Phase I/Ib study of inavolisib (INAVO) alone and in combination with endocrine therapy ± palbociclib (PALBO) in patients (pts) with <i>PIK3CA</i> -mutated, hormone receptor–positive, HER2-negative locally advanced/metastatic breast cancer (HR+, HER2–

1004 Background: INAVO, a highly potent and selective PI3Kα inhibitor that also promotes degradation of mutated p110α, is approved by the FDA in combination with PALBO + fulvestrant (FULV) for PIK3CA -mutated, HR+, HER2–, endocrine-resistant advanced BC. HG is a common on-target side effect of PI3K inhibitors. There are limited data for PI3K inhibitors in prediabetic/obese pts. Data from prediabetic/obese pts with HR+, HER2– LA/mBC treated with INAVO from a Phase I/Ib study (GO39374; NCT03006172) are reported here. Methods: Adults ≥ 18 years of age received INAVO alone (Arm A), + letrozole (LET) + PALBO (Arm B), + LET (Arm C), + FULV (Arm D), + FULV + PALBO (Arm E), or + FULV + PALBO + primary prophylactic metformin (Arm F). Data are reported across all arms unless indicated. Pts with baseline risk factors for HG were defined by HbA 1c ≥5.7%, fasting blood glucose ≥ 100 mg/dL, or body mass index ≥ 30 kg/m 2 . Adverse events (AEs) were reported using NCI-CTCAE v4, which utilizes fasting laboratory glucose values for HG severity grading, rather than clinical interventions used in v5. Results: Clinical cut-off was Jan 1, 2024. From190 pts treated, 110 (57.9%) were prediabetic/obese; their median time on INAVO was 222 days (range, 7 to 2,152) and mean cumulative dose intensity was 91.8%. Most prediabetic/obese pts discontinued INAVO due to progressive disease (82 [74.5%]); six (5.5%) discontinued INAVO due to an AE (one due to HG). HG was reported in 80.9% of prediabetic/obese pts (grade 3–4: 34.5%). In pts with two risk factors, 87.9% reported HG (grade 3–4: 39.4%). Among pts with HG, median time to onset was 14 days (range, 1 to 1,674) and 86.0% of events resolved by clinical cut-off. Median time to improvement or resolution of first worst grade ≥ 2 event was 8 days (range, 1 to 64). INAVO dose interruptions, reductions, and discontinuations due to HG were reported in 41.8%, 13.6%, and 0.9% of pts, respectively. The most common anti-HG medications were metformin (52.7%; biguanide; concomitant use in Arm F excluded), empagliflozin (25.5%; SGLT-2 inhibitor), sitagliptin (22.7%; DPP-4 inhibitor), and pioglitazone (13.6%; thiazolidinedione); insulin was used in 8.2% of pts. Median time to metformin start (excluding Arm F) was 14 days (range, 1 to 1,710); the median start dose was 1,000 mg total daily; and the highest daily start dose was 2,000 mg. More than one anti-HG medication was often needed. Conclusions: A high proportion of prediabetic/obese pts were included in GO39374. In most of these pts, HG was manageable with dose interruptions and oral anti-HG medications, most commonly metformin. Data support the use of INAVO in prediabetic/obese pts; further investigation of INAVO in pts with diabetes is warranted. Clinical trial information: NCT03006172 .