The Safety and Efficacy of Pembrolizumab as an Immunotherapy Treatment for Breast Cancer

Abstract

Recent clinical trials on cancer immunotherapy drugs have demonstrated improved breast cancer patient outcomes. Pembrolizumab, a cancer immunotherapy checkpoint inhibitor, has been utilized in clinical breast cancer trials due to its reasonable safety profile. Pembrolizumab acts on cancer cells by blocking programmed death-ligand-1 (PD-L1), allowing our adaptive immune system to function as it normally would. PD-L1 is a cell surface protein that induces T cell apoptosis upon binding to PD-1 receptors on T cells, a key mechanism for immune evasion. Through measuring overall response rate (ORR) and pathological complete response (pCR), researchers have measured the efficacy of Pembrolizumab. While it was generally found that there was no statistically significant difference for ORR, the data collected for pCR shows a statistically significant difference in patients who received pembrolizumab treatment compared to those who received the control. This data offers promising results that pembrolizumab could potentially improve breast cancer patient survival outcomes.

Introduction

Breast cancer is one of the most prevalent forms of cancer worldwide, accounting for nearly 685,000 deaths among females in 2020. With a high mortality rate, finding treatments to improve patient outcomes is critical [1]. Chemotherapy is a widely used part of many patients' treatment plan that works by targeting rapidly dividing cells in the body. However, it cannot distinguish between cancerous and healthy cells, leading to the damage of healthy cells and causing a range of side effects, both short-term and long-term. Cancerous tumors can also become resistant to chemotherapy, which is common for some of the most aggressive forms of breast-cancer such as triple-negative breast cancer (TNBC). Because of these issues, researchers are evaluating the efficacy and safety of other cancer treatments, such as immunotherapies. Scientists have designed many clinical trials to evaluate the efficacy and safety of several immunotherapy drugs, one of these is called pembrolizumab. 

Generally, immunotherapies aim to utilize the body’s natural immune system to recognize and eliminate cancer cells, often by overcoming the mechanisms tumor cells use to bypass the immune system. Pembrolizumab is an immune checkpoint protein that acts by blocking PD-L1 on cancer tumor cells [2]. Immune checkpoints are important regulators in activating T cells that play a role in preventing anti-self-responses such as autoimmunity [3]. T cells are adaptive immune cells that act as host defense against foreign bodies. They have PD-1 receptors that bind PD-L1 on cancer cells. When this binding occurs, an inhibitory signal is triggered in the T cell, causing the T cell to shut down its CD4+ helper T cell or CD8+ cytotoxic killer T-cell [4]. Thus, the host loses an important immune function that is necessary for pathogen erasure, as this allows the cancer cells to bypass the immune system [4]. Pembrolizumab allows the T cell to function normally by preventing PD-L1 from binding to the PD-1 receptor and sending out an inhibitory signal [4]. While PD-L1 is expressed on the majority of cells throughout the body to regulate immune system responses, cancer cells have evolved mechanisms to upregulate PD-L1 expression on their cell surface, which allows them to be targeted by pembrolizumab [2]. 

Although chemotherapy treatments are still one of the most common breast cancer treatments, recent studies reveal that immunotherapy checkpoint inhibitor treatments may improve patient outcomes. This review will examine the efficacy of pembrolizumab as an immunotherapy treatment for breast cancer through clinical trials by measuring overall response rate (ORR) and pathological complete responses (pCR). Additionally, this paper will also examine the safety of pembrolizumab as a drug used in human breast cancer clinical trials. 

Safety of Pembrolizumab as a Breast Cancer Immunotherapy 

Evaluating a drug’s safety is important in understanding potential adverse effects as well as potential side effects. To determine whether pembrolizumab’s therapeutic effects outweighs the potential side effects, Cortes et al. (2020) wanted to determine the safety profile of pembrolizumab+chemotherapy [5]. Safety was measured in patients who had received at least one dose of the treatment, according to the National Cancer Institute Common Terminology Criteria for Adverse Events grading system [5]. This system classifies adverse events on a 5 point grading system, where 1 is defined as mild and 5 is death. They found that the incidence of grade 3 or 4 immune-mediated adverse events was higher in the pembrolizumab+chemotherapy group (5%) compared to the placebo+chemotherapy group (0%), which was expected [5]. Immune-mediated adverse events are autoimmune conditions that arise after a patient has been treated with an immune checkpoint inhibitor such as pembrolizumab. The researchers determined that the safety profile of pembrolizumab+chemotherapy was consistent with the known toxic effects of pembrolizumab and with the toxicities commonly observed in chemotherapy treatments, suggesting that there are no new or unexpected risks [5].        

Another clinical trial, designed by Winer et al. (2021), studied the safety profile of pembrolizumab compared to chemotherapy according to the same grading system used by Cortes et al [6]. A total of 622 patients were randomly assigned to 1 of 2 patient populations: a pembrolizumab group and a chemotherapy group [6]. They determined that 14% of the pembrolizumab group and 36% of the chemotherapy group had grade 3 or 4 treatment related adverse effects [6]. Overall, the researchers of the study found that the rate of adverse events in the pembrolizumab group was consistent with previously established safety profiles of pembrolizumab monotherapy [6], once again indicating that there are no new risks of the drug. Together, Cortes et al. (2020) and Winer et al. (2021) highlight the manageable safety profile of pembrolizumab, making it a safe treatment option for breast cancer patients. 

Efficacy of Pembrolizumab Immunotherapy in Clinical Trials

Overall Response Rate

The effectiveness of pembrolizumab can be quantified through a measure called overall response rate (ORR), which measures the percentage of patients whose cancer shrinks or disappears after treatment. Studies performed by Ho et al. (2020), Cortesi et al. (2023), and Wilkerson et al. (2024) evaluated this measurement as an approach to determine treatment efficacy. Cortesi et al. (2023) used a phase 2, 2 stage Simon's design study, which is often used for phase 2 cancer clinical trials [7]. The patient population included 22 patients over the age of 18 with BRCA1/2-related metastatic breast cancer (mBC), a cancer in which breast cancer cells spread to other parts of the body [7]. Each patient received carboplatin, a chemotherapy drug, every 3 weeks for 6 courses along with 200 mg of pembrolizumab until disease progression or toxicity [7]. Disease progression was defined by objective tumor growth.The patients were prohibited from using other therapies during the treatment, such as other chemotherapies or radiotherapy [7]. The results of this study did not demonstrate a statistically significant overall response rate in patients as their goal was a 70% or greater overall response rate [7]. While this was not achieved, the ORR was 43% [7]. The researchers found how a larger improvement in ORR was observed when pembrolizumab+carboplatin were the patient's first line of treatment for mBC rather than their second line of treatment. This finding suggests that clinicians should consider incorporating immunotherapy treatments earlier in the treatment course, rather than saving them for later lines of treatments [7]. 

Similar to this design, Ho et al. (2020) used a phase 2, Simon 2-stage, single-arm trial for patients who were 18 years or older with biopsy proven metastatic triple-negative breast cancer (mTNBC) [8]. Single-arm trials are designed to have only one experimental group. The patients were required to have at least one tumor not treated with prior radiation [8]. Patients in the clinical trial were given 600 centigrays of radiotherapy (RT) 5 times over 5 to 7 days [8]. While 600 cGy of radiotherapy delivered over 5–7 days is commonly used in clinical trial settings, standard cancer treatment regimens typically involve lower doses administered over a longer duration. Pembrolizumab was administered intravenously at a dose of 200 mg for 1 to 3 days after the first RT and then every 3 weeks [8]. They evaluated the overall response rate of the tumors not previously treated with radiation after 13 weeks [8]. The results of this study showed that the ORR for the entire cohort of patients was 17.6% with a 95% confidence interval of 4.7% to 44.2% [8]. While this number seems to be promising, it is difficult to assess the statistical significance of the data as there is no control to compare the results to [8]. Additionally, the wide range of the 95% confidence interval suggests that there may be some variability and that the true response rate could be significantly lower than 17.6%. 

In another study, Wilkerson et al. (2024) studied ORR alongside other efficacy measures through a phase II clinical trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in mTNBC [9]. These patients received 3 cycles of CNP and drug administration was continued until diagnosis of a progressive disease or other intolerable adverse circumstances [9]. The overall response rate for a cohort of 30 patients was 48%, indicating that nearly half of the patients in this study showed some degree of tumor shrinkage [9]. 

Overall, these three studies suggest that in terms of overall response rate, it is hard to determine if pembrolizumab has a statistically significant effect. While the studies had similar methodologies and respective conclusions, the subtle differences between them offer various perspectives. The studies from Wilkerson et al. (2024) and Cortesi et al. (2023) both administered carboplatin, a form of chemotherapy, along with the immunotherapy treatment, while the study by Ho et al. (2020) treated the patients with radiation therapy along with the immunotherapy treatment [7-9]. Additionally, the study conducted by Wilkerson et al. (2024) focused on patients with mTNBC, similarly to the study by Ho et al. (2020). Patients with TNBC are typically younger and have a higher risk of experiencing early recurrence prior to treatment [10]. The fact that the statistical conclusions of each of these studies differs offers interesting perspectives, and reminds readers to be open-minded when reading results of clinical trials due to the limitations. The main limitation of each of these studies is the sample size which raises questions on how generalizable the conclusions are. Although there were crucial differences between the studies, both studies provided foundational knowledge on their research methodologies.

Pathological Complete Response

While an increase in overall response rate may be beneficial to determining the efficacy of Pembrolizumab as a cancer immunotherapy, pathological complete response (pCR) is a better indicator of efficacy as it signifies the complete absence of cancer cells in a tissue sample post-treatment. Several research studies have aimed to evaluate the efficacy of Pembrolizumab immunotherapy in cancer treatments through measuring the pCR which is the time point in which there is no sign of cancer in tissue samples following treatment. Schmid et al. (2020) and Pusztai et al. (2024) both carried out clinical trials that focused on this measurement. Schmid et al. (2020) designed a study with two patient populations, both of which had previously untreated early TNBC [11]. One patient group received pembrolizumab-chemotherapy while the other group received placebo-chemotherapy treatments [11]. This study was designed to be a randomized, phase 3, double-blind trial in which patients had both neoadjuvant and adjuvant phases of randomized treatment that was either pembrolizumab or placebo [11]. After the neoadjuvant phase, a pathologist assessed the pCR according to pathological states [11]. The pathologist determined that 64.8% of patients in the pembrolizumab chemotherapy group had a complete response while 51.2% of patients in the placebo group had a complete response, suggesting that the pembrolizumab group had a statistically higher rate compared to the placebo [11]. It was also observed that the benefits of the pembrolizumab-chemotherapy with respect to pCR was consistent across subgroups such as PD-L1-expression [11].

Similarly, the clinical trial performed by Pusztai et al. (2024) randomized patients with early-stage TNBC to receive either placebo or pembrolizumab [12]. In the first neoadjuvant phase (cycles 1-4), patients received pembrolizumab or placebo with carboplatin and paclitaxel chemotherapy drugs [12]. In the second phase (cycles 5-8), treatment continued with pembrolizumab or placebo in combination with doxorubicin/epirubicin and cyclophosphamide [12]. After surgery, patients received nine cycles of adjuvant pembrolizumab or placebo, with discontinuation allowed for disease progression, recurrence, or adverse events [12]. A blinded pathologist was used to assess the pCR [12]. It was found that pembrolizumab not only increased the rate of pCR compared to the placebo group, but also improved the event free survival amongst the patients who did not have a pCR [12]. They measured pCR by Residual Cancer Burden (RCB) [12]. Ultimately, it was noted that Pembrolizumab shifted TNBC patients into lower RCB categories when compared to the placebo group, indicating that there was a larger group of individuals in the pembrolizumab group that achieved pCR compared to the placebo group [12]. This study concluded by stating that patients with high-risk, early-stage TNBC have been approved for pembrolizumab combined with chemotherapy as neoadjuvant treatment, followed by surgery and then continued as single-agent adjuvant treatment.

The studies by both Schmid et al. (2020) and Pusztai et al. (2024) suggest that pembrolizumab immunotherapy treatments in conjunction with chemotherapy for TNBC increases the rate of pCR [11-12]. Despite these findings, each clinical trial used 1 blinded pathologist for assessing the pCR which raises questions on the potential for subjectivity, variability, and human error. While the blinding may remove subjectivity, the variability between the 2 pathologists of the different studies could likely skew the results. Additionally, both studies focused solely on patients with early-stage breast cancer. By excluding those with later-stage disease, the findings may not fully represent all breast cancer patients. Immunotherapy treatments may have different efficacy profiles in patients with advanced or metastatic breast cancer due to the altered tumor microenvironment, increased tumor heterogeneity, and the presence of additional comorbidities. As a result, the generalizability of the trial results to later-stage breast cancer patients remains uncertain, and further studies are needed to assess the efficacy of the immunotherapy drug across different stages of disease.

Conclusion

Breast cancer is the most commonly diagnosed cancer in women and is the second most common cause of cancer death amongst women worldwide [13]. Treatment options include surgery, chemotherapy, radiation, and more recently, immunotherapy [13]. Research has determined that pembrolizumab, an immunotherapy drug, could potentially improve breast cancer patient survival rates. While the data seems promising, several limitations such as the sample size restricts researchers from being able to make generalizable conclusions about the benefits of pembrolizumab across all breast cancer patients. The challenge with clinical trials are the various variables. For instance, researchers were faced with the decision of administering pembrolizumab as a monotherapy, or as combination therapy with chemotherapy or radiation therapy. They then had to decide whether patients were in the early or late stage, if they had high PD-L1 expression on their cancer cells, or if their cancer had been previously treated. This allows for many different designs of clinical trials with potentially variable results, which is what future research studies should consider. However, if more research comes out with results that determine that pembrolizumab is beneficial for breast cancer patients, it would offer the potential to increase the rate of breast cancer patient survival.

About the Author: Annie Rhee

Annie Rhee graduated from the University of California, Davis in June 2025 with a B.S. in Neurobiology, Physiology, and Behavior. She is passionate about bridging scientific research and clinical practice, a pursuit that has fueled her commitment to a career as a physician. To work toward this goal, she worked as an EMT with the UC Davis Fire Department, gaining invaluable hands-on experience in patient care. She also conducted molecular and cellular biology research in the laboratories of Dr. Mark Winey and Dr. Ted Powers, using Tetrahymena thermophila, a unique model organism, to study a pathway commonly involved in cancer. She chose to write a paper on cancer immunotherapies after taking PMI126: Fundamentals of Immunology, which sparked an interest in the role the immune system plays in cancer patients. The idea that the immune system can be taught to recognize and fight diseases like cancer reveals the incredible potential of modern medicine. During her free time, Annie enjoys running and reading.

Author’s Note

I wrote this paper for an audience with a general understanding in science and biology. Recently, I took Fundamentals of Immunology, where I developed a newfound passion for the field of immunology. In particular, I became fascinated by the biological mechanisms underlying cancer immunotherapies. My grandmother’s breast cancer diagnosis allowed me to witness firsthand the profound impact of this disease on individuals. As there is still no cure, ongoing research remains crucial in the search for new and more effective treatments. This paper aims to provide individuals with a clear understanding of the latest developments in breast cancer immunotherapies, including mechanisms, efficacy, and clinical applications. While there is forward progress in breast cancer research, there is still much to discover in improving immunotherapy effectiveness and accessibility for breast cancer patients.

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