ASCO 2019: Clinical Outcomes According to PD-L1 Status and Age in the Prospective International SAUL Study of Atezolizumab for Locally Advanced or Metastatic Urothelial Carcinoma or Non-UC of the Urinary Tract

Chicago, IL (UroToday.com) Atezolizumab is a monoclonal antibody targeting PD-L1 that has been one of the primary immune checkpoint inhibitors leading the immune-checkpoint inhibitor (ICI) wave. In the setting of bladder cancer, it is an approved therapy for locally advanced/metastatic urothelial carcinoma (UC) based on IMvigor210 and IMvigor211 phase II and III trials.1,2

Following its approval, the single-arm SAUL3 study looked at a broader generalized patient population and found that it had a median overall survival (OS) of 8.7 months and a safety profile consistent with previous atezo trials.  Specifically, in the study, patients with locally advanced/metastatic UC or non-UC of the urinary tract received atezo 1200 mg every 3 weeks until disease progression or unacceptable toxicity. However, as it was a broader population-based study, populations excluded from IMvigor211 (renal impairment, ECOG PS 2, treated asymptomatic CNS metastases, stable controlled autoimmune disease, concomitant steroids, HIV positive, non-UC) were eligible. The primary endpoint of the study was safety, while OS and objective response rate (ORR) were secondary endpoints. Predefined subgroup analyses included outcomes according to PD-L1 status (characterized by VENTANA SP142) and age in the overall population (and the IMvigor211-like subgroup for PD-L1). The study protocol is summarized below:
ASCO 2019 SAUL study design

Between Nov 2016 and Mar 2018, 1004 pts were enrolled, but only 997 received atezolizumab. In the overall analysis that has already been published,3 the authors found the median treatment duration was 2.8 mo (range 0-19), 22% of patients remained on treatment and 8% discontinued because of toxicity. Grade ≥3 adverse events occurred in 45% of patients. The found that the median OS was 8.7 mo (95% confidence interval [CI] 7.8-9.9), the 6-mo OS rate was 60% (95% CI 57-63%), median PFS was 2.2 mo (95% CI 2.1-2.4), and the ORR was 13% (95% CI 11-16%; 3% complete responses).

The patient characteristics stratified by age and PD-L1 status are shown below:
ASCO 2019 SAUL baseline characteristics

The groups are pretty evenly balanced. Small differences are:

  • Proportion of patients with 0 lines of prior therapy is slightly higher in the IC2/3 cohort than in the IC0/1 cohort
  • Proportion of patients diagnosed with stage IV metastatic disease and proportion of patients with 0 lines of prior therapy is slightly higher in older patients

In this specific poster, the authors report outcomes according to PD-L1 status and age. First, with regards to safety, incidences of grade ≥3 treatment-related adverse events were similar irrespective of PD-L1 status (overall IC 0/1 vs 2/3: 11% vs 16%; IMvigor211-like IC 0/1 vs 2/3: 11% vs 15%) and age (≥65 y: 13%; ≥75 y: 12%; ≥80 y: 10%). Reasons for treatment discontinuation were similar across subgroups, except for slightly fewer patients in the IC 2/3 subgroup discontinuing because of disease progression, consistent with the more favorable outcome in these patients.

Oncologic secondary outcomes, stratified by PD-L1 status and age, are noted below in Figure 2 and Table 3:
ASCO 2019 SAUL PD L1 OS status

Based on these results, the OS and ORR appear more favorable in patients with higher PD-L1 expression - IC 2/3 vs IC 0/1 subgroups (overall and in the IMvigor211-like population). Further subgroup analysis specifically looking at patients based on number of prior treatments, they did note the best response patients with IC 2/3 and 0 prior lines of therapy for metastatic disease - median OS was 18.6 months (95% CI 8.5–18.8 months)

Atezolizumab appeared to be effective and well tolerated across subgroups including elderly patients and regardless of PD-L1 status. In this analysis, it OS and ORR appeared to be enhanced in the IC2/3 cohort compared to the IC0/1 cohort, consistent with prior studies – however, as this is a single arm study, no conclusions can be drawn re: prognostic vs. predictive ability.

Clinical Trial #: NCT02928406

Final results are expected in 2022, 4 years after enrollment of the last patient.

Presented by: Cora N. Sternberg, MD, FACP, Weill Cornell Medicine, New York City, NY

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Balar AV et al. IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. doi: 10.1016/S0140-6736(16)32455-2. Epub 2016 Dec 8. Erratum in: Lancet. 2017 Aug 26;390(10097):848.
  2. Powles T, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. doi: 10.1016/S0140-6736(17)33297-X. Epub 2017 Dec 18. Erratum in: Lancet. 2018 Oct 20;392(10156):1402.
  3. Sternberg CN, et al. Primary Results from SAUL, a Multinational Single-arm Safety Study of Atezolizumab Therapy for Locally Advanced or Metastatic Urothelial or Nonurothelial Carcinoma of the Urinary Tract. Eur Urol. 2019 Mar 22. pii: S0302-2838(19)30201-5. doi: 10.1016/j.eururo.2019.03.015. [Epub ahead of print]
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