ASCO Direct™ Washington DC: Dr Isaacs Discusses Results from INAVO120
Presenter
Claudine Isaacs, MD, FRCPC, Georgetown University
Conference
2024 ASCO Direct™ Washington DC
The Bottom Line
The INAVO120 study explored the efficacy of inavolisib, a phosphatidyl inositol 3 kinase (PI3K) inhibitor type drug, in combination with the cyclin-dependent kinase 4/6 inhibitor drug palbociclib and the selective estrogen receptor degrader (SERD) fulvestrant for patients with hormone receptor-positive (HR+), Human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC) in the first line setting, for patients who had relapsed on or within 12 months of completing their adjuvant endocrine therapy, and whose tumors had a mutation in the PIK3CA gene. Results reported at 2024 Annual Meeting of the American Society of Clinical Oncology (ASCO) showed that the combination significantly improved the endpoint of progression-free survival (PFS), although the regimen had some notable side effects. In her presentation at the 2024 ASCO Direct™ Washington DC conference, Dr Claudine Isaacs from Georgetown University considered these findings in the context of previous findings from the CAPItello-291 study of capivasertib for patients with AKTpathway-altered tumors.
Background
Patients with HR+/HER2− metastatic breast cancer (mBC) are typically managed with endocrine therapy (ET) combined with targeted agents like CDK4/6 inhibitors (CDK4/6i). Disease progression in these patients, however, presents a challenge, particularly in those who relapse on, or shortly after, completing their adjuvant endocrine therapy, and in tumors with PIK3CA mutations or alterations in the AKT pathway. The INAVO120 and CAPItello-291 studies provide an example of how pathway-targeted agents may enhance clinical outcomes in these patients.
Trial Design and Patients
The INAVO120 Study
Design: This was a Phase III randomized trial comparing inavolisib plus palbociclib and fulvestrant versus placebo with the same backbone regimen in patients with PIK3CA-mutated HR+/HER2− mBC as first line therapy for advanced disease.
Patient Population: The study included those patients who relapsed during, or shortly after completing their ET. About 50% of patients had liver metastases, and many had received prior chemotherapy or ET for their disease.
Endpoints: PFS was the primary endpoint, with secondary endpoints including safety and adverse event profiles.
CAPItello-291 Study
Design: This was a Phase III randomized trial assessing capivasertib plus fulvestrant versus placebo plus fulvestrant in patients with AKT pathway-altered tumors who had progressed on prior ET and CDK4/6i either in the metastatic setting, or within 12 months of completing adjuvant therapy with an aromatase inhibitor. Patients were allowed to have received up to 2 prior lines of endocrine therapy and 1 prior line of chemotherapy in the advanced setting.
Endpoints: PFS was the primary endpoint with secondary outcomes including safety and tolerability.
Main Trial Results
INAVO120
PFS Improvement: Results presented at ASCO 2024 showed the median PFS was 15 months with inavolisib compared to 7.3 months in the placebo arm—an improvement that Dr Isaacs described as both significant and clinically meaningful.
Landmark Analysis: At 12 months, 56% of patients in the inavolisib arm were progression-free, as compared to 33% in the control group.
CAPItello-291
PFS Improvement: Patients with AKT-altered tumors showed a median PFS of 7.2 months with capivasertib versus 3.6 months with placebo. The overall population also benefited, with a 4.2-month PFS improvement.
Secondary Findings: Even patients without AKT pathway alterations showed some benefit, suggesting capivasertib's broader activity.
Adverse Events and Toxicities
INAVO120
Common Adverse Events: Hyperglycemia, diarrhea, rash, and stomatitis occurred frequently, findings which were reflective of the known toxicity profile of PI3K inhibitors.
Management: Approximately half of patients experienced significant adverse events requiring proactive management.
CAPItello-291
Safety Profile: There were lower rates of hyperglycemia with capivasertib as compared to other PI3K inhibitors like alpelisib. Diarrhea and rash were reported but were generally manageable.
Discontinuation Rates: Treatment-related adverse events led to discontinuation in 13% of patients in the capivasertib arm, which was significantly lower than the 25% seen with alpelisib in similar studies.
Conclusions and Faculty Insights
Dr Isaacs emphasized the importance of the recent findings from INAVO 120, as well as the previously reported finding from CAPItello-291 for refining targeted therapy options for HR+/HER2− mBC. In the case of INAVO120, the significant PFS benefit highlights the potential of inavolisib in high-risk, PIK3CA-mutated populations. Toxicities, however, require careful patient selection and management. Earlier findings from CAPItello-291 show that capivasertib offers a promising alternative to PI3K inhibitors, particularly for patients with AKT pathway alterations. The relatively favorable safety profile for capivasertib may also expand its use beyond the selected population studied in the trial. Dr Isaacs also noted the practical challenges associated sequencing such therapies, and advocated for the use of molecular profiling to assess tumor mutations at both diagnosis, and at the time of progression, as a means to guide treatment. She also highlighted the need for further studies to address long-term outcomes, sequencing strategies, and patient quality of life for patients on these therapies.
Speaker Disclosure Information: Dr Isaacs reported the following disclosures for this presentation: Consultancies: AstraZeneca, Genentech, Gilead, ION, Merck, Medscape, MJH Holdings, Novartis, Pfizer, PUMA, Seagen; Royalties: Wolters Kluwer (Up to Date); McGraw Hill (Goodman and Gillman); Institutional Research Support: Tesaro/GSK; Seattle Genetics; Pfizer; AZ; BMS; Genentech; Novartis; Regeneron.