Neoadjuvant Pembrolizumab/Chemo, Adjuvant Pembrolizumab Boosts OS in High-Risk Early TNBC

Neoadjuvant pembrolizumab (Keytruda) combined with chemotherapy followed by adjuvant pembrolizumab monotherapy significantly improved overall survival (OS) vs preoperative chemotherapy in patients with high-risk, early-stage, triple-negative breast cancer (TNBC), according to data from a prespecified interim the phase 3 KEYNOTE-522 study (NCT03036488).¹

Additional data from a prespecified interim analysis conducted by an independent data monitoring committee also indicated that no new safety signals were reported with the agent, and the toxicity profile proved to align with prior reports.

These data will be shared at an upcoming conference and discussed with regulatory authorities, according to a news release issued by Merck.

“This is a significant milestone, as it is the first time an immunotherapy-based regimen has demonstrated a statistically significant overall survival benefit compared to chemotherapy alone in patients with high-risk early-stage triple-negative breast cancer,” Gursel Aktan, MD, PhD, vice president of global clinical development at Merck Research Laboratories, stated in a news release. “To have achieved overall survival from this landmark study is highly encouraging and builds upon the positive pathological complete response [pCR] and event-free survival [EFS] results that led to approvals for this regimen around the world.”

The prospective randomized, placebo-controlled, phase 3 trial enrolled patients who were at least 18 years of age with newly diagnosed TNBC of either T1c/N1-2 or T2-4/N0-2 and an ECOG performance status of 0 or 1.² They also needed to provide a tissue sample for PD-L1 evaluation.

Study participants (n = 1174) were randomly assigned 2:1 to receive neoadjuvant treatment with pembrolizumab at 200 mg once every 3 weeks (n = 784) or placebo (n = 390) plus chemotherapy followed by surgery and subsequent adjuvant treatment with single-agent pembrolizumab at 200 mg once every 3 weeks or placebo.

Chemotherapy was comprised of carboplatin at area under the curve (AUC) 5 every 3 weeks or AUC 1.5 once weekly plus paclitaxel at 80 mg/m2 once weekly for cycles 1 to 4 and doxorubicin at 60 mg/m2 once every 3 weeks/epirubicin at 90 mg/m2 once every 3 weeks plus cyclophosphamide at 600 mg/m2 once every 3 weeks for cycles 5 to 8. The adjuvant phase began from the first adjuvant treatment and included radiation therapy; treatment was administered for cycles 5 to 8.

Stratification factors included nodal status (positive vs negative), tumor size (T1/T2 vs T3/T4), and carboplatin schedule (once weekly vs once every 3 weeks).

pCR (defined as ypT0/Tis, ypN0) and EFS served as the study’s co-primary end points. Key secondary end points included pCR (defined as ypT0, ypN0, and ypT0/Tis); pCR, EFS, and OS in the subset of patients with PD-L1 positivity; and safety.

Data from the primary analysis of the study showed that neoadjuvant pembrolizumab/chemotherapy followed by adjuvant pembrolizumab significantly improved pCR (ypT0/Tis, ypN0) vs neoadjuvant chemotherapy followed by adjuvant placebo in the overall population, at 64.8% (95% CI, 59.9%-69.5%) and 51.2% (95% CI, 44.1%-58.3%), respectively (difference, 13.6 percentage points; 95% CI, 5.4%-21.8%; P = .000555).2,3 At a median follow-up of 39.1 months (range, 30.0-48.0), the pembrolizumab regimen was also found to significantly improve EFS vs the placebo regimen (HR, 0.63; 95% CI, 0.48-0.82; P = .00031).^2,4 Data from KEYNOTE-522 led to the July 2021 FDA approval of neoadjuvant pembrolizumab plus chemotherapyfollowed by adjuvant pembrolizumab in patients with high-risk, early-stage TNBC.⁵

Across the pembrolizumab and placebo arms, the median age was 48.5 years (range, 22-80). Moreover, 13.5% of those in the pembrolizumab arm and 12.6% of those in the placebo arm had an ECOG performance status of 1; 83.7% and 81.3% had PD-L1 positivity. Slightly more than half of patients received carboplatin once weekly (57.3% vs 57.2%) and had positive nodal involvement (51.7% vs 51.3%). The majority had a tumor size of T1/T2 (74.0% vs 74.4%).

Additional data showed that at a median follow-up of 63.1 months, the 60-month EFS rate in the pembrolizumab arm was 81.3% vs 72.3% in the placebo arm (HR, 0.63; 95% CI, 0.49-0.81).2 EFS favored pembrolizumab over placebo in all key subgroups analyzed on the trial.

At the time of the fourth interim analysis, which had a data cutoff date of March 23, 2021, the HR for EFS in those who achieved a pCR was 0.73 (95% CI, 0.39-1.36); in those who did not achieve a pCR, the HR for EFS was 0.70 (95% CI, 0.52-0.95). At the time of the sixth interim analysis, which had a data cutoff date of March 23, 2023, the HR for EFS in those who achieved a pCR was 0.65 (95% CI, 0.39-1.08); in those who did not achieve a pCR, the HR for EFS was 0.72 (95% CI, 0.54-0.96).

The distant progression-free or distant recurrence-free survival rate at 36 months with pembrolizumab was 87.0% vs 80.7% with placebo (HR, 0.61; 95% CI, 0.46-0.82). At 60 months, these respective rates were 84.4% and 76.8% (HR, 0.64; 95% CI, 0.49-0.84).

Previously reported safety data⁴ showed that any-grade adverse effects (AEs) were experienced by 99.2% of those in the pembrolizumab arm, with 82.4% of patients experiencing grade 3 or higher AEs. Treatment-related AEs (TRAEs) occurred in 98.9% of patients who received pembrolizumab plus chemotherapy; 77.1% of patients experienced grade 3 or higher TRAEs. The most common TRAEs included nausea (any grade, 63.2%; grade ≥3, 3.4%), alopecia (60.2%; 0%), anemia (54.8%; 18.0%), neutropenia (46.9%; 34.5%), fatigue (42.1%; 3.6%), diarrhea (30.4%; 2.6%), increased alanine aminotransferase (26.1%; 5.5%), vomiting (25.5%; 2.4%), asthenia (25.3%; 3.6%), rash (25.0%; 1.5%), constipation (24.0%; 0%), decreased neutrophil count (23.6%; 18.6%), increased aspartate aminotransferase (20.1%; 2.6%), and peripheral neuropathy (19.7%; 2.6%).

Immune-mediated AEs that were any grade occurred in 33.5% of those who received the pembrolizumab regimen; these effects were grade 3 or higher for 12.9% of patients. Immune-mediated AEs included hypothyroidism (any grade, 15.1%; grade ≥3, 0.5%), severe skin reaction (5.7%; 4.7%), hyperthyroidism (5.2%; 0.3%), adrenal insufficiency (2.6%; 1.0%), pneumonitis (2.2%; 0.9%), thyroiditis (2.0%; 0.3%), and hypophysitis (1.9%; 1.3%).

References

1. Merck announces phase 3 KEYNOTE-522 trial met its overall survival (OS) endpoint in patients with high-risk early-stage triple negative breast cancer (TNBC). News release. May 28, 2024. Accessed May 28, 2024. https://www.merck.com/news/merck-announces-phase-3-keynote-522-trial-met-its-overall-survival-os-endpoint-in-patients-with-high-risk-early-stage-triple-negative-breast-cancer-tnbc/
2. Schmid P, Cortés J, Dent RA, et al. LBA18 Pembrolizumab or placebo plus chemotherapy followed by pembrolizumab or placebo for early-stage TNBC: Updated EFS results from the phase III KEYNOTE-522 study. Ann Oncol. 2023;34(suppl 2):S1257. doi:10.1016/j.annonc.2023.10.008
3. 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
4. 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
5. FDA approves KEYTRUDA (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, then continued as single agent as adjuvant treatment after surgery. News release. Merck. July 27, 2021. Accessed May 28, 2024. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-treatment-of-patients-with-high-risk-early-stage-triple-negative-breast-cancer-in-combination-with-chemotherapy-as-neoadjuvant-treatment-then-continued/