Safety analyses of the INAVO120 randomised phase III trial of inavolisib or placebo with palbociclib–fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative, endocrine-resistant advanced breast cancer

BACKGROUND: INAVO120 (NCT04191499) demonstrated significantly improved progression-free/overall survival with inavolisib plus palbociclib-fulvestrant versus placebo plus palbociclib-fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative, endocrine-resistant advanced breast cancer. We provide comprehensive analyses of key selected adverse events and their management. MATERIALS AND METHODS: Inavolisib was given 9 mg orally once daily on days 1-28 of each 28-day cycle; palbociclib, at 125 mg orally once daily on days 1-21; fulvestrant, at 500 mg intramuscularly on days 1 and 15 of cycle 1, and every ∼28 days thereafter. Supportive therapies were used as clinically indicated. Key selected adverse events assessed included hyperglycaemia, stomatitis/mucosal inflammation, rash and diarrhoea, graded per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS: Data cut-off was 29 September 2023; median follow-up was 21.3 months (range 0-43.1; inavolisib arm) and 21.5 months (0.1-40.3; placebo arm). Inavolisib dose interruptions, reductions and discontinuations due to hyperglycaemia were observed in 27.2%, 2.5% and 0.6% of patients, respectively; the median time to first onset was 7.0 days (range 2.0-955.0). Metformin was the most commonly used antihyperglycaemic. No patients in the prediabetic population discontinued inavolisib due to hyperglycaemia. Inavolisib dose interruptions, reductions and discontinuations due to rash were observed in 1.2%, 0.6% and 0% of patients, respectively; the median time to first onset was 29.0 days (range 1.0-952.0). Topical hydrocortisone was most commonly used. Inavolisib dose interruptions, reductions and discontinuations due to stomatitis/mucosal inflammation were observed in 9.9%, 3.7% and 0.6% of patients, respectively; the median time to first onset was 13.0 days (range 1.0-610.0). Dexamethasone mouthwash was most commonly used. Inavolisib dose interruptions, reductions and discontinuations due to diarrhoea were observed in 6.8%, 1.2% and 0% of patients respectively; the median time to first onset was 13.0 days (range 1.0-610.0). Loperamide was most commonly used. Data were largely comparable across regions and ages. Inavolisib's safety profile was consistent with that of long-term treated populations. CONCLUSIONS: This analysis demonstrates the generally consistent, manageable and tolerable safety profile of inavolisib plus palbociclib-fulvestrant. Key selected adverse events were generally reversible and were controlled by concomitant medications and dose modifications.