Pembrolizumab regimen confers ‘durable and robust’ benefit in triple-negative breast cancer
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SAN ANTONIO — Use of pembrolizumab with neoadjuvant chemotherapy and as monotherapy in the adjuvant setting provided a durable EFS benefit for patients with early-stage triple-negative breast cancer, according to study results.
The benefit persisted across key subgroups, as well as among patients who did or did not achieve pathologic complete response, 5-year follow-up from the randomized phase 3 KEYNOTE-522 trial presented at San Antonio Breast Cancer Symposium showed.
“Compared with other breast cancer subtypes, recurrence events in triple-negative breast cancer occur relatively early,” Peter Schmid, MD, PhD, clinical director of St. Bartholomew Breast Cancer Centre in London and lead of the Centre for Experimental Cancer Medicine at Barts Cancer Institute, told Healio.
“We usually see 70% of events after 3 years, and we expect to see 85% to 90% of events after 5 years,” Schmid added. “We have robust 5-year data to definitively show the benefit is maintained.”
Triple-negative disease is the most aggressive breast cancer subtype. It accounts for 15% to 20% of breast cancer cases and disproportionately affects young women.
In KEYNOTE-522 — the first phase 3 trial to evaluate immunotherapy for early breast cancer — researchers assessed the addition of the anti-PD-1 monoclonal antibody pembrolizumab (Keytruda, Merck) to neoadjuvant chemotherapy, followed by adjuvant pembrolizumab.
The trial included 1,174 adults with previously untreated, nonmetastatic, centrally confirmed triple-negative breast cancer. All patients had stage T1c N1-2 or T2-4 N0-2 disease.
Researchers assigned 784 patients to 200 mg pembrolizumab every 3 weeks in combination with neoadjuvant chemotherapy (four cycles of paclitaxel and carboplatin, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide). The other 390 patients received chemotherapy plus placebo.
All patients underwent definitive surgery and received radiation therapy as indicated. Depending on randomization, they received adjuvant pembrolizumab or placebo. Adjuvant treatment continued for up to nine cycles, or until disease recurrence or unacceptable toxicity.
Pathologic complete response — defined as ypT0/Tis ypN0, meaning clearance of the cancer from the breast after chemotherapy — and EFS served as dual primary endpoints. Secondary endpoints included OS, efficacy in the subset of patients with PD-L1-positive disease, and safety.
Treatment groups were well-balanced with regard to age, ECOG performance status, PD-L1-positivity, tumor size and nodal involvement.
Previously reported results showed statistically significant improvements in pathologic complete response and EFS with pembrolizumab.
At SABCS, Schmid presented updated EFS results after median follow-up of 63.1 months.
By this time, 145 patients (18.5%) assigned pembrolizumab and 108 patients (27.7%) assigned placebo experienced an EFS event (HR = 0.63; 95% CI, 0.49-0.81).
Results showed 5-year EFS rates of 81.3% with pembrolizumab and 72.3% with placebo (HR = 0.63; 95% CI, 0.49-0.81). Median EFS had not been reached in either group.
All five sensitivity analyses demonstrated “durable and robust” EFS benefit with pembrolizumab, Schmid and colleagues wrote.
The EFS benefit appeared consistent across subgroups, including those assessed by nodal status (positive, HR = 0.67; 95% CI, 0.49-0.93; negative, HR = 0.56; 95% CI, 0.38-0.84), disease stage (stage II, HR = 0.59; 95% CI, 0.43-0.82; stage III, HR = 0.71; 95% CI, 0.48-1.05), PD-L1 expression (combined positive score [CPS] 1, HR = 0.64; 95% CI, 0.48-0.85; CPS < 1, HR = 0.57; 95% CI, 0.33-0.98; CPS 10, HR = 0.54; 95% CI, 0.35-0.83; CPS < 10, HR = 0.71; 95% CI, 0.52-0.96), menopausal status (premenopausal, HR = 0.63; 95% CI, 0.44-0.89; postmenopausal, HR = 0.64; 95% CI, 0.45-0.91), HER2 status (2+, HR = 0.65; 95% CI, 0.4-1.07; 0-1+, HR = 0.63; 95% CI, 0.47-0.84) and lactate dehydrogenase level (> upper limit of normal, HR = 0.56; 95% CI, 0.34-0.93; upper limit of normal, HR = 0.67; 95% CI, 0.5-0.89).
“The question always tends to come up about whether everyone with stage II or stage III disease really needs the addition of immune therapy,” Schmid said. “With smaller cancers — T2N0 — some clinicians may say “I’m not giving you immune therapy because your outlook is really good.’ However, the HR for that group with the addition of pembrolizumab was 0.49 and the 5-year EFS delta is 10%. ... I think the benefit is difficult to ignore, and I struggle to come up with a reason why we shouldn’t give immune therapy.”
A prespecified, nonrandomized exploratory analysis showed higher 5-year EFS rates with pembrolizumab among patients who achieved pathologic complete response (92.2% vs. 88.2%) and among those who did not achieve pathologic complete response (62.6% vs. 52.3%).
Researchers observed no new safety signals with pembrolizumab. Investigators will continue to follow patients for OS.
“That will be an event-driven analysis and we haven’t seen the events we require, which is hugely encouraging,” Schmid said. “Events are occurring slower than we thought they would, which I think is driven by the benefit of immune therapy even among patients who had residual disease.”
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Schmid P, et al. Abstract LB01-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
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