Defactinib with avutometinib in patients with solid tumors: the phase 1 FRAME trial

Abstract

Use of signal transduction inhibitors as single agents to treat cancer leads to resistance because of the plasticity of intracellular signaling, and combination therapy can overcome this. We describe the first-in-human trial of avutometinib (RAF-MEK clamp) and defactinib (focal adhesion kinase inhibitor) in patients with solid tumors. The trial met its primary endpoint and recommended a phase 2 dose and schedule. The recommended phase 2 dose and schedule for a 28-day cycle was determined to be avutometinib 3.2 mg once a day, twice weekly (Monday and Thursday or Tuesday and Friday), and defactinib 200 mg twice a day, seven days a week. Both drugs were administered orally on a 3 weeks 'on' and 1 week 'off' basis. The pharmacokinetics and pharmacodynamics were consistent with previous reports of avutometinib and defactinib used as single agents. Key findings include an objective response rate of 42.3% (11 of 26; 95% confidence interval 23.4-63.1) and a median progression-free survival of 20.1 months (95% confidence interval 11.2-43.9) in patients with low-grade serous ovarian cancer. This study demonstrates the importance of intermittent dosing schedules in combined targeting of the mitogen-activated protein kinase and focal adhesion kinase pathways to improve tolerability, and has acquired proof of concept of anti-tumor activity against low-grade serous ovarian cancer, a tumor relatively resistant to chemotherapy. ClinicalTrials.gov identifier NCT03875820 .

Fig. 1. Schema of the dose escalation and dose expansion part of the trial.

Dose levels 2a and 2b were explored in parallel after dose level 1 had been deemed safe by the safety review committee. Dashed lines indicate that dose level 3 was not explored in the dose escalation part of the trial because stopping criteria were met for dose level 2b. Dose level 2a was selected for the dose expansion part of the trial. After ten patients in the KRAS^M NSCLC cohort and seven in the ST biopsy cohort had been treated with dose level 2b, the decision was made to update the RP2D to dose level 1 (the detailed rationale is provided in the main text). Other expansion cohorts include LGSOC, RAS-mutant CRC, PC, RAS–RAF mutant endometrioid subtype of gynecological cancers (ovarian, endometrial, endometriosis-related) (EOC); G12V-specific KRAS mutant nonsmall cell lung cancer (KRAS^G12V NSCLC). ST biopsy cohort, solid tumors (enriched for those with RAS mutations who were eligible for one pretreatment and two post treatment biopsies).

Fig. 2. Pharmacodynamic evaluation.

Biopsies were done in nine patients with a biopsy pretreatment, biopsy 4–24 h after a single dose of avutometinib (run-in dose) taken within 3–7 days of the first dose of combination therapy and a third biopsy during combination therapy 4–24 h of avutometinib dose taken within 2 weeks of the start of cycle 2. Levels of p-MEK and p-ERK were quantified in antibody bead-based assays in flash-frozen tissue and levels of p-FAK were quantified using immunohistochemistry. a, Samples from eight of nine patients passed quality control checks for p-MEK assessment in all three samples. The fold change in median fluorescence intensity (MFI) units is shown on the y axis. Horizontal dashed line represents baseline. b, Samples from four of nine patients passed the quality control checks for p-ERK assessment in all three samples. The fold change in MFI units is shown on the y axis. Open circles represent a patient with screening p-ERK levels below the lower limit of detection of the assay. Horizontal dashed line represents baseline. c, It was possible to detect cytoplasmic p-FAK in all three samples from seven patients. Absolute histochemical (H) score is shown on the x axis.

Fig. 3. Best overall response and PFS in patients with LGSOC treated on study.

a, Best overall response in patients with LGSOC in the dose escalation and dose expansion parts of the study. Dashed horizontal line represents −30%, which is considered a partial response as per response evaluation criteria for solid tumours (RECIST 1.1). b, Progression free survival (PFS) of all patients with LGSOC in the study. Histograms in gray indicate previous treatment with prior MEK inhibitors.

Extended Data Fig. 1. Best overall response in colorectal, pancreatic cancer and NSCLC patients of patients on study.

A. Reduction in size in tumors in the patients with KRAS mutated colorectal cancer and pancreatic cancer expansions. B. Reduction size in tumors in patients with KRAS mutated NSCLC in the escalation, KRAS mutated NSCLC expansion and KRAS G12V mutation cohort. NSCLC: Non-small cell lung cancer.

Extended Data Fig. 2. Progression free survival of LGSOC patients by KRAS mutation status.

Kaplan-Meier curves of progression free survival (PFS) for LGSOC patients by KRAS mutation status, from the first combination dose in the REP population. LGSOC: low-grade serous ovarian cancer. REP: Response evaluable patients.

Extended Data Fig. 3. Response in brain metastasis.

Patient with a diagnosis of LGOSC with brain metastasis was treated in the dose escalation in dose level 1 which is the recommended phase 2 dose. The patient had radiotherapy to brain metastases 6 months prior to trial entry. The patient, further had neurosurgery 2 months prior to trial entry. A. Pretreatment scans showing MRI bilateral brain metastasis. B. Representative sections form MRI scans showing reduction in flair and size of brain metastasis. MRI = magnetic resonance imaging. T1 = T1 weighted longitudinal relaxation time.