INAVO120 trial

By Dr. Arya Mariam Roy
of Roswell Park Comprehensive Cancer Center


Development of endocrine resistance remains a challenge in the management of HR-positive HER2-negative breast cancer (HR+ HER2- BC). Alterations in PI3K signaling are one of the major factors of endocrine resistance, with mutations in PIK3CA occurring in approximately 40% of HR+ HER2- BC cases (1) . The prevention of endocrine resistance is possible through combination triplet therapy, including endocrine therapy, CDK 4/6 inhibitors, and PIK3CA inhibitors. Inavolisib, a highly potent and selective PI3Kα inhibitor, facilitates specific degradation of mutated PI3Kα, demonstrating anti-tumor activity alone and in combination with endocrine therapy and Palbociclib in preclinical models (NCT03006172) (2) . The INAVO120 trial, a phase III study, investigated the efficacy and safety of the combination of inavolisib with palbociclib and fulvestrant in metastatic PIK3CA mutant HR+ HER2- BC (NCT04191499). Dr. Komal Jhaveri presented the trial at the San Antonio Breast Cancer Conference (Jhaveri et al. Phase III study of inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: INAVO120 primary analysis. SABCS 2023)


Patients with PIK3CA-mutated HR+ HER2- metastatic or advanced breast cancer experiencing progression during or within 12 months of completing adjuvant endocrine therapy were enrolled in the trial. Key eligibility criteria included fasting glucose < 126 mg/dL and HbA1c <6.0%. The trial randomized patients 1:1 to receive inavolisib + Palbociclib + fulvestrant (intervention arm) or placebo + Palbociclib + fulvestrant (control arm) (Total N= 325). Patients were followed up until progression or toxicity. The median progression-free survival (PFS) was significantly higher in the intervention arm compared to placebo (15 vs 7.3 months, HR = 0.43, 95% CI = 0.32 – 0.59, p<0.0001). The 18-month PFS was also higher in the inavolisib combination arm (46.2% vs 21.1%). PFS improvement was observed with the triplet therapy in both primary (11.4 vs 3.7 months, HR = 0.39, 95% CI = 0.24 – 0.61) and secondary (18.2 vs 9.7 months, HR = 0.55, 95% CI = 0.38 – 0.80) endocrine resistance. Overall survival (OS) data are not mature, but interim analysis shows an improved survival trend in the triplet arm (median OS: NR vs 31.1, HR = 0.64, 95% CI = 0.43 – 0.97, p= 0.0338). Median follow-up was 21.3 months. The objective response rate (ORR) was higher in the inavolisib combination arm (ORR = 58.4% vs 25%). Stomatitis (51.2% vs 26.5%), hyperglycemia (58.6% vs 8.6%), diarrhea (48.1% vs 16%), rash (25.3% vs 17.3%) were common in the inavolisib combination arm. Grade 3-4 hyperglycemia was observed in 5.6% of patients in the inavolisib arm, and 6.2% discontinued inavolisib treatment in the combination arm due to adverse events.


The combination of inavolisib with palbociclib and fulvestrant demonstrated a significant improvement in progression-free survival (PFS) with a manageable safety profile in patients with PIK3CA-mutant HR+ HER2-advanced breast cancer who experienced recurrence on or within 12 months of adjuvant endocrine therapy. This triplet combination may represent a new standard of care for this patient population. The enrolled study population primarily consisted of Asian patients, with minimal enrollment of African Americans, limiting the analysis of the drug combination in diverse racial and ethnic groups. The trial also had a higher percentage of patients who had received adjuvant tamoxifen, and this subgroup appeared to derive greater benefit from the triplet therapy. Although the drug was well-tolerated in the study population, it is worth noting that the population was carefully selected for a lower risk of hyperglycemia, which may not fully represent the real-world population. There is a need for increased inclusion of minorities, as well as pre-diabetic and type-II diabetic patients in future studies of this drug combinations.



1. Guerrero-Zotano A, Mayer IA, Arteaga CL. PI3K/AKT/mTOR: role in breast cancer
progression, drug resistance, and treatment. Cancer Metastasis Rev. 2016;35(4):515-24.
2. Fuso P, Muratore M, D'Angelo T, Paris I, Carbognin L, Tiberi G, et al. PI3K Inhibitors in
Advanced Breast Cancer: The Past, The Present, New Challenges and Future Perspectives.
Cancers (Basel). 2022;14(9).


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