Pembrolizumab Combo Yields Significant pCR in High-Risk ER+ Breast Cancer

“[The] addition of pembrolizumab to neoadjuvant chemotherapy led to a statistically significant increase in pCR in the intention-to-treat [ITT] population,” according to Joyce O’Shaughnessy, MD.

Improvements in pathologic complete response (pCR) occurred in patients with early-stage, high-risk, estrogen receptor (ER)–positive, HER2-negative breast cancer who received pembrolizumab (Keytruda) plus neoadjuvant chemotherapy followed by adjuvant pembrolizumab and endocrine therapy across key subgroups, according to findings from the phase 3 KEYNOTE-756 trial (NCT03725059) presented during the 2023 San Antonio Breast Cancer Symposium (SABCS).¹

As previously reported at the 2023 ESMO Congress, at a median follow-up of 33.2 months (range, 9.7-51.8), 24.3% of patients who were given pembrolizumab (n = 635) achieved a pCR (defined as ypT0/Tis and ypN0) compared with 15.6% of those given placebo (n = 643), meeting a primary end point of the trial (∆, 8.5; 4.2–12.8; P = .00005).^1,2 A pCR defined as ypT0 and ypN0 was reported in 21.3% and 12.8% of patients in the pembrolizumab and placebo arms, respectively (∆, 8.3; 4.2–12.4), and a pCR defined as ypT0/Tis was observed in 29.4% and 18.2% of patients, respectively (∆, 11.0; 6.5–15.7).

New data from subgroup analyses presented at the 2023 San Antonio Breast Cancer Symposium showed that when broken down by disease stage, those with stage II disease who received pembrolizumab (n = 399) experienced a pCR of 25.8% vs 16.7% for those given placebo (n = 408; ∆, 9.1; 3.5–14.8).1 Within the group of patients with stage III disease, pembrolizumab (n = 236) elicited a pCR of 21.6% vs 13.6% with placebo (n = 235; ∆, 8.0; 1.1–14.9). Those with clinical lymph node involvement at baseline experienced a higher pCR with pembrolizumab (n = 570) than what was achieved with placebo (n = 582), with rates of 25.1% and 15.8%, respectively (∆, 9.3; 4.6–13.9). In the group of patients with negative lymph node status, those who received pembrolizumab (n = 65) achieved a pCR of 16.9% vs 13.1% in those given placebo (n = 61; ∆, 3.8; –9.2–16.7).

The benefits of pembrolizumab over placebo were also observed irrespective of geographic region. In the group of patients from China, those given pembrolizumab (n = 88) or placebo (n = 91) experienced pCRs of 12.5% and 9.9%, respectively (∆, 2.6; –7.0–12.5). In the subset of patients from Eastern Europe, the pCRs achieved with pembrolizumab (n = 139) and placebo (n = 130) were 29.5% and 16.2%, respectively (∆, 13.3; 3.3–23.2). In patients from all other countries, those given the immunotherapy (n = 408) experienced a pCR of 25.0% vs 16.6% in those who received placebo (n = 422; ∆, 8.4; 2.9–13.9).

The benefit derived with pembrolizumab increased with increasing PD-L1 expression. In the group of patients with a PD-L1 combined positive score (CPS) of less than 1, pembrolizumab (n = 153) elicited a pCR of 7.2% vs 2.6% with placebo (n = 154; ∆, 4.5; –0.4–10.1). In the group of patients with a PD-L1 CPS ranging from 1 to 9, pCRs achieved with pembrolizumab (n = 229) and placebo (n = 230) were 15.7% and 9.1%, respectively (∆, 6.4; 0.4–12.7). In those with a PD-L1 CPS of 1 or higher, pCR rates were 29.7% and 19.6% with pembrolizumab (n = 482) and placebo (n = 489), respectively (∆, 9.8; 4.4–15.2). In those with a PD-L1 CPS of 10 or higher, the pCR achieved with pembrolizumab (n = 253) was 42.3% vs 29.0% with placebo (n = 259; ∆, 13.2; 4.9–21.4). Lastly, in the group of patients with the highest PD-L1 expression, a CPS of 20 or higher, the pCR rates achieved with pembrolizumab (n = 125) and placebo (n = 129) were 53.6% and 36.4%, respectively (∆, 17.4; 5.1–29.1).

When evaluating by ER status and PD-L1 expression, pembrolizumab continued to elicit higher pCRs than placebo. In the subgroup of patients with a PD-L1 CPS of 1 or higher and ER positivity of less than 10%, the pCR rate with pembrolizumab (n = 33) was 57.6% vs 33.3% with placebo (n = 39; ∆, 24.2; 1.0–45.1). In those with a PD-L1 CPS of at least 1 who had ER positivity of 10% or higher and who were given pembrolizumab (n = 449) or placebo (n = 450), the pCRs were 27.6% and 18.4%, respectively (∆, 9.2; 3.7–14.6). In the group of patients with a PD-L1 CPS of less than 1 who had ER positivity of 10% or higher and who received pembrolizumab (n = 152), the pCR was 7.2%; in those who received placebo (n = 150), the pCR was 2.7% (∆, 4.6; –0.4–10.2).

“[The] addition of pembrolizumab to neoadjuvant chemotherapy led to a statistically significant increase in pCR in the intention-to-treat [ITT] population,” Joyce O’Shaughnessy, MD, Celebrating Women Chair in Breast Cancer Research at Baylor University Medical Center and director of the Breast Cancer Research Program at Texas Oncology, US Oncology, in Dallas, Texas, said in a presentation of the data. “A larger magnitude of pCR benefit was observed in patients with node-positive disease, higher PD-L1 CPS thresholds, and ER-low tumors [defined as less than 10%].”

Patients with locally confirmed invasive ductal breast carcinoma who had T1c to T2 disease and 1 to 2 positive lymph nodes or T3 to T4 disease with 0 to 2 positive lymph nodes were enrolled in the KEYNOTE-756 trial. Patients needed to have centrally confirmed ER-positive, HER2-negative, grade 3 disease and they could not have received prior treatment.

A total of 1278 participants were randomly assigned 1:1 to receive pembrolizumab at 200 mg or placebo every 3 weeks for 4 cycles in combination with paclitaxel at 80 mg/m2 weekly for 12 weeks. This was followed by pembrolizumab at 200 mg or placebo plus either doxorubicin at 60 mg/m2 every 3 weeks or epirubicin at 100 mg/m2 every 3 weeks in combination with cyclophosphamide at 600 mg/m2 every 2 or 3 weeks for 4 cycles. After definitive surgery, patients went on to receive adjuvant pembrolizumab at 200 mg every 3 weeks or placebo for 6 months paired with endocrine therapy for up to 10 years and concurrent or sequential radiation therapy if indicated.

Participants were stratified by geographic location. Those in Eastern Europe were substratified by PD-L1 status (CPS ≥1 vs <1) and those in all other countries were substratified by PD-L1 status (CPS ≥1 vs CPS <1), nodal status (positive vs negative), anthracycline schedule (every 2 weeks vs every 3 weeks), and ER positivity (1% to 9% vs ≥10%). Within China, there were no substratification factors.

The dual primary end points of the trial are pCR per local pathologist assessment at the time of definitive surgery in the ITT population and investigator-assessed event-free survival (EFS) in the ITT population. Secondary end points include evaluation of pCR by alternative definitions (ypT0, ypN0, and ypT0/Tis); overall survival (OS); pCR, EFS, and OS in the subgroup of patients with a PD-L1 CPS of 1 or higher; and safety. Residual cancer burden assessment serves as an exploratory end point.

“The total alpha was 2.5%, 1-sided, split between the 2 primary end points,” O’Shaughnessy explained. “The prespecified statistical analysis plan focused first on pCR, allocating an initial alpha of 0.5% to this primary end point and 2% to EFS. If improvement in pCR was statistically significantly higher with pembrolizumab vs placebo, the alpha of the pCR analysis is transferred to analysis of EFS. If EFS is significantly positive, the EFS alpha is transferred to analysis of OS.”

Interim analysis 1 was conducted approximately 10 months after the last patient was randomized and included all who underwent randomization and “who had or should have completed surgery at that time,” O’Shaughnessy noted. The data cutoff date for the analysis was May 25, 2023. “It was the final and only analysis for pCR and the first EFS interim analysis. At interim analysis 1, the prespecified P value boundary for significance for pCR was .005 and for EFS, [it] was .000459.”

The treatment arms were generally well balanced with regard to key patient characteristics, according to O’Shaughnessy. The median age of patients in both the pembrolizumab and placebo arms was 49 years (range, 19-82). In the immunotherapy arm, 75.9% of patients had a PD-L1 CPS of 1 or higher and 39.8% had a CPS of 10 or higher; these rates were 76.0% and 40.3%, respectively, in the placebo arm. In the pembrolizumab arm, 13.9% of patients were from China, 21.9% were from Eastern Europe, and 64.3% were from other countries; these rates were 14.2%, 20.2%, and 65.6%, respectively, in the placebo arm.

Most patients across the pembrolizumab and placebo arms had stage II disease (62.8% vs 63.5%) and the remainder had stage III disease (37.2% vs 36.5%). Most patients received anthracyclines every 3 weeks (65.4% vs 66.1%) rather than every 2 weeks (28.8% vs 29.1%); 5.8% of those in the pembrolizumab arm and 4.8% of those in the placebo arm did not start treatment. Regarding tumor size in the pembrolizumab arm, 63.3% had T1/T2 disease and 36.7% had T3/T4 disease; in the placebo arm, these rates were 64.2% and 35.8%, respectively. The majority of patients across the arms had positive nodal involvement at baseline (89.8% vs 90.5%) and ER positivity of 10% or higher (94.6% vs 93.3%).

“Residual cancer burden from 0 to 3 represents increasingly larger residual disease in the breast and/or axillary lymph nodes at definitive surgery,” O’Shaughnessy said. “The addition of pembrolizumab to neoadjuvant chemotherapy shifted more patients from lower risk to lower residual cancer burden categories.”

Of those who received pembrolizumab, 35% had a residual cancer burden of 0 or 1 vs 23.6% of those who were given chemotherapy. Moreover, 40.8% of those given pembrolizumab and 45.3% of those who received placebo had a residual cancer burden of 2; 20.5% and 28.9% of patients, respectively had a burden of 3.

“Patients who received less than the planned chemotherapy doses had lower pCR rates, although pCR rates were improved with pembrolizumab, regardless of chemotherapy exposure,” O’Shaughnessy said.

Just under 86% (85.6%; n = 543) of patients in the pembrolizumab arm had full chemotherapy exposure, defined as weekly doses of paclitaxel for 10 to 12 doses, doxorubicin every 2 or 3 weeks for 4 doses or epirubicin every 2 or 3 weeks for 4 doses, and cyclophosphamide every 2 or 3 weeks for 4 doses, regardless of exposure to the immunotherapy; 14.4% (n = 91) had less than full exposure. In the placebo arm, these rates were 87.8% (n = 563) and 12.2% (n = 78), respectively.

In the subset of patients with full chemotherapy exposure, pembrolizumab elicited a pCR of 26.2% vs 16.9% with placebo (∆ 9.3; 4.5–14.1). In those with less than full exposure, these rates were 13.2% and 6.4%, respectively (∆ 6.8; –2.6–16.2).

Immune-mediated AE rates proved to be consistent with the known toxicity profile of neoadjuvant pembrolizumab and chemotherapy. No new safety concerns were observed, according to O’Shaughnessy.

Specifically, any-grade immune-mediated adverse effects (AEs) occurred in 32.8% of those who received the immunotherapy vs 7.0% of those given placebo; these effects were grade 3 to 5 for 7.1% and 1.2% of patients, respectively. Serious immune-mediated AEs occurred in 6.2% of those in the pembrolizumab arm vs 1.7% of those in the placebo arm, but none of these AEs resulted in death. Immune-mediated AEs led to discontinuation of any agent for 7.7% of those in the pembrolizumab arm and 1.6% of those in the placebo arm.

The most common immune-mediated AEs experienced by at least 5 patients in either the pembrolizumab or placebo arm included hypothyroidism (17.5% vs 1.7%), hyperthyroidism (9.0% vs 0.5%), and pneumonitis (2.8% vs 1.4%).

“The study is powered to evaluate EFS as the dual primary end point. The EFS results are immature and continue to be evaluated,” O’Shaughnessy concluded.

Editor’s Note: O’Shaughnessy disclosed receiving honoraria for serving on consulting or advisory boards (2022-2023) from AbbVie Inc., Agendia, Aptitude Health, AstraZeneca, Carrick Therapeutics, Daiichi Sankyo, Eisai, Fishawack Health, G1 Therapeutics, GlaxoSmithKline, Genentech, Gilead Sciences, Immunomedics, Lilly, Loxo Oncology, Merck, Novartis, Ontada, Pfizer, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Roche, Samsung Bioepis, Sanofi, Seagen, and Stemline Therapeutics. Research funding was provided by Merck Sharp & Dohme LLC.

References

1. Cardoso F, O’Shaughnessy J, McArthur H, et al. Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2– breast cancer: KEYNOTE-756. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS01-02.
2. Cardoso F, McArthur HL, Schmid P, et al. LBA21 KEYNOTE-756: phase III study of neoadjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo), followed by adjuvant pembro or pbo + endocrine therapy (ET) for early-stage high-risk ER+/HER2– breast cancer. Ann Oncol. 2023;34(suppl 2):S1260-S1261. doi:10.1016/j.annonc.2023.10.011