Adjuvant Pembrolizumab Sustains Benefit Across TNBC Subgroups

Neoadjuvant pembrolizumab (Keytruda) plus chemotherapy followed by adjuvant pembrolizumab resulted in a statistically significant and clinically meaningful improvement in event-free survival (EFS) in patients with early-stage triple negative breast cancer (TNBC). The robustness of these data was confirmed in prespecified subgroup analyses of the phase 3 KEYNOTE-522 (NCT03036488) presented at the 2021 San Antonio Breast Cancer Symposium.

Results from the primary EFS analysis showed that the 784 patients treated with pembrolizumab plus chemotherapy followed by pembrolizumab EFS events occurred in 15.7% of patients compared with 23.8% among 390 patients in the placebo plus chemotherapy followed by placebo arm (HR 0.63; 95% CI, 0.48-0.82; P = .00031). Both cohorts had a median follow-up of 39.1 months (range, 30.0-48.0). The 36-month EFS rates were 84.5% vs 76.8%, respectively.

Investigators performed 5 additional EFS sensitivity analyses (SAs) in addition to the primary EFS analysis. Each additional analysis included the same 5 definitions of an event as the primary analysis: local disease progression precluding definitive surgery, local recurrence, distant progressive disease, distant recurrence, and death from any cause. The primary analysis and SA 1 also considered positive margin at last surgery and a second primary cancer as EFS events; the 2 analyses had identical EFS event criteria with alternate censoring rules.

Additional criteria added to each SA were as follows: SA 2 included new anticancer therapy for metastatic disease as an EFS event, SA 3 included positive margin at last surgery, SA 4 included only the 5 EFS events shared by all the analyses, and SA 5 added positive margin at last surgery, second primary cancer (nonbreast), and second primary breast cancer.

In SA 1, 14.3% of patients experienced an event in the experimental arm vs 21.5% in the control arm (HR 0.64; 95% CI, 0.48-0.84). The 36-month EFS rates were 85.3% vs 77.9%, respectively.

Patients in the experimental arm of SA 2 had an EFS event occurrence of 15.7% compared with 23.8% in the control group (HR 0.63; 95% CI, 0.48-0.82). In SA 3 these rates were 15.6% vs 23.1%, respectively (HR 0.65; 95% CI, 0.50-0.85) with 36-month EFS rates of 84.6% vs 77.5%, respectively. EFS events occurred in 14.8% vs 22.6% of patients in the experimental vs control arms, respectively, in SA 4 (HR 0.63; 95% CI, 0.48-0.84). Finally, in SA 5 events occurred in 16.1% of patients in the experimental cohort and 24.4% of patients in the control arm (HR 0.63; 95% CI, 0.48-0.82).

“The treatment benefit with pembrolizumab in each SA was consistent with the primary analysis,” said Peter Schmid, MD, PhD, a professor of medicine at Cancer Research UK Barts Centre in London, England. “This shows the robustness of the primary EFS results. These results support pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a new standard-of-care treatment regimen for patients with high-risk, early-stage TNBC.”

Pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab also improved EFS results regardless of nodal status. In patients with node-negative disease, events reported for 11.4% of patients experimental group compared with 18.6% in the control arm (HR 0.58; 95% CI, 0.37-0.91). The 36-month EFS rate was 88.6% in the experimental arm (n = 376) vs 82.2% in the control arm (n = 194). Patients with node-positive disease had events at a rate of 19.6% vs 29.1% in the experimental and control arms, respectively (HR 0.65; 95% CI, 0.46-0.91). The 36-month EFS rates were 80.7% in the experimental arm (n = 408) vs 71.5% in the control arm (n = 196).

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Patients also saw benefit with pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab regardless of disease stage. Patients with stage II disease had EFS events reported at a rate of 11.7% vs 18.6% in the experimental and control arms, respectively (HR 0.60; 95% CI, 0.42-0.86). The 36-monnth EFS rates were 88.6% in the experimental arm (n = 590) vs 81.7% in the control arm (n = 291). EFS events were reported in 27.8% vs 39.8%, respectively, for those with stage III disease; the 36-month EFS rates were 71.8% (n = 194) vs 62.0% (n = 98), respectively.

The benefit extended to patients regardless of menopausal status with HRs of 0.62 (95% CI, 0.42-0.91) and 0.64 (95% CI, 0.44-0.93) favoring adjuvant pembrolizumab for patients who were premenopausal and postmenopausal, respectively. Additionally, those with HER2-positivity of 2+ per immunohistochemistry (HR, 0.73; 95% CI, 0.43-1.24) and those with HER2 status 0 to 1 by immunohistochemistry (HR, 0.60; 95% CI, 0.44-0.82) also saw a benefit with the experimental regimen.

“All subgroups appear to derive a comparable EFS benefit, including those by nodal stages and disease stage,” Schmid added.

KEYNOTE-522 randomized a total of 1174 adult patients in a 2:1 manner into the experimental or placebo groups. To be eligible for the trial, patients must have a new diagnosis of TNBC of either stage T1c N1-2 or T2-4 N0-2, an ECOG performance status no greater than 1, and be able to provide a tissue sample for PD-L1 assessment. Stratification factors included nodal status (positive vs negative), tumor size (T1/T2 vs T3/T4), and carboplatin schedule (weekly vs once every 3 weeks).

Baseline characteristics were well-balanced between the 2 arms. Patients in the experimental arm were node-positive at a rate of 51.7% vs 51.3% in the control group, and most patients in both groups were disease stage II (75.3% vs 74.6%). In terms of menopausal status, 55.9% of patients in the experimental cohort were premenopausal compared with 56.7% in the control group.

Both arms of the trial were treated in 2 neoadjuvant treatment phases, with each phase consisting of 4 cycles over 12 weeks. Patients in the experimental arm received chemotherapy plus pembrolizumab 200 mg once every 3 weeks; those in the control arm received placebo in place of pembrolizumab. Both cohorts went to surgery at 12 weeks. The experimental group continued with pembrolizumab 200 mg in the 27-week adjuvant phase and the other arm continued with placebo.

The primary end points of the trial were pathologic control rate (pCR) assessed by the local pathologist and investigator assessed EFS. Secondary end points included pCR by alternative definitions, overall survival, and safety. The exploratory analyses included EFS sensitivity analyses and EFS in patient subgroups.

Regarding safety, treatment-related adverse events (TRAEs) occurred in 98.9% and 99.7% of patients in the experimental and control groups, respectively. Grade 3 to 5 AEs were present in 77.1% of patients in the experimental group vs 73.3% in the control arm. Serious AEs occurred in 34.1% of patients in the experimental arm, 0.5% of AEs led to death and 27.7% led to discontinuation in this group. AEs leading to death occurred in 0.3% of patients in the control group and led to discontinuation 14.1% of the time.

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Common grade 1 to 2 TRAEs occurring in the adjuvant phase of treatment in the experimental arm included arthralgia (8.5%), rash (6.0%), and pruritus (5.1%). TRAEs in the control group of grade 1 to 2 in the control group consisted of arthralgia (6.9%), asthenia (5.1%), and fatigue (4.8%), among others. Immune-mediated AEs of any grade occurred in the adjuvant phase at a rate of 10.2% and 6.0%, in the experimental and control arms, respectively.

“The rate of adverse events (AEs) with pembrolizumab was low, especially in the adjuvant setting,” Schmid said.

Table of Contents


  1. Schmid P, Cortes J, Dent R, et al. KEYNOTE-522 study of neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy, followed by adjuvant pembrolizumab vs placebo for early-stage TNBC: event-free survival sensitivity and subgroup analyses. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; Virtual. Abstract GS1-01.

— Update: 11-02-2023 — found an additional article ASCO Guideline Rapid Update Addresses the Use of Neoadjuvant Pembrolizumab in High-Risk Early-Stage Triple-Negative Breast Cancer from the website for the keyword adjuvant pembrolizumab breast cancer.

By Mindy Tanzola, PhD
May 25, 2022
Adjuvant pembrolizumab breast cancer

A rapid update to the ASCO Guideline on neoadjuvant therapy for breast cancer adds a recommendation on the use of pembrolizumab in patients with high-risk early-stage triple-negative breast cancer.1 The update follows a recent analysis from the randomized phase III KEYNOTE-522 trial that showed a significant event-free survival benefit with the addition of pembrolizumab to standard neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery in patients with high-risk triple-negative breast cancer.

The results from this study led to the U.S. Food and Drug Administration (FDA) approval of pembrolizumab in this setting.3 “This is the first FDA approval of an immunotherapy agent in early-stage breast cancer,” noted Larissa A. Korde, MD, MPH, FASCO, of the National Cancer Institute, and Guideline Co-Chair. 

Updated Recommendation

In the 2022 ASCO Guideline update, pembrolizumab at 200 mg every 3 weeks or 400 mg every 6 weeks is recommended in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery, for patients with T1cN1–2 to T2–4N0 (stage II/III) early-stage triple-negative breast cancer.1 Adjuvant pembrolizumab may be given concurrently with, or after completion of, radiation therapy. Under the previous version of the guideline, developed before these data were available, there was insufficient evidence to support adding immune checkpoint inhibitors to standard neoadjuvant chemotherapy for patients with triple-negative breast cancer.4 Thus, this rapid update provides an important revision to that recommendation. 

Evidence for Guideline Update

KEYNOTE-522 was a randomized, multicenter, double-blind, placebo-controlled trial designed to compare neoadjuvant carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide plus either pembrolizumab (784 patients) or placebo (390 patients), followed by pembrolizumab or placebo administered every 3 weeks for up to nine cycles after surgery, in patients with previously untreated stage II/III triple-negative breast cancer.

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After a median follow-up of 39.1 months, pembrolizumab plus neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery was associated with a significant improvement in event-free survival over placebo plus chemotherapy, with 3-year event-free survival rates of 84.5% and 76.8%, respectively (hazard ratio = 0.63, 95% confidence interval = 0.48–0.82; P < .001). The overall survival data are not yet mature; 3-year overall survival rates are 89.7% and 86.9%, respectively. 

The most frequent grade ≥ 3 treatment-related adverse events were hematologic (Table 1). Endocrine disorders, including hypo- or hyperthyroidism, adrenal insufficiency, thyroiditis, and hypophysitis, occurred more frequently in the pembrolizumab/chemotherapy arm than in the placebo/chemotherapy arm, at 26.8% and 9.1%, respectively. 

“Careful attention should be paid to screening and following patients for these side effects that can be lifelong among patients being treated with pembrolizumab,” said Dawn L. Hershman, MD, MS, FASCO, of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, and Guideline Co-Chair. The guideline specifies the need for careful screening for, and management of, common toxicities, given that immune-related adverse events from pembrolizumab can be severe and permanent. 

Ongoing Questions

Looking ahead, an area of interest is whether the event-free survival benefit with neoadjuvant and adjuvant pembrolizumab translates into an improvement in overall survival with continued follow-up. Dr. Korde noted that if the final KEYNOTE-522 overall survival analysis does show a significant survival benefit with pembrolizumab that “this would be an important step forward for patients with triple-negative breast cancer.” The guideline authors also note that uncertainty remains concerning the optimal adjuvant treatment for these patients. Clinical trials have demonstrated an independent benefit with adjuvant capecitabine in patients with triple-negative breast cancer and with adjuvant olaparib in patients with BRCA germline mutations, each without pembrolizumab.5,6 There are no data to support the use of pembrolizumab in combination with either capecitabine or olaparib. 


1. Korde LA, Somerfield MR, Hershman DL, et al: Use of immune checkpoint inhibitor pembrolizumab in the treatment of high-risk, early-stage triple negative breast cancer: ASCO guideline rapid recommendation update. J Clin Oncol. April 13, 2022 (early release online).

2. Schmid P, Cortes J, Dent R, et al: Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 386:556-567, 2022.

3. U.S. Food and Drug Administration: FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. Available at Accessed March 22, 2022. 

4. Korde LA, Somerfield MR, Carey LA, et al: Neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer: ASCO guideline. J Clin Oncol 39:1485-1505, 2021.

5. Masuda N, Lee SJ, Ohtani S, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017

6. Tutt ANJ, Garber JE, Kaufman B, et al: Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384:2394-2405, 2021.

Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, April 20, 2022. All rights reserved.


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