JAVELIN Bladder 100: Paradigm shifts for maintenance therapy in advanced bladder cancer

Adding the PD-L1 inhibitor avelumab to best supportive care in the maintenance setting yields significant survival benefit compared with best supporting care alone for patients with advanced bladder cancer who have stable disease following first-line platinum-based chemotherapy, an interim analysis of the JAVELIN Bladder 100 study shows.  

Overall survival (OS) was significantly longer with the addition of avelumab in the overall patient population and was especially pronounced in patient subgroup with PD-L1-positive status, reported Dr Thomas Powles of the Barts Cancer Institute in London, UK, during the virtual ASCO 2020 Meeting. [ASCO 2020, abstract LBA1]

Although 65–75 percent of patients with advanced bladder cancer typically achieve disease control with first-line chemotherapy, Powles explained that progression-free survival (PFS) and OS are short because of chemo-resistance. “[Also,] outcomes with second-line treatment are poor, because the disease is aggressive and grows rapidly.”

“The maintenance setting is an attractive time for using a checkpoint inhibitor. Disease control is achieved with the initial chemotherapy, and this provides time for the immune therapy to have an effect,” he said. “Instead of waiting for disease to progress after chemotherapy — which it will quickly do in patients with advanced urothelial cancer [UC] — adding avelumab significantly improves survival.”

Avelumab has been approved for patients with advanced UC who had progressed on platinum-based chemotherapy. The current study represents the first maintenance trial to demonstrate a survival benefit in patients with advanced UC with stable disease following first-line chemotherapy.

Participants in the multinational, open-label, phase III trial were 700 patients (median age 69–70 years) with unresectable locally advanced or metastatic UC whose disease did not progress after four to six cycles of standard chemotherapy of gemcitabine with either carboplatin or cisplatin. They were randomized 1:1 to receive first-line maintenance therapy with avelumab plus best supportive care or best supportive care alone.

Survival benefit across the board  

The addition of avelumab for maintenance therapy significantly extended OS by 7 months in patients with advanced UC compared with best supportive alone (median, 21.4 vs 14.3 months; hazard ratio [HR], 0.69; p<0.001), over a median follow-up period of 19 months.

“The median OS [of 21.4 months] for avelumab … is notably the longest OS ever documented in a phase III metastatic UC trial in any line of therapy and superior to best supportive care alone,” commented panel discussant Dr Elizabeth Plimack from Fox Chase Cancer Center in Philadelphia, Pennsylvania, US.

The coprimary endpoint of OS in patients with PD-L1+ status was also significantly longer in the avelumab arm than the supportive care alone arm (median, 17.1 months vs not reached; HR, 0.56; p<0.001).

Similar results in favour of avelumab were seen across key subgroups including different types of first-line chemotherapy, best response to first-line chemotherapy, and regardless of visceral metastases.

“Avelumab first-line maintenance in patients whose disease has not progressed with platinum-based induction chemotherapy represents a new standard first-line treatment for advanced UC,” said Powles.

Furthermore, PFS based on independent radiology review was significantly prolonged with the addition of avelumab (median, 3.7 vs 2.0 months; HR, 0.62; p<0.001) in the overall population. Again, the difference between groups was particularly prominent among patients with PD-L1-positive disease, in favour of avelumab (median, 5.7 vs 2.1 months; HR, 0.56; p<0.001).   

Adverse events (AEs) of any grade occurred in 98 percent of the patients in the avelumab arm compared with 77 percent  in the best supportive care alone arm. The rates of grade ≥3 AEs were 47.4 percent vs 25.2 percent, respectively — with urinary tract infection (4.4 percent vs 2.6 percent) being the most common, followed by anaemia (3.8 percent vs 2.9 percent), haematuria (1.7 percent vs 1.4 percent), fatigue (1.7 percent vs 0.6 percent), and back pain (1.2 percent vs 2.3 percent).

“There were no grade 4 or 5 immune-related AEs [with avelumab] … [and] hypothyroidism was the commonest immune-related AE,” reported Powles. “High-dose corticosteroids were given to only 9 percent of the patients.”

Paradigm shifts for mUC

“JAVELIN 100 ushers in two paradigm shifts in metastatic UC,” highlighted Plimack. “[Firstly, the data] provide a new framework around which to consider a treatment break vs maintenance therapy post-platinum [and secondly], they mark a shift in the selection of first-line systemic therapy.”

“In the front line, … platinum-based chemotherapy remains the best initial therapy for these patients. It has the highest overall response rate. There's a tail on the curve, with durable treatment-free survival for some, and it sets your patient up for the best chance at OS to their subsequent checkpoint inhibitor,” she stated.  

Furthermore, platinum-based chemotherapy does not require PD-L1 testing for treatment selection, and it is unlikely that a nonresponder to platinum would have benefited from frontline checkpoint inhibition, even if they are positive for PD-L1 expression, explained Plimack.   

“In the post-platinum setting, switch maintenance is preferred over a treatment break as the timing for next-line checkpoint inhibitor therapy in patients with stable disease or response. This delays progression of disease and potentially its symptoms,” Plimack pointed out.

“However, OS can be similar only if access to second-line checkpoint is guaranteed,” she added.