Study of FAK (Defactinib) and PD-1 (Pembrolizumab) Inhibition in Advanced Solid Malignancies (FAK-PD1)

Programmed cell death receptor 1 (PD-1) blockade is a well-tolerated novel cancer immunotherapy with monotherapy response rates of 20-50% in tumour types such as bladder, melanoma, renal and non-small cell lung cancer (NSCLC), along with durable benefit. However, other tumour types (such as pancreatic cancer) have been poorly responsive and it is likely that the activity of PD-1 blockade is limited in many patients by the presence of additional immunosuppressive tumour microenvironment interactions. The investigators have recently shown in preclinical studies that Focal Adhesion Kinase (FAK) inhibition can re-model multiple aspects of the tumour immune microenvironment, shifting the balance from inhibitory Tregs, TAMs, CAFs & MDSCs, to one which supports an active CD8+ T cell adaptive immune response, suitable for synergistic anti-PD-1 therapy.

The current clinical study will explore whether FAK inhibition (defactinib/VS-6063) can be safely and tolerably combined with PD-1 blockade (pembrolizumab), with early indications of improved anticancer immunotherapy from this novel combination. The investigators will focus on three key tumour types, all cancers in clear need of improved therapies. NSCLC, aiming to augment the moderate monotherapy activity of PD-1 blockade; pancreatic cancer, aiming to release immunological activity in this otherwise resistant cancer; and, finally, mesothelioma, where emerging data suggests both agents may have monotherapy activity, including a potential additional mode of action via synthetic lethality of FAK inhibition in the ~50% of mesothelioma with NF2 mutation.

Phase I/IIa clinical study of defactinib (VS-6063, FAK inhibitor) in combination with pembrolizumab (anti-PD-1) therapy, initially in an "all-comers" dose escalation phase, and subsequently in expansion cohorts at the optimal doses in patients with: (a) pancreatic cancer; (b) NSCLC; and (c) mesothelioma. Safety, tolerability and clinical activity will be explored, as well as extensive translational work to characterise the biological effects and explore potential predictive and pharmacodynamic biomarkers.

PHASE I

Dose-escalation in an "all-comers" phase I population, with treatment-refractory advanced solid malignancies, unselected by tumour type as follows:

Cohorts 200 mg (IV) pembrolizumab every 3 weeks: plus 200 mg (oral) defactinib twice daily 200 mg (IV)pembrolizumab every 3 weeks: plus 400 mg (oral) defactinib twice daily

PHASE II

Expansions in pancreatic ductal adenocarcinoma, non-small cell lung cancer & mesothelioma (each 15-16 evaluable patients).

Pancreatic

Pancreatic expansion for response assessment (single arm). Optional paired biopsies prior to treatment and after 14 days of treatment. Concurrent therapy with pembrolizumab + defactinib (VS-6063) from the start (c.f. NSCLC & mesothelioma expansions below). 15 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 6.

• Classic "stromal" cancer, where the tumour microenvironment is believed to limit the activity of multiple agents. However broad preclinical data for various approaches to re-modelling the tumour microenvironment to permit immunotherapy.
• Minimal single-agent anti-PD-1/PD-L1 activity, explores hypothesis of conversion to sensitivity and predictive biomarkers for this.

NSCLC

NSCLC paired-biopsy expansion for tissue biomarkers. Mandatory biopsies prior to treatment and after around 14 days of treatment. 1:1 randomised split of patients having their on-treatment biopsy after concurrent therapy, or after a defactinib (VS-6063) monotherapy run-in. 16 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 11.

• Moderate single-agent anti-PD-1/PD-L1 activity explores hypothesis of amplification of sensitivity and predictive biomarkers for this.
• Paired-biopsy assessment of proof of mechanism biomarkers (FAK signalling, tumour immune microenvironment).

Mesothelioma

Mesothelioma paired-biopsy expansion for tissue biomarkers. Mandatory biopsies prior to treatment and after around 14 days of treatment. 1:1 randomised split of patients having their on-treatment biopsy after concurrent therapy, or after a defactinib (VS-6063) monotherapy run-in). 16 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 11.

• Emerging single-agent immune checkpoint, as well as potential FAK-inhibitor activity, explores hypothesis of multi-modal combination activity (microenvironment, checkpoint and synthetic lethality), as well as predictive biomarkers for this.
• Paired-biopsy assessment of proof of mechanism biomarkers (FAK signalling, tumour immune microenvironment).