At ESMO 2024, a host of significant abstracts will be presented, highlighting cutting-edge advancements in breast cancer treatment. From pivotal Phase III trials to novel therapeutic approaches, the conference will showcase groundbreaking data across various settings, including early and advanced/metastatic breast cancer.

In the early breast cancer setting, the spotlight will be on follow-up data presentations by Novartis and Merck, set to unveil crucial updates from their pivotal Phase III trials. Novartis will reveal outcomes from the NATALEE trial, focusing on KISQALI (ribociclib) in HR+/HER2− early breast cancer in both older and younger patients while Merck will present data from the KEYNOTE-522 study evaluating neoadjuvant pembrolizumab in high-risk early-stage TNBC.

In the advanced/metastatic setting, several companies are ready to make waves with breakthrough data, with few novel molecules data reveals as well, including Pfizer’s first-in-class CDK4-selective inhibitor (PF-07220060) and next-generation CDK2-selective inhibitor (PF-07104091) in HR+/HER2- metastatic breast cancer, Accutar Biotechnology’s Chimeric estrogen receptor degrader (AC699) Phase I data in breast cancer and Shangai/Sorrento’s Trop2 Antibody-Drug Conjugate (ESG401) Phase I/II data in China. 

Excitement builds around PD-1xVEGF bispecific antibodies, with anticipated updates on Akeso Biopharma/Summit Therapeutics’ ivonescimab and Biotheus/BioNTech’s PM8002/BNT327, stepping up their way as first-line treatment for TNBC.

However, AstraZeneca faces a setback as its capivasertib fails to meet primary endpoints in the CAPItello-290 Phase III trial for metastatic TNBC, a highly anticipated abstract. Despite this, AstraZeneca will still make a significant impact with additional data on ENHERTU (trastuzumab deruxtecan) from the Phase III DESTINY-Breast-12 and DESTINY-Breast06 studies, exploring HER2+ advanced/metastatic breast cancer and HER2-ultralow tumors in HR+ metastatic breast cancer.

Unveiling the latest in Breast Cancer

• Abstract Number – LBA 19
• Abstract Type – Proffered Paper session
• Indication - Metastatic triple-negative breast cancer (mTNBC)

Title: AstraZeneca dealt with a blow after its flagship breast cancer drug TRUQAP did not improve overall survival in a Phase III TNBC trial after receiving restrictive approval in HR+/HER2- breast cancer type

Executive Summary:  AstraZeneca's Phase III CAPItello-290 trial of capivasertib + paclitaxel in metastatic TNBC failed to meet its primary endpoints for overall survival, with results to be presented at ESMO 2024.

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As per DelveInsight, there were approximately 44,600 incident cases of TNBC in the United States, in 2023. It has been observed that, collectively, mutations in PIK3CA, AKT1, and alterations in PTEN affect approximately 35% of patients with TNBC. 1st-line treatment for advanced or metastatic TNBC usually consists of chemotherapy alone or in combination with immunotherapy with options generally associated with response rates between 30 to 50%.

Recently, in June 2024, AstraZeneca provided an update on its Phase III CAPItello-290 trial evaluating TRUQAP (capivasertib), a first-in-class, potent, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3), in combination with paclitaxel in patients with locally advanced or metastatic TNBC. The company stated that the combo failed to meet its dual primary endpoints of improvement in OS versus chemotherapy and placebo either in the overall trial population or in a subgroup of patients that had tumors with specific biomarker alterations (PIK3CA, AKT1 or PTEN). The company will be presenting these results as a late-breaking abstract at the ESMO 2024 conference. 

Despite modest advances, triple-negative breast cancer remains one of the most challenging forms of disease to treat due to the lack of known actionable biomarker targets, and chemotherapy-based regimens continue to be the mainstay of treatment. While the CAPItello-290 trial results have not shown hope, they provide important information to further understand understanding of the role of the PI3K/AKT pathway in this aggressive form of breast cancer where patients are in urgent need of new treatments.

This recent blow comes after TRUQAP received approval from the US FDA in 2023, in combination with fulvestrant for patients with HR+/HER2- locally advanced or metastatic breast cancer with one or more AKT pathway mutations. While AstraZeneca originally hoped for approval for all HR+/HER- patients, but unfortunately the green light came with a restrictive label. The FDA only approved TRUQAP for patients with AKT pathway mutations despite statistical significance in its primary endpoint in the wider patient population. The same combination was also recommended for approval in Europe in April 2024.

Despite the miss in TNBC, AstraZeneca continues to evaluate TRUQAP combinations across a range of cancers. The Phase III CAPItello-292 study, for instance, is looking at TRUQAP plus Faslodex and CDK4/6 inhibitors in patients with HR+/HER2- locally advanced, unresectable or metastatic breast cancer. In addition, TRUQAP is being tested in prostate cancer in combination with docetaxel and Johnson & Johnson’s prostate cancer drug ZYTIGA in the Phase III  CAPItello-280 and CAPItello-281 studies, respectively.

• Abstract Number – 240P and 235MO
• Abstract Type – Poster and Mini oral session 
• Indication - HR+/HER2− Early Breast Cancer

Title:  Elevating HR+/HER2− Early Breast Cancer Care: Novartis’ Ribociclib’s Performance in the NATALEE Trial

Executive Summary: Novartis’ KISQALI shows promising results in the NATALEE trial for HR+/HER2− early breast cancer, potentially expanding its market from metastatic to early-stage treatment, with data for both younger and older patients expected at ESMO 2024.

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Despite adjuvant endocrine therapy, approximately one-third of those diagnosed with stage II and more than half of those diagnosed with stage III HR+/HER2- early breast cancer (EBC) experience cancer recurrence.

Novartis’s NATALEE trial is a pivotal Phase III study assessing the efficacy and safety of KISQALI (ribociclib) combined with a nonsteroidal aromatase inhibitor (NSAI) in patients with HR+/HER2− early breast cancer, where recurrence risk remains a major concern, particularly for high-risk patients.

The drug has consistently demonstrated OS benefit while preserving or improving quality of life across three Phase III trials in metastatic breast cancer. Updates to the NCCN Guidelines for breast cancer, released in January 2023, recommend KISQALI as the only Category 1 preferred CDK4/6 inhibitor for first-line treatment of patients with HR+/HER2- metastatic breast cancer when combined with an aromatase inhibitor.

The latest data presented at the 2024 ASCO annual meeting demonstrated that ribociclib plus endocrine therapy showed an improvement in rates of invasive disease-free survival (iDFS), distant recurrence-free survival (DRFS), and distant disease-free survival (DDFS) in high-risk EBC patients with N0 disease. Furthermore, results announced at the San Antonio Breast Cancer Symposium (SABCS) in December 2023 showed KISQALI plus ET, lowered the risk of cancer recurrence by 25.1%, along with consistent clinically meaningful iDFS benefit across key pre-specified subgroups. 

Currently, available targeted therapies are approved only for a small proportion of patients, leaving a large number of people diagnosed with HR+/HER2- early breast cancer at risk of cancer returning, particularly those with high-risk N0 tumors. Novartis is set to present data from the Phase III NATALEE trial in both older and younger patients with HR+/HER2− early breast cancer in two separate abstracts at the ESMO 2024 conference, supporting its potential to benefit a broader range of patients. As per the company, the NATALEE data has been submitted to the US FDA and EMA in 2023, and further submissions to global authorities are ongoing, with the expected regulatory decision in 2H 2024.

With substantial efficacy in the NATALEE trial for early breast cancer, KISQALI could dramatically expand its market from its current use in the metastatic setting. The most direct competition for KISQALI in the early-stage breast cancer setting comes from VERZENIO, which has been approved in the adjuvant setting for HR+/HER2− high-risk early breast cancer based on the results of the monarchE trial. Abemaciclib’s role in reducing recurrence in early breast cancer gives it a strong foothold in the market. 

• Abstract Number – 637P
• Abstract Type – Poster
• Indication – Breast Cancer

Title:  Accutar Biotechnology to Present Phase I data of AC699: The Next-Gen Chimeric Estrogen Receptor Degrader in Breast Cancer

Executive Summary: AC699, a novel chimeric estrogen receptor degrader (CERD), is being evaluated in a Phase I trial for breast cancer, showing promising early results in safety and anti-tumor activity

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Endocrine therapy plays a crucial role in treating the more than 200,000 patients diagnosed annually with ER+/HER2- breast cancer. While selective ER degraders (SERDs) have extended progression-free survival in these patients, their use as monotherapy has demonstrated limited overall response rates (ORR). AC699, a novel chimeric estrogen receptor degrader (CERD), works by binding, ubiquitinating, and degrading ERα, facilitated by its interaction with an E3 ligase. This mechanism of action may result in greater specificity and more complete target blockade compared to SERDs. 

The drug is being evaluated in a Phase I trial for breast cancer, with key results expected at ESMO 2024. As a new therapeutic approach, AC699 holds significant potential for patients who have developed resistance to traditional endocrine therapies like SERMs and degraders SERDs. 

Previously at ASCO 2024, preliminary data from this Phase I trial of AC699 showed encouraging safety, tolerability, and anti-tumor activity at doses up to 300 mg taken orally once daily. The upcoming results at ESMO 2024 are expected to provide deeper insights into the potential of CERDs in breast cancer treatment. If AC699 proves successful, it could present an alternative to conventional endocrine therapies and CDK4/6 inhibitors. Additionally, a Phase II study is set to begin enrollment in 2024.

AC699 is part of the growing field of PROTAC (proteolysis-targeting chimeras) technology. Other companies are exploring similar degradation strategies, which may create competition in the next few years if they demonstrate clinical efficacy.

Top 10 Key Abstracts for Breast cancers