KEY TAKEAWAYS
- Part A of an ongoing phase 1/2 study assessed the tolerability of CFI-402411 in combination with pembrolizumab and as a single agent in advanced malignancies.
- CFI-402411 showed well-tolerance with manageable adverse events. Positive responses were observed in monotherapy and CPI combination for previously exposed patients.
Preliminary findings indicate a tolerable safety profile for CFI-402411 (a highly potent HPK1 inhibitor) and notable efficacy signals observed in specific tumor types.
In the ongoing phase 1/2 trial, researchers analyzed the initial segment (Part A) employing a 3+3 design to assess the daily CFI-402411 dose with subsequent dose expansion.
For Part B, they investigated the combination of CFI-402411 with pembrolizumab (200mg) utilizing a BOIN design and dose expansion in tumors eligible for pembrolizumab.
Dose limiting toxicity (DLT) was defined as any grade ≥3 toxicity occurring in cycle 1, with the starting dose set at 80mg.
As of May 2, 2023, the trial has enrolled 59 patients (A: 40 patients; B: 19 patients). In the United States, eligible patients had prior checkpoint inhibitor (CPI) treatment. Common.
Diagnoses for Part A included colorectal (11 patients), melanoma (6 patients), pancreatic (5 patients), and non-small cell lung and prostate cancers (2 patients each).
For Part B, prevalent diagnoses comprised head and neck squamous cell (3 patients) and esophageal, non-small cell lung, and small cell lung cancers (2 patients each).
Part A examined 9 dose levels (80 – 800mg), while Part B tested 5 dose levels (60 – 400mg) to date.
Immune-related adverse events (irAEs) were noted in 7 patients (A: 18%) and 5 patients (B: 26%). Grade ≥3 adverse events occurred in 25 patients (A: 63%) and 10 patients (B: 53%). Serious adverse events (SAEs) were reported in 21 patients (A: 53%) and 11 patients (B: 58%).
Diarrhea was the most common treatment-emergent adverse event (TEAE) (A: 73%; B: 47%), related adverse event (A: 63%; B: 42%), irAE (A: 15%; B: 11%), and grade ≥3 adverse event in A (18%).
In Part B, the most common grade ≥3 adverse events were pulmonary embolism (PE) and AST increase (11% both). The predominant SAEs were sepsis (A: 15%) and PE (B: 11%).
Diarrhea emerged as the most common dose-limiting toxicity (DLT) at 400mg plus pembrolizumab, as well as at 800mg, 720mg, and 640mg in monotherapy doses.
Disease control rates (complete response, partial response, or stable disease ≥6 weeks from baseline) at 3 months were 18% (A) and 29% (B).
Notably, two head and neck squamous cell carcinoma (HNSCC) patients achieved a partial response (A: 400mg) and confirmed a complete response (B: 60mg plus pembrolizumab).
Another HNSCC patient (B: 400mg plus pembrolizumab) experienced a 16% reduction in tumor lesion size at week 5 and remains in the study.
Additionally, one renal cell carcinoma patient achieved long-term stable disease, lasting 2 years. Importantly, all four patients had prior exposure to checkpoint inhibitors.
The tolerability of CFI-402411 was revealed during the study and was characterized by a manageable adverse event (AE) profile.
Encouraging responses were observed both in the monotherapy setting and when administered in conjunction with checkpoint inhibitors (CPI) in patients previously exposed to CPIs.
Currently, the expansion of monotherapy in Part A at the 560mg dose is in progress, specifically targeting head and neck squamous cell carcinoma (HNSCC) and renal cell carcinoma (RCC).
Source: https://jitc.bmj.com/content/11/Suppl_1/A835
Clinical Trial: https://clinicaltrials.gov/study/NCT04521413
Papadopoulos KP, Laurie SA, Spira A, et al741 TWT-101: a first-in-clinic study of CFI-402411, a hematopoietic progenitor Kinase-1 (HPK1) inhibitor, as single agent or combined with pembrolizumab in subjects with advanced solid malignanciesJournal for ImmunoTherapy of Cancer 2023;11:doi: 10.1136/jitc-2023-SITC2023.0741
