Phase 2 Trial Highlights Potential of Inavolisib for PIK3CA-Mutated Cancers

3D illustration of a tumor sample under a microscope: © catalin - stock.adobe.com

Inavolisib (GDC-0077) therapy demonstrated a positive safety profile and disease control in patients with refractory locally advanced or metastatic solid tumors harboring PIK3CA mutations, according to data from the phase 2 CRAFT trial (NCT04551521; EudraCT 2019-003192-18) presented at the 2024 ESMO Congress.

At a median follow-up of 11.2 months, efficacy-evaluable patients (n = 25) achieved a disease control rate of 60% at week 8 and 32% at week 16. At week 8, 4 patients had experienced a partial response (PR), and 15 total had disease control. At week 16, 6 patients of the original 15 patients who had disease control at week 8 transitioned to progressive disease, including 1 patient who had achieved a PR; 8 patients had disease control comprised of a response or stable disease (SD). One tumor-related death was reported at week 16 among the patients who had disease control at week 8.

Additionally, the median progression-free survival was 3.52 months, and the 12-month overall survival 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,” 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 wrote in a poster presentation of the data.

The Design of CRAFT

CRAFT is an open-label, 7-arm study evaluating the efficacy of combinations of molecularly targeted agents and PD-L1 inhibition with atezolizumab (Tecentriq) in patients with cancers harboring targetable molecular alterations. The analysis presented at ESMO focused on arm 5 of CRAFT.

Each arm of the study evaluated the treatment of adult patients with locally advanced/metastatic cancer refractory to 1 or more treatments, and patients were selected based on molecular tumor characteristics. Arm 1 included patients with BRAF V600E/K mutations; arm 2 featured patients with ERBB2 amplification/overexpression and activating ERBB2 mutations; arm 3 included patients with ALK rearrangements/mutations; arm 4 enrolled those with aberrations predicting increased PI3K-AKT pathway activity; arm 5 included patients with activating PIK3CA mutations; arm 6 included patients with aberrations predicting increased RAF-MEK-ERK pathway activity; and arm 7 featured patients with alterations predicting anti–PD-L1/anti–PD-1 sensitivity.

Patients were excluded from enrollment if they presented with either a hematologic malignancy or primary brain cancer.

A total of 101 patients were enrolled onto CRAFT, and 72 were treated. In arm 5, 25 patients received oral inavolisib at 9 mg once daily in 28-day cycles. Notably, the trial utilized a Simon’s optimal 2-stage design with 14 patients accrued in stage I. If 4 or more patients achieve disease control, consisting of a response or SD per RECIST 1.1 criteria at day 110, an additional 11 patients were accrued in stage II.

Treatment With Inavolisib

The 25 patients with PIK3CA-mutated tumors enrolled onto arm 5 of CRAFT were selected based on results from gene-panel testing, whole-genome sequencing/whole-exon sequencing, and transcriptome analyses in NCT MASTER; for 21 of these patients, a broad molecular analysis in NCT MASTER was available.

Notably, the most frequently observed PIK3CA mutations were E545K (n = 10), E542K (n = 6), H1047R/L (n = 3). Five patients had double mutations in PIK3CA.

In total, 7 patients achieved disease control at week 16. They included a male patient 50 years of age with esophageal squamous cell carcinoma and a E545K alteration who had SD; a male 51 years of age with chordoma and a E545K alteration who had SD; a male patient 70 years of age with urethral squamous cell carcinoma and a E542K alteration who achieved a PR; a female 51 years of age with cervical squamous cell carcinoma and an H1047R alteration who had SD; a female patient 69 years of age with anal squamous cell carcinoma and an E545K alteration who had a PR; a male 79 years of age with salivary duct carcinoma and a G1049R alteration who had a PR; and a male 66 years of age with chordoma harboring both E453K and Q546R alterations who achieved SD.

The most frequently noted adverse effects in arm 5 included hyperglycemia (46%), diarrhea (46%, fatigue (29%), and constipation (17%), which all occurred at mostly grade 1 or 2.

“Further investigations regarding possible predictors for response and mechanisms of resistance are ongoing,” study authors concluded.

REFERENCE:

Heilig CE, Teleanu MV, Desuki A, et al. Inavolisib in cancers with activating PIK3CA mutations: results from the CRAFT trial. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 198P.