EFS Benefit With Neoadjuvant Pembrolizumab/Chemo Combo, Adjuvant Pembrolizumab Upheld in High-Risk Early TNBC

Neoadjuvant pembrolizumab (Keytruda) combined with chemotherapy followed by adjuvant pembrolizumab compared with placebo plus chemotherapy continued to show a clinically meaningful improvement in event-free survival (EFS) in patients with high-risk, early-stage triple-negative breast cancer (TNBC), according to 5-year data from the phase 3 KEYNOTE-522 trial (NCT03036488) presented during the 2023 San Antonio Breast Cancer Symposium.¹

At a median follow-up of 63.1 months, the 5-year EFS rate was 81.3% with neoadjuvant pembrolizumab/chemotherapy followed by adjuvant pembrolizumab compared with 72.3% in those who received placebo/chemotherapy plus placebo (HR, 0.63; 95% CI, 0.49-0.81).

“These results overall provide further support for pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a standard-of-care for patients with high-risk, early-stage triple-negative breast cancer,” lead study author Peter Schmid, FRCP, MD, PhD, professor, cancer medicine, centre lead, Centre of experimental Cancer Medicine, director, Barts Breast Cancer Centre, said in an oral presentation during the meeting.

To be eligible for enrollment in the prospective, randomized, placebo-controlled, phase 3 KEYNOTE-522 trial, patients had to be at least 18 years of age with newly diagnosed TNBC that was either T1c N1-N2 or T2-T4 N0-N2. An ECOG performance status of 0 or 1 was also required, as well as a tissue sample for PD-L1 assessment.

Patients were randomized 2:1 to receive neoadjuvant pembrolizumab at 200 mg every 3 weeks plus carboplatin and paclitaxel for cycles 1 to 4 for 12 weeks followed by doxorubicin/epirubicin plus cyclophosphamide for cycles 5 to 8 for 12 weeks, or the chemotherapy regimens plus placebo. Following surgery, patients then either received pembrolizumab at 200 mg every 3 weeks for cycles 1 to 9 for 27 weeks or placebo.

The neoadjuvant phase was defined as starting from the first neoadjuvant treatment and ending following definitive surgery and included posttreatment; the adjuvant phase of the study was defined as starting from the first adjuvant treatment and includes radiation treatment as indicated and also posttreatment.

The primary end points were pathologic complete response (pCR; ypT0/Tis ypN0) and EFS; secondary end points were pCR (ypT0 ypN0 and ypT0/Tis) and safety. Investigators are also examining pCR, EFS, and OS in the PD-L1–positive population.

At the first interim analysis, neoadjuvant pembrolizumab and chemotherapy had demonstrated a statistically significant and clinically meaningful increase in pCR (ypT0/Tis ypN0) of 13.6% compared with placebo/chemotherapy (P <.001).² At the second interim analysis, which had a median follow-up of 39.1 months, the neoadjuvant pembrolizumab regimen followed by adjuvant pembrolizumab led to a clinically meaningful and statistically significant improvement in EFS vs placebo (HR, 0.63; P <.001).³ The 3-year EFS rates were 84.5%and 76.8%, respectively (HR, 0.63; 95% CI, 0.48-0.82; P = .00031).

These interimKEYNOTE-522 findings served as the basis for the July 2021 FDA approval of this combination regimen in this patient population.⁴

At the meeting, Schmid shared additional data that looked at subgroups within the KEYNOTE-522 trial with longer follow-up. In patients with stage II disease, the 5-year EFS rates were 85.6% and 77.5% in the pembrolizumab and placebo arms, respectively (HR, 0.59; 95% CI, 0.43-0.82). In those with stage III disease, these rates were 68.2% and 57.1% (HR, 0.71; 95% CI, 0.48-1.05).

When evaluated by baseline clinical nodal status, patients with negative nodes who received the pembrolizumab regimen experienced a 5-year EFS rate of 86.3% vs 77.8% in those who received the placebo regimen (HR, 0.56; 95% CI, 0.38-0.84). In patients with positive nodes, these rates were 76.8% and 67.0%, respectively (HR, 0.67; 95% CI, 0.49-0.93).

In patients with baseline T2N0 disease, the 5-year EFS rates were 87.8% vs 77.9% in patients who received pembrolizumab/chemotherapy followed by pembrolizumab vs placebo/chemotherapy followed by placebo, respectively (HR, 0.49; 95% CI, 0.31-0.78).

Investigators also evaluated EFS by baseline disease stage in patients with and without a pCR. In patients with stage II disease and a pCR, the 5-year EFS rates were 94.2% and 89.8% in the pembrolizumab and placebo arms, respectively (HR, 0.56; 95% CI, 0.30-1.06); these rates were 69.2% and 59.1%, respectively, in patients without a pCR (HR, 0.67; 95% CI, 0.46-0.97). For those with stage III disease who had a pCR, the 5-year EFS rates were 85.1% and 81.4% with pembrolizumab and placebo, respectively (HR, 0.80; 95% CI, 0.34-1.87). In those without a pCR, these rates were 46.8% and 38.2%, respectively (HR, 0.86; 95% CI, 0.55-1.34).

In patients with negative nodes and a pCR, the 5-year EFS rates were 95.3% with the pembrolizumab regimen compared with 91.0% with the placebo treatment (HR, 0.53; 95% CI, 0.22-1.24). In those with no pCR and negative nodes, these EFS rates were 70.4% and 56.9%, respectively (HR, 0.57; 95% CI, 0.36-0.91).

In those who had positive nodes and a pCR, the 5-year EFS rates were 89.3% vs 84.8% with pembrolizumab/chemotherapy followed by pembrolizumab compared with placebo/chemotherapy followed by placebo (HR, 0.68; 95% CI, 0.36-1.28); these rates were 55.7% and 48.8%, respectively, in patients without a pCR and positive nodes (HR, 0.86; 95% CI, 0.59-1.24).

The EFS benefit with pembrolizumab was upheld with the longer follow-up across other study subgroup and sensitivity analyses, including PD-L1 combined positive score, menopausal status, HER2 status, lactate dehydrogenase levels, inclusion for new anticancer treatment for metastatic disease, excluding positive margin at last surgery, excluding positive margin at last surgery and second primary malignancy, and including second primary breast cancer.

Finally, investigators explored distant recurrence rates as a first EFS event by pCR (ypT0/Tis ypN0). In patients who had a pCR, the distant recurrence rates were 4.4% and 6.5% in the pembrolizumab (n = 22) and placebo (n = 14) arms, respectively; in those without a pCR who received pembrolizumab (n = 50) or placebo (n = 41), these rates were 17.3% and 23.7%, respectively.

“The incidence of brain metastases as a first EFS event was low in both treatment groups, with a numerically lower incidence in the pembrolizumab group with 2.3% compared with the placebo group at 3.3%,” Schmid said in his conclusion.

Because this was event-driven analysis, Schmid added that the OS follow-up is still ongoing as the OS events have not yet occurred and that biomarker findings from KEYNOTE-522 will be presented in 2024.

Schmid cited the following disclosures: honoraria from AstraZeneca, Daiichi Sankyo, Gilead, Merck Sharp & Dohme LLC, Novartis, Pfizer, Roche, Sanofi, and Seagen; consulting or advisory roles for AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Genentech, Lilly, Medac, MSD, Novartis, Pfizer, Roche, Sanofi, and Seagen; research funding to institution from Astellas Pharma, AstraZeneca, Genentech, Gilead, Medivation Inc, MSD, Novartis, OncoGenex, and Roche; funding for KEYNOTE-522 provided by MSD; and medical writing assistance provided by Christabel Wilson, MSc, of ICON plc and was funded by MSD.

References

1. Schmid P, Cortés J, Dent R, et al. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for early-stage triple-negative breast cancer: Updated event-free survival results from the phase 3 KEYNOTE-522 study. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract LBO1-01.
2. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549
3. Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. doi:10.1056/NEJMoa2112651
4. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. FDA. News release. July 27, 2021. Accessed December 8, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer