In patients with metastatic urothelial carcinoma (mUC),(bladder cancer) immunotherapy treatment yielded worse overall survival (OS) during the first 12 months compared with carboplatin-based chemotherapy, a superior OS at 36 months based on a large, retrospective cohort study recently published in European Urology.

Background: Safety Issues with Immunotherapies (e.g. Keytruda, Tecentriq)

Apparently, in May 2018, there was a safety alert and European Medicines Agency (EMA) actions started paving the way for clinical guidance. The safety warning of 2018 involved the FDA warning against the use of single-agent checkpoint inhibitors in the first-line setting for patients with PD-L1-low expressing platinum-eligible urothelial carcinoma. It followed a decrease in the overall survival with Keytruda and Tecentriq versus a platinum-based chemotherapy. As of May 2018, the agencies now restrict immunotherapy use to patients with cisplatin-ineligible mUC (bladder cancer) who are PD-L1 positive or who are ineligible for any platinum-containing chemotherapy.

The EMA and FDA safety alerts were based on early reviews of 2 ongoing phase III trials of platinum-eligible patients, KEYNOTE-361 and IMvigor130; hence, the full results of these trials is unknown and their applicability to routine clinical practice cannot be certain, reports Silas Inman of Targeted Oncology.

The Study

The study is titled Effectiveness of First-line Immune Checkpoint Blockade versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer.

Consisting of 2,017 patients, the study included 487 who received immunotherapy and 1,530 who received carboplatin-based chemotherapy (chemo). The baseline characteristics were generally similar between the groups except for two exceptions including 1) patients receiving immunotherapy had a higher ECOG performance status (ECOG 2, 33% vs. 24%) and 2) higher Elixhuaser comorbidity score (>5,14% vs. 5.8%).

The median follow-up was 7.2 months (range, 3.2-14). During follow-up, there were 1219 deaths (939 in chemotherapy group vs. 280 in immunotherapy group), reports Silas Inman at Targeted Oncology. During the first 12 months, the hazard ratio (HR) was 1.37 for immunotherapy treatment (95% Cl, 1.5-1.62; P<.001). After the first 12 months, the HR was 0.50 (95% CL, 0.30-0.85%; P=.001).

Study Team Uses Flatiron EHR Data

The study investigators utilized the oncology-focused Flatiron Health electronic health record (EHR) database acquired by Roche. The database includes de-identified data from more than 280 academic and community oncology practices representing more than 280 academic and community oncology practices involving more than 2.1 million patients with cancer.

Data involving cohort was similar (e.g. age, race, gender, etc.) for those in the U.S. afflicted with bladder cancer on Surveillance, Epidemiology and End Results (SEER) data from 2004 to 2014, although the Flatiron Health data set covered between years 2011 to 2018 right after the FDA safety alert.

For full list of chemotherapy and immunotherapy definitions for purpose of study visit the source below.


In summarizing the results, clinical investigator Emily Feld, MD, with the University of Pennsylvania noted, “In this study, we demonstrate the patients treated with immunotherapy had a 37% increase in the hazard of death in the first 12 months after the initiation of therapy, but among those who survived 1 year, there was a 50% lower hazard of death beyond 12 months after the initiation of therapy.” Dr. Feld, applying some interpretation continued “These results suggest that clinicians and patients should carefully balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy”

The immunotherapy group had a median OS of 9 months while the median OS for the chemotherapy group was 11 months. The authors uncovered that the estimated OS rate in the immunotherapy group was lower at 12 months than in the immunotherapy group  (40% [95% CI, 34%-45%] vs 46% [95% CI, 43%-49%]; P = .05). But once the study team reviewed data over a 36 month period, there was a noticeable shift in the favor of immunotherapy as that group had a higher survival rate (28% [95% CI, 22%-35%] vs 13% [95% CI, 11%-16%]; P <.001).

In regard to PD-L1 stratified analysis, the authors noted, although exploratory in nature, it suggests that PD-L1 negative patients have inferior survival with immunotherapy relative to chemotherapy, which supports EMA and FDA label revision restricting immunotherapy to use by mUC patients (bladder cancer) whose tumors are PD-L1 positive (approximately 30% of all tumors).


The investigators (e.g. Feld et al) note that the risk-benefit profile with immunotherapy is not favorable for all bladder cancer patients and note their findings of improved short-term survival with chemotherapy but superior long-term survival with immunotherapy offer a consideration to the formulation of a rational to consider first-line combination of chemotherapy and immunotherapy to drive maximum survival for as many patients as possible.

This actual consideration is being explored by the ongoing KEYNOTE-361 (Merck) and IMvigor (Roche) clinical trials.

Lead Research/Investigators

Emily Feld, University of Pennsylvania

Source: Targeted Oncology

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