitabine and cisplatin or carboplatin. Improvement in parameters of overall survival in both the overall population and the PD-L1 positive population was seen and has led to the US FDA approval of avelumab as maintenance therapy for metastatic urothelial cancer. This manuscript further discusses the highlights of the study, patient population, and considerations regarding choice of therapy for maintenance avelumab.

KEYWORDS:

• Metastatic urothelial cancer
• avelumab
• immunotherapy
• maintenance therapy

Bladder cancer is expected to occur in about 73,750 patients in the US in 2020 and is expected to cause 14,830 deaths.¹ Metastatic bladder cancer has overall poor prognosis with a 5-y overall survival rate of only <5%. While the standard of care has been implemented with the use of cisplatin-based chemotherapy, responses are oftentimes lacking in durability and recent improvements in survival has been shown with the use of checkpoint inhibitors especially in the setting of post-chemotherapy failure with current availability of five different checkpoint inhibitor drugs.² While maintenance therapy has been explored in the past in metastatic urothelial cancers, it has been found to be negative for most studies, including the use of lapatinib.³ The concept of maintenance therapy remains attractive however, such that patients who may respond to upfront chemotherapy can achieve good consolidation of response by giving a treatment that would be more durable with lack of overlapping side-effects with chemotherapy.

JAVELIN Bladder 100 was a phase III trial which investigated maintenance therapy with avelumab, a checkpoint inhibitor targeting PD-L1, in patients with non-progressive stage IV urothelial carcinoma previously treated with platinum-containing chemotherapy in both the overall population and the PD-L1-positive population.⁴ This study was conducted as an international, multicenter, and open-label trial which included 700 patients who received either avelumab and best supportive care (n = 350) or best supportive care alone as the control (n = 350). Of the 700 patients, 358 (51.1%) patients had PD-L1-positive tumors, with 189 (57.6%) in the avelumab group and 169 (56.3%) in the control group. Avelumab was given as a dose of 10 mg/kg intravenously every 2 weeks with antihistamine and acetaminophen prior to the first four infusions to mitigate infusion-related reactions along with as-needed best supportive care while the control received best supportive care when needed without any other maintenance therapy. Best supportive care constituted treatments such as supportive care with antibiotics, pain management, hydration, nutritional support, and palliative local radiotherapy. Treatment under the study was continued until disease progression, withdrawal of consent, severe adverse events, or death. The primary end point was overall survival (OS) in both overall and PD-L1-positive populations and secondary end points consisted of progression-free survival (PFS), objective response, time to response, duration of response, disease control, and safety.

The trial was positive with findings showing a significantly longer overall survival seen in the avelumab maintenance therapy group than the control group in both the overall population and the PD-L1-positive population. Within the overall population studied, the 1-y overall survival rates for the avelumab group was 71.3% versus 58.4% in the control group while the median survival time was 21.4 months versus 14.3 months. Similarly, in the PD-L1-positive population, the 1-y overall survival was 79.1% for the avelumab group compared with 60.4% in the control group. Within the patients who were negative for PD-L1, the median overall survival length was 18.8 months in the avelumab group and 13.7 months in the control group.

In both the overall and the PD-L1-positive populations, PFS was also longer for those in the avelumab group compared to the control group. In the overall population, the median PFS was 3.7 months in the avelumab group compared to 2.0 months in the control group and similarly, in the PD-L1-positive group, the median PFS was 5.7 months and 2.1 months, respectively. Longer PFS for the avelumab group in the PD-L1-negative population was also observed.

A confirmed objective response which encompasses both complete response and partial response for both populations was determined to be 9.7% in the overall avelumab group compared to 1.4% in the control group alongside 13.8% in the PD-L1-positive avelumab group compared to 1.2% in the control group. The median time to objective response was 2 months within all groups in both populations except for the PD-L1-positive group in which it was 2.8 months. Disease control was recorded in 144 patients (41.1%) within the avelumab group and in 96 (27.4%) in the control group within the overall population and in 83 patients (43.9%) and 47 (27.8%), respectively, in the PD-L1-positive population.

The median duration of treatment was calculated to be 24.9 weeks in the avelumab group and 13.1 weeks in the control group. The side-effect profile showed no new signals with adverse events considered related to the treatment including most commonly, fatigue, pruritis, urinary tract infections, diarrhea, arthralgia, asthenia, constipation, and back pain which were recorded in 337 patients (98.0%) in the avelumab group and in 268 patients (77.7%) in the control group with grade 3 adverse effects observed in 163 patients (47.4%) and 87 (25.2%), respectively. Adverse effects were the reason 41 patients (11.9%) in the avelumab group discontinued their involvement in the trial and 2 deaths within the avelumab group were attributed to toxicity of the treatment. Immune-related adverse effects were observed in 101 patients (29.4%) being treated with avelumab maintenance therapy although none of these were grade-4 or fatal.

The results of Javelin Bladder 100 provide the first level 1 evidence showing switch maintenance therapy with a checkpoint inhibitor yields improvement in overall survival in both the overall population as well as the PD-L1 population of patients with metastatic urothelial cancers, though benefit was seen across the population of patients regardless of PD-L1 staining. This benefit to overall survival was seen despite more subsequent treatment including immune checkpoint inhibitors (61.7%) used within the control group, suggesting that early treatment yields the benefit. However, there has been frequent comparisons to this dataset to a smaller phase II trial (HCRN GU14-182) that looked at pembrolizumab,⁵ but with a primary endpoint of PFS that similarly yielded positive results at 5.4 months for pembrolizumab compared to 3 months for placebo with hazard ratio (HR) = 0.65; log-rank P =.04, and while overall survival was a secondary endpoint, the pembrolizumab arm yielded an OS of 22 months compared to 18.7 months for placebo.

The clinical question that is often raised is the interchangeability of pembrolizumab with avelumab since dosing schedule is different (pembrolizumab may be given every 6 weeks whereas avelumab has to be given every 2 weeks based on pharmacokinetic studies), pembrolizumab was based on a phase II trial whereas avelumab was based on a phase III trial, and there was a cap on the number of cycles for pembrolizumab given for 24 months whereas avelumab was given until progression or if intolerance or toxicity were to occur. The primary endpoints were also different across both trials. In addition, there are questions with regard to which population of patients would derive the most benefit. While the objective responses in the Javelin trial are largely secondary to the likely responses seen with initial chemotherapy use, there is a prevailing thought that patients who presents with aggressive disease would be best served by maintenance therapy, rather than the previous standard of care which entails waiting for progressive disease after completion of 4–6 cycles of chemotherapy, before instituting further active therapy.

In summary, the principle of maintenance therapy with use of checkpoint inhibitors has currently been established as a viable treatment approach as a result of these trials. This has set a new standard of care upon which future trials should be based on.

Disclosure statement

JAC serves on advisory board of EMD Serono.