Inavolisib Shows Promising Disease Control Rates, Safety in Patients With PIK3CA-Mutated Solid Tumors

Results of a CRAFT interim efficacy analysis demonstrate that treatment with inavolisib (GDC-0077) show promising disease control rates in a cross-entity patient population, including those who have rare tumors. Further details and data were presented at the European Society of Medical Oncology 2024 Congress, which was held September 13 to 17 in Barcelona, Spain.¹

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CRAFT, or Continuous ReAssessment with Flexible ExTension in Rare Malignancies, is an ongoing open-label, 7-arm, cross-entity phase 2 clinical trial (NCT04551521) investigating the efficacy of molecularly targeted agents and PD-L1 inhibition with atezolizumab (Tecentriq; Roche) in cancers with targetable molecular alterations. Adult patients with locally advanced or metastatic cancer refractory to 1 or more medical treatments enrolled and placed 1 of the following 7 groups depending on their disease state: BRAF V600E/K mutations (arm 1); ERBB2 amplification or overexpression and activating ERBB2 mutations (arm 2); ALK rearrangements or mutations (arm 3); aberrations predicting increased PI3K-AKT pathway activity (arm 4); activating PIK3CA mutations (arm 5); aberrations predicting increased RAF-MEK-ERK pathway activity (arm 6); and alterations predicting anti-PD-L1/anti PD-1 sensitivity (arm 7). Those with hematologic or primary brain cancers were excluded from the trial. The results presented in the ESMO presentation are about arm 5.^1,2

In arm 5, patients received 9 mg of inavolisib once per day. For all 7 arms, statistics are based on a Simon’s optimal 2-stage design in which 14 patients are accrued in stage I. If at least 4 patients achieve disease control at day 110—whether complete or partial control (CR/PR), or stable disease (SD) according to RECIST 1.1—then an additional 11 patients will be accrued in stage II. If 3 or fewer patients achieve disease control, then that study arm will be stopped.^1-3

The primary outcome measure is disease control rate, and the secondary outcome measure is progression-free survival (PFS) which will be assessed at a median follow-up of 24 months. Additional exploratory outcomes include the PFS ratio, overall survival, and patient-reported outcomes.^1-3

Analysis results from April 2024 indicate that 91 total patients were registered, and 63 were treated during CRAFT’s duration. Of those treated, 25 patients had PIK3CA-mutated tumors in arm 5. Fourteen patients accrued in stage 1 demonstrated a disease control rate of approximately 36% at day 110, including 2 PRs (1 urothelial cancer and 1 thyroid cancer). This led to the accrual of an additional 11 patients in stage II until March 2024.¹

According to the investigators, the most common toxicity was hyperglycemia. A total of 10 patients showed disease control at the interim tumor assessment at the 8-week period, whereas 7 are still on treatment with a pending tumor assessment. This first analysis demonstrates that inavolisib has promise in patients with rare tumors who are trying to achieve disease control.¹

In May 2024, the FDA granted priority review to inavolisib when in combination with palbociclib (Ibrance; Pfizer) and fulvestrant (Faslodex; AstraZeneca) for the treatment of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2 (HER2)-negative breast cancer with a PIK3CA mutation. The decision followed positive findings from the phase 3 INAVO120 clinical trial (NCT04191499), which demonstrated positive PFS, and significantly reduced risk of worsening disease compared with a placebo regimen.⁴

Ongoing research and further analysis will be necessary to further solidify inavolisib’s role in the breast cancer space. The CRAFT trial is still ongoing to clarify inavolisib’s efficacy and safety in other disease states.^1,4

REFERENCES

1. Heilig, CE, Teleanua, M-V, Desuki, A, et al. Abstract 198P — Inavolisib in cancers with activating PIK3CA mutations: Results from the CRAFT trial. Presented at: European Society of Medical Oncology Congress; Barcelona, Spain. September 13 to 17, 2024.

2. CRAFT: The NCT-PMO-1602 Phase II Trial. ClinicalTrials.gov identifier: NCT04551521. Updated May 22, 2024. Accessed September 17, 2024. https://clinicaltrials.gov/study/NCT04551521

3. Heilig CE, Horak P, Kreutzfeldt S, et al. Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial. ESMO Open. 2021;6(6):100310. doi:10.1016/j.esmoop.2021.100310

4. Gerlach, A. FDA Grants Inavolisib Priority Review for Treatment of PIK3CA-Mutated Breast Cancer. Pharmacy Times. May 31, 2024. Accessed September 18, 2024. https://www.pharmacytimes.com/view/fda-grants-inavolisib-priority-review-for-treatment-of-pik3ca-mutated-breast-cancer