Inavolisib (GDC-0077) has shown potential in treating patients with refractory locally advanced or metastatic solid tumors harboring PIK3CA mutations, according to data from the phase 2 CRAFT trial (NCT04551521) presented at the 2024 ESMO Congress. The study highlighted a positive safety profile and encouraging disease control with inavolisib therapy.
Efficacy and Outcomes
At a median follow-up of 11.2 months, efficacy-evaluable patients (n = 25) achieved a disease control rate (DCR) of 60% at week 8 and 32% at week 16. By week 8, 4 patients experienced a partial response (PR), and 15 had disease control. However, by week 16, 6 of the initial 15 patients with disease control progressed, including one who had achieved a PR. Ultimately, 8 patients maintained disease control, characterized by either a response or stable disease (SD). One tumor-related death was reported at week 16 among patients who initially had disease control at week 8.
The median progression-free survival (PFS) was 3.52 months, and the 12-month overall survival (OS) rate was 51%.
"Inavolisib had a favorable safety profile and led to a DCR of 60% at 8 weeks and 32% week 16 in this cross-entity patient population," wrote lead study author Christoph E Heilig, MD, of the Department of Translational Medical Oncology, National Center for Tumor Diseases, Heidelberg and German Cancer Research Center, and colleagues, in a poster presentation.
Trial Design
The CRAFT trial is an open-label, multi-arm study evaluating the efficacy of combining molecularly targeted agents and PD-L1 inhibition with atezolizumab in patients with cancers harboring targetable molecular alterations. The analysis presented at ESMO focused on arm 5 of the CRAFT trial.
Each arm of the study assessed the treatment of adult patients with locally advanced/metastatic cancer refractory to one or more treatments, selected based on molecular tumor characteristics. Arm 5 specifically included patients with activating PIK3CA mutations. Patients with hematologic malignancies or primary brain cancer were excluded.
A total of 101 patients were enrolled in the CRAFT trial, with 72 receiving treatment. In arm 5, 25 patients received oral inavolisib at 9 mg once daily in 28-day cycles. The trial employed a Simon’s optimal two-stage design, initially enrolling 14 patients. If at least 4 patients achieved disease control, defined as a response or SD per RECIST 1.1 criteria at day 110, an additional 11 patients were enrolled.
Patient Characteristics and Treatment Response
The 25 patients with PIK3CA-mutated tumors in arm 5 were selected based on gene-panel testing, whole-genome sequencing/whole-exon sequencing, and transcriptome analyses in NCT MASTER. Broad molecular analysis in NCT MASTER was available for 21 of these patients.
The most frequently observed PIK3CA mutations were E545K (n = 10), E542K (n = 6), and H1047R/L (n = 3). Five patients had double mutations in PIK3CA.
Seven patients achieved disease control at week 16, including individuals with esophageal squamous cell carcinoma, chordoma, urethral squamous cell carcinoma, cervical squamous cell carcinoma, anal squamous cell carcinoma, and salivary duct carcinoma. These patients harbored various PIK3CA mutations, such as E545K, E542K, H1047R, and G1049R.
Safety Profile
The most frequently reported adverse effects in arm 5 included hyperglycemia (46%), diarrhea (46%), fatigue (29%), and constipation (17%), predominantly grade 1 or 2.
Ongoing Research
"Further investigations regarding possible predictors for response and mechanisms of resistance are ongoing," the study authors concluded, highlighting the need for continued research to optimize the use of inavolisib in PIK3CA-mutated cancers.
