The 2023 annual meeting of the American Association for Cancer Research (AACR) was held in Orlando, USA, from April 14th to 19th, 2023. Various important basic and clinical research results were presented at the conference, including the latest results of a Phase I study of IBI351 monotherapy in patients with advanced solid tumors from China. According to the latest data from this Phase I dose-escalation study (NCT05005234), the Phase II recommended dose of IBI351 monotherapy for advanced KRAS G12C mutated non-small cell lung cancer (NSCLC) patients shows good safety and promising efficacy.
The report mentions that the KRAS G12C mutation occurs in approximately 13% of NSCLC patients worldwide, but it is observed only in 2.9%~4.3% of NSCLC patients in China. This Phase I study observed the application of IBI351 in 74 patients with advanced solid tumors carrying the KRAS G12C mutation. Among these, 6 were colorectal cancer patients, 1 was a pancreatic cancer patient, and 67 NSCLC patients made up the largest group. The inclusion criteria for patients were as follows: pathologically confirmed tumors with the KRAS G12C mutation, standard treatment failure or intolerance, ECOG performance status scores of 0 or 1, and no prior treatment with KRAS inhibitors. The dose was escalated from 250 mg QD to 900 mg QD or from 450 mg BID to 750 mg BID. The primary endpoints of this study were safety, tolerability, and the exploration of the maximum tolerated dose and recommended Phase II dose of the KRAS inhibitor. Secondary endpoints included pharmacodynamics and antitumor activity as defined by RECIST v1.1.
Although the maximum tolerated dose was not reached, antitumor activity was observed in patients given 600 mg BID. Among the 30 NSCLC patients who received the 600 mg dose, 66.7% had partial remission (PR). In the overall patient population (n=67), 61.2% achieved partial remission. No complete remissions (CR) were observed. 30% of patients in the 600 mg group achieved disease stability, while 31.3% of the overall patient group achieved disease stability. Disease progression was observed in 2 patients after treatment.
The objective response rate (ORR) for the 600 mg dose group and the overall population was 66.7% (95% CI: 47.2%~82.7%) and 61.2% (95% CI: 48.5~72.9%), respectively, with no statistically significant difference (p>0.05). The confirmed ORR for the 600 mg dose group was 53.3% (95% CI: 34.3%~71.7%), with a disease control rate of 96.7% (95% CI: 82.8%~99.9%). These results make the 600 mg BID dose the recommended Phase II dose by researchers.
The study did not reach the median duration of response (DOR), but the 6-month DOR rate for the 600 mg group was 75.4% (95% CI: 39.8~91.7%).
The median progression-free survival (PFS) follow-up time for the 600 mg BID dose was 8.1 months, with a median PFS of 8.2 months (95% CI: 5.5 – not completed). There were 14 PFS events; the 6-month PFS rate was 58.9% (95% CI: 39.0%~74.3%), and the 9-month PFS rate was 47.3% (95% CI: 26.1~65.8%). PFS data is still maturing.
The median age of patients in this trial was 65 years (range, 42~76 years). 98.5% had adenocarcinoma pathology, and 38.8% had brain metastases. Most patients (53.7%) had previously received at least one line of systemic treatment, and 44.8% had received ≥2 lines of systemic treatment. One patient case shared in the report reflected this: the patient was a 70-year-old with a KRAS G12C mutation in NSCLC, with brain, left lymph node, and bone metastases. They had a history of various combination treatments. After 2 cycles of IBI351 treatment, the patient achieved partial remission, with persistent remission of the brain metastasis tumor. The patient experienced a grade 3 elevation of γ-glutamyl transferase (which decreased over time), as well as grade 2 rash, itching, and elevated serum amylase. At the time of the report, the patient was still participating in the study, with the efficacy being partial remission.
In terms of safety results, 94.0% of patients experienced treatment-related adverse events (TRAE) of any grade, of which 31.3% were grade 3 or higher TRAEs. The most common TRAEs were anemia (43.3%), itching (28.4%), elevated alanine aminotransferase (28.4%), elevated aspartate aminotransferase (28.4%), fatigue (22.4%), proteinuria (22.4%), and elevated bilirubin (20.9%). Grade 3 or higher TRAEs included anemia (7.5%), fatigue (4.5%), elevated alanine aminotransferase (1.5%), proteinuria (1.5%), and elevated bilirubin (1.5%). However, no TRAEs led to treatment discontinuation or death.
