PD-L1 Immune Cell Expression Critical to Atezolizumab Efficacy in TNBC

Leisha A. Emens, MD, PhD

Improvements observed in progression-free survival (PFS) and overall survival (OS) with the addition of first-line atezolizumab (Tecentriq) to nab-paclitaxel (Abraxane) in patients with metastatic triple negative breast cancer (TNBC) or inoperable locally advanced TNBC are exclusive to those patients with PD-L1 expression ≥1% in immune cells, according to a biomarker subgroup analysis of the phase III IMpassion130 study.¹

Exploratory analyses of other biomarkers that included PD-L1 expression on tumor cells, intratumoral CD8+ T cells, stromal tumor-infiltrating lymphocytes, and BRCA1/2 mutation status, confirmed the importance of PD-L1 expression on immune cells in predicting clinical benefit derived from atezolizumab and nab-paclitaxel, said study co-author Leisha A. Emens, MD, PhD. She presented the data at the 2018 San Antonio Breast Cancer Symposium.

“PD-L1 expression on tumor cells did not provide additional information beyond PD-L1 immune cell status,” said Emens, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at the University of Pittsburgh Medical Center. “PD-L1 immune cell expression was the best predictor of clinical benefit as the patient subgroups with tumor-infiltrating immune cells or cytotoxic T cells derived clinical benefit with atezolizumab plus nab-paclitaxel if their tumors were also PD-L1 immune cell-positive. PFS and OS results were consistent regardless of BRCA1/2 mutation status.”

The data support the routine testing for PD-L1 immune cell status to determine whether patients might benefit from atezolizumab plus nab-paclitaxel, she added.

PD-L1 in the IMpassion130 patient population was expressed primarily on tumor-infiltrating immune cells (41%). Twenty-seven percent had low levels at 1% to <5%, and 14% had levels in their immune cells at ≥5%. In contrast, only 9% of study had PD-L1 expression on tumor cells. Most of the patients with PD-L1 expression on tumor cells also had PD-L1 expression on their immune cells, Emens noted, with only 2% having PD-L1 expression exclusively on tumor cells.

Among the subgroup with PD-L1—negative immune cells, as first reported here, the median PFS was 5.6 months in both treatment arms (HR, 0.94; 95% CI, 0.78-1.13; P = .5152).

The interaction between PD-L1 immune cell status and the difference in PFS between treatment arms was significant (P = .0055).

A similar association was detected between PD-L1 status and OS in the subgroup with PD-L1-positive immune cells. The median OS was 25.0 months in the arm assigned to atezolizumab and nab-paclitaxel compared with 15.5 months in those assigned to placebo and nab-paclitaxel (HR, 0.62; 95% CI, 0.45-0.86; P = .0035). There was no treatment effect observed in the PD-L1 immune cell-negative subpopulation, with a median OS of 18.9 months and 18.4 months, respectively (HR, 1.02; 95% CI, 0.79-1.31; P = .9068).

The test for interaction between PD-L1 immune cell status and difference in OS between the treatment arm was significant (P = .0178).

There were trends toward associations between PD-L1 immune cell positivity and worse PFS and OS.

“Taken together, these data definitively show that PD-L1 immune cell positivity is predictive of both PFS and OS benefit with atezolizumab and nab-paclitaxel,” Emens said.

The benefit to the combination on PFS and OS was significant in patients with low and high levels of PD-L1 expression on their immune cells. This suggests that an expression level of 1% may represent a threshold for identifying those benefits who are likely to benefit clinically from this combination,” Emens said.

IMpassion130 evaluated atezolizumab plus chemotherapy versus placebo and nab-paclitaxel in treatment-naïve patients with metastatic TNBC. Patients were randomized 1:1 to receive nab-paclitaxel at 100 mg/m² intravenously on days 1, 8, and 15 of the 28-day cycle with atezolizumab at 840 mg intravenously (n = 451) on days 1 and 15 of a 28-day cycle or with placebo (n = 451). Treatment was given until disease progression or unacceptable toxicity.

The coprimary endpoints were PFS and OS in both the ITT and PD-L1—positive populations. PD-L1 expression was defined as positive if expression was at least 1% on tumor-infiltrating immune cells.

Other biomarker analyses performed in IMPassion130 were outcomes according to intratumoral CD8+ T cells by immunohistochemistry and stromal tumor-infiltrating lymphocytes by H&E, and BRCA1/2 mutation status.

“Pre-existing immune biology has been associated with clinical benefit from other agents that target the PD-1 pathway in other cancer types,” Emens said. “So, in these exploratory analyses, we sought to evaluate whether this immune biology as well as the BRCA1/2 mutation status were associated with clinical benefit from atezolizumab with nab-paclitaxel.”

Among patients with CD8+ T cells in their tumors, benefit on PFS and OS was observed only if their tumors were also PD-L1 immune cell-positive. The HRs in this group were 0.33 (95% CI, 0.13-0.67; P = .03) for PFS and 0.25 (95% CI, 0.06-1.02; P = .05) for OS with combination therapy.

In contrast, the HRs in patients with CD8+ tumors but PD-L1 immune cell negativity were 0.89 (95% CI, 0.66-1.20; P = .45) for PFS and 0.77 (95% CI, 0.50-1.17; P = .21) for OS. Among the 280 patients who were positive for both CD8+ expression and PD-L1 immune cell expression, significant benefit was derived from the combination for both PFS (HR, 0.61; 95% CI, 0.46-0.80; P £.005) and OS (HR, 0.55; 95% CI, 0.38-0.80; P ≤ 005).

Similarly, PD-L1 immune cell-negative patients whose tumors had stromal TILs derived no clinical benefit from the addition atezolizumab—the HR for PFS was 0.99 (95% CI, 0.62-1.57; P = .97) and the HR for OS was 1.53 (95% CI, 0.76-3.08; P = .24). In contrast, patients whose tumors contained stromal TILs and expressed PD-L1 on immune cells had a significant improvement in PFS (HR 0.53; 95% CI, 0.38-0.74; P ≤.005) and OS (HR 0.57; 95% CI, 0.35-0.92; P = .02) with the chemoimmunotherapy.

Of patients evaluable for BRCA mutation status, 15 had BRCA1/2 mutant tumors. These patients had a significant improvement in PFS with chemoimmunotherapy only if their tumors were also PD-L1 immune cell-positive (HR, 0.45; 95% CI, 0.21-0.96; P = .04). Investigators also observed a trend toward improvement in OS (HR 0.87; 95% CI, 0.26-2.85; P = .82).

“I would note that these data are somewhat limited by the small patient numbers,” Emens said. “However, they do show that mutations in BRCA- and PD-L—expressing immune cells are independent biomarkers, and patients with BRCA1 or -2 mutated tumors derived clinical benefit only if their tumors were also PD-L1 immune cell-positive.”

In the primary analysis, as presented previously, atezolizumab plus nab-paclitaxel resulted in a statistically significant PFS benefit in the intent-to-treat (ITT) population compared with placebo plus nab-paclitaxel (HR, 0.80; 95% CI, 0.69-0.92; P = .0025) and a trend toward improved OS (HR, 0.84; 95% CI, 0.69-1.02; P = .0840).²

Among patients with PD-L1—positive tumors, both PFS (HR, 0.62; 95% CI, 0.49-0.78; P <.001) and OS (HR, 0.62; 95% CI, 0.45-0.86) were clinically meaningful with the addition of atezolizumab.

In the PD-L1 immune cell-positive subpopulation, the median PFS was 7.5 months in patients randomized to the atezolizumab-nab-paclitaxel combination compared with 5.0 months in patients assigned to placebo plus nab-paclitaxel (HR, 0.62; P <.0001).

References

1. Emens LA, Loi S, Rugo HS, et al. IMpassion130: Efficacy in immune biomarker subgroups from the global, randomized, double-blind, placebo-controlled, phase III study of atezolizumab + nab-paclitaxel in patients with treatment-naïve, locally advanced or metastatic triple-negative breast cancer. In: Proceedings from the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. Abstract GS1-04.
2. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;3 79:2108-21.

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