PD-L1 Assays Demonstrate

Hope S. Rugo, MD, director of Breast Oncology Clinical Trials Investigation at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center

Hope S. Rugo, MD

An exploratory biomarker substudy of Impassion130 demonstrated clinical activity of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) in a subgroup of patients with triple-negative breast cancer (TNBC) who had immune cell (IC) PD-L1 expression by the SP142 immunohistochemistry (IHC) assay, regardless of the site of the tumor sample (primary or metastatic).¹

However, concordance between 3 PD-L1 assays examined was “subpar” and the assays cannot be considered equivalent, reported Hope S. Rugo, MD, at the ESMO Congress 2019.

Compared with the SP142 assay, “the 22C3 and SP263 PD-L1 assays identified a greater patient population, and SP142 positivity was encompassed within the positive tests for both of these antibodies,” said Rugo, director of Breast Oncology Clinical Trials Investigation at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

Impassion130 was the first phase III trial to demonstrate clinical benefit of immunotherapy in patients with PD-L1-positive metastatic TNBC. Based on this study, the combination of atezolizumab and nab-paclitaxel was approved in the United States and Europe for this indication. In Impassion130, PD-L1 expression in ICs was evaluated using the Ventana PD-L1 SP142 IHC assay with a ≥1% cutoff. “However, questions remain about how to best identify patients who can benefit from this combination of atezolizumab and nab-paclitaxel,” Rugo said.

The retrospective post-hoc analysis presented here evaluated the most commonly used PD-L1 assays to estimate PD-L1 prevalence, analytic concordance with SP142, and clinical activity. “We also included an evaluation of important factors related to PD-L1 testing and their relationship to clinical outcome,” she said.

In Impassion130, PD-L1 status using the SP142 antibody predicted progression-free survival (PFS) and overall survival (OS) with the combination of atezolizumab and nab-paclitaxel compared with nab-paclitaxel alone. The absolute improvement in median OS in the PD-L1-positive population was 7 months (HR, 0.71; 95% CI, 0.54-0.93). In contrast, there was no impact on either PFS or OS in patients with PD-L1—negative disease using the SP142 assay.²

Questions have arisen about the optimal tissue source for PD-L1 testing, said Rugo, so the relationship between the source of tissue (primary or metastatic) and outcome in Impassion130 was evaluated as part of the post-hoc analysis.

“Overall, tissue obtained from the breast was more likely to be PD-L1—positive than tissue obtained from a metastatic distant site,” she said. “However, the median time from collection of samples to randomization was only 61 days, so even though tissue was obtained from [the] primary breast [site], it was close to the start of therapy in the metastatic setting.”

PD-L1 status appeared to vary by the anatomic site from which tissue was obtained. Some 44% of patients in whom tissue was obtained from the primary tumor were PD-L1—positive by the SP142 assay, compared with 36% of patients from whom tissue was obtained from a metastatic site (P = .014).

Regardless of the source of tissue, however, PD-L1 status predicted benefit from atezolizumab. In those patients in whom tissue was obtained from the primary tumor, both PFS (HR, 0.61; 95% CI, 0.47-0.81) and OS (HR, 0.79; 95% CI, 0.57-1.09) favored the addition of atezolizumab. In patients in whom tissue was obtained from a metastatic tumor, the PFS (HR, 0.69; 95% CI, 0.46-1.03) and OS (HR, 0.55; 95% CI, 0.32-0.93) similarly favored the atezolizumab arm.

Central testing was performed of the Ventana PD-L1 SP142, Dako 22C3, and Ventana PD-L1 SP263 assays, and read by pathologists trained and qualified to read IC ≥1% (SP142 and SP263) and combined positive score ≥1 ([CPS] 22C3).

The biomarker evaluable population consisted of 614 patients, representing 68% of the intention-to-treat (ITT) IMpassion130 population. In this cohort, 46% were PD-L1 IC-positive using SP142 versus 41% in the ITT population. The improvement in PFS in the biomarker evaluable population with the addition of atezolizumab was slightly greater.

“The different assays identified different percentages of cases that are positive for PD-L1,” said Rugo. “More tumors were classified as positive for PD-L1 using the 2 alternative antibodies and assays (81% with 22C3 and 75% with SP263).

“Almost all SP142-positive cases are captured by either 22C3 CPS or SP263,” she said. “However, about one-third of patients’ tumors were positive for PD-L1 using only 1 of [these] 2 assays. The overall percentage of agreement between SP142 and 22C3 was 64% and between SP142 and SP263 was 69%.

Previous studies have demonstrated a correlation between the percent stromal tumor-infiltrating lymphocytes (TILs) and the clinical outcome in TNBC. In Impassion130, patients whose tumors tested positive for PD-L1 IC using SP142 and 1 of the other 2 antibodies (ie, double-positive ICs) had the highest percentage of TILs compared with patients whose testing was positive by only 1 of the other 2 assays.

The HRs for PFS and OS in favor of atezolizumab plus nab-paclitaxel compared with placebo plus nab-paclitaxel were relatively similar between groups who were PD-L1-positive using the 3 assays. However, with SP142, the absolute difference in PFS with the addition of atezolizumab was 4.2 months and the absolute benefit in OS was 9.4 months. For 22C3-positive patients, the absolute benefit in PFS and OS was 2.1 and 2.4 months, respectively, and for SP263-positive patients, these absolute differences were 2.2 and 3.3 months, respectively.

Clinical outcomes were evaluated in biomarker evaluable subpopulations with the following results:

• Among patients who were positive for PD-L1 by both SP142 and 22C3, the absolute benefit with the addition of atezolizumab on median PFS was 4.4 months and the absolute benefit on OS was 9.3 months.
• Among those whose tumors were positive for PD-L1 by 22C3 alone, the absolute benefit for PFS was 1.7 months and there was no difference in OS.
• As expected, among patients whose tumors were negative by both SP142 and 22C3, there was no advantage on median PFS and median OS with the addition of the checkpoint inhibitor.
• Among patients who were positive for PD-L1 by both SP142 and SP263, the absolute benefit with the addition of atezolizumab on median PFS was 4.2 months and the absolute benefit on median OS was 9.4 months.
• Among those whose tumors were positive for PD-L1 by SP263 only, the absolute benefit for median PFS was 1.6 months and there was no difference in median OS.
• Negativity for PD-L1 by both SP142 and SP263 predicted no benefit from the addition of atezolizumab.

References

1. Rugo HS, Loi S, Adams S, et al. Performance of PD-L1 immunohistochemistry (IHC) assays in unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC): Post-hoc analysis of IMpassion130. Presented at ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA20.
2. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/NEJMoa1809615

<<< View more from the 2019 ESMO Congress