By: Anuja Antony and Dorys Lopez
Our chief medical officer, Dr. Anuja Antony, represented SimBioSys at the ESMO 2022 conference last month. Among the many exciting advances and developments in the breast cancer field, two topics took center stage: 1) antibody-drug conjugates (ADCs) and 2) human epidermal growth factor 2 (HER2)-low cancer. Several presentations focused on updates in immunotherapy (IO) for breast cancer, although this topic took a backseat this time.
Antibody drug conjugates (ADCs)
ADCs have increasingly gained interest due to their inherent versatility. Dr. Barbara Pistilli gave a detailed description of how these drugs are constructed and what the general mechanism of action is. ADCs have three components: an antibody backbone, a payload, and a linker. The antibody enables selective distribution into the tumor tissue, the payload accounts for the cytotoxic agent, and the linker connects the payload to the antibody. The target can be seen as a 4th (external) component of ADCs, as it plays an important role in the construct design. ADCs act mainly as a “trojan horse” where they selectively deliver the toxic payload into the cells expressing their cognate target. However, these molecules have additional mechanisms of action, one being the bystander effect, in which a drug’s activity extends to neighboring cells that do not express the ADC target.
Dr. Pistilli also highlighted the importance of the spatial distribution of the target, which was explained in detail by Dr. Maria Fernanda Mosele. Dr. Mosele presented data from the DAISY trial clearly showing that the HER2-spatial distribution impacts trastuzumab deruxtecan (T-DXd) activity. She observed different responses to T-DXd according to HER2-levels in different regions of the tumor.
Dr. Aditya Bardia presented an overview of the clinical applications for ADCs. Two ADCs have already shown success in the clinic and have been approved for HER2-low and triple negative (TNBC) metastatic breast cancer subtypes – these ADCs being T-DXd (DESTINY-Breast 04) and sacituzumab govitecan (SG, ASCENT). There are many more ADCs in the pipeline targeting different molecules and using different payloads. As Dr. Lisa Carey stated, ADCs will likely become the dominant means of cytotoxic drug delivery.
Dr. Bardia also discussed the use of ADCs in combination with DNA damage repair (DDR) agents in a staggered schedule that avoids overlapping toxicity while maintaining efficacy, a concept he evaluated in a study that combined sacituzumab govitecan with PARPi drugs in concurrent versus staggered schedules.
The use of ADCs in combination with immunotherapy (IO) is also being investigated in several different trials. Sacituzumab govitecan in combination with pembrolizumab is being evaluated as a therapy for metastatic TNBC in the ASCENT-03 trial. The combination of neoadjuvant sacituzumab govitecan and pembrolizumab for TNBC is being evaluated in the NeoSTAR trial. The DESTINY-breast 08 trial is set to evaluate T-DXd in combination with IO and other agents in HER2-low metastatic breast cancer.
HER2-low breast cancer
With the advent of anti-HER2 targeted therapies, the outcome of HER2-positive breast cancer has dramatically changed. Whereas this cancer subtype used to be viewed as one of the most aggressive breast cancer types, it is now considered one of the most treatable, showing some of the best outcomes.
As we gain more knowledge into the biology of HER2 breast cancer subtypes, current treatments and classifications must adapt accordingly. HER2-positive breast cancer is a good example of how the traditional binary classification of HER2 does not paint a full picture. HER2 classification has changed in recent years from a binary (either –positive or -negative) classification, to a gradated one, encompassing -positive, -low and -negative HER2 breast cancers. In his talk, Dr. Paolo Tarantino further expanded on the HER2 classification, proposing a dynamic rather than the current static classification, given the HER2 expression changes over the course of the disease.
Earlier this year at ESMO Breast Cancer 2022, Dr. Penault Llorca raised the question of whether the new HER2-low classification was indeed a clinical entity. Similarly, at ASCO earlier this year and now at ESMO, there were recurrent comments about the need for more sensitive tools to help better define HER2 status in breast cancer. Ultimately, the current consensus is that HER2-low breast cancer is not an independent subtype or clinical entity, but rather a targetable entity dependent on hormone receptor (HR) status.
HER2-low breast cancers can be targeted with anti-HER2 therapy, as was successfully shown in the DESTINY-Breast 04 trial, first presented by Dr. Shanu Modi at ASCO. The results showed a remarkable improvement in progression-free survival (PFS) and overall survival (OS) in HER2-low metastatic patients upon treatment with the anti-HER2 therapy T-DXd. The follow-up question from this trial is: “how low can we go?” The Destiny-Breast 06 trial, currently recruiting, will include HER2-ultra-low patients to investigate what is the lowest threshold of HER2 expression needed to activate T-DXd.
Immunotherapy
Many different aspects of IO are still being evaluated in breast cancer. Dr. Sherene Loi talked about tumor-infiltrating lymphocyte (TILS) in breast tumors. Despite breast cancer not being as immunogenic as other types of solid tumors (e.g., melanoma), TILs play an important prognostic role in early-stage TNBC. In fact, the quantity of TILs is predictive of the PD-L1 inhibition benefit in patients. Dr. Loi proposed a tumor classification scheme based on percentage (%) of TILs, which she showed can either raise or lower the traditional AJCC stage designations in early stage TNBC.
Dr. Marlene Kok presented the first results from the BELLINI trial. This trial is the first to select TNBC patients based on TILS and is evaluating nivolumab (anti-PD-1) in combination with novel immune-checkpoint inhibitor (ICI) ipilimumab (anti-CTLA-4) in early stage TNBC. As Dr. Loi showed in her talk and Dr. Kok reiterated, high levels of TILs correlate with good prognosis in early TNBC. Dr. Kok showed improved partial radiological response after four weeks of combined therapy and doubling of CD8 T-cells and/or IFN-gamma in both cohorts.
The most exciting news in the realm of IO was not in breast cancer, but instead in colon cancer. Dr. Myriam Chabali presented the results of the NICHE-2 study that evaluated neoadjuvant immune checkpoint inhibition in locally advanced mismatch repair deficient (dMMR) colon cancer. The striking results showed a jump from the 5-7% pathologic response achieved with neoadjuvant chemotherapy to a 95% pathologic response with neoadjuvant immunotherapy. Both the NICHE-1 (n=32) and NICHE-2 (n=112) studies showed similar results. With these promising data, neoadjuvant immunotherapy could become the new standard of care for dMMR colon cancer patients.
