Glecirasib with or without Cetuximab in previously treated CRC with KRAS mutation - Lancet Gastroenterol Hepatol

The study published in *Lancet Gastroenterology & Hepatology* investigates the efficacy and safety of glecirasib (JAB-21822), a novel covalent small molecule KRASG12C inhibitor, as monotherapy or in combination with the anti-EGFR antibody cetuximab in patients with previously treated colorectal cancer (CRC) harboring KRASG12C mutations. Below is a detailed summary:

### Background:

KRASG12C mutations are present in approximately 4% of patients with colorectal cancer and are associated with poor prognosis, reduced treatment response rates, and lower overall survival. Resistance to KRASG12C inhibitors has been linked to EGFR signaling, making combination therapies targeting KRASG12C and EGFR an area of interest for improving outcomes in these patients.

### Study Design:

Two open-label, non-randomized trials were conducted:

1. **JAB-21822-1002**: Evaluating glecirasib monotherapy (phase 1 dose escalation and phase 2a expansion).

2. **JAB-21822-1007**: Evaluating glecirasib in combination with cetuximab (phase 1b dose escalation and phase 2 expansion).

Participants were adults (≥18 years) with histologically or cytologically confirmed advanced or metastatic CRC harboring KRASG12C mutations. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and at least one measurable lesion per RECIST criteria. For phase 1, participants were required to have failed, been unsuitable for, or refused standard of care treatment. For phase 2, patients must have received at least first-line standard of care and experienced disease progression or intolerance.

• **Monotherapy Trial**: Participants received oral glecirasib at 800 mg once daily in 21-day treatment cycles until disease progression, intolerable toxicity, or withdrawal.
• **Combination Trial**: In addition to glecirasib (800 mg once daily), cetuximab was administered intravenously (initial loading dose of 400 mg/m² followed by either 250 mg/m² weekly or 500 mg/m² biweekly).

### Primary Endpoints:

• **Monotherapy Trial**:
• Phase 1: Safety (treatment-emergent adverse events, serious adverse events, dose-limiting toxicities, etc.).
• Phase 2a: Objective response rate (ORR, defined as complete or partial response).
• **Combination Trial**:
• Phase 1b: Dose-limiting toxicities, maximum tolerated dose, and recommended phase 2 dose.
• Phase 2: Objective response rate.

### Findings:

#### Monotherapy Trial:

• **Safety**:
• Among 44 patients, treatment-emergent adverse events (TEAEs) occurred in 100% of patients, with 53% experiencing grade ≥3 TEAEs.
• Treatment-related adverse events (TRAEs) were reported in 87% of patients, with 27% experiencing grade ≥3 TRAEs.
• Serious TEAEs were observed in 33% of patients, but none were treatment-related.
• No dose-limiting toxicities or clinically significant unexpected laboratory values of grade ≥3 were observed.
• **Efficacy**:
• Objective response rate was 23% (95% CI 11–38), with ten partial responses out of 44 patients.

#### Combination Trial:

• **Safety**:
• Among 47 patients, TEAEs occurred in 100% of patients, with 19% experiencing grade 3 or 4 TRAEs.
• The most common TRAEs included rash (83%), increased blood bilirubin (62%), increased conjugated bilirubin (36%), elevated alanine aminotransferase (34%), and anemia (32%).
• Serious TRAEs occurred in 9% of patients and included interstitial lung disease, pleural effusion, pericardial effusion, pyrexia, and rash. No treatment-related deaths were reported.
• **Efficacy**:
• Objective response rate was 50% (95% CI 35–65), with 23 partial responses out of 46 patients.

### Interpretation:

The study demonstrated that glecirasib monotherapy and its combination with cetuximab are promising treatment options for patients with advanced, refractory colorectal cancer harboring KRASG12C mutations. The combination therapy showed higher efficacy (50% ORR) compared to monotherapy (23% ORR), suggesting that simultaneous inhibition of KRASG12C and EGFR signaling pathways may overcome resistance mechanisms and enhance clinical outcomes.

### Safety Profile:

Both monotherapy and combination therapy were generally well tolerated, with manageable adverse events. The incidence of grade 3 or 4 TRAEs was similar between the two trials (20% for monotherapy and 19% for combination therapy). Serious TRAEs were rare, and no treatment-related deaths were observed.

### Conclusion:

Glecirasib, either as monotherapy or in combination with cetuximab, represents a promising therapeutic strategy for KRASG12C-mutated CRC. The results support further exploration of glecirasib-based combinations in earlier lines of treatment or in broader patient populations. The combination approach, in particular, warrants further investigation as it demonstrated enhanced efficacy compared to monotherapy.

### Future Directions:

Further studies are needed to:

1. Optimize glecirasib-based combination regimens.

2. Evaluate treatment in earlier disease stages or lines of therapy.

3. Investigate mechanisms of resistance to KRASG12C inhibitors.

4. Explore biomarkers for predicting response to therapy.

These trials are registered with ClinicalTrials.gov (NCT05009329 and NCT05194995) and remain active but are no longer recruiting participants.