Avenzo Reports Updated Phase 1 Data for AVZO-021 Showing Clinical Activity and Favorable Tolerability in Heavily Pretreated HR+/HER2- Breast Cancer
Avenzo Therapeutics has announced updated clinical findings from the Phase 1 portion of its ongoing Phase 1/2 clinical study evaluating AVZO-021, the company’s investigational cyclin-dependent kinase 2 (CDK2) selective inhibitor, in patients with advanced cancers. The latest results, presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated encouraging antitumor activity and a favorable safety profile in heavily pretreated patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer.
The updated dataset further supports the growing scientific rationale for targeting CDK2 as a strategy to overcome resistance that develops following treatment with CDK4/6 inhibitors, which remain a cornerstone of therapy for HR+/HER2- metastatic breast cancer. Despite the success of CDK4/6 inhibitors, many patients eventually experience disease progression, creating a significant unmet need for new therapeutic approaches capable of addressing treatment resistance.
According to Avenzo, AVZO-021 continues to demonstrate the potential to serve as a differentiated therapy in this setting, combining clinical activity with a tolerability profile that may support both monotherapy and combination treatment strategies.
Addressing Resistance in HR+/HER2- Breast Cancer
HR+/HER2- breast cancer is the most common subtype of breast cancer and accounts for the majority of metastatic breast cancer diagnoses. Over the past decade, the introduction of CDK4/6 inhibitors combined with endocrine therapy has dramatically improved outcomes for many patients, delaying disease progression and extending survival.
However, resistance to CDK4/6 inhibition remains a major challenge. As tumors evolve, cancer cells frequently activate alternative pathways that allow them to continue proliferating despite ongoing treatment. One of the key mechanisms implicated in this resistance process is activation of CDK2 signaling.
Growing evidence suggests that CDK2 plays a critical role in enabling tumor cells to bypass CDK4/6 blockade, making it an attractive Avenzo therapeutic target for patients whose disease has progressed following standard treatment.
Dr. Manish R. Patel, Director of Drug Development at Florida Cancer Specialists and Sarah Cannon Research Institute, highlighted the importance of this approach, noting that patients who progress after CDK4/6 inhibitor therapy have relatively few treatment options available.
He explained that CDK2 is increasingly recognized as an important driver of resistance in HR+/HER2- breast cancer and that the updated AVZO-021 data continue to provide encouraging evidence supporting the therapeutic potential of selective CDK2 inhibition.
Phase 1 Study Evaluates Monotherapy and Combination Therapy
The ongoing Phase 1/2 study is investigating AVZO-021 both as a single agent and in combination with fulvestrant, an endocrine therapy commonly used in advanced HR-positive breast cancer.
Using a March 30, 2026 data cutoff for safety analyses, investigators reported results from 64 treated patients. Of these, 51 patients with advanced solid tumors received AVZO-021 monotherapy across dose levels ranging from 20 mg to 250 mg once daily. An additional 13 patients with HR+/HER2- breast cancer received AVZO-021 in combination with fulvestrant at dose levels of either 150 mg or 200 mg once daily.
The patient population represented a heavily pretreated group. Among all 51 patients treated with monotherapy, the median number of prior therapies received in the metastatic setting was three. Importantly, every patient with HR+/HER2- breast cancer had previously been treated with at least one CDK4/6 inhibitor, while approximately one-quarter had received two or more prior CDK4/6 inhibitor regimens.
These characteristics underscore the advanced nature of the disease and the limited treatment options available to many participants enrolled in the study.
Clinical Activity Demonstrated Across Multiple Patient Groups
Efficacy analyses were based on a May 7, 2026 cutoff date and included 39 evaluable patients.
Among these individuals were 26 patients with HR+/HER2- breast cancer or CCNE1-amplified solid tumors treated with AVZO-021 monotherapy at doses of 150 mg once daily or higher. The analysis also included 13 patients with HR+/HER2- breast cancer treated with AVZO-021 in combination with fulvestrant.
One of the most notable findings involved progression-free survival among patients with HR+/HER2- breast cancer.
Across all monotherapy dose levels, the median progression-free survival for 33 HR+/HER2- breast cancer patients reached 5.3 months. These patients had received a median of four prior lines of Avenzo therapy in the metastatic setting, reflecting a population with advanced and treatment-resistant disease.
The median follow-up period was 8.4 months, providing a meaningful timeframe for evaluating disease control and durability of benefit.
Researchers also observed a high disease control rate among patients receiving higher-dose monotherapy.
Among 20 efficacy-evaluable HR+/HER2- breast cancer patients treated with AVZO-021 at doses of 150 mg once daily or above, the disease control rate reached 85%. Disease control included both objective responses and prolonged stabilization of disease.
Tumor Responses Observed in Monotherapy and Combination Arms
Additional evidence of antitumor activity was seen in the objective response data.
Among 26 efficacy-evaluable patients receiving AVZO-021 monotherapy, four patients achieved tumor responses. Three of these responses were confirmed according to standard response assessment criteria, while one additional patient achieved an unconfirmed response and remained on treatment pending confirmatory imaging.
The combination arm also produced encouraging results.
Among 13 efficacy-evaluable HR+/HER2- breast cancer patients treated with AVZO-021 alongside fulvestrant, two patients achieved confirmed responses.
Notably, all responding patients remained on therapy at the time of data cutoff, suggesting sustained clinical benefit. Three patients had continued treatment for more than 48 weeks, indicating the potential durability of response associated with AVZO-021.
These findings support further evaluation of the Avenzo therapy both as a standalone treatment and as part of combination strategies aimed at addressing resistance in hormone receptor-positive breast cancer.
Favorable Safety Profile Continues to Differentiate AVZO-021
In addition to demonstrating clinical activity, AVZO-021 continued to exhibit a manageable safety profile.
Historically, inhibitors targeting cyclin-dependent kinases have often been associated with substantial gastrointestinal and hematologic toxicities. Such adverse events can limit treatment duration and reduce patient quality of life.
The updated Phase 1 data suggest that AVZO-021 may offer a differentiated safety profile compared with less selective kinase inhibitors.
The most commonly reported treatment-emergent adverse events occurring in more than 20% of patients included nausea, fatigue, anemia, and vomiting.
Importantly, the majority of adverse events were classified as Grade 1 or Grade 2, indicating relatively mild to moderate severity.
The low incidence of severe gastrointestinal and hematologic toxicities continues to support the potential use of AVZO-021 in combination regimens, where tolerability is often a critical consideration.
Pharmacokinetic Data Support Continuous Target Inhibition
Researchers also reported updated pharmacokinetic and pharmacodynamic findings that further support the clinical development of AVZO-021.
Data indicated that continuous CDK2 target coverage was achieved at dose levels of 90 mg once daily and higher. Sustained target inhibition is considered important for maximizing Avenzo therapeutic effectiveness against cancer cells that rely on CDK2 signaling.
The study also found comparable drug exposure levels between patients receiving AVZO-021 as monotherapy and those receiving the drug in combination with fulvestrant.
This observation suggests that no significant drug-drug interactions are occurring between the two therapies, supporting continued development of the combination approach.
Additionally, investigators reported no meaningful food effect in a pilot substudy, indicating that dosing flexibility may be possible in future clinical use.
Researchers also observed decreases in circulating tumor DNA (ctDNA), providing additional biological evidence that the Avenzo therapy is exerting antitumor activity.
Avenzo believes the emerging clinical profile of AVZO-021 supports broader exploration of combination treatment approaches.
The company is currently evaluating AVZO-021 together with AVZO-023, its selective CDK4 inhibitor, in combination with fulvestrant as part of the ongoing ORION-1 Phase 1/2 clinical study.
This strategy is based on the hypothesis that simultaneous targeting of CDK4 and CDK2 may more effectively suppress the escape mechanisms that drive resistance in HR+/HER2- breast cancer.
Dr. Mohammad Hirmand, Co-founder and Chief Medical Officer of Avenzo Therapeutics, stated that the latest data continue to reinforce confidence in AVZO-021’s clinical potential.
He noted that the combination of encouraging efficacy signals and favorable tolerability supports continued advancement of the program as the company works to develop meaningful new treatment options for patients whose cancers have progressed after current standards of care.
As enrollment and follow-up continue, future updates from the ORION-1 study are expected to provide additional insights into the role that selective CDK2 inhibition may play in the evolving treatment landscape for hormone receptor-positive breast cancer.
About Avenzo Therapeutics
Avenzo Therapeutics is a clinical-stage biotechnology company focused on developing next-generation oncology therapies for patients. The company’s pipeline includes potentially differentiated small molecules and antibody-drug conjugates (ADCs). Avenzo’s small molecule inhibitors, AVZO-021 and AVZO-023, are novel, highly potent and selective inhibitors of CDK2 and CDK4, respectively, which are key enzymes involved in cell cycle regulation. AVZO-021 is being studied in a Phase 1/2 study for the treatment of advanced solid tumors and in combinations in HR+/HER2- metastatic breast cancer.
AVZO-021 and AVZO-023 are being studied in the ORION-1 Phase 1/2 study for the treatment of HR+/HER2- metastatic breast cancer, where AVZO-023 is administered in combination with endocrine Avenzo therapy, with or without AVZO-021. Avenzo’s first ADC drug candidate, AVZO-1418, is a potentially differentiated EGFR/HER3 bispecific ADC that is being studied in the AVENTINE-1 Phase 1/2 study for the treatment of advanced solid tumors. Avenzo’s second ADC drug candidate, AVZO-103, is a potentially differentiated Nectin4/TROP2 bispecific ADC that is being studied in the BEACON-1 Phase 1/2 study for the treatment of advanced solid tumors. Avenzo is headquartered in San Diego, California.
