IMvigor010 Misses DFS End Point in Muscle-Invasive Urothelial Carcinoma

Maha H. A. Hussain, MB ChB

The phase 3 IMvigor010 trial comparing adjuvant atezolizumab (Tecentriq) with observation in patients with muscle-invasive urothelial carcinoma (MIUC) failed to meet its primary endpoint of disease-free survival (DFS), according to primary analysis data presented at the 2020 ASCO Virtual Scientific Program.

At a median follow-up of 21.9 months, the DFS rate in each arm was 52%. The median DFS was 19.4 months (95% CI, 15.9-24.8) with atezolizumab versus 16.6 months (95% CI, 11.2-24.8) for observation (HR, 0.89; 95% CI, 0.74-1.08; 2-sided P = .2446). IMvigor010 (NCT02450331), the first phase 3 study of an immune checkpoint inhibitor (ICI) in MIUC, enrolled 809 patients at a high risk of recurrence following primary resection, 406 of whom were randomized to atezolizumab, and 403 to observation.¹

"This difference did not translate to a significant hazard ratio," said lead author Maha H. A. Hussain, MD, deputy director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University's Feinberg School of Medicine in Chicago, Illinois.

The 18-month DFS rate was 51% (95% CI, 46-56) and 49% (95% CI, 44-54) in the atezolizumab and observation arms, respectively. Beyond IMvigor010's overall population, atezolizumab also failed to confer a DFS advantage in patient subgroups stratified by PD-L1 status. "Irrespective of the PD-L1 status, there were no trends in favor of atezolizumab in both arms," Hussain said.

The PD-L1 IC0/1 subgroup included 210 patients who were randomized to atezolizumab and 207 assigned to observation. The rate of DFS events was 56% and 58%, respectively (HR, 0.81; 95% CI, 0.63-1.05). Among patients in the PD-L1 IC2/3 subgroup, the rate of DFS was 48% in the 196 patients in the atezolizumab arm and 45% in the 196 patients under observation (HR, 1.01; 95% CI, 0.75-1.35).

"I would point out that there appears to be a prognostic effect for IC23 PD-L1 status [when compared with] the IC0 and IC1, as reflected by a better disease-free survival," Hussain said.

No trends favored atezolizumab across any of the prespecified clinical subgroups including the overall population and patients with bladder staging (n = 755); upper tract staging (n = 54); patients who received prior neoadjuvant chemotherapy (n = 385); positive pathologic node status (n = 420), pT2N0 (n = 73), pT3N0 (n = 243), and pT4N0 (n = 65); as well as various geographic subgroups.

Median OS and AEs

The median overall survival (OS) was not reached in either arm, and the rate of survival events was 29% with the ICI and 31% with observation. The HR was 0.85 (95% CI, 0.66-1.09; P = .1951). Data from the interim OS analysis is not yet mature and follow-up is ongoing, Hussain said. She added that additional exploratory biomarkers and subgroup analyses "may warrant further study."

Atezolizumab's safety profile was consistent with what was seen in prior investigations of the single-agent in the advanced UC setting, but investigators observed more treatment continuation due to adverse events (AEs) in IMvigor010 compared with other studies in metastatic UC with atezolizumab monotherapy. The events that prompted discontinuation were mostly skin and gastrointestinal in nature. AEs leading to atezolizumab discontinuation affected 16% of patients receiving the ICI; 33% of patients required AEs dose interruption. Data was not available for either of these measures in the placebo arm.

AEs of any cause were observed in 94% of atezolizumab-treated participants and in 79% of placebo-receiving patients. Serious AEs and grade 3/4 AEs of any cause were also more common with atezolizumab (31% vs 18%; 37% vs 20%). The rate of grade 5 AEs was 2% in each arm.

Grade 1/2 AEs of special interest also occurred at a higher incidence in the atezolizumab group according to Hussain, who said the most common treatment-emergent AEs were pruritus, fatigue, diarrhea, and rash.

Study Design

To be eligible for IMvigor010, patients were required to undergo radical cystectomy or nephroureterectomy with lymph node dissection 14 weeks or earlier prior to registration. Patients were not permitted to receive postsurgical radiation or adjuvant chemotherapy. If a patient had not received neoadjuvant chemotherapy, the patient had to be ineligible for or declined cisplatin-based adjuvant chemotherapy. Additional eligibility criteria included an ECOG performance status of 0 to 2 and tissue available for PD-L1 testing.

Patients were randomized 1:1 to 1200 mg of atezolizumab once every 3 weeks for a maximum of 16 cycles or 1 year or observation, conducted once every 3 weeks. To assess disease recurrence and survival, tumor assessments were performed once every 12 weeks from years 1 to 3; once every 24 weeks from year 4 to year 5 and at year 6.

Although atezolizumab monotherapy did not translate to a statistically significant DFS benefit in this patient population, advancing the MIUC treatment paradigm is critical due to the lethality of the disease despite treatment with curative intent and the absence of conclusive, level 1 evidence for adjuvant chemotherapy in this setting, where up to 50% of patients are not eligible for standard-of-care neoadjuvant, cisplatin-based chemotherapy.

Evaluations of atezolizumab's efficacy in this space are ongoing, said Hussain. "Other clinical trials [of] atezolizumab monotherapy and [atezolizumab in] combination [with other agents] are underway in a variety of disease settings in UC," Hussain concluded.

Hussain MHA, Powles T, Albers P, et al. IMvigor010: primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31. Abstract 5000. doi:10.1200/JCO.2020.38.15_suppl.5000

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