JDQ443 is an investigational covalent KRAS G12C inhibitor derived from a structure-based drug design followed by extensive optimization of two dissimilar prototypes. In preclinical models, JDQ443 potently inhibited KRAS G12C cellular signaling and proliferation in a mutant-selective manner and demonstrated dose-dependent antitumor activity. According to the data presented at the ASCO 2023, at the data cutoff on February 1, 2023, around 96 patients (the safety data set) were there across dose escalation, food effect (FE), and dose-expansion cohorts. Moreover, in the efficacy data set, 27 patients with NSCLC were from dose escalation and FE cohorts. Apart from that, the preliminary ORR was found to be 57.1% (8/14) at the recommended dose for expansion of 200 mg BID, followed by a disease control rate of 92.9%.
In terms of safety, Treatment related adverse events (TRAEs) were of low frequency and low-grade events, with the following parameters achieved.
- No Grade 4-5 TRAEs
- No nausea, vomiting, or diarrhea higher than Grade 2
- Overall, ALT (alanine aminotransferase) and AST (aspartate aminotransferase) elevations were having low frequency and short duration events
KOL insights
“KontRASt-01 shows safety and preliminary efficacy of JDQ443 monotherapy in KRAS mutant NSCLC (and other solid tumors).” –Expert Opinion.
Conclusion
KRAS is the most frequently mutated of the three RAS genes, followed by NRAS and HRAS. The human KRAS gene is located on chromosome 12p12.1, encoded by six exons located at positions 12 and 13 in exon 1 and less frequently in codons 61, 63, 117, 119, and 146. KRAS protein is evenly expressed by most tissues but overexpressed only by a few, namely, skeletal muscle, myocardium, uterus, adrenal cortex, and certain bone marrow stem cells, which are otherwise rarely involved in KRAS-related carcinogenesis. The emblematic KRAS mutant cancers are pancreatic, colorectal, and lung adenocarcinomas. Around 30% of NSCLC cases have KRAS mutations in the United States, followed by 25% in Europe and 15% in Japan. Among all KRAS mutations in NSCLC, G12C contributes the most.
To overcome the resistance observed with other KRAS G12C inhibitors, JDQ443 was designed with a novel binding mechanism that forms novel interactions with KRAS under the switch II pocket, irreversibly trapping KRAS G12C in the inactive, GDP-bound state. Compared with the available KRAS G12C inhibitors sotorasib (LUMAKRAS) and adagrasib (KRAZATI), JDQ443’s structure reaches residue C12 without any interaction with residue H95. The company is evaluating different trials of JDQ443 in monotherapy as well as in combination therapy.
Lastly, as per DelveInsight’s estimates, we expect that JDQ443 as monotherapy could reach a peak revenue of approximately USD 200 million in 2032 in the United States for locally advanced or metastatic KRAS G12C mutant NSCLC. Additionally, the combination of JDQ443 with trametinib and cetuximab could reach a peak revenue of approximately USD 150 million in 2032 in the United States
