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SABCS 2021 | Key clinical trials investigating immunotherapy in HER2+ and HR+ breast cancer

Giuseppe Curigliano, MD, PhD, University of Milan and European Institute of Oncology, Milan, Italy, provides the rational for exploring the role of immunotherapy in HER-positive and hormone receptor (HR)-positive breast cancer and outlines key clinical trials. The Phase Ib/II trial PANACEA (NCT02129556) investigated the combination of trastuzumab and pembrolizumab in patients with HER2-positive metastatic breast cancer who had been heavily pretreated, demonstrating significant rates of progression-free survival (PFS). Phase III KATE3 (NCT04740918) explored the combination of trastuzumab emtansine plus atezolizumab in HER2-positive and PDL1-positive locally advanced or metastatic breast cancer, also showing significant PFS rates compared to the active comparator. The Phase III trial Astefania (NCT04873362) examined trastuzumab emtansine in combination with atezolizumab in patients with invasive breast cancer who are HER2- and PDL-1- positive. Prof. Curigliano additionally describes clinical trials investigating HR-positive breast cancer. Preliminary signs of activity were observed in the Phase II GELATO (NCT03147040) trial evaluating the combination of carboplatin plus atezolizumab specifically in patients with metastatic invasive lobular breast cancer. Further, a trial was reported evaluating treatment for patients with HR-positive, HER2-negative breast cancer with AC chemotherapy for three cycles followed by immune and endocrine therapy in the neoadjuvant setting. This trial was designed in regards to PAM50 molecular subtypes and it was noted that only patients with the basal-like subtype achieved pathologic complete response (pCR). Lastly, HER2 vaccines are discussed for patients with both HER2-positive and HER2-low breast cancer. This interview took place at the San Antonio Breast Cancer Symposium 2021 in San Antonio.

Transcript (edited for clarity)

Ladies and gentlemen, good afternoon. My name is Giuseppe Curigliano. I work at the European Institute of Oncology in Milan. During the San Antonio Breast Cancer Symposium, I addressed the topic of immunotherapy beyond the triple-negative breast cancer. Specifically, I provided the rationale to explore the role of immunotherapy in HER2-positive and in HR-positive disease.

In HER2+ disease, we already have preliminary data from two trials: a proof-of-concept trial, that is the PANACEA trial published two years ago, and the prospective randomized trial, that was the Phase II trial...

Ladies and gentlemen, good afternoon. My name is Giuseppe Curigliano. I work at the European Institute of Oncology in Milan. During the San Antonio Breast Cancer Symposium, I addressed the topic of immunotherapy beyond the triple-negative breast cancer. Specifically, I provided the rationale to explore the role of immunotherapy in HER2-positive and in HR-positive disease.

In HER2+ disease, we already have preliminary data from two trials: a proof-of-concept trial, that is the PANACEA trial published two years ago, and the prospective randomized trial, that was the Phase II trial. In both trials, we have a response rate and progression-free survival rate that is improved when we combine HER2 therapy plus immune checkpoint inhibitors. In the first trial, the combination was trastuzumab and pembrolizumab in heavily pre-treated patients and the inclusion criteria was only for HER2-positive and PDL1-positive disease. In the second trial, there was combination of T-DM1 and atezolizumab. And also in the context of this trial, eligibility was based on PD-L1 positivity.

Both trials, of course, provided the rationale to explore immunotherapy in a largest trial that is the KATE3, including a larger population of patients that are HER2-positive, and I would like to remind that another report on trial in HER2+ is the Astefania trial exploring the role of T-DM1 plus atezolizumab in the high-risk population in the post neoadjuvent setting, so this is specifically a trial designed for patients with HER2-positive disease following neoadjuvant chemotherapy and with residual disease following surgery.

What about HR+ in this case? The only two trials that I would like to mention are the GELATO trial and the GIADA trail. Why? Because finally, in HR-positive disease, we don’t have such strong evidence of potential activity of immuno-checkpoint Inhibitors. In the GELATO trial, it was explored the combination of carboplatin and immuno-checkpoint inhibitors for metastatic patients with invasive lobular cancer, where usually we have upregulation of gene signature set that can be related to a potential predictive response to immuno-checkpoint inhibitors.

In the GELATO trial, the preliminary science of activity has been observed with these activities. In the GIADA trail, we have a new area of uncertainness for HR-positive, HER2- negative disease, and in the trial, we have a combination of AC for 3 cycles, followed by immunotherapy and endocrine therapy in the neoadjuvant setting.

This study has been designed to assess according to PAM50 molecular subtype, the molecular intrinsic subtype of patients included in the GIADA trial, and not surprisingly, the patients who achieved the pathological complete response were only the patients with the basal-like subtype.

So, in the HR-positive disease, we need to wait for FL7 results in which chemotherapy plus nivolumab is being explored in both neo-adjuvant setting in the adjuvant setting in the high-risk, HR-positive population, including also ER-low, that we know very well are patients that usually are more similar to triple-negative rather to HR+ disease.

In conclusion, when we consider immunotherapy in the population beyond triple-negative and we explore the activity in HER2-positive and HR-positive disease. In my opinion, we have a strong rationale to explore the combination in HER2-postive disease where the immune response is more effective and where we have preliminary data of potential efficacy. Less rationale, maybe, to explore the activity in HR-positive, HER2-negative disease where, of course, we have mutation instability, we have less expression of neoantigens.

I believe that in the future, much more role there will be for potential role of vaccines in this population. Preliminary studies explored the activity of HER2 vaccines in both HER2-positive and HER2-low disease, demonstrating a potential benefit in preventing the appearance of invasive disease when used in HER2+ DCIS, and also, a potential immune response was induced using the two part trials that have been completed in the beginning of 2000.

Now that we have such advanced technologies to produce vaccines, also due to the pandemic of COVID-19, I believe there will be a revival for the use of cancer vaccines in the future. The more neoantigens we will discover, the more powerful this approach can be, mainly in the prevention setting or potentially in the adjuvant setting.

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Disclosures

Consultation fees from Pfizer, Roche, Astra Zeneca, BMS, Daichii Sankyo, Seagen, Gilead, Novartis, Lilly; Ellipsis, Merck

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