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Adding a PD-L1 inhibitor to neoadjuvant chemotherapy increased the rate of pathologic complete response (pCR) in triple-negative breast cancer (TNBC), particularly when the immunotherapy was started first, a placebo-controlled trial showed.

Patients who received durvalumab (Imfinzi) in addition to chemotherapy had a pCR rate of 53.4% versus 44.2% with placebo and chemotherapy. The difference did not attain statistical significance, except in a subgroup of patients who started the PD-L1 inhibitor 2 weeks before chemotherapy. In that subgroup, the odds of achieving pCR more than doubled with durvalumab.

"Based on these results, priming with durvalumab seems warranted for investigation in future trials," Sibylle Loibl, MD, of the German Breast Group in Neu-Isenburg, and co-authors concluded in . "It supports further investigation of durvalumab as treatment of early TNBC patients with higher tumor load, as pCR in small tumors is often achieved with chemotherapy alone."

The results added to evidence from a previous study that showed significant improvement in pCR with the addition of pembrolizumab (Keytruda) to chemotherapy for patients with newly diagnosed TNBC. Data from the neoadjuvant trials and other completed and ongoing studies reflect improved understanding of how PD-1/L1 inhibitors work and how that information can be applied to breast cancer, said Leisha Emens, MD, PhD, of the University of Pittsburgh Hillman Cancer Center.

"We now have an approved indication in breast cancer, and I think that represents real progress," she told 名媛直播. "We have a biomarker we can use to select patients, so we can enrich for patients who are more likely to respond and avoid giving the drug to patients who have no chance of responding. A study of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) showed essentially no activity in patients with PD-L1 negative tumors. Early data for HER2-positive patients also [are] interesting.

"I think we've learned that using these drugs earlier in the course of metastatic disease is likely to be more effective. I think we have a lot to learn about how to convert 'cold' tumors to 'hot' tumors, but a number of studies are exploring combinations to identify a rational way to do that. We have to think about how the immune system is primed and what we need to do to induce T-cells and cause a tumor to respond. All in all, though, I think we've made a lot of progress."

Gaining Momentum

As compared with the success in multiple other tumors, the immune checkpoint inhibitor drug class had a in breast cancer, as objective responses were durable but infrequent. However, as experience with the drugs increased and understanding of the mechanisms and limitations improved, clinical success followed. The landmark IMpassion130 trial showed that the addition of atezolizumab to nab-paclitaxel significantly improved progression-free survival (PFS) and overall survival in metastatic TNBC.

Earlier this year, the FDA made atezolizumab the first PD-1/L1 inhibitor to have an approved indication in breast cancer (PD-L1-positive locally advanced or metastatic TNBC).

Prior to the durvalumab neoadjuvant study, investigators in the reported that the addition of pembrolizumab to chemotherapy led to a pCR rate of 60% in patients with TNBC versus 20% for patients who received only neoadjuvant chemotherapy. Patients with hormone receptor-positive/HER2-negative breast cancer had pCR rates of 34% with pembrolizumab and 13% without.

The pre-existing immunogenicity of TNBC, reflected by the presence of stromal tumor-infiltrating lymphocytes (sTILs), provided a biologic rationale for evaluating immunotherapy. Additionally, previous studies showed that immune checkpoint inhibitors improved survival in several types of cancer, and the IMpassion130 results extended the survival benefit to PD-L1-positive metastatic TNBC, Loibl and co-authors noted in the introduction to their findings.

Neoadjuvant Trial

For the phase II durvalumab study, known as , investigators at centers throughout Germany enrolled patients with newly diagnosed nonmetastatic TNBC. All patients received the same neoadjuvant chemotherapy regimen: nab-paclitaxel followed by dose-dense epirubicin/cyclophosphamide. They were randomized to durvalumab or placebo. Initially, patients started the PD-L1 inhibitor or placebo 2 weeks before chemotherapy (the window phase). Tissue from tumor biopsies were analyzed for receptor status, PD-L1 expression, sTILs, and the Ki-67 proliferation marker.

The data and safety monitoring committee decided that the average time to the actual start of chemotherapy (47.7 days) was too long, and the protocol was amended to eliminate the window phase. Of the 174 patients recruited for the trial, 117 enrolled prior to the amendment.

The primary efficacy endpoint was pCR, defined as no invasive or noninvasive tumor residuals in the breast or axillary lymph nodes (ypT0 ypN0). Patients with nodal involvement and who did not undergo axillary lymph node dissection were considered non-pCR, regardless of tumor response in the breast or lymph nodes.

The 174 patients had a median age of 49.5, 65% had stage ≥IIA disease, 14% had high sTILs, and 87% were PD-L1 positive.

The 9-point absolute difference in pCR rate in favor of durvalumab corresponded to an odds ratio (OR) of 1.45, which did not reach statistical significance (P=0.224). In the subgroup of patients enrolled while the window phase was in effect, treatment with durvalumab was associated with statistically significant improvement in pCR (61.0% vs 41.4%). The absolute difference corresponded to an odds ratio of 2.22 (95% CI 1.06-4.64, P=0.035).

In both treatment groups, high sTIL concentration was associated with significantly higher pCR rate (P<0.01). Investigators reported a trend toward improved pCR in PD-L1-positive tumors, including tumor-cell PD-L1 in the durvalumab arm (P=0.045) and immune cell PD-L1 in the placebo arm (P=0.040)

The most common immune-related adverse event in the durvalumab arm was thyroid dysfunction (all grades, 47%).

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