ESMO 2019: IMvigor130: Efficacy and Safety from a Phase 3 Study of Atezolizumab as Monotherapy or Combined with Platinum-based Chemotherapy vs Placebo + PBC in Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma

Barcelona, Spain (UroToday.com) Cisplatin based chemotherapy has been the standard of care first line therapy for metastatic urothelial carcinoma (mUC) for several decades. However, up to 50% of patients may not be medically eligible for cisplatin chemotherapy, and so efficacious alternative first line regimens are required. Based on phase 2 data, the FDA has approved both pembrolizumab (anti-PD1) and atezolizumab (anti-PDL1) as first line therapies for mUC based on phase II data showing efficacy and durable response from the KEYNOTE052 and IMvigor 210 trials, though long term outcomes have not yet been reported for these trials. The impact of first line combination immunotherapy and chemotherapy on patient outcomes in mUC has not been tested.

In this presentation, Dr. Enrique Grande presented final progression-free survival and interim overall survival data for IMvigor130, a trial that ultimately randomized patients with locally advanced or mUC in a 1:1:1 fashion to either atezolizumab monotherapy, atezolizumab + platinum/gemcitabine, or placebo + platinum/gemcitabine. Stratification and endpoint criteria are shown below. The choice of platinum agent was left to the treating team to decide. 

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Patient cohorts were relatively well-balanced. Of note, 52% of patients that were eligible for cisplatin therapy only received carboplatin.

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Combination therapy with atezolizumab and platinum based chemotherapy offered a statistically significant benefit with regards to radiographic progression free survival, with hazard ratio shown below. Exploratory subgroup analysis suggests that patients who received cisplatin, and those with the highest levels of PD-L1 and best performance status, benefitted from the combination regimen. Combination therapy also doubled the rate of complete response relative to the other two arms.

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Interim overall survival data suggests a benefit to combination therapy as well (HR 0.83, 95% CI: 0.69-1.00, one-sided P = 0.027), with only cisplatin therapy (relative to carboplatin) associated with survival benefit.

In the comparison of atezolizumab monotherapy with platinum/gemcitabine chemotherapy, interim overall survival does not show a statistically significant survival benefit for immunotherapy, though this may stratify by PD-L1 expression levels. Results from the immunotherapy monotherapy arm show comparable overall response rates (23%) as seen in the IMvigor210 phase 2 data.

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The overall toxicity profile of each arm was consistent with the toxicity profile of each tested drug.

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In summary, the IMvigor130 trial data presented represents the first immune checkpoint inhibitor study to show progression-free survival benefit for first-line treatment of locally advanced and mUC patients. Atezolizumab monotherapy, currently approved on a conditional basis by the FDA, may have benefit relative to chemotherapy in longer term follow-up, though this benefit may be limited to PD-L1 highly expressing tumors.

Presented by: Enrique Grande, MD, Medical Oncologist and Head of the Medical Oncology Service at MD Anderson Cancer Center Madrid, Madrid, Spain

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain

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