Positive EU Opinion Granted to Avelumab for Frontline Maintenance in Locally Advanced or Metastatic Urothelial Carcinoma

The European Medicine Agency’ s Committee for Medicinal Products for Human Use (CHMP) has granted a positive opinion to avelumab (Bavencio) as a single agent, frontline maintenance option for adult patients with locally advanced or metastatic urothelial carcinoma who are free of disease progression after platinum-based chemotherapy.¹

The recommendation was based on data from the phase 3 JAVELIN Bladder 100 trial (NCT02603432), in which maintenance avelumab plus best supportive care (BSC) demonstrated a significant 7.1-month improvement in median overall survival (OS) versus BSC alone in the frontline treatment of this patient population.

The median OS with avelumab/BSC was 21.4 months (95% CI, 18.9-26.1) vs 14.3 months with BSC alone (95% CI, 12.9-17.9), which indicated a reduction in the risk of death of 31% in the overall patient population (hazard ratio [HR], 0.69; 95% CI, 0.56-0.86; 2-sided P = .001).^2,3

“Patients living with locally advanced or metastatic urothelial carcinoma in Europe are in urgent need of more treatment options that have the potential to extend their lives,” Chris Boshoff, MD, PhD, chief development officer of Oncology, Global Product Development, at Pfizer, stated in a press release. “The OS results from JAVELIN Bladder 100 show the potential benefits of a first-line maintenance approach with [avelumab] as a significant advancement for patients with locally advanced or metastatic urothelial carcinoma.”

In the multicenter, international, open-label, parallel-arm, randomized phase 3 trial, investigators evaluated frontline avelumab maintenance paired with BSC (n = 350) vs BSC alone (n = 350) in 700 patients with unresectable, locally advanced or metastatic urothelial carcinoma who did not progress on 4-6 cycles of standard gemcitabine plus either cisplatin or carboplatin.

Participants had achieved either a complete response, a partial response, or stable disease with previous chemotherapy. In the trial, they were administered treatment 4-10 weeks following induction chemotherapy. Fifty-one percent of patients had tumors that expressed PD-L1.

Patients enrolled on the trial received intravenous avelumab at a dose of 10 mg/kg every 2 weeks in 4-week treatment cycles. BSC was comprised of antibiotics, nutritional assistance, correction of metabolic disorders, symptom control, and pain management.

The co-primary objectives of JAVELIN Bladder 100 was OS in all patients randomized on the trial and in those whose tumors were PD-L1 positive. Key secondary end points included progression-free survival (PFS), antitumor activity, pharmacokinetics, immunogenicity, predictive biomarkers, safety, and patient-reported outcomes in the co-primary populations.

At a median follow-up of 19.6 months in the investigative arm and 19.2 months in the control arm, additional data demonstrated that the median OS had not yet been reached in those whose tumors had PD-L1 positivity vs 17.1 months in those given BSC alone (HR, 0.56; 95% CI, 0.40-0.79; P =.0003).

Moreover, the median PFS in the overall population was 3.7 months with avelumab/BSC vs 3.7 months with BSC alone per blinded independent central review (HR, 0.62; 95% CI, 0.52-0.75; P <.001). The HR for PFS was also found to favor those with PD-L1–positive tumors at 0.56 (95% CI, 0.43-0.73).

Regarding safety, 344 patients in the avelumab cohort and 345 patients in the BSC-alone cohort were examined and the monoclonal antibody was found to have favorable tolerability. Ninety-five percent of patients given avelumab experienced all-grade, any-cause toxicities vs 77.7% of those given BSC alone. Moreover, grade 3 or 4 adverse effects (AEs) were reported by 47.4% of those in the investigative arm vs 25.2% of those in the control arm.

The most frequently reported grade 3 or higher AEs in the avelumab/BSC and BSC-alone cohorts were urinary tract infection (4.4% vs 2.6%, respectively), 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%).

“[Avelumab] is the only immunotherapy treatment to demonstrate in the first-line setting the ability to help patients with locally advanced or metastatic urothelial carcinoma live longer,” Danny Bar-Zohar, MD, global head of Development for the Biopharma business of Merck KGaA, added in the release. “Now with this positive opinion, we have come a big step closer to being able to offer a new option that may shift the treatment paradigm for patients in Europe.”

In June 2020, the FDA granted approval to avelumab for use as a maintenance treatment in patients with locally advanced or metastatic urothelial carcinoma that had not progressed with frontline platinum-based chemotherapy based on findings from JAVELIN Bladder 100.

Previously, in 2017, the agent received an FDA accelerated approval for use in patients with locally advanced or metastatic urothelial carcinoma who have progressive disease during or following a platinum-based chemotherapy, or who have progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-based chemotherapy.

References

1. Bavencio (avelumab) receives positive CHMP opinion for first-line maintenance treatment of locally advanced or metastatic urothelial carcinoma. News release. EMD Serano, Merck KGaA, and Pfizer Inc. December 11, 2020. Accessed December 11, 2020. https://bit.ly/3m8bxLB

2. Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1

3. Immunotherapy following chemotherapy offers extended survival to patients with advanced urothelial cancer. News release. ASCO. May 28, 2020. December 11, 2020. https://bit.ly/2TO5SPz