1409P - DEnosumab in combination with PD-1 checkpoint blockade for MAINtenance therapy of KRAS-mutant advanced NSCLC after first-line immunotherapy: A prospective, single-arm, phase II trial (DEMAIN)

Background

Currently, there is still an unmet therapeutic need for patients (pts) with KRAS-mutated (mut) non-small cell lung cancer (NSCLC). Preclinical models have demonstrated the potential efficacy of the receptor activator for NF-κB ligand (RANKL) inhibitor in KRAS-mutant NSCLC. However, no clinical trials have been conducted to confirm the efficacy and safety of RANKL inhibitor combined with PD-1 inhibitors in this subset of pts.

Methods

Eligible pts had advanced KRAS-mutated NSCLC and were receiving first-line PD-1 inhibitor-based therapy. Pts were treated with PD-1 inhibitor (q3w) and denosumab (120 mg, q4w) for subsequent maintenance therapy regardless of bone metastases. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), overall survival (OS) and safety. Biological samples were retained for exploratory analysis.

Results

As of 30 March 2023, 20 pts were recruited for maintenance therapy, of which 13 (65.0%) pts had bone metastases. The median age was 65.5 (range: 40-74) years and the majority of patients were male (75.0%). Median PFS (mPFS) for the entire treatment course (mPFS1) and maintenance therapy (mPFS2) was 329 (95% CI: 277-380) days and 196 (95% CI: 145-247) days, respectively. Median OS was not reached. The most common adverse events (AEs) were dental symptoms (20%) and hypothyroidism (10%), and one (5%) pt discontinued the treatment due to grade 2 immuno-hepatitis. No grade 3-4 AEs occurred. Subgroup analysis suggested a greater survival benefit in patients with KRAS ^G12C mutation than in patients with KRAS ^non-G12C mutation (mPFS1, p=0.026; mPFS2, p=0.049). Interestingly, patients with bone metastases (mPFS1, p=0.138; mPFS2, p=0.100) appeared to benefit more than those without. Exploratory analysis (n=14) suggested that neither baseline tissue RANKL levels nor baseline blood soluble RANKL levels were associated with the survival benefit.

Conclusions

The combination of denosumab and PD-1 inhibitors demonstrated anti-tumor activity in the advanced KRAS-mutated NSCLC with a good safety profile, which warrants further investigation.

Clinical trial identification

Chinese Clinical Trial Registry (ChiCTR2100047759).

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.