Immunotherapy and Chemotherapy Combinations Show Promise for High-Risk HR+/HER2– Breast Cancer

Each year, 70% of breast cancer diagnoses are hormone receptor positive (HR+)/HER2 negative (HER2–), explained Julia L. Ziegengeist, PharmD, BCOP, during a presentation at the 2024 American College of Clinical Pharmacy (ACCP) Annual Meeting. With each diagnosis, it is important to identify the patient’s hormone receptor status, their HER2 expression, and BRCA1 and BRCA2 mutations, as this information can help dictate their treatment.¹

“The majority at 91% of diagnoses each year are early stage and localized or regional, which is fortunate, because the total relative 5-year survival rate is 95.1% in that setting. However, when we get down to distant or metastatic disease, this goes down to 35.4%,” said Ziegengeist, a clinical pharmacist coordinator in breast medical oncology at the Levine Cancer Institute in Atrium Health in Charlotte, North Carolina, during the ACCP presentation. “There's a variety of treatment modalities that we utilize in this setting. Of course, we're all familiar with chemotherapy in the neoadjuvant or adjuvant setting.”¹

Ziegengeist noted that neoadjuvant chemotherapy is particularly important to tell downstage tumors or for some of those higher risk patients with inflammatory, node positive breast cancer. Ziegengeist explained further, “Surgery, of course, is a mainstay, and we can utilize our genomic risk assays in this setting in order to help dictate some of that adjuvant chemotherapy as well as radiation.”¹

Adjuvant chemotherapy can be utilized particularly for patients who have several positive lymph nodes. Image Credit: © Framestock - stock.adobe.com

Adjuvant chemotherapy can be utilized particularly for patients who have several positive lymph nodes, according to Ziegengeist. Adjuvant endocrine therapy has been a mainstay, and there are some targeted therapies that can be added on as well.¹

“But the goal of utilizing all of these modalities is to get to that decreased risk of recurrence,” Ziegengeist said. “When we look at our neoadjuvant or adjuvant chemotherapy in this setting, our preferred treatment options are docetaxel or taxotere and cyclophosphamide.”¹

Additionally, Ziegengeist noted that doxorubicin hydrochloride and cyclophosphamide (AC) every 3 weeks can be used, followed by paclitaxel or cyclophosphamide, methotrexate, and fluorouracil.¹

“Essentially, none of these therapies are 100%, so how can the survival and rate of recurrence be improved? One of the emerging treatment strategies being investigated is immunotherapy,” Ziegengeist said. “Right now, pembrolizumab is the only immune checkpoint inhibitor that we utilize in early-stage breast cancer, specifically for stage 2 or 3 triple-negative disease based on the KEYNOTE-522 trial [NCT03036488] that demonstrated an improved [pathological complete response (pCR)] rate and then event-free survival as well.”^1,2

According to Ziegengeist, investigators in the KEYNOTE-522 trial looked at the addition of immunotherapy to chemotherapy in patients with metastatic HR+ disease, but they did not observe a survival benefit in this setting. However, the addition of immunotherapy may prove more beneficial in early-stage disease.¹

“Some toxicities that we see from KEYNOTE-522 are things that are not surprising with the addition of immunotherapy. But just as a reminder, we do have some of those unfortunately irreversible side effects with things like hypothyroidism at 15%, so it's definitely not a benign addition to chemotherapy, which is already kind of difficult to tolerate,” Ziegengeist said.¹

KEYNOTE-756

Another trial of note for early stage, HR+ breast cancer is KEYNOTE-756 (NCT03725059), explained Ziegengeist. In this trial, patients with grade 3 HR+/HER2– breast cancer were enrolled. The investigators did include some patients who are higher risk of inflammatory breast cancer, and they did not require that the patients be PD-L1 positive, but they did stratify the results for either status.^1,3

Patients were randomized 1 to 1 to weekly paclitaxel for 12 doses with pembrolizumab (Keytruda; Merck) or placebo, followed by AC or epirubicin and cyclophosphamid for 4 cycles with pembrolizumab. AC could be dosed every 2 weeks or every 3 weeks, but the majority of patients received every 3 week dosing. After surgery, patients went on to pembrolizumab adjuvantly for 9 doses with endocrine therapy.¹

According to Ziegengeist, the results showed an improved pCR rate of about 8.7% with the addition of pembrolizumab. Overall survival was still immature, but they did look at an interesting secondary end point of pCR rates based on the amount of chemotherapy a patient received. The investigators also defined full chemotherapy exposure as patients who got at least 4 doses of AC and at least 10 doses of paclitaxel, and when patients received that full amount, they actually had a closer to 10% benefit.¹

“These results highlight the importance of getting patients to receive as much of the whole chemotherapy as possible,” Ziegengeist said. “We saw the predicted safety outcomes here related to immune-mediated adverse effects. We also looked at a variety of other subgroups and looked at [combined positive score (CPS)] scores and ER positivity, and everybody ultimately benefited from the addition of pembrolizumab, but particularly those patients who had a CPS score of greater than or equal to 1 and an ER of about 1% to 10%, who actually had a 24% benefit.”¹

CheckMate 7FL

In the CheckMate 7FL trial (NCT04109066) investigators looked at a similar patient population in terms of clinical staging, but they also include some lower risk patients with grade 2 disease and an ER of 1% to 10%. Again, in this trial, PD-L1 positivity was not required. During the trial, patients were randomized to weekly paclitaxel for 12 doses with nivolumab (Opdivo; Bristol Myers Squibb) every 3 weeks, followed by AC with nivolumab, either dosed 2 weeks or every 3 weeks.^1,4

“In this one, it was kind of 50/50 whether or not patients got AC every 2 weeks or every 3 weeks. After surgery, they had nivolumab monthly for 7 doses along with endocrine therapy, and what they found was about a 10% benefit in that pCR rate,” Ziegengeist said. “Again, looking at all of the subgroups, particularly for those CPS scores greater than or equal to 20, patients actually had a 52.3% absolute change in their pCR rate. So that was pretty impressive.”¹

Improved pCR Rates

In combination, Ziegengeist explained that these trials results show that immunotherapy, in addition to chemotherapy, in these high risk patients can help with the pCR rate, without any additional, unexpected safety signals. The difference in pCR rates between those who completed all the chemotherapy vs those that did not also helps to highlight the significance of supporting patients to complete the chemotherapy as well.¹

“With both of these trials, we do know that there's specific subgroups of patients that may benefit more than others, but we're kind of awaiting more of those survival results, and particularly overall survival, before I think we can really incorporate this into clinical practice,” Ziegengeist said. “But it's definitely going to be something to be on the lookout for in the future.”¹

REFERENCE

1. Ziegengeist JL. BCOP Clinical Session — Treatment Advancements and Evidence for Emerging Therapies in Hormone Receptor-Positive Breast Cancer. Presented at: 2024 American College of Clinical Pharmacy Annual Meeting; October 12-15, 2024; Phoenix, Arizona.

2. Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-522/​KEYNOTE-522). Clinicaltrials.gov. Updated on July 12, 2024. Accessed October 16, 2024. https://clinicaltrials.gov/study/NCT03036488

3. Study of Pembrolizumab (MK-3475) Versus Placebo in Combination With Neoadjuvant Chemotherapy & Adjuvant Endocrine Therapy in the Treatment of Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/​HER2-) Breast Cancer (MK-3475-756/​KEYNOTE-756). Clinicaltrials.gov. Updated on December 18, 2023. Accessed October 16, 2024. https://clinicaltrials.gov/study/NCT03725059?term=NCT03725059&rank=1

4. Study of Nivolumab Versus Placebo in Combination With Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy in Participants With High-risk, Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor Receptor 2-Negative (HER2-) Primary Breast Cancer (CheckMate 7FL). Clinicaltrials.gov. Updated on March 12, 2024. Accessed October 16, 2024. https://clinicaltrials.gov/study/NCT04109066?term=NCT04109066&rank=1