Phase I/Ib Trial of Inavolisib Plus Palbociclib and Endocrine Therapy for PIK3CA-Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced or Metastatic Breast Cancer

Abstract

Purpose: To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110α that promotes the degradation of mutated p110α, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with PIK3CA-mutated, hormone receptor-positive/human epidermal growth factor receptor 2-negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172).

Methods: Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability.

Results: Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response.

Conclusion: Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.

FIG 1.

Flow diagram: (A) Inavo + Palbo + Letro arm and (B) Inavo + Palbo + Fulv arm. Fulv, fulvestrant; Inavo, inavolisib; Letro, letrozole; Palbo, palbociclib.

FIG 2.

Best percentage change from baseline in tumor SLD in the (A) Inavo + Palbo + Letro arm and (B) Inavo + Palbo + Fulv arm (safety-evaluable population with measurable disease). X indicates the mutation result obtained from a PCR-based test that does not distinguish the exact amino acid change (ie, H1047X as opposed to H1047R or H1047Y, etc) and/or as provided by sites. Active is defined as on study treatment as of the clinical cutoff date. Time on treatment: purple shading indicates study treatment of at least 6 months. cCR, confirmed complete response; cPR, confirmed partial response; Fulv, fulvestrant; HEL, helical domain; Inavo, inavolisib; KIN, kinase domain; Letro, letrozole; mul, multiple mutations; Palbo, palbociclib; PCR, polymerase chain reaction; PD, progressive disease; SD, stable disease; SERD, selective estrogen receptor antagonist and degrader; SLD, sum of longest diameters; uPR, unconfirmed partial response.

FIG 3.

Pharmacodynamic and pathophysiologic biomarker analyses. (A) % change from baseline to D15 of treatment in markers of proliferation (Ki67) and PI3K pathway activity (pAKT, pS6) as assessed by IHC (Inavo + Palbo + Letro arm; no paired IHC data available Inavo + Palbo + Fulv arm). Dose (mg), PIK3CA mutation type, and best overall response for each patient are shown. (B) MAF for PIK3CA as assessed by ctDNA at baseline (C1D1) and at 15 days on treatment (C1D15), grouped by best overall response. X indicates a mutation result obtained from a PCR-based test that does not distinguish the exact amino acid change (ie, H1047X as opposed to H1047R or H1047Y, etc) and/or as provided by sites. C, cycle; D, day; Fulv, fulvestrant; HEL, helical domain; IHC, immunohistochemistry; Inavo, inavolisib; KIN, kinase domain; Letro, letrozole; MAF, mutation allele frequency; mul, multiple mutations; NA, not available; pAKT, phosphorylated AKT; Palbo, palbociclib; PCR, polymerase chain reaction; PD, progressive disease; PR, partial response; pS6, phosphorylated S6; SD, stable disease.

FIG A1.

Inavo dose normalized steady state plasma (A) AUC_0-24 and (B) C_min following multiple doses of Inavo administered as a single agent or in the presence of concomitant medications. AUC_0-24, area under the concentration-time curve from 0 to 24 hours after dosing; C_min, minimum plasma concentration observed; Fulv, fulvestrant; Inavo, inavolisib; Letro, letrozole; Palbo, palbociclib.