Inavolisib (GDC-0077) has shown promising disease control rates in patients with PIK3CA-mutated solid tumors, including rare cancers, according to an interim efficacy analysis from the CRAFT trial presented at the European Society of Medical Oncology (ESMO) Congress 2024. The open-label, multi-arm, phase 2 trial (NCT04551521) is evaluating molecularly targeted agents and PD-L1 inhibition in cancers with specific molecular alterations.
CRAFT Trial Design and Results
The CRAFT trial includes seven arms, each targeting different molecular alterations. Arm 5 specifically focuses on patients with activating PIK3CA mutations who received 9 mg of inavolisib once daily. The primary outcome measure is disease control rate (DCR), with progression-free survival (PFS) as a secondary endpoint.
An analysis from April 2024 included 25 patients with PIK3CA-mutated tumors in arm 5. Results showed a DCR of approximately 36% at day 110, with 2 partial responses (PRs) observed in patients with urothelial cancer and thyroid cancer. According to the investigators, the most common toxicity was hyperglycemia. At the 8-week interim tumor assessment, 10 patients showed disease control, and 7 remained on treatment with pending tumor assessments.
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 that 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.
Detailed Efficacy Data
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%.
PIK3CA Mutations and Patient Characteristics
The most frequently observed PIK3CA mutations in the trial were E545K (n = 10), E542K (n = 6), and H1047R/L (n = 3). Five patients had double mutations in PIK3CA. Disease control at week 16 was observed in patients with various tumor types and PIK3CA mutations, including esophageal squamous cell carcinoma (E545K), chordoma (E545K), urethral squamous cell carcinoma (E542K), cervical squamous cell carcinoma (H1047R), anal squamous cell carcinoma (E545K), salivary duct carcinoma (G1049R), and chordoma (E453K and Q546R).
Safety Profile
The most frequently reported adverse events in arm 5 were hyperglycemia (46%), diarrhea (46%), fatigue (29%), and constipation (17%), primarily grade 1 or 2 in severity.
Regulatory Context and Future Directions
In May 2024, the FDA granted priority review to inavolisib in combination with palbociclib (Ibrance; Pfizer) and fulvestrant (Faslodex; AstraZeneca) for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2 (HER2)-negative breast cancer harboring a PIK3CA mutation. This decision was based on positive results from the phase 3 INAVO120 clinical trial (NCT04191499), which demonstrated improved PFS compared to placebo.
Ongoing research aims to further clarify inavolisib’s role in treating various cancers and to identify potential predictors of response and mechanisms of resistance.
