PLN-101095 Combined with Pembrolizumab Shows Promising Activity in ICI-Refractory Solid Tumors
核心洞察
Interim data from a Phase 1 trial showed 50% objective response rate in patients receiving PLN-101095 with pembrolizumab at the highest dose tested (1000 mg BID), with confirmed partial responses across multiple tumor types including NSCLC (搜索), melanoma (搜索), and cholangiocarcinoma (搜索).
The integrin αvβ8 (搜索) and αvβ1 inhibitor PLN-101095 was generally well tolerated across all doses, with rash (33.3%), fatigue (22.2%), and squamous cell carcinoma/keratoacanthoma (22.2%) being the most common treatment-emergent adverse events.
The novel combination targets the TGF-β (搜索) pathway to potentially overcome immune checkpoint inhibitor resistance by increasing immune cell infiltration into the tumor microenvironment, offering hope for patients with limited treatment options.
Pliant Therapeutics has reported encouraging interim results from an ongoing Phase 1a/b trial (NCT06270706) evaluating the combination of PLN-101095 with pembrolizumab in patients with immune checkpoint inhibitor (ICI)-refractory advanced solid tumors (搜索).
The data, presented from the first three of five potential cohorts, demonstrated notable antitumor activity, particularly at the highest dose tested to date. Among six patients receiving PLN-101095 at 1000 mg twice daily (cohort 3) in combination with pembrolizumab, three achieved confirmed partial responses, representing a 50% objective response rate (ORR).
Promising Efficacy Across Multiple Tumor Types
The responses observed in cohort 3 spanned diverse cancer types, highlighting the potential broad applicability of this treatment approach:
- A non-small cell lung cancer (NSCLC) patient experienced a confirmed partial response with a 74% reduction in tumor size at week 18, with the initial response observed at week 10
- A cholangiocarcinoma patient achieved a confirmed partial response with a 48% reduction in tumor size at week 42, with the initial response noted at week 34
- A melanoma patient showed a confirmed partial response with a 42% reduction in tumor size at week 27, with the initial response seen at week 18
All three responding patients remain on treatment, according to the company. The other three patients in cohort 3 experienced unconfirmed disease progression.
"We are encouraged by these early responses given the refractory nature of the patient population enrolled in this trial," said Éric Lefebvre, MD, Chief Medical Officer of Pliant Therapeutics. "We look forward to sharing the final results from this trial in the future."
Trial Design and Patient Population
The open-label study enrolled patients with histologically or cytologically confirmed advanced or metastatic solid tumors for which pembrolizumab was indicated who had evidence of disease progression following prior treatment with the agent. Eligible patients were required to have at least one measurable lesion per RECIST 1.1 criteria, a life expectancy of at least three months, and no effective available therapeutic options.
A total of nine patients with six different tumor types were enrolled across the first three cohorts:
- Cohort 1 (n=1): PLN-101095 at 250 mg twice daily
- Cohort 2 (n=2): PLN-101095 at 500 mg twice daily
- Cohort 3 (n=6): PLN-101095 at 1000 mg twice daily
The treatment regimen consisted of PLN-101095 monotherapy for the first 14 days, followed by combination therapy with pembrolizumab (200 mg intravenously every three weeks) beginning on day 15. The dose-limiting toxicity (DLT) period began no earlier than day 35.
Safety Profile
Across all doses tested, PLN-101095 was generally well tolerated. Any-grade treatment-emergent adverse effects (TEAEs) occurred at a rate of 66.7% across all cohorts. The most common TEAEs occurring in at least two patients were rash (33.3%), fatigue (22.2%), and squamous cell carcinoma of skin/keratoacanthoma (22.2%).
In cohort 3 specifically, patients experienced any-grade TEAEs (66.7%), TEAEs during the monotherapy period (50.0%), TEAEs leading to discontinuation of PLN-101095 (16.7%), grade 3 or higher TEAEs (33.3%), and serious TEAEs (33.3%).
Mechanism of Action and Scientific Rationale
PLN-101095 is an oral small molecule inhibitor of integrins αvβ8 and αvβ1. The scientific rationale for combining this agent with pembrolizumab stems from the role of transforming growth factor-β (TGF-β (搜索)) in fostering an immunosuppressive tumor microenvironment that contributes to immune checkpoint inhibitor resistance.
Activated TGF-β (搜索) has been shown to create an immunosuppressive tumor microenvironment that contributes to ICI resistance and treatment failure. By blocking integrins αvβ8 and αvβ1, PLN-101095 prevents the activation of TGF-β, potentially stimulating immune activation by increasing immune cell infiltration into the tumor microenvironment.
In preclinical studies, PLN-101095 demonstrated monotherapy activity in reducing tumor volume and increased CD8+ T cell infiltration. When combined with an anti-PD-1 monoclonal antibody, it elicited a dose-dependent reduction in tumor volume and increased CD8+ T cell tumor infiltration compared with anti-PD-1 therapy alone.
Next Steps
The Phase 1 trial is currently enrolling patients to the fourth of five potential cohorts, which is examining PLN-101095 at a dose of 1000 mg three times per day in combination with pembrolizumab.
The primary endpoints of the study include the incidences of TEAEs, serious AEs, and DLTs, while secondary endpoints encompass ORR, disease control rate, and pharmacokinetic measures.
These interim results suggest that the combination of PLN-101095 and pembrolizumab may offer a new treatment option for patients with ICI-refractory advanced solid tumors (搜索), a population with significant unmet medical needs. The ability to potentially overcome resistance to immune checkpoint inhibitors could represent an important advancement in cancer immunotherapy.