Atezolizumab plus chemotherapy improves PFS in metastatic urothelial carcinoma
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Atezolizumab plus platinum-based chemotherapy prolonged PFS as first-line therapy for patients with metastatic urothelial carcinoma, according to results of the randomized phase 3 IMvigor130 trial published in The Lancet.
The combination also exhibited a safety profile consistent with that of either treatment alone.
“Platinum-based chemotherapy has been standard first-line treatment for metastatic urothelial cancer for decades,” Matthew D. Galsky, MD, director of genitourinary medical oncology and professor of urology, medicine and medical oncology at The Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai, told Healio. “Immune checkpoint blockade, with PD-1/PD-L1 inhibitors, became the first new class of drugs approved for treatment of this disease after decades of clinical drug development without major success. Those drugs were initially approved for patients progressing after first-line platinum-based chemotherapy and subsequently as first-line treatment for patients considered cisplatin-ineligible. However, most of these approvals were based on single-arm phase 2 studies.”
The IMvigor130 trial enrolled 1,213 adults with locally advanced or metastatic urothelial cancer receiving treatment across 221 sites in 35 countries.
Galsky and colleagues randomly assigned patients to atezolizumab (Tecentriq, Genentech) plus platinum-based chemotherapy (group A; n = 451), atezolizumab monotherapy (group B; n = 362) or placebo plus platinum-based chemotherapy (group C; n = 400).
Chemotherapy consisted of IV gemcitabine dosed at 1,000 mg/m² on days 1 and 8 of each 21-day cycle plus IV carboplatin area under the curve 4.5 mg/mL per min or IV cisplatin 70 mg/m² on day 1 of each cycle. Patients in group A and group B received IV atezolizumab dosed at 1,200 mg on day 1 of each cycle.
Investigator-assessed PFS and OS per RECIST version 1.1 in group A vs. group C — and OS for group B vs. group C if OS was positive for group A vs. group C — served as co-primary endpoints.
Median follow-up for survival was 11.8 months (interquartile range [IQR], 6.1-17.2).
Results showed median PFS of 8.2 months (95% CI, 6.5-8.3) in group A compared with 6.3 months (95% CI, 6.2-7) in group C (stratified HR = 0.82; 95% CI, 0.7-0.96).
Results of the first interim analysis showed median OS of 16 months (95% CI, 13.9-18.9) in group A compared with 13.4 months (95% CI, 12-15.2) in group C (stratified HR = 0.83; 95% CI, 0.69-1). This result did not cross the prespecified interim efficacy boundary for statistical significance.
Researchers also compared OS between patients in group B and a specific predefined population of group C. Median OS was 15.7 months (95% CI, 13.1-17.8) in group B compared with 13.1 months (95% CI, 11.7-15.1) in group C (stratified HR = 1.02; 95% CI, 0.83-1.24).
“The formal comparison that we have for this trial is the final analysis of PFS for atezolizumab plus chemotherapy vs. chemotherapy alone, which showed the combination of atezolizumab plus chemotherapy resulted in a significant prolongation of PFS,” Galsky told Healio. “The interim OS analysis for these treatment groups favored the combination but did not meet the interim threshold for significance. The trial is now continuing to the final survival analysis.”
Thirty-four percent of patients in both group A and group C and 6% of patients in group B experienced adverse events that led to withdrawal of any agent. Adverse events that led to discontinuation of atezolizumab or placebo occurred among 11% of patients in group A, 6% of patients in group B and 7% of patients in group C.
“This trial and another trial changed standard of care and introduced a biomarker-based treatment strategy for the first time in metastatic urothelial cancer,” Galsky told Healio. “Even before the trial completed accrual, in an unplanned analysis, the data and safety monitoring committee had noticed that patients randomly assigned to atezolizumab monotherapy who had tumors with low PD-L1 expression demonstrated an increased risk for death compared with chemotherapy. This ultimately led to a change of the labeled indication for atezolizumab for first-line treatment of cisplatin-ineligible patients with metastatic urothelial cancer, limiting the indication to patients with high PD-L1-expressing tumors.”
Although there was no formal analysis of atezolizumab alone compared with either chemotherapy group, the survival curve appeared to favor atezolizumab vs. chemotherapy for patients with high PD-L1-expressing tumors, Galsky added.
“Now that we have seen the interim analysis of the atezolizumab monotherapy vs. chemotherapy groups, what we see in the intent-to-treat cohort is the survival curves initially favor chemotherapy and then cross at approximately 10 months to favor atezolizumab,” Galsky told Healio. “A formal analysis of these treatment groups will occur in the future, but for now, these findings reinforce the current labeled indication for atezolizumab as first-line treatment for patients ineligible for cisplatin or deemed ineligible for chemotherapy in general.”
For more information:
Matthew D. Galsky, MD, can be reached at Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, 1 Gustave L Levy Place, New York, NY 10029; email: matthew.galsky@mssm.edu.
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