I had the great pleasure of presenting data from the first in human phase I trial of PLN-101095, which is a first in class dual αvβ8/αvβ1 integrin inhibitor, given both as monotherapy and also in combination with pembrolizumab in patients with advanced solid tumours refractory to immune checkpoint  inhibitors.

The whole scientific premise to this particular trial is that in response to sustained immune activity solid tumours utilise integrin αvβ8 and αvβ1 activation of TGF-β to suppress and escape immune control. With that in mind, PLN-101095 was designed to potently block integrin αvβ8- and αvβ1-driven activation of TGF-β locally in a tumour microenvironment. This is different from previous strategies of systemically targeting the active TGF- β cytokine or the TGF-β receptor kinase or specific isoforms of TGF-β. PLN-101095 selectively enhances T-cell interferon gamma effector function and reduces fibroblast activation and also fibrotic tumour stroma, and the combination with orthogonal IO approaches such as with anti-PD-1/PD-L1 inhibitors is a rational approach.

So overall the inhibition of integrin αvβ8 and αvβ1was believed to block the activation of TGF-β, to reduce immunosuppression, thereby leading to a new or reinvigorated cancer immune response. PLN-101095 promotes immune checkpoint inhibitor responsiveness by inhibiting TGF-β and increasing interferon gamma expression. By doing this it actually shifts solid tumours to a high interferon gamma signature, immune checkpoint inhibitor responsive state.

That provided the rationale for this phase I open-label dose-escalation study in patients with solid tumours with prior immune checkpoint inhibitor resistance. We escalated through different dose levels from a starting dose of 250mg given twice daily up to a top dose of 2000mg b.i.d. of PLN-101095. We also combined this with pembrolizumab in patients who had prior PD-1 therapy with documented disease progression. All patients had to have primary or secondary resistance by SITC definitions. The primary and secondary endpoints included treatment-emergent adverse events, serious treatment-emergent adverse events and also dose limiting toxicities as well as pharmacokinetics, whilst exploratory endpoints included exploration of anti-tumour activity and also changes in blood-based biomarkers.

Overall we treated a total of 16 patients, this included a whole range of different tumour types, including lung cancer, cholangiocarcinoma, head and neck squamous cell cancer and renal cell carcinoma. PLN-101095 was generally well tolerated. The most common treatment-related adverse event was rash but all these rashes were grade 1-2. There was one treatment-related rash that was reported during the monotherapy period but otherwise these were primarily observed within two days of starting the combination therapy.

Pharmacokinetics showed a sustained IC90 coverage at doses at 1000mg b.i.d or greater and a pharmacokinetic profile supported continuous pharmacologic inhibition with b.i.d. dosing at steady state.

Responses were observed in patients with secondary immune checkpoint inhibitor resistance. We observed four iRECIST responses, including one complete response, two partial responses and one unconfirmed partial response. The immune checkpoint inhibitor secondary resistance overall response rate was 30% and the disease control rate was 60%. Overall we observed clinically significant durable responses in three out of the four iRECIST responses at doses of 1000mg b.i.d. and greater.

We also observed, interestingly, that there were increases in interferon gamma during monotherapy which may act as a potential biomarker of TGF-β inhibition and this will, indeed, be studied further in our dose expansion cohorts which are currently ongoing.

So, to conclude, PLN-101095 was generally well tolerated in the dose escalation part of this phase I trial with no new safety concerns emerging when the integrin inhibitor was combined with pembrolizumab. Early signals of anti-tumour activity were observed in patients with immune checkpoint inhibitor secondary resistance with an overall response rate of 30% and a disease control rate of 60%, especially when we treated these patients with both PLN-101095 plus pembrolizumab. Circulating interferon gamma may be a potential biomarker for early prediction of treatment response and dose expansion cohorts are now planned for initiation in the second half of 2026.

These data for PLN-101095 with pembrolizumab suggest the potential to meet a high unmet treatment need amongst these patients with secondary immune checkpoint inhibitor resistance with no new safety concerns.