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Year : 2021  |  Volume : 37  |  Issue : 3  |  Page : 295-296

First-line maintenance immunotherapy in advanced urothelial cancers: Practice changing implications of the JAVELIN bladder 100 trial

Department of Urology, AIIMS, Bhubaneshwar, Odisha, India

Date of Submission02-Oct-2020
Date of Decision23-Oct-2020
Date of Acceptance12-Mar-2021
Date of Web Publication1-Jul-2021

Correspondence Address:
Santosh Kumaraswamy
Department of Urology, AIIMS, Bhubaneshwar, Odisha
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/iju.IJU_534_20

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How to cite this article:
Kumaraswamy S. First-line maintenance immunotherapy in advanced urothelial cancers: Practice changing implications of the JAVELIN bladder 100 trial. Indian J Urol 2021;37:295-6

How to cite this URL:
Kumaraswamy S. First-line maintenance immunotherapy in advanced urothelial cancers: Practice changing implications of the JAVELIN bladder 100 trial. Indian J Urol [serial online] 2021 [cited 2022 Dec 1];37:295-6. Available from:

   Summary Top

The JAVELIN Bladder 100 trial evaluated the benefits of Avelumab, a PD-L1 inhibitor, on the overall survival (OS) and progression-free survival (PFS), as the first-line maintenance immunotherapy in patients with advanced bladder cancer who did not progress after initial platinum-based chemotherapy.[1] This phase three multi-institutional multi-national collaborative trail recruited biopsy-proven, unresectable, locally advanced or metastatic urothelial tumors, who had responded (stable disease [SD], partial [PR], and complete response [CR]) to 4–6 cycles of gemcitabine with either cisplatin or carboplatin. Eligible patients were randomized 1:1 to receive either Avelumab 10 mg/kg + best supportive care (BSC) or BSC alone. The plan was to continue the treatment as long as possible in each arm, and the analysis was planned when 76.2% of the recruited population had died. Three hundred and fifty patients were randomized into each group, with a median duration of follow-up of 19.6 months and 19.2 months in the Avelumab + BSC and the BSC alone groups, respectively. The primary endpoint was OS. The secondary endpoints comprised of PFS, objective response rate, and adverse events. All these were evaluated among the two cohorts - the total recruited patients and the PD-L1 positive patients (51% were PD-L1 positive).

The OS significantly improved with Avelumab + BSC as compared to BSC alone in the overall recruited patients (Hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.56, 0.86; P = 0.0005) as well as the PD-L1 positive patients (HR 0.56; 95% CI 0.40, 0.79; P = 0.0003). Patients in the avelumab + BSC group had a better OS (Overall patients-21.4 vs. 14.3 months; PD-L1+ patients - not estimated vs. 17.1 months). The principal secondary endpoint, PFS, also improved significantly in the Avelumab group compared to the BSC alone group (Overall patients - 3.7 vs. 2 months; PD-L1 + patients - 5.7 vs. 2.1 months). HR for PFS was 0.62 (95% CI 0.52, 0.75) in the overall patients and 0.56 (95% CI 0.43, 0.73) in the PD-L1-positive patients. Regarding the safety, any grade adverse events in the Avelumab + BSC group vs the BSC alone group were reported in 98.0% versus 77.7% of the patients and grade ≥3 adverse events were reported in 47.4% versus 25.2% of the patients. The most common Grade 3 events were anemia (3.8% vs. 2.9%), urinary tract infection (4.4% vs. 2.6%), and hematuria (1.7% vs. 1.4%). Thyroid-related disorders were the most common immune related adverse events and no grade 4–5 adverse event were recorded. The authors concluded that the maintenance checkpoint inhibition therapy significantly improved the OS and the PFS compared to the treatment break followed by the second-line treatment in all the patients with advanced urothelial cancer responding to the primary chemotherapy.

   Commentary Top

Advanced urothelial carcinomas are aggressive tumors, with variable response to platinum-based chemotherapy. Those who respond (SD, PR, or CR) eventually have early disease progression with an OS of 14–15 months.[2] These patients have an option of second-line systemic therapy when they progress after an initial treatment break. Because of the rapid disease progression and the deteriorating general condition, only a fraction of these patients receive second-line treatment. PD-L1 inhibitors have emerged as the standard second-line therapy.[3] However, only a small fraction of these patients achieve durable benefits when the disease has already progressed.

Contrary to this classical approach, a maintenance checkpoint inhibitor is an attractive strategy, where the initial tumor control with chemotherapy provides time for the immunotherapy to act. Furthermore, initiating it early will result in more patients availing the treatment. The JAVELIN bladder 100 trial delivered on its promises with a significantly improved OS (21.4 vs. 14.3 months) and PFS (3.7 vs. 2 months) compared to BSC alone irrespective of the PD-L1 status. To assess the real clinical significance, maintenance avelumab therapy should ideally be compared with delayed second-line Avelumab therapy available to all the patients who progresed on BSC alone. A caveat in the design of this trial is that the control group received BSC alone and not the second-line immunotherapy. Although the patients were allowed to cross over in the case of progression, only 41% received immunotherapy in this trial. How much cross over is usually expected? Another trial investigating similar maintenance with Pembrolizumab puts this value at approximately 70%.[4] This questions the real advantage of maintenance therapy compared to the delayed therapy.

Nevertheless, the clinical progression is variable after first-line chemotherapy, and the maintenance approach will at least ensure that most of the patients avail immunotherapy irrespective of the PD-L1 status. Scientifically speaking, while the subset with PD-L1 positive status are expected to have better outcomes as compared to the PD-L1 negative patients, this was not so in the present trial.

With a cost of approximately Rupees Two lakhs per month (cost of Avelumab in India) and an absolute survival benefit of 7 months with minimal adverse effects, affordability may be an issue with this treatment protocol .

Financial support and sponsorship: Nil.

Conflicts of interest: There are no conflicts of interest.

   References Top

Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med 2020;383:1218-30.  Back to cited text no. 1
von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;18:3068-77.  Back to cited text no. 2
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015-26.  Back to cited text no. 3
Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, et al. Randomized double-blind phase ii study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J Clin Oncol 2020;38:1797-806.  Back to cited text no. 4


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