Avelumab maintenance extends OS in advanced urothelial carcinoma
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Avelumab switch maintenance prolonged OS among patients with advanced urothelial carcinoma whose disease did not progress after first-line chemotherapy, according to study results presented during the ASCO20 Virtual Scientific Program.
The results — yielded from an interim analysis of the randomized phase 3 JAVELIN Bladder 100 trial — represent the largest OS benefit reported with immunotherapy in the frontline setting for patients with advanced urothelial cancer.
The findings suggest the anti-PD-L1 antibody avelumab (Bavencio; EMD Serono, Pfizer) should be a new first-line standard of care for patients whose tumors respond to or are stable after platinum-based induction chemotherapy, researchers concluded.
“This study is certainly practice changing,” Petros Grivas, MD, PhD, medical oncologist at Seattle Cancer Care Alliance, clinical director of the genitourinary cancers program at University of Washington School of Medicine and associate member of the clinical research division at Fred Hutchinson Cancer Research Center, told Healio. “The difference is significant, both statistically and clinically. Now, we know that this switch maintenance approach can maintain the benefit achieved with front-line chemotherapy so we don’t have to wait until the platinum-refractory setting to give additional treatment.”
Bladder cancer — which is due primarily to urothelial carcinoma — is the sixth most common cancer in the United States. An estimated 200,000 people worldwide died of the disease in 2018.
First-line platinum-based chemotherapy is an active regimen for advanced urothelial carcinoma. Response rates typically range from 50% to 60% with gemcitabine-cisplatin, and from 35% to 40% with gemcitabine-carboplatin, Grivas said.
“With either platinum-based chemotherapy regimen, the challenge is that these responses are not durable, and even patients whose tumors respond or demonstrate stable disease have a median PFS of about 7 to 8 months,” Grivas said. “So there has been an urgent unmet need to improve outcomes for patients with metastatic urothelial cancer.”
PD-1/PD-L1 inhibitors are standard second-line treatment for patients whose disease progressed after platinum-based chemotherapy. However, only an estimated 25% to 55% of patients actually receive second-line treatment, and a small percentage derive durable benefit, according to study background.
Avelumab has been approved in the United States for treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after platinum-containing chemotherapy.
The JAVELIN Bladder 100 study assessed whether starting avelumab with best supportive care for patients in response or with stable disease after induction chemotherapy instead of providing best supportive care alone would improve outcomes.
The trial — led by Thomas Powles, MD, PhD, FRCP, professor of genitourinary oncology and director of Barts Cancer Centre in London — included 700 patients with unresectable locally advanced or metastatic urothelial carcinoma who either achieved response to or demonstrated stable disease after four to six cycles of gemcitabine with either cisplatin or carboplatin.
Researchers randomly assigned patients 1:1 to best supportive care with or without maintenance avelumab dosed at 10 mg/kg via IV every 2 weeks. Treatment continued until disease progression, unacceptable toxicity or withdrawal.
Investigators stratified patients by their response to first-line chemotherapy (complete/partial response vs. stable disease) and metastatic site (visceral vs. nonvisceral disease).
OS — assessed among all randomly assigned patients, as well as those with PD-L1-positive tumors (51%; n = 358) as determined by the Ventana PD-L1 (SP263) Assay (Roche Diagnostics) — served as the primary endpoint. Secondary endpoints included PFS, objective response, safety, tolerability and patient-reported outcomes.
Median follow-up was more than 19 months in both groups.
Results showed the addition of avelumab to best supportive care significantly extended OS among all patients (median, 21.4 months vs. 14.3 months; HR = 0.69; 95% CI, 0.56-0.86), as well as among patients with PD-L1-positive tumors (median, not reached vs. 17.1 months; HR = 0.56; 95% CI, 0.4-0.79).
Researchers observed the OS benefit across all other prespecified subgroups, including those based on age, ECOG performance status, best response to first-line chemotherapy, site of baseline metastases and creatinine clearance.
PFS analysis by blinded independent central review showed a statically significant benefit with avelumab among all patients (median, 3.7 months vs. 2 months; HR = 0.62; 95% CI, 0.52-0.75) and among those with PD-L1-positive tumors (HR = 0.56; 95% CI, 0.43-0.73).
“The maintenance setting is attractive timing for using a checkpoint inhibitor,” Powles said in a press release. “Patients have gone through chemotherapy and the disease is under control but, instead of waiting for disease to progress after chemotherapy — which it will quickly do in patients with advanced urothelial cancer — adding avelumab significantly improves survival.”
Patients assigned best supportive care alone were not allowed to cross over to treatment with avelumab; however, many patients received subsequent therapy at the time of progression. Researchers intend to continue following patients to see how long responses are maintained.
“It is important to mention that avelumab was well-tolerated, and this is very much in line with what we have seen from previous immune checkpoint inhibitors in urothelial cancer,” Powles said.
The agent exhibited a safety profile consistent with that observed in prior immunotherapy studies.
A higher percentage of patients assigned avelumab experienced any-grade treatment emergent adverse events (98% vs. 77%). They also were more likely to experience grade 3 or higher treatment emergent adverse events (47.4% vs. 25.2%), the most common of which were urinary tract infection (4.4% vs. 2.6%), anemia (3.8% vs. 2.9%), hematuria (1.7% vs. 1.4%) and fatigue (1.7% vs. 0.6%).
“Given the efficacy outcomes and the absence of new safety signals, I think this renders this strategy the new standard of care just if there is no progression after induction front-line chemotherapy,” Grivas told Healio. “It’s also important to emphasize that this affects ‘all-comers.’ There is no need to check any biomarker. This is very exciting for our patients, considering how hard it has been to improve outcomes in this challenging disease.” – by Mark Leiser
Reference:
Powles T, et al. Abstract LBA1. Scheduled for presentation at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Disclosures: Pfizer funded this study as part of an alliance between Pfizer and Merck KGaA, Darmstadt, Germany. Grivas reports research funding to his institution from Bavarian Nordic, Bristol-Myers Squibb, Clovis Oncology, Debiopharm, Immunomedics, Merck and Pfizer, as well as consultant/advisory roles with AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Driver Inc., EMD Serono, Exelixis, Foundation Medicine, Genzyme, GlaxoSmithKline, Heron, Janssen, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, Roche and Seattle Genetics. Powles reports honoraria from, consultant/advisory roles with, research funding from or travel, accommodations or expenses from Astellas, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche, GlaxoSmithKline, Ipsen, Merck, Merck Sharp & Dohme, Novartis, Pfizer and Seattle Genetics.
Perspective
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Arlene O. Siefker-Radtke, MD
At the plenary session of this year’s ASCO20 Virtual Scientific Program, avelumab joined pembrolizumab in proving a survival benefit when using an immune checkpoint inhibitor for metastatic urothelial cancer.
Researchers involved in this maintenance trial randomly assigned patients who had stable disease or better following a gemcitabine/platinum combination to best supportive care with or without avelumab. Given the improved survival with avelumab, it is clear that the use of an immune checkpoint inhibitor is here to stay as a standard-of-care treatment for patients with urothelial cancer.
Many are now asking whether it is better to give treatment in the maintenance setting in first response or to wait until progressive disease. How much was survival influenced by the exclusion of patients who progressed on chemotherapy? Would the survival difference have been as great if more patients received immunotherapy upon progression?
These single-agent questions soon may be irrelevant with the mounting enthusiasm for checkpoint combinations with antibody-drug conjugates, targeted agents and other immune-modulating strategies. We now need to build upon these successful sequences and combinations by increasing our understanding of how novel agents enhance or modulate the immune response. Only then will we be able to move from a maximal tolerated dose strategy that annihilates both the tumor and the tissue microenvironment at significant toxicity to a biologically effective dose strategy that modulates the immune environment with better activity and less harm for our patients.
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Lee S. Schwartzberg, MD, FACP
This is a good approach from the clinical perspective. A lot of these patients with bladder cancer tend to have comorbidities and the maintenance approach is an interesting idea. Of course, there are a fair number of patients who are platinum-ineligible in this setting because of decreased renal function, so it wouldn’t apply to a substantial number of patients with advanced urothelial cancer. However, for those who are candidates, this is an intriguing way to approach the combination of chemotherapy and an immune checkpoint inhibitor.
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Powles T, et al. Abstract LBA1. Scheduled for presentation at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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