Understanding Pembrolizumab: A New Immunotherapy for High-Risk Early-Stage Triple-Negative Breast Cancer

Table of Contents

• Key Points
• What Is Triple-Negative Breast Cancer?
• How the Research Was Conducted
• The Path to Pembrolizumab: Earlier Immunotherapy Trials
• Key Findings: What the KEYNOTE-522 Trial Showed
• Side Effects and Safety Considerations
• Biomarkers: Predicting Who Will Benefit
• Ongoing Research: Clinical Trials Currently Underway
• What This Means for Patients
• Study Limitations
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Pembrolizumab plus chemotherapy improved pathologic complete response to 64.8% vs 51.2% in the KEYNOTE-522 trial.
• The 3-year event-free survival was 84.5% with pembrolizumab-chemotherapy versus 76.8% with placebo-chemotherapy.
• Benefit occurred regardless of PD-L1 status in early-stage TNBC, unlike in metastatic disease.
• Grade 3 or higher treatment-related adverse events occurred in 77.1% of pembrolizumab patients versus 73.3% with placebo.
• The FDA approved pembrolizumab for high-risk early-stage TNBC in July 2021, changing the standard of care.

What Is Triple-Negative Breast Cancer?

Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancers. It is called "triple-negative" because the cancer cells lack three key features that doctors normally test for: estrogen receptors (ER), progesterone receptors (PR), and overexpression of the HER2-neu protein. Because these "targets" are absent, many of the highly effective targeted therapies used for other breast cancer types do not work for TNBC.

TNBC is a biologically aggressive disease that disproportionately affects younger women and women of color compared to other breast cancer subtypes. While relapse rates have decreased over time with modern treatment approaches, TNBC still carries an unfavorable prognosis due to the lack of well-defined molecular targets. Fortunately, these targets are only recently beginning to be understood, and substantial research is underway to identify biomarkers for relapse and to develop better treatment approaches.

Historically, TNBC was treated as a single disease, but comprehensive molecular analysis has revealed that it is actually a complex and biologically heterogeneous group of diseases. Gene expression profiling has identified five distinct intrinsic molecular subtypes of breast cancer, and the vast majority of basal-like tumors are TNBCs (more than 90%). TNBCs are also enriched for mutations in the TP53 gene, a critical tumor suppressor. Researchers have further described six unique molecular signatures of TNBC: basal-like 1 and 2, mesenchymal and mesenchymal-stem-like, immunomodulatory, and luminal androgen receptor groups, each with different responses to chemotherapy and, more recently, immunotherapy.

About 20% of unselected TNBC patients harbor defects in the BRCA1 and BRCA2 genes (either inherited or acquired), which leads to a deficiency in the cell's ability to repair DNA damage through homologous recombination. This defect also means these tumors may be sensitive to PARP inhibitors, a class of drugs specifically designed to exploit DNA repair weaknesses in cancer cells. Other dysregulated signaling pathways commonly seen in TNBC include alterations in the RAS/RAF/MEK, PI3K/AKT/mTOR, and JAK/STAT3 pathways, and early investigations suggest that targeting these pathways with multikinase inhibitors is promising.

For years, the mainstay of systemic therapy for high-risk, early-stage TNBC has been neoadjuvant chemotherapy (chemotherapy given before surgery) based on anthracyclines and taxanes. This approach has remained largely unchanged for several years. Researchers describe a "TNBC paradox": patients with early-stage TNBC tend to achieve higher responses to neoadjuvant chemotherapy, yet they also have a higher propensity for early disease recurrence, often spreading to internal organs (visceral involvement).

For patients who have residual disease (cancer remaining) after standard neoadjuvant therapy, the prognosis remains poor, with an approximately 30–40% risk of recurrence. Novel therapeutic approaches are urgently needed. The recent approval of pembrolizumab plus chemotherapy greatly expands the treatment options available and improves cure rates for patients with high-risk, early-stage TNBC.

How the Research Was Conducted

The cornerstone of this research is the KEYNOTE-522 trial, a phase III, randomized, double-blind, placebo-controlled study—the first trial of its kind to evaluate pembrolizumab in early-stage TNBC in both the neoadjuvant (before surgery) and adjuvant (after surgery) settings. A double-blind design means that neither the patients nor the doctors knew who was receiving the active drug versus the placebo, which helps ensure unbiased results.

Eligible patients were those with newly diagnosed, high-risk, early-stage TNBC, defined as tumors that were either cT1c with lymph node involvement (N1-2) or larger tumors (cT2-4) with or without lymph node involvement, according to the American Joint Committee on Cancer (AJCC) staging system. Patients with active autoimmune disease requiring systemic treatment within the previous 2 years, those with clinically significant comorbid conditions or immunodeficiency, and those requiring immunosuppressive therapy were excluded from the trial.

A total of 1,174 patients were randomized in a 2:1 fashion—meaning two patients received pembrolizumab for every one patient who received placebo. The treatment plan was as follows:

1. Step 1 (Neoadjuvant, cycles 1–4): Patients received pembrolizumab (200 mg intravenously every 3 weeks) or placebo, combined with carboplatin (given weekly or every 3 weeks) plus weekly paclitaxel for 4 cycles.
2. Step 2 (Neoadjuvant, cycles 5–8): Patients then received an anthracycline (either doxorubicin or epirubicin) plus cyclophosphamide every 3 weeks for 4 additional cycles.
3. Step 3 (Surgery): After completing neoadjuvant therapy, patients underwent definitive surgery. Radiation therapy was given if clinically indicated.
4. Step 4 (Adjuvant): After surgery, patients received adjuvant pembrolizumab or placebo to complete a full year of treatment. If radiation therapy was given, adjuvant pembrolizumab was started either concurrently with radiation or at least 2 weeks after radiation concluded.

Notably, adjuvant capecitabine—a chemotherapy pill sometimes used after neoadjuvant treatment—was not permitted in this trial. The primary endpoints of the study were pathologic complete response (pCR), defined as no invasive cancer in the breast or lymph nodes at the time of surgery (ypT0/Tis ypN0), and event-free survival (EFS) in the intention-to-treat population. Key secondary endpoints included safety, overall survival (OS), and pCR in the PD-L1–positive population. PD-L1 expression was measured using the PD-L1 IHC 22C3 pharmDx assay, and tumors with a combined positive score (CPS) of 1 or higher were considered PD-L1 positive.

The Path to Pembrolizumab: Earlier Immunotherapy Trials

Before pembrolizumab reached the early-stage setting, researchers first tested immune checkpoint inhibitors in advanced (metastatic) TNBC. In March 2019, the drug atezolizumab (Tecentriq) plus nab-paclitaxel became the first checkpoint inhibitor granted accelerated FDA approval for PD-L1–positive advanced TNBC, based on the results of the Phase III IMpassion130 trial. However, a follow-up trial called IMpassion131, which tested atezolizumab plus paclitaxel, failed to demonstrate an improvement in progression-free survival. After review, the FDA no longer supported the accelerated approval, and the manufacturer voluntarily withdrew the indication in the United States.

In November 2020, the FDA approved pembrolizumab in combination with taxane or platinum chemotherapy for patients with PD-L1–positive advanced TNBC (defined as a CPS of ≥10 according to the DAKO 22C3 companion diagnostic), based on the phase III KEYNOTE-355 study. These advances in the metastatic setting paved the way for trials in early-stage disease.

Several key studies shaped the field:

• IMpassion031 (Phase III): Atezolizumab plus anthracycline-cyclophosphamide and taxane-based chemotherapy improved the pCR rate to 58% (95% confidence interval [CI], 50 to 65) compared with 41% (95% CI, 34 to 49) with placebo, an absolute difference of 17 percentage points (95% CI, 6 to 27; one-sided p=0.0044).
• NeoTRIPaPDL1 (Phase III): Neoadjuvant carboplatin plus nab-paclitaxel with or without atezolizumab did not significantly improve the pCR rate—48.6% with atezolizumab versus 44.4% without (odds ratio [OR] 1.18; 95% CI, 0.74 to 1.89; p=0.48).
• TONIC (Phase II): In metastatic TNBC, a short course of anthracycline (doxorubicin) chemotherapy before nivolumab produced the highest response rate to immunotherapy, with an objective response rate of 35% compared to other immunomodulating strategies. This suggested that anthracyclines may play a key role in "priming" the immune system.
• GeparNuevo (Phase II): Patients who received an initial 2-week "window" of single-agent durvalumab before neoadjuvant chemotherapy had a more pronounced improvement in pCR rate than those receiving combination therapy alone: 61.0% with durvalumab versus 41.4% with placebo (OR 2.22, 95% CI, 1.06 to 4.64, p=0.035).
• I-SPY 2 (Phase II): Adding pembrolizumab to neoadjuvant chemotherapy approximately doubled pCR rates and shifted the residual cancer burden distribution to lower disease burden.
• KEYNOTE-173 (Phase Ib): This trial treated patients with a pembrolizumab run-in for cycle 1, followed by a taxane with or without carboplatin, then doxorubicin and cyclophosphamide. It demonstrated promising anti-tumor activity and a manageable toxicity profile.

Collectively, these trials established the foundation for the FDA Breakthrough Therapy designation of pembrolizumab and ultimately led to the pivotal KEYNOTE-522 trial.

Key Findings: What the KEYNOTE-522 Trial Showed

The results of KEYNOTE-522 were practice-changing. At the first interim analysis, among the first 602 patients randomized, the pCR rate was 64.8% (95% CI, 59.9 to 69.5) with pembrolizumab-chemotherapy versus 51.2% (95% CI, 44.1 to 58.3) with placebo-chemotherapy—an absolute difference of 13.6 percentage points (95% CI, 5.4 to 21.8, p=0.00055). This means that nearly two out of three patients receiving pembrolizumab had no detectable cancer at the time of surgery.

One of the most notable findings was that the benefit of pembrolizumab occurred across all patient subgroups, regardless of PD-L1 status. This is different from the metastatic setting, where PD-L1 status predicts benefit. In the PD-L1–positive population, the pCR rate was 68.9% with pembrolizumab versus 54.9% with placebo. In the PD-L1–negative population, the pCR rate was 45.3% with pembrolizumab versus 30.3% with placebo. Approximately 80% of patients in each treatment arm had PD-L1–positive disease.

The 3-year event-free survival (EFS) rate—the proportion of patients alive without disease recurrence, progression, or death—was 84.5% with pembrolizumab-chemotherapy versus 76.8% with placebo-chemotherapy, a 7.7% absolute improvement. In the pembrolizumab-treated group, 15.7% (n=123 of 784) of patients experienced any disease-related event or death, compared with 23.8% (n=93 of 390) in the placebo group—a hazard ratio (HR) of 0.63 (95% CI, 0.48 to 0.82, p=0.00031). In plain terms, patients receiving pembrolizumab had a 37% lower risk of disease-related events or death during the follow-up period.

The distant recurrence rate (cancer spreading to distant organs) was 7.7% (n=60 of 784) in the pembrolizumab group versus 13.1% (n=51 of 390) in the placebo group. Among patients who achieved a pCR, the EFS rate was 94.4% with the pembrolizumab-containing regimen and 92.5% with placebo. But among patients with residual disease after neoadjuvant therapy—the higher-risk group—the EFS rate was 67.4% with pembrolizumab versus 56.8% with placebo. This suggests that adjuvant pembrolizumab is potentially most critical for patients who do not achieve a pCR.

In the PD-L1–positive population, EFS events occurred in 14.9% of the pembrolizumab group versus 21.5% of the placebo group (HR 0.67, 95% CI, 0.49 to 0.92). In the PD-L1–negative population, EFS events occurred in 19.5% versus 36.2% (HR 0.48, 95% CI, 0.28 to 0.85). There was also a trend toward improved overall survival (OS) with the addition of pembrolizumab (89.7% versus 86.9% at 3 years), although the data were still immature at the time of reporting. Distant progression- or recurrence-free survival was 87.0% with pembrolizumab versus 80.7% with placebo.

On July 26, 2021, the FDA approved pembrolizumab for the treatment of patients with high-risk, early-stage TNBC, immediately altering the longstanding treatment paradigm.

Side Effects and Safety Considerations

As with any cancer treatment, the improved efficacy of pembrolizumab must be weighed against its added toxicity. The incidence of treatment-related adverse events (TRAEs) of grade 3 or higher across all treatment phases was 77.1% in the pembrolizumab-chemotherapy group and 73.3% in the placebo-chemotherapy group. This includes a higher rate of grade 3 or higher side effects among pembrolizumab patients, reflecting the addition of an immunotherapy drug to an already intensive chemotherapy regimen.

Deaths related to treatment occurred in 0.5% (n=4 patients) of the pembrolizumab group and 0.3% (n=1 patient) of the placebo group. The deaths in the pembrolizumab group were attributed to sepsis, pneumonitis (lung inflammation), pulmonary embolism (blood clot in the lung), and autoimmune encephalitis (immune-related brain inflammation). These are rare but serious events that require prompt recognition and treatment.

Most treatment-related adverse events occurred during the neoadjuvant phase, were of low grade, and were largely attributed to the chemotherapy itself. Adverse events of special interest (immune-related side effects) occurred in 38.9% of patients treated with pembrolizumab versus 18.3% with placebo. Grade 3 or higher adverse events of special interest occurred in 12.9% and 1.8% of patients, respectively. The most common severe immune-related side effects in the pembrolizumab group included:

• Severe skin reactions (3.8% of patients)
• Infusion reactions (2.6%)
• Adrenal insufficiency (1.3%), a condition where the adrenal glands do not produce enough hormones

Treatment-related adverse events that led to discontinuation of any therapy occurred in 27.7% of the pembrolizumab group versus 14.1% of the placebo group. Specifically, grade 3–5 immune-related adverse events (irAEs) occurred in 14.9% of the pembrolizumab group versus 2.1% of the placebo group, and led to treatment discontinuation in 10.9% and 2.6% of patients, respectively. In the adjuvant setting (after surgery), grade 3–5 irAEs occurred in 2.9% and 0.3% of patients in the pembrolizumab and placebo groups, respectively.

The addition of carboplatin (an extra chemotherapy drug) in the neoadjuvant setting, plus the use of neoadjuvant followed by adjuvant pembrolizumab (a full year of immunotherapy), means that improved efficacy must be considered in the context of added toxicity. The researchers emphasize that comprehensive patient education about immune-related side effects is an essential part of clinical care. Rare and potentially long-lasting immune-related side effects will need to be closely monitored in the future.

Biomarkers: Predicting Who Will Benefit

TNBC is considered to have the highest immunogenic potential of all breast cancers. It is enriched for BRCA germline mutations, has a higher somatic mutation load, and produces more tumor-associated neoantigens (abnormal proteins that the immune system can recognize). However, TNBC tumors are rarely associated with microsatellite instability, another marker used to predict immunotherapy response. Early-stage and advanced-stage breast cancers differ in their tumor and immune cell microenvironments, and these differences may impact how well immunotherapy works at different disease stages.

PD-L1 status is an established predictive biomarker for immune checkpoint inhibitor therapy in metastatic TNBC. Preclinical research has shown that high levels of tumor-specific CD8+ T cells (a type of immune cell) soon after neoadjuvant immunotherapy exposure predict long-term survival. In contrast to the metastatic setting, the clinical benefit of immunotherapy-based treatment in early-stage TNBC exists independently of PD-L1 expression, although patients with PD-L1–positive tumors achieved numerically higher pCR rates in the KEYNOTE-522 trial.

Interestingly, data from the GeparNuevo trial suggested that where PD-L1 is expressed matters. There was a trend toward higher pCR rates in PD-L1–positive tumors, which was significant for PD-L1 expression in tumor cells in the durvalumab arm (p=0.045) and for PD-L1 expression in immune cells in the placebo arm (p=0.040). Tumor mutational burden (TMB)—the number of mutations in the tumor DNA—combined with an immune gene expression profile also predicted pCR in that study.

Another promising biomarker is tumor-infiltrating lymphocytes (TILs)—immune cells that have migrated into the tumor. The presence of stromal TILs (sTILs, immune cells in the connective tissue around the tumor) is prognostic in TNBC and is associated with higher pCR rates to neoadjuvant chemotherapy. A pooled analysis of 3,771 patients treated with neoadjuvant therapy showed that a 10% increase in sTILs was associated with longer disease-free survival in TNBC patients. The phase III BIG 02–98 trial demonstrated that both sTILs and intratumoral TILs (iTILs, immune cells inside the tumor) were highest in highly proliferative tumors and were associated with estrogen receptor (ER) and HER2 negativity. Increasing lymphocytic infiltration at the time of diagnosis was significantly associated with a favorable prognosis in the ER-negative/HER2-negative subgroup, particularly in the lymphocyte-predominant breast cancer (LPBC) subgroup, defined as approximately 50–60% TILs in the tumor specimen.

Higher TIL levels in residual disease (cancer remaining after neoadjuvant treatment) have also been associated with improved recurrence-free survival and overall survival in TNBC. However, some studies report heterogeneity in the predictive nature of TILs depending on their location—stromal versus intratumoral. In the GeparNuevo trial, while the presence of sTILs was associated with pCR, iTILs on pre-treatment baseline biopsy did not predict pCR. This highlights the need for further investigation of spatial immunophenotyping in TNBC, as the pre-treatment tumor microenvironment and dynamic changes in TIL composition in response to therapy may hold key implications for therapeutic strategies.

Despite this deeper understanding, developing suitable biomarkers to guide immunotherapy in early-stage TNBC remains an area of significant need. Standardizing biomarker assay methods and interpretation before introducing new biomarkers into clinical practice will be essential. Identifying and targeting immune suppression regulators within the tumor microenvironment that contribute to immunotherapy resistance—or predict benefit from checkpoint inhibition—will help achieve a more personalized therapeutic approach and balance the risks of immunotherapy-related toxicity.

Ongoing Research: Clinical Trials Currently Underway

Multiple clinical trials are currently testing pembrolizumab and other immune-modulating strategies in early-stage TNBC, aiming to further improve outcomes and reduce toxicity. Notable ongoing trials include:

• NeoPACT (NCT03639948): A phase II neoadjuvant study of pembrolizumab combined with carboplatin and docetaxel in early-stage TNBC, with pCR as the primary outcome and recurrence-free survival as the secondary outcome, enrolling 121 patients.
• NCT04427293: A window-of-opportunity trial (12 patients) evaluating one cycle of lenvatinib plus pembrolizumab before standard treatment, with the goal of evaluating changes in tumor-infiltrating lymphocytes (TILs).
• NCT03199040: A phase I trial (18 patients) testing a neoantigen DNA vaccine with or without durvalumab in patients with residual TNBC after neoadjuvant therapy, focusing on safety.
• NCT04331067: A phase Ib/II trial (50 patients) comparing cabiralizumab (an immunotherapy targeting macrophages) plus nivolumab with carboplatin and paclitaxel versus nivolumab alone with the same chemotherapy, measuring changes in TILs and tumor-associated macrophages.
• BreastVax (NCT04454528): A phase Ib/II trial (36 patients) evaluating different sequences of radiation therapy and pembrolizumab before surgery, or upfront surgery, to assess feasibility.
• NCT02957968: A phase II trial (32 patients) testing neoadjuvant pembrolizumab plus decitabine (a drug that affects gene expression) followed by doxorubicin/cyclophosphamide and paclitaxel, measuring increases in TILs.
• NCT04373031: A phase II trial (30 patients) evaluating neoadjuvant pembrolizumab regimens.

These ongoing studies will help refine how immunotherapy is used, potentially identifying which patients benefit most and how to combine immunotherapy with other agents to improve cure rates while minimizing side effects.

What This Means for Patients

The approval of pembrolizumab combined with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab monotherapy, represents a revolutionary change in the treatment of high-risk, early-stage TNBC. For the first time, an immunotherapy agent has been shown to improve both pCR rates and long-term event-free survival in this patient population, addressing an urgent unmet need.

For patients, this means a new standard of care that offers a better chance of cure. The KEYNOTE-522 results show that the benefit is seen across all subgroups, regardless of PD-L1 status. This is particularly important because it means patients do not need to have a PD-L1–positive tumor to benefit from the treatment—unlike in the metastatic setting, where PD-L1 testing is required before using pembrolizumab.

Achieving a pCR remains a powerful predictor of good outcomes. In the trial, patients who achieved pCR had excellent 3-year EFS rates (94.4% with pembrolizumab and 92.5% with placebo). The largest difference between the two treatment groups was seen in patients with residual disease after neoadjuvant therapy: 67.4% EFS with pembrolizumab versus 56.8% with placebo. This 10.6 percentage point difference suggests that the year of adjuvant pembrolizumab is especially valuable for patients who still have cancer at the time of surgery.

However, this treatment is more intensive. It adds carboplatin to the neoadjuvant regimen and extends treatment with a full year of immunotherapy after surgery. Patients should have thorough discussions with their oncology team about the expected benefits and the risks of immune-related side effects, some of which can be serious or even life-threatening. Comprehensive education about recognizing and reporting symptoms of immune-related adverse events early is a critical part of safe treatment delivery.

Study Limitations

While the KEYNOTE-522 results are practice-changing, it is important to understand the limitations of the research. First, overall survival data were still immature at the time of publication; the trend toward improved OS (89.7% versus 86.9%) was encouraging but not yet statistically definitive. Longer follow-up is needed to confirm a survival benefit.

Second, the trial had specific eligibility criteria. Patients with active autoimmune disease requiring systemic treatment within the previous 2 years, those with clinically significant comorbid conditions or immunodeficiency, and those requiring immunosuppressive therapy were excluded. This means the results may not fully apply to patients with these conditions, and the risk-benefit balance may be different in those populations.

Third, adjuvant capecitabine—an established treatment option for patients with residual disease after neoadjuvant chemotherapy—was not permitted in the KEYNOTE-522 trial. Therefore, how to sequence or combine capecitabine with adjuvant pembrolizumab in clinical practice remains an open question.

Fourth, while pembrolizumab showed benefit regardless of PD-L1 status in early-stage disease, the optimal biomarkers for selecting patients who will benefit most have not been fully defined. Standardization of biomarker assays and interpretation methods is still needed before these can be used routinely in clinical care.

Finally, the added toxicity of combining carboplatin with pembrolizumab and a full year of immunotherapy must be carefully weighed. Rare and potentially long-lasting immune-related adverse events require ongoing monitoring, and the long-term safety profile in the adjuvant setting continues to be evaluated.

Recommendations for Patients

If you or a loved one has been diagnosed with high-risk, early-stage triple-negative breast cancer, here are key steps to consider:

1. Ask about pembrolizumab: Discuss with your oncologist whether

   Frequently Asked Questions

   What is triple-negative breast cancer (TNBC)?

   Triple-negative breast cancer (TNBC) is a biologically aggressive form of breast cancer that lacks estrogen receptors, progesterone receptors, and HER2-neu overexpression. This means common targeted therapies don't work for it. It accounts for about 15–20% of all breast cancers and disproportionately affects younger women and women of color.

   What is pembrolizumab (Keytruda) and how is it used for early-stage TNBC?

   Pembrolizumab is an immunotherapy drug that helps the immune system fight cancer. In the KEYNOTE-522 trial, it was given with chemotherapy before surgery and continued alone after surgery for a full year. The FDA approved this combination in July 2021 for high-risk, early-stage triple-negative breast cancer.

   Who is eligible for pembrolizumab plus chemotherapy for early-stage TNBC?

   Eligibility in the KEYNOTE-522 trial included newly diagnosed, high-risk, early-stage TNBC with tumors that were cT1c with lymph node involvement or larger tumors (cT2-4) with or without lymph node involvement. Patients with active autoimmune disease requiring systemic treatment within 2 years, significant comorbidities, or immunosuppressive therapy were excluded.

   What do the results of the KEYNOTE-522 trial mean for patients?

   In the trial, adding pembrolizumab to chemotherapy improved the pathologic complete response rate to 64.8% versus 51.2% with chemotherapy alone. The 3-year event-free survival improved from 76.8% to 84.5%. This benefit was seen regardless of PD-L1 status, meaning patients don't need to test positive for PD-L1 to potentially benefit.

   What are the side effects of pembrolizumab plus chemotherapy for early-stage TNBC?

   Treatment-related adverse events of grade 3 or higher occurred in 77.1% of patients receiving pembrolizumab-chemotherapy versus 73.3% with placebo. Immune-related side effects were more common with pembrolizumab, including severe skin reactions, infusion reactions, and adrenal insufficiency. Rare deaths were reported, including from sepsis, pneumonitis, pulmonary embolism, and autoimmune encephalitis.

   Will I need PD-L1 testing before receiving pembrolizumab for early-stage TNBC?

   No. In early-stage TNBC, the clinical benefit of pembrolizumab exists independently of PD-L1 expression, according to the KEYNOTE-522 trial. This is different from metastatic TNBC, where PD-L1 testing is required. Even patients with PD-L1-negative tumors saw improved outcomes with the pembrolizumab-containing regimen.

   What are the limitations of the KEYNOTE-522 trial results?

   Overall survival data were immature at publication, showing a trend but not a definitive survival benefit. The trial excluded patients with autoimmune disease, significant comorbidities, or immunosuppression. Adjuvant capecitabine was not permitted, so how to combine it with adjuvant pembrolizumab is unknown. Optimal biomarkers for selecting patients are not yet defined, and added toxicity must be weighed.