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Effectiveness of first-line immune checkpoint blockade versus carboplatin-based chemotherapy for metastatic urothelial cancer

  • Emily Feld 1,
  • Joanna Harton 2,
  • Neal J. Meropol 3,
  • Blythe J.S. Adamson 3,
  • Aaron Cohen 3,
  • Ravi B. Parikh 1,
  • Matthew D. Galsky 4,
  • Vivek Narayan 1,
  • John Christodouleas 1,
  • David J. Vaughn 1,
  • Rebecca A. Hubbard 2,
  • Ronac Mamtani 1
1 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA 2 Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 3 Flatiron Health, New York, NY, USA 4 Tisch Cancer Institute, Mount Sinai, New York, NY, USA

Publication: European Urology, Volume 76, Issue 4, October 2019, Pages 524-532

Background

Limited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1)-negative patients receiving immunotherapy. Final results from these trials are unknown.

Objective

To compare survival in cisplatin-ineligible mUC patients receiving first-line immunotherapy versus those receiving carboplatin-based chemotherapy.

Design, setting, and participants

We conducted a retrospective cohort study of 2017 mUC patients receiving first-line carboplatin-based chemotherapy (n = 1530) or immunotherapy (n = 487) from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record–derived database.

Outcome measurements and statistical analysis

The primary outcomes were overall survival (OS), comparing 12- and 36-mo OS, and hazard ratios before and after 12 mo. Propensity score–based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression model estimates of comparative effectiveness.

Results and limitations

IPTW-adjusted OS rates in the immunotherapy group were lower at 12 mo (39.6% [95% confidence interval {CI} 34.0–45.3%] vs 46.1% [95% CI 43.4–48.8%]) but higher at 36 mo (28.3% [95% CI 21.8–34.7%] vs 13.3% [95% CI 11.1–15.5%]) relative to the chemotherapy group. Immunotherapy treatment demonstrated inferior OS during the first 12 mo relative to carboplatin-based chemotherapy (IPTW-adjusted hazard ratio [HR] 1.37, 95% CI 1.15–1.62), but superior OS beyond 12 mo (IPTW-adjusted HR 0.50, 95% CI 0.30–0.85). Limitations include retrospective design and potential unmeasured confounding.

Conclusions

In the setting of mUC, clinicians and patients should carefully consider how to balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy.

Patient summary

To determine the optimal first-line therapy for metastatic bladder cancer patients who are unfit for cisplatin, we compared carboplatin-based chemotherapy versus immunotherapy using real-world data. Survival in the 1st year of treatment was lower with immunotherapy relative to chemotherapy, but for patients surviving beyond the 1st year, immunotherapy was superior.

Expert's summary

By Dr. Soria

In this retrospective original article, the authors aimed to compare the efficacy of carboplatin-based chemotherapy (CT) with that of systemic immunotherapy (IO) as first-line treatment for metastatic or locally advanced urothelial cancer patients ineligible for cisplatin-based CT. For the purpose of the study, the Flatiron Health database has been consulted and data from 1530 patients receiving CT and 487 patients receiving IO have been analyzed. To diminish the risk of selection bias inherent to the retrospective nature of the study, a propensity score-based analysis has been conducted. When compared to CT group, overall survival (OS) rates of patients treated with IO were lower at 12 months (39.6% vs 46.1%), but higher at 36 months (28.3% vs 13.3%). These findings should be taken into consideration in the treatment-related decision-making process, and patients should be informed about the short-term benefit of CT against the long-term benefit of IO.

Expert's comment

By Dr. Soria

In the recent years, the advent of IO revolutionized the paradigm of treatment of advanced and metastatic urothelial carcinoma, with the promise to extend this effect also to the other phases of disease, such as the neoadjuvant as well as the adjuvant settings. To date, the standard treatment for cisplatin eligible patients with advanced/metastatic urothelial carcinoma is represented by primary cisplatin-based CT. Based on guidelines recommendations, in the first line setting, IO should be reserved for those patients who are ineligible to cisplatin due to impaired renal function, unsatisfactory performance status, hear loss, peripheral neuropathy and heart failure. In this contest, Atezolizumab and Pembrolizumab have recently received an accelerated FDA approval for the first line treatment of metastatic cisplatin-ineligible patients who show a high PD-L1 tissue expression.

However, this approval was mainly based on surrogate endpoints such as overall and complete response rates and not on OS data. Moreover, since there are no available comparisons between CT and IO in this setting, uro-oncologists are facing a reality in which both treatments can be administered and, most of the times, the choice is left at physicians’ discretion. The study by Feld et al, even if carrying the limitations of a national dataset-based study and of its retrospective nature, provided interesting results that, awaiting those coming from phase III trials, could be used in daily clinical practice to counsel patients about systemic therapy. Carboplatin-based CT showed to be superior to IO in terms of short-term OS (12 months) but inferior after 36 months. This is probably due to the characteristics of response that we observe with IO. Actually, early decreased survival in the IO group could be explained by the patients who do not respond to IO and, less frequently, to the reported phenomenon of hyperprogression. Conversely, long-term benefit associated to IO is probably related to the peculiarity of IO to confer a durable response in a non-negligible percentage of patients; this phenomenon is only rarely observed with CT.

These data suggest that some subgroups of patients (probably those with high-volume disease) still may benefit from CT, and pave the way forward combination therapies (CT+IO) in this setting, as we recently demonstrated by the interesting results of IMVIGOR-130 trial (atezolizumab as monotherapy or in combination with platinum-based CT vs placebo + platinum-based CT in previously untreated locally advanced/metastatic urothelial cancer).