Neoadjuvant/Adjuvant Pembrolizumab Regimens Lower RCB in ER+ Breast Cancer

News
Article

The latest KEYNOTE-756 data highlight the surgical outcomes of patients with high-risk early-stage estrogen receptor–positive breast cancer.

Peter Fasching, MD  University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Bavarian Cancer Research Center

Peter Fasching, MD

University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Bavarian Cancer Research Center

Neoadjuvant pembrolizumab (Keytruda) plus chemotherapy, followed by adjuvant pembrolizumab combined with endocrine therapy, lowered residual cancer burden (RCB) and did not have an impact on adverse effects (AEs) compared with neoadjuvant placebo/chemotherapy and adjuvant placebo/endocrine therapy in patients with early-stage, high-risk estrogen receptor (ER)–positive, HER2-negative breast cancer, according to an analysis from the phase 3 KEYNOTE-756 trial (NCT03725059).1

“I’m just too enthusiastic about the data,” lead study author Peter Fasching, MD, discussed in an interview with CancerNetwork®. “If you have groups [with pCRs of] 3% vs over 55%, just biologically spoken, that must be something that can be solved by science, and we need to solve it. There must be some major impact on science, figuring out why these huge differences in these subgroups are visible in the KEYNOTE-756 study.”

Previously, first interim analysis results from KEYNOTE-756 had demonstrated an improved pathologic complete response (pCR) with the pembrolizumab regimens vs placebo at 24.3% vs 15.6%, respectively, with an estimated difference of 8.5 percentage points (P = .00005).2

Safety was a secondary end point of the trial, while RCB was an exploratory outcome measure. Results showed that there were more patients on pembrolizumab vs placebo with RCB-0 at 24.7% vs 15.6%, respectively, as well as RCB-1 (10.2% vs 8.1%).

In the interview, Fasching, of the University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Bavarian Cancer Research Center, in Erlangen, Germany, discussed the phase 3 KEYNOTE-756 data on a more granular level and highlighted what the clinical implications may be for this ER-positive breast cancer population.

CancerNetwork: Could you explain the significance of the first interim analysis results of KEYNOTE-756 regarding improvement in pCR in patients receiving pembrolizumab plus chemotherapy vs placebo plus chemotherapy?

Fasching: Looking at the KEYNOTE-756 study, it’s important to remember that in hormone receptor [HR]–positive disease the question is: which patient should get chemotherapy, and which patients benefit from chemotherapy? This is a general question that is not yet perfectly resolved with a multigene test. We’re doing a big part of explaining which patients should or should not get chemotherapy.

However, we’re still not very good at predicting which patients respond and do not respond. The KEYNOTE-756 study is a very important study because it introduces immuno-oncology and the microenvironment of the tumor into that question. The KEYNOTE-756 study addressed patients who would be at a higher risk of recurrence of [tumors that were] ER positive or negative and were grade 3, with additional risk factors based on tumor size and nodal status. They were randomly assigned to standard chemotherapy vs the addition of pembrolizumab before surgery in the neoadjuvant setting.

Then, very similar to the triple-negative breast cancer [TNBC] KEYNOTE-522 study [NCT03036488], they continued pembrolizumab for another 6 months. The primary results were presented some months ago. There, we could see that the pCR rate increased from 15.6% to 24.3%, jumping over this 20% that many doctors would consider a threshold to decide for or against the chemotherapy. There are some very interesting results in the subgroups as well. That deserves some attention because they shed light on which subgroups of patients benefit with regard to pCR from the treatment in a very impressive manner.

Beyond the statistically significant improvement in pCR, how does the study define success in terms of surgical outcomes for patients receiving pembrolizumab?

In taking these results, it’s very important to look at neoadjuvant studies because in that context, treatment decisions for or against primary surgery or neoadjuvant chemotherapy are made. It’s very important to understand how effective these treatments are for surgeons—looking at the surgery itself and whether the treatment would impact their planned approach in any means. Then, of course, the rate of mastectomy is very important to look at, [as well as] the patients who would not be eligible for surgery after the treatment for any reasons.

The results say that there is no impact on the mastectomy rates by this treatment. Both randomization arms had a mastectomy rate of approximately 55%. There is also no impact on the therapy management. It’s also very important to look at this additional treatment that might come with additional AEs, which may have an impact on the time from the end of the neoadjuvant treatment to the start of the surgery.

[Findings show that] surgery can be performed on time. In both arms, the median time was approximately 1 month, and after surgery, the uptake of the adjuvant therapy was approximately 1.2 months in both randomization arms, so the treatment doesn’t have an effect on the therapy management, and it doesn’t affect the type of the surgery that is performed.

In your experience, how can a shift towards lower RCB categories, such as less bulky residual disease, induce a clinically significant benefit for patients undergoing surgery?

Now we come to the interesting part of the whole KEYNOTE-756 study. We do know that in many patients who are HR-positive, chemotherapy basically doesn’t work. There has been a lot of overtreatment over time recorded, especially up to 10 years ago, where it changed a little bit. We use less chemotherapy in patients with HR-positive breast cancer, and the multigene test did their part in reducing the use of chemotherapy further.

Looking at any biomarkers in the KEYNOTE-756 study is of tremendous importance, and the RCB is one of them. We also looked at ER expression levels, and we also looked at PD-L1 expression levels. Looking at these different biomarkers, let it be RCB or other factors, we get a very good impression about how beneficial that treatment is for some subgroups of patients. For example, at the expression of PD-L1…you can see that there are groups of patients with a low or nonexistent expression, where the pCR is just about 7%. That can be going up to almost 54%. It’s a huge difference when the PD-L1 expression is 20 or higher in the combined positive score.

Very similarly, we can also see that it’s dependent on ER expression. We can see in a subgroup of patients who just have a slight expression of ER, where adding pembrolizumab can get a pCR of up to 64%. That’s something never seen before in patients with HR-positive breast cancer. You can imagine that scientists are very keen on investigating that further because in some subgroups, you have a pCR of under 3%, and in other subgroups, you have pCR rates of over 55%. [These are] huge differences.

I’m convinced with the KEYNOTE-756 study that having a benefit for patients with regard to pCR rate and having the majority of patients over the pCR rate that are of high relevance or RCB in the majority of patients of 30% and higher, [adds to this for] patients. This study will also be very important to shape the understanding of cancer-based treatments and immuno-oncology–based treatments in the HR-positive patient population.

Although the rate of any post-surgical AEs were similar, were there any specific types of complications more prevalent in the pembrolizumab arm that surgeons should be aware of?

We should make no mistake: any additional treatment comes with additional AEs. In patients with TNBC, the use of pembrolizumab in the neoadjuvant and adjuvant setting has already become a standard since the approval of the pembrolizumab in early breast cancer. Many patients have been treated, and large experience has built up in the community using these drugs, and we do know the AEs.

We know the immuno-oncology AEs, and we do know about the burden with regard to fatigue that comes up with patients. However, the good news for KEYNOTE-756 is that there were no additional or different safety signals observed compared with [treatment] in patients with TNBC or in the metastatic setting where this has been used for longer. We still must deal with the therapy management of these drugs, and we must deal with the immuno-oncology AEs that flare up a few weeks after the start of the treatment. There are autoimmune and endocrine AEs that we must be aware of like hypothyroidism effects on the adrenal gland or other endocrine illogical AEs. But again, there are no additional or different AEs that we were not already aware of.

Many colleagues might say that we want to wait for the prognostic data because they have not been published yet. This is the surrogate for prognosis—a pCR rate—and in a HR-positive disease, it’s still disputed how far a benefit of pCR also translates to a benefit with regard to prognosis. Many colleagues feel like we need a little bit of more data to weigh the benefits in HR-positive disease and of adding the immuno-oncology drugs vs the AEs that are definitely there that we will burden the patients with when we start to use the treatment.

Can you expand on how the findings from this study impact treatment decisions for this early-stage high-risk population?

The drug is not yet approved for patients with HR-positive breast cancer. These are theoretical thoughts right now. There are some colleagues who feel we will have to wait for the prognostic data to make final decisions, and whether this should be implemented as a standard in patients with HR-positive or HR-negative breast cancer and a high recurrence risk. Let’s not forget: it’s not the majority of HR-positive patients; we are talking about a small proportion with grade 3 disease with additional risk factors for having a bad prognosis. There’s definitely a medical need to improve treatment for these patients.

Now, I’m coming back to my personal opinion and looking at the subgroups where many patients have pCR rates over 30%, and in some smaller subgroups over 50%, or even over 60%. How high does the pCR rate have to be for me to decide that it is something I want my patients to experience? Can I eliminate the tumor in every second patient or in 2 of 3 patients? It’s very implicative to think there must be some subgroups where everybody would agree that pCR is high enough, so this treatment should be given to the patients even if you do not know about the prognostic data yet.

These are very preliminary thoughts concerning the treatment and interpretation of the data that are out there. Everybody is very enthusiastic to see that the pCR rate goes now over 20%. It’s something we were pursuing in the neoadjuvant studies for a very long time in HR-positive breast cancer. Secondly, to have subgroups with tremendously high pCR; we have to find out why that is, and how we can utilize that knowledge for making informed decisions in the clinical setting.

Were there any limitations in the surgical outcomes data collected in the study that you feel warrant further investigation?

These are treatment studies; these are not studies that are specifically concerned with surgical problems. It’s not a study that wants to establish new surgical procedures. The data are collected as far as it goes for the treatment decision. In the immuno-oncology setting, it would be very interesting to see how the treatment has an impact on the planned surgery without neoadjuvant therapy vs adjuvant therapy [and see] how that changes.

There was a discussion with the old margins and the new margins, especially in the immuno-oncology setting. How many patients do progress under the therapy and must have premature surgery because the treatment is terminated prematurely? The KEYNOTE-756 study is a study to establish the efficacy of the treatment. The surgical data collected is to see whether there’s any negative impact on the therapy management as far as it goes for the surgical aspects, but it’s not a core question of the studies. It’s still a therapy study.

Looking ahead, are there specific areas you would like to see for future research on immunotherapy and its impact on surgical procedures for breast cancer or other breast cancer subtypes?

We try to minimize the impact of surgery on the patients with regard to AEs. We want to minimize the impact as far as it goes for the extent of the tissue that’s being removed. The more extensive the surgery of the axilla is, the more likely [the patient is] to get lymphedema of the arms. We always try to minimize any impact on the patient.

There are studies going on with how far you can minimize the surgical invasiveness, omitting lymph node dissection, and minimizing the impact on the breast. There are even studies on the way in which patients do still need a surgery. Although there’s a good consensus, there might be a chance for reducing further impact on the axilla; further studies minimizing the extent of the surgery in the breasts are still very early, and some of them are inconclusive. We are always trying to minimize the impact.

From a surgical standpoint, how do you envision immunotherapy potentially changing the landscape of breast cancer treatment in the coming years?

With neoadjuvant therapy, there needs to be good collaboration and coordination between the oncologist and the surgeon. Having these modern treatments as part of the treatment schedule is [integral to] the interdisciplinary approach of the oncologist and of the surgeons to working well together. The removal of the tumor is still the cornerstone of any cancer treatment to be the basis for any additional impact on prognosis. Any treatment that helps to improve the prognosis of the patients is something that will be implemented in that context.

I wouldn’t bother to think too much on what the surgical impact is like if the therapy management has no impact negatively. The whole interdisciplinary team of oncologists, surgeons, radiotherapists, and plastic surgeons will do anything that would improve the prognosis of the patient. It’s just one more treatment that needs to be incorporated in that interdisciplinary approach. Everybody needs to be informed. Everybody needs to know the data and be able to counsel the patients if they have a question that concerns their aspect of the treatment.

References

  1. Fasching P, Bardia A, Liu Z, et al. Surgical outcomes from the phase 3 KEYNOTE-756 study of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab plus endocrine therapy for early-stage high-risk ER+/HER2− breast cancer. Presented at: 25th Annual American Society for Breast Surgeons Annual Meeting; April 10-14, 2024; Orlando, FL. Abstract 1688403.
  2. Cardoso F, McArthur HL, Schmid P, et al. 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
Related Videos
Immunotherapy may be an “elegant” method of managing colorectal cancer, says Gregory Charak, MD.
Administering neoadjuvant therapy to patients with colorectal cancer may help surgical oncologists attain a negative-margin resection.
Laparoscopy may reduce the degree of pain or length of hospital stay compared with open surgery for patients with colorectal cancer.
ZAP-X may provide submillimeter accuracy when administering radiation to patients with brain tumors.
Tailoring neoadjuvant therapy regimens for patients with mismatch repair deficient gastroesophageal cancer represents a future step in terms of research.
Not much is currently known about the factors that may predict pathologic responses to neoadjuvant immunotherapy in this population, says Adrienne Bruce Shannon, MD.
Quantifying disease volume to help identify potential recurrence following surgery may be a helpful advance, according to Sean Dineen, MD.
Sean Dineen, MD, highlights the removal of abdominal wall lesions and other surgical strategies that may help manage symptoms in patients with cancer.
Data highlight that patients who are in Black and poor majority areas are less likely to receive liver ablation or colorectal liver metastasis in surgical cancer care.
Findings highlight how systemic issues may impact disparities in outcomes following surgery for patients with cancer, according to Muhammad Talha Waheed, MD.
Related Content