Moving on Up: Maintenance Therapy Extends OS in Bladder Cancer

Is maintenance therapy with an immune checkpoint inhibitor a good idea for patients with advanced bladder cancer who do not progress after initial chemotherapy?

Yes, and furthermore this approach offers "a new first-line standard of care for advanced urothelial cancer," said Thomas Powles, MD, professor of genitourinary oncology and director of the Barts Cancer Centre in London, UK.

Powles was discussing "first-line maintenance therapy" with avelumab (Bavencio, EMD Serono and Pfizer) from the JAVELIN Bladder 100 Trial.

Results from this trial will be presented at the plenary session of the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because the coronavirus pandemic. ASCO chief medical officer Richard Schilsky, MD, PhD, highlighted this abstract as one of three from the plenary session that were "practice-changing."

Powles provided a glimpse of the results at a pre-meeting press briefing.

The trial involved 700 patients who had not progressed after at least four cycles of first-line, platinum-based chemotherapy. Maintenance therapy with avelumab improved overall survival by 7.1 months when compared with best supportive care (BSC) alone.

The median OS was 21.4 months for avelumab plus BSC vs 14.3 months for BSC alone (hazard ratio [HR], 0.69; P = .0005).

An expert not involved with the study was impressed with the outcome.

"The data are encouraging and we look forward to FDA review, and hopefully approval [in this setting]," said Padmanee Sharma, MD, PhD, a genitourinary medical oncologist at the University of Texas MD Anderson Cancer Center in Houston.

Avelumab is already approved for use in advanced urothelial cancer, but in a second-line setting, like a number of other immune checkpoint inhibitors.

"Instead of Waiting for Cancer to Return"

Powles commented that about 65% to 75% of patients with advanced urothelial cancer have disease control with first-line chemotherapy, but that progression-free survival (PFS) and OS are "short" because of chemo-resistance.

Many patients do not receive second-line treatment with immunotherapy and only a "minority" achieve durable clinical benefit, he added.

"Instead of waiting for the cancer to return," which it will do "quickly," Powles suggested that maintenance with immunotherapy should become the standard of care.

"Our findings should give hope to many patients with advanced urothelial cancer who face a very challenging and difficult condition," coauthor Petros Grivas, MD, PhD, clinical director of the Genitourinary Cancers Program at the Seattle Cancer Care Alliance (SCCA), said in a statement. He was the gobal coprincipal investigator of the JAVELIN Bladder 100 trial.

"People with advanced urothelial cancer generally have a poor prognosis, and most experience cancer progression (growth) within 8 months after initiation of first-line chemotherapy," he said.

"We are very excited with these results, which indicate that immunotherapy with avelumab first-line maintenance could offer a new treatment option that helps patients live longer. Even if this is likely not a complete cure and may cause potential side effects in some patients, the significant prolongation of overall survival is clearly a remarkable improvement, while many treated patients may not experience significant side effects from this approach," he added.

The safety profile was "manageable" and consistent with other studies of avelumab, Powles reported.

All-causality adverse events (AEs) were reported at any grade in 98% vs 77.7% in the avelumab plus BSC vs BSC alone groups; AEs of grade 3 or higher were 47.4% vs 25.2%. The most frequent grade ≥3 AEs were urinary tract infection (4.4% vs 2.6%), anemia (3.8% vs 2.9%), hematuria (1.7% vs 1.4%), fatigue (1.7% vs 0.6%), and back pain (1.2% vs 2.3%).

The results from JAVELIN with avelumab show the "largest survival benefit" seen so far in advanced urothelial cancer in the maintenance setting, according to ASCO press materials.

Has there ever been a survival benefit found with maintenance therapy?

No, according to a 2019 review in Future Oncology . Three prospective randomized controlled trials (of vinflunine, sunitinib, and lapatinib, respectively) did not reveal any significant oncologic benefit vs placebo.

But in a phase 2 randomized controlled trial involving 107 patients, maintenance pembrolizumab provided longer PFS compared with placebo (5.4 vs 3.2 months, [HR, 0.64; 95% confidence interval, CI, 0.41 - 0.98]).

This pembrolizumab trial showed a "similar PFS hazard ratio" to that seen with avelumab in JAVELIN, Powles commented, noting however that the pembrolizumab trial was not designed to look at survival.

Even Better Response Among PD-L1-Positive Patients

JAVELIN patients had unresectable locally advanced or metastatic urothelial carcinoma and were treated with gemcitabine with either cisplatin or carboplatin.

Just over half (51%) of these patients had tumors that were PD-L1-positive (+).

The maintenance therapy strategy was even more effective in these patients. Avelumab plus BSC significantly prolonged OS vs BSC alone in patients with PD-L1+ tumors (HR, 0.56; 1-sided P = .0003). Median OS was not reached vs 17.1 months, respectively.

An OS benefit was also observed across all prespecified subgroups, including those patients with visceral metastases.

Commenting on the study, Sharma said she would like to see more detailed outcome data related to the number of chemotherapy cycles administered (the range was 4 to 6) and information on the amount of time between the end of chemo to the start of avelumab. Powles commented that his international team has not looked at number of cycles and outcome, nor the time from completion of chemotherapy and randomization. "They are both valid questions for the future," he said.

The study was funded by Pfizer. Powles and many of the coauthors have financial relationships with Pfizer and other pharmaceuticals. Sharma has disclosed no relevant financial relationships.

2020 American Society of Clinical Oncology annual meeting: Abstract LBA1. To be presented May 31, 2020.

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