Immunotherapy in mUC Yields Better Long-term OS Than Chemotherapy, Retrospective Study Shows

In patients with metastatic urothelial carcinoma, immunotherapy treatment yielded worse overall survival during the first 12 months compared with carboplatin-based chemotherapy, but a superior OS at 36 months. These results from a large, retrospective cohort study were published recently in <em>European Urology</em>.

Emily Feld, MD

In patients with metastatic urothelial carcinoma (mUC), immunotherapy treatment yielded worse overall survival (OS) during the first 12 months compared with carboplatin-based chemotherapy, but a superior OS at 36 months. These results from a large, retrospective cohort study were published recently inEuropean Urology.1

During the first 12 months, the hazard ratio (HR) was 1.37 for immunotherapy treatment (95% CI, 1.15-1.62;P<.001). After the first 12 months, the HR was 0.50 (95% CI, 0.30-0.85;P= .001).

“In this study, we demonstrate that patients treated with immunotherapy had a 37% increase in the hazard of death in the first 12 month 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,” wrote the study authors, led by Emily Feld, MD, of the University of Pennsylvania. “These results suggest that clinicians and patients should carefully balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy.”

This study grew out of a need for clinical guidance following asafety alert from the FDAand the European Medicines Agency (EMA). The agencies reported decreased survival in patients with mUC who did not express PD-L1 and were treated with immunotherapy compared with platinum-based chemotherapy.2,3As of May 2018, the agencies now restrict immunotherapy use to patients with cisplatin-ineligible mUC who are PD-L1 positive or who are ineligible for any platinum-containing chemotherapy.4

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. “[Therefore,] the full results are unknown and applicability to routine clinical practice is uncertain,” Feld et al wrote.

In the current study, the authors used data from the Flatiron Health electronic health record (EHR)-derived database, which includes de-identified data from more than 280 academic and community oncology practices representing more than 2.1 million patients with cancer. The cohort is similar in age, race, and gender to the US population with advanced urothelial carcinoma based on Surveillance, Epidemiology, and End Results (SEER) data from 2004 to 2013, although the Flatiron Health data span the years between 2011 and August 31, 2018, shortly after the FDA’s safety alert.

The study sample included patients diagnosed with stage IV urothelial carcinoma (bladder, renal pelvis, ureter, or urethra), and those diagnosed with early-stage urothelial carcinoma who later developed metastatic disease and began first-line therapy. Exclusion factors included a lack of systemic therapy for advanced bladder cancer, clinical trial participation for first-line agents, a lag of 90 days or more between diagnosis and treatment planning. Patients were also ineligible if they received first-line agents not listed in the National Comprehensive Cancer Network (NCCN) guidelines for systemic therapy of mUC.

The authors defined carboplatin-based chemotherapy as an NCCN guideline—recommended carboplatin-containing doublet or other evidence-based carboplatin-containing regimen. Immunotherapy treatment was defined as single-agent nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), durvalumab (Imfinzi), or avelumab (Bavencio).

The primary outcome was OS and the secondary endpoint was second-line therapy—free survival, defined as the time from the start of first-line therapy to the earliest of the start date of second-line therapy or death.

The study population consisted of 2017 patients. Of these, 487 received immunotherapy and 1530 received carboplatin-based chemotherapy. Baseline characteristics were generally similar between treatment groups, with 2 exceptions: patients receiving immunotherapy had a higher ECOG performance status (ECOG 2, 33% vs 24%) and a higher Elixhauser 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).

The immunotherapy group had a median OS of 9 months, while the median OS of the chemotherapy group was 11 months. The authors found 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). However, this did not hold true at 36 months, when patients in the immunotherapy group had a higher survival rate (28% [95% CI, 22%-35%] vs 13% [95% CI, 11%-16%];P<.001).

Feld et al determined that 818 patients (41%) went on to receive second-line therapy. Among the patients who received first-line immunotherapy, 22% received second-line treatment, whereas 47% of the initial chemotherapy patients did. Both groups had similar rates of estimated second-line therapy—free survival at 12 months, with 26% in the immunotherapy group (95% CI, 21%-31%) and 24% in the chemotherapy group (95% CI, 43%-49%,P= .5). By 36 months, second-line therapy—free survival was higher in the immunotherapy group (28% [95% CI, 22%-35%] vs 13% [95% CI, 11%-16%];P<.001).

Given the timing of the FDA’s safety advisory, only 7% of the study population received PD-L1 testing. This was consistent with the original label indication for immunotherapy, which did not mandate PD-L1 testing for cisplatin-ineligible patients. In an exploratory subgroup analysis, the authors found that 6-month survival was highest for PD-L1—positive patients treated with immunotherapy and lowest for PD-L1–negative patients treated with immunotherapy compared to patients treated with chemotherapy.

“Although exploratory in nature, our PD-L1—stratified analysis also suggests that PD-L1–negative patients have inferior survival with immunotherapy relative to chemotherapy, supporting the EMA and FDA label revision restricting immunotherapy use to mUC patients whose tumors are PD-L1 positive (approximately 30% of all tumors),” the study authors wrote. “Future studies should compare patient outcomes associated with a biomarker guided versus an unguided treatment strategy.”

Feld et al conclude that the risk-benefit profile with immunotherapy is not favorable for all patients with mUC. “The long-term benefit [of immunotherapy compared to chemotherapy] may not have been captured in the early review of the phase III trials upon which the EMA and FDA’s label restriction was based,” they wrote. “Our findings of improved short-term survival with carboplatin-based chemotherapy but superior long-term survival with immunotherapy provide a rationale for considering first-line combination of chemotherapy and immunotherapy in an effort to achieve maximal survival for all patients. This is currently being explored in the ongoing trials KEYNOTE-361 and IMvigor130.”


  1. Feld E, Harton J, Meropol NJ, et al. Effectiveness of First-line Immune Checkpoint Blockade Versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer [published online July 27, 2019].Eur Urol. doi: 10.1016/j.eururo.2019.07.032.
  2. European Medicines Agency. EMA restricts use of Keytruda and Tecentriq in bladder cancer. Published January 6, 2018. Accessed August 6, 2019.
  3. FDA Alerts Health Care Professionals and Oncology Clinical Investigators about an Efficacy Issue Identified in Clinical Trials for Some Patients Taking Keytruda (pembrolizumab) or Tecentriq (atezolizumab) as Monotherapy to Treat Urothelial Cancer with Low Expression of PD-L1. U.S. Food and Drug Administration website. Updated August 16, 2018. Accessed August 6, 2019.
  4. FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. U.S. Food and Drug Administration website. Updated July 5, 2018. Accessed August 6, 2019.