Interpreting JAVELIN Bladder 100: Avelumab in Metastatic Urothelial Carcinoma

Ignacio Duran, MD, PhD, reflects on the JAVELIN Bladder 100 trial, which analyzed avelumab as frontline maintenance therapy in metastatic urothelial carcinoma.


Ignacio Durán, MD, PhD: Let me review the data for the JAVELIN Bladder 100 trial. I mentioned it before, but I’ll get more to into the precise design of the study and the major outcomes. JAVELIN 100 was designed to test the value of a switch maintenance strategy with a drug targeting PD-L1, called avelumab [Bavencio]. Basically, the study tried to test the benefits of continuing with avelumab [Bavencio] after receiving chemotherapy based in platinum 4 to 6 cycles and obtaining some degree of benefit. JAVELIN 100 included about 700 patients who did not have progression after receiving chemotherapy, for 4 or 6 cycles, with cisplatin-gemcitabine or carboplatin-gemcitabine. Then the patient had a treatment-free interval that was 4 to 10 weeks from the last dose of chemotherapy. These patients were randomized to either avelumab [Bavencio] at a dosage of 10 mg/kg every 2 weeks until progression or best supportive care.

What was the primary end point? It was overall survival in the entire population but also in patients considered PD-L1 positive. What were the main results? Median overall survival was 21.4 months for the experimental arm vs 14.3 months for the control arm. That was statistically significant. The hazard ratio was 0.69. This is an impressive benefit, which is statistically significant and, more important, clinically meaningful. That was the result from the first interim analysis. We continued to analyze the data later, and the benefit was maintained with a similar hazard ratio. The overall survival benefit for patients who were high expressers of PD-L1 was even more remarkable. The hazard ratio was 0.56 in that population. Overall survival was not reached. The median was not reached for the experimental arm vs 17 months in the control arm. This is the key design and the key efficacy data.

Safety is always a critical question. Safety in JAVELIN 100 was not a major concern…. Among patients who were treated with avelumab [Bavencio], about a third presented what we call immune-related adverse events, although only a minority were really severe. About 7% of the patients had a grade 3 immune-related adverse event, and 9% required high doses of steroids for the treatment of this immune-related adverse event. In summary, I would say that safety was not a major concern in general in JAVELIN 100 with the use of avelumab [Bavencio] every 2 weeks.

No other maintenance strategies in bladder cancer have succeeded. From a historical perspective, there were different attempts in the past looking at maintenance. One of the studies was called the MAJA study. That was a maintenance study with vinflunine [Javlor]. Patients who received chemotherapy were treated with vinflunine [Javlor]. This study was reported and not so long ago updated. It demonstrated a benefit in progression-free survival for the maintenance zone that did not succeed at showing a benefit in overall survival. It’s also true that we should refer to another smaller study, the Hoosier [Cancer Research Network] study, which tested the same hypothesis with pembrolizumab [Keytruda]. Patients with metastatic bladder cancer after receiving a maximum of 8 cycles of chemotherapy were randomized to receive pembrolizumab [Keytruda] or placebo in this case. The crossover was permitted. That study was small, about 108 patients. It was an academic study. It was not a large multicenter, multicountry study. It was able to demonstrate a benefit in progression-free survival, but it did not demonstrate a benefit in overall survival. A number of reasons could explain those results. The first 1 is because the study was not powered to demonstrate an improvement in overall survival. The second 1 is because this study allowed crossover: patients who progressed in the control arm were rapidly crossed and received treatment rapidly, so they could benefit. Those 2 reasons could explain the lack of benefits. In summary, other than the avelumab [Bavencio] maintenance study, JAVELIN 100, you can mention the Hoosier study with pembrolizumab [Keytruda] and the MAJA study years ago.

Transcript edited for clarity.

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