Promising Results Suggest a Larger Role for Immunotherapy in TNBC

Leisha A. Emens, MD, PhD

Although most breast tumors are not immunogenic, evidence indicates that triple-negative breast cancer (TNBC) expressing PD-L1 is a strong candidate for immunotherapy, explained Leisha A. Emens, MD, PhD, in a presentation on recent trials of immunotherapy alone and in combination with anti—PD-1 therapy.

“For many years, people considered breast cancer to be immunologically inert. There [are] actually a lot of data collected over the past decade or two showing that breast cancer can be immunogenic,” she told her audience at the 4th Annual International Congress on Immunotherapies in Cancer^® hosted by Physicians’ Education Resource^®, LCC (PER^®).

“TNBC cannot be treated with HER2-targeted agents or endocrine therapy, but it is the breast cancer most likely to be immune activated and contain T cells,” said Emens, a professor of medicine in the Division of Hematology/Oncology and coleader of the Hillman Cancer Immunology and Immunotherapy Program at the University of Pittsburgh Medical Center in Pennsylvania. That makes it a high-value target for cancer immunotherapy, she added.

Several targeted therapies are available to treat HER2-positive disease, but currently only PARP inhibitors are approved for patients with TNBC. However, analyses of the phase III IMpassion130 trial suggest that the anti—PD-L1 monoclonal antibody atezolizumab (Tecentriq) in combination with nab-paclitaxel (Abraxane) confers a consistent survival advantage for patients with PD-L1–positive metastatic TNBC.

IMpassion130 evaluated the atezolizumab/nab-paclitaxel combination versus placebo and nab-paclitaxel in treatment-naïve patients with metastatic TNBC. Patients were randomly assigned to receive nab-paclitaxel 100 mg/ m² on days 1, 8, and 15 of a 28-day cycle with atezolizumab 840 mg (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.

In the primary analysis, atezolizumab plus nab-paclitaxel resulted in a statistically significant progression-free survival (PFS) benefit in the intention-to-treat population compared with placebo plus nab-paclitaxel (HR, 0.80; 95% CI, 0.69-0.92; P = .0025) and demonstrated a trend toward improved overall survival (OS; HR, 0.84; 95% CI, 0.69-1.02; P = .0840).¹

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

Emens said data from IMpassion130 were the first findings from a large clinical trial (N = 902) to demonstrate a clinical benefit associated with immunotherapy for patients with breast cancer. The FDA approved the combination in March 2019 based on the trial results, which showed that atezolizumab/ nab-paclitaxel reduced the risk for progression or death by 40% compared with nab-paclitaxel alone in patients with unresectable locally advanced or metastatic PD-L1—positive TNBC.

Emens and her colleagues conducted a biomarker analysis of the IMpassion130 data to determine whether immune biology and BRCA1/2 mutation status were associated with clinical benefit in patients assigned to the combination. Investigators randomized patients 1:1 to the combination or nab-paclitaxel and assessed for PD-L1 on tumor cells, intratumoral CD8, stromal tumor-infiltrating lymphocytes (TILs), BRCA1/2 mutational status, and estrogen receptor/progesterone receptor/ HER2 status.

In data first presented at the 2018 San Antonio Breast Cancer Symposium, Emens and her team found a 2.5-month PFS benefit in patients with PD-L1 expressed on immune cells assigned to the combination (7.5 vs 5.0 months; HR, 0.62; 95% CI, 0.49- 0.78; P <.0001).¹

Similarly, investigators observed an OS benefit with the combination for this same subgroup (25.0 vs 15.5 months; HR, 0.62; 95% CI, 0.45-0.86; P = .0035). No treatment effect was observed in the PD-L1 immune cell—negative subpopulation (Table).²

PD-L1 in the IMpassion130 patient population was expressed primarily on tumor-infiltrating immune cells (41%). Twenty-seven percent of patients had low levels of 1% to <5%, and 14% had immune cell levels ≥5%. In contrast, only 9% of study participants 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 patients with CD8-positive T cells in their tumors, investigators observed a benefit for PFS (HR, 0.33; 95% CI, 0.13-0.87; P = .03) or OS (HR, 0.25; 95% CI, 0.06- 1.02; P = .05) only in tumors that were also PD-L1 immune cell positive. Patients who were positive for both CD8-positive expression and PD-L1 immune cell expression derived significant benefit 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).

“CD8-positive T cells, in and of themselves, in the absence of PD-L1 immune cell expression, really don’t correlate with clinical benefit,” Emens said. “The money seems to be in PD-L1 expression in the immune cells for selecting patients who can benefit from this chemoimmunotherapy combination.”

Table. Consistent Benefit for Atezolizumab/Nab-Paclitaxel Across All PD-L1 Subgroups in IMpassion130² (Click to Enlarge)

Of those evaluable for BRCA1/2 mutation status, only patients whose tumors were also PD-L1 immune cell positive derived a significant improvement in PFS with the combination (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).

Activity in the Neoadjuvant Setting

Emens called KEYNOTE-522 “very exciting.” It is the first randomized, prospective, placebo-controlled clinical trial of neoadjuvant pembrolizumab (Keytruda) in early TNBC. In findings first presented at the European Society for Medical Oncology Congress 2019, pembrolizumab plus platinum-containing chemotherapy extended the pathological complete response (pCR) rate by 13.6 percentage points (64.8% vs 51.2%) compared with chemotherapy alone.³

Patients were assigned pembrolizumab 200 mg every 3 weeks (n = 784) or placebo (n = 390). All patients received 4 cycles of carboplatin plus paclitaxel followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. Following surgery, adjuvant pembrolizumab was continued for 9 cycles or until disease recurrence or unacceptable toxicity. Event-free survival (EFS) and pCR were dual primary end points for the study.

In the PD-L1—positive group (n = 498), the pCR rate was 68.9% in the experimental arm compared with 54.9% in the placebo arm, respectively. In PD-L1–negative patients (n = 97), the pCR rate was 45.3% with pembrolizumab versus 30.3% with placebo.

“It didn’t matter whether patients had PD-L1—positive disease or not,” Emens added. “Unlike in the metastatic setting, PD-L1 expression, at least in this early result with this particular regimen, didn’t seem to identify patients who were more likely to benefit.”

At 18 months, the EFS rate was 91.3% in the combination arm and 85.3% in the placebo arm. In the early PFS analysis, fewer patients in the pembrolizumab arm experienced EFS events compared with placebo (7.4% vs 11.8%; HR, 0.63; 95% CI, 0.43-0.93). Emens said the results “suggest a trend” toward an EFS benefit with pembrolizumab, but the data require more follow-up.

References

1. Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple- negative breast cancer. N Engl J Med. 2018;379(22):2108- 2121. doi: 10.1056/NEJMoa1809615.
2. 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. Cancer Res. 2019;79(suppl 4; abstr GS104). doi: 10.1158/1538- 7445.SABCS18-GS1-04.
3. Schmid P, Cortés J, Dent R, et al. KEYNOTE-522: phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early-stage high-risk triple-negative breast cancer. Presented at: European Society for Medical Oncology Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA8_PR.

PD-L1 immune cell—negative patients whose tumors had stromal TILs derived no clinical benefit from the addition of atezolizumab. 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.