D-1553 is a novel oral and potent KRAS G12C inhibitor being developed by InventisBio. In vitro and in vivo antitumor activity of D-1553 alone or in combination with other therapies were evaluated in KRAS G12C mutated cancer cells and xenograft models. D-1553 showed selective and potent activity against mutated GDP-bound KRAS G12C protein. D-1553 selectively inhibited ERK phosphorylation in NCI-H358 cells harboring KRAS G12C mutation. Compared to the KRAS WT and KRAS G12D cell lines, D-1553 selectively inhibited cell viability in multiple KRAS G12C cell lines, and the potency was slightly superior to sotorasib and adagrasib.
Data from adult patients with CRC with KRAS G12C mutation who have been treated with D-1553 in Phase I/II study (NCT04585035) was presented in a poster session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. The study’s primary endpoint was to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of D-1553 in patients with KRAS G12C mutated locally advanced or metastatic solid tumors.
A total of 24 patients with previously heavily treated locally advanced or metastatic CRC were enrolled and received D-1553 600 mg (n = 23) or 800 mg (n = 1) BID monotherapy. Around 95% of patients had stage IV disease and 66.7% had ≥2 prior lines of therapies. The median treatment duration was 5.72 (1.51–11.83) months with a median follow-up of 8.31 (2.46–15.01) months.
D-1553 demonstrated a confirmed ORR of 20.8% (5/24) and DCR was 95.8% (23/24) with a median PFS of 5.42 months. The overall survival rate at 6 months was 95.8%. At the data cutoff date, 37.5% (9/24) of pts remain on study treatment. As far as safety is concerned treatment-related adverse events (TRAEs) of any grade occurred in 58.3% of the patients (14/24), most were Grade 1 or 2 in severity. A total of 12.5% of patients had grade 3/4 TRAEs (alanine aminotransferase increased, diarrhea, hypertension, and hypokalaemia). No TRAEs were fatal or resulted in D-1553 discontinuation. The most common (≥5%) TRAEs (any grade) were increased alanine aminotransferase or aspartate aminotransferase, increased total bilirubin or conjugated bilirubin, diarrhea, hypothyroidism and nausea.
KOL insights
“D-1553 expressed anti-cancer activity as monotherapy and enhanced tumor growth inhibition or regression in combination with other targeted therapies In colorectal cancer PDX models, TGI ranged from 60.9 to 105.7%, with 3/9 models showing tumor regression.”–Expert Opinion.
Conclusion
InventisBio's novel and potent KRAS G12C inhibitor, D-1553, exhibited promising antitumor activity in a Phase I/II study involving heavily pretreated colorectal cancer patients with the KRAS G12C mutation, D-1553 showed an objective response rate of 20.8% and a disease control rate of 95.8%. However, it is important to note that most KRAS inhibitors are being investigated in combination with cetuximab, a targeted therapy commonly used in colorectal cancer (CRC). These combination approaches have shown improved objective response rates (ORR) in CRC patients. Considering this, it is anticipated that the combination cohort of the ongoing study will likely yield better outcomes. This study aims to assess the safety and efficacy of D-1533 as a monotherapy as well as in combination with cetuximab or chemotherapy in patients with locally advanced or metastatic CRC. By combining D-1533 with other treatment modalities, there is a potential for enhanced therapeutic benefits in this patient population
