Phase Ib study of inavolisib (INAVO) + weekly paclitaxel (wP) in patients (pts) with locally advanced/metastatic (LA/m) incurable solid tumors: Safety, pharmacokinetics (PK), and preliminary antitumor activity.

1062 Background: wP is commonly used for treating solid tumors as a single agent or in combination with targeted agents. However, it has an unfavorable benefit–risk profile when given with pan-PI3K inhibitors or alpelisib. INAVO, a potent and selective PI3Kα inhibitor that also promotes mutated p110α degradation, was FDA approved in combination with palbociclib + fulvestrant for hormone receptor-positive, HER2-negative (HR+, HER2–), endocrine-resistant advanced breast cancer (BC) following recurrence on/after completing adjuvant endocrine therapy. We report data from INAVO + wP in pts with LA/m solid tumors from a Phase Ib study (CO42800; ISRCTN45319897). Methods: Eligible pts had progressed after standard systemic therapy. In part 1 (dose-escalation phase; 3+3 design), pts with LA/m incurable solid tumors received INAVO 6 mg/9 mg orally daily (PO QD) + wP (80 mg/m 2 ). In part 2 (dose-expansion phase), pts with LA/m incurable PIK3CA -mutated solid tumors (triple-negative BC [TNBC]; HR+, HER2– BC; others) received INAVO 9 mg PO QD (recommended dose from part 1) + wP. Primary endpoint: Safety/tolerability in parts 1 and 2. Secondary endpoints: Preliminary antitumor activity in part 2 (only TNBC and HR+, HER2– BC data are available); PK in parts 1 and 2. Results: Of 66 pts enrolled (parts 1 and 2), four received no treatment and eight were still on treatment at clinical cutoff (Oct 11, 2024). Reasons for study discontinuation were per protocol study completion (56.1%), death (16.7%), pt withdrawal (9.1%), loss to follow-up (1.5%), and other (4.5%). There were no dose-limiting toxicities. In safety-evaluable pts (n = 62), grade 3, 4, and 5 adverse events (AEs) occurred in 59.7%, 3.2%, and 0% of pts, respectively. One pt discontinued INAVO due to AEs; INAVO dose modifications (reduction/interruption) due to AEs occurred in 61.3% of pts. The most common AEs ( > 10% of pts) were diarrhea (61.3%), hyperglycemia (51.6%), and anemia (45.2%). Neutropenia (24.2%) and diarrhea (8.1%) were the most common grade 3–4 AEs. Serious AEs occurred in 30.6% of pts (mostly single AEs in individual pts, and unrelated to study treatment).In part 2, confirmed overall response rate in pts with TNBC (n = 20) was 50.0% and in pts with HR+, HER2– BC (n = 19) it was 36.8%. Median duration of confirmed response was 7.4 mo (95% confidence interval 5.2, 11.5) and 12.8 mo (3.7, not evaluable), respectively; median progression-free survival, 7.0 mo (3.5, 9.3) and 7.4 mo (6.2, 14.7). PK of INAVO and wP at Cycle 1, Day 15 were comparable to historic data. Conclusions: In CO42800, INAVO + wP was well tolerated in pts with LA/m solid tumors, including those with a PIK3CA mutation, with no new safety signals or drug–drug interactions observed. Encouraging preliminary antitumor activity shown in pts with HR+, HER2– BC or TNBC supports further investigation. Clinical trial information: ISRCTN45319897 .

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