Real-world efficacy of cabozantinib in combination with pemetrexed and carboplatin followed by pemetrexed-cabozantinib maintenance as first-line therapy for metastatic KRAS-mutant lung adenocarcinoma.

278

Background: KRAS-mutant advanced non-small-cell lung cancers (NSCLC) have shown suboptimal outcomes on standard chemo-immunotherapy. Cabozantinib, a multi-kinase inhibitor targeting MET, VEGFR, and AXL, may overcome resistance mechanisms here and enhance chemotherapy efficacy. We evaluated the clinical outcomes of a novel triplet regimen comprising pemetrexed, carboplatin, and cabozantinib in treatment-naïve patients with metastatic KRAS-mutant NSCLC. Methods: This was a multi-center prospective study of 25 patients with metastatic adenocarcinoma lung harboring KRAS mutations (EGFR/ALK/ROS1 negative), treated with 1st-line palliative chemotherapy with pemetrexed, carboplatin combined with cabozantinib 20mg once daily follwed by pemetrexed-cabozantinib maintenance. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included overall survival (OS), safety and tolerance. Results: The cohort (n = 25) had a median age of 61 years, predominantly male (68%) with history of smoking (72%). Most common sites of metastasis were bone (72%), lung (48%) and pleura (24%); 72% were ECOG PS 1 and 28% were PS 2. Most common KRAS variant was G12C (44%) followed by G12D (24%) and G12V (16%). Co-mutations were present in 36%; most common was TP53 mutation (28%). The ORR was 64% (16/25). At a median follow-up of 37 months, the median PFS was 10.1 months (95% CI: 7.0–16.0). The median OS was 17.2 months (95% CI: 8.8–NR). In multivariate analysis, baseline ECOG PS was the strongest predictor of outcomes, with PS 2 associated with significantly inferior PFS (p < 0.01). Age > 60 years (HR 2.49, p = 0.04) and presence of co-mutations (HR 2.25, p = 0.075) were independent risk factors for progression. Pleural metastasis was associated with significantly prolonged PFS (HR 0.31, p = 0.04). There was no significant difference in outcomes between KRAS G12C and non-G12C variants (p = 0.53). Fatigue was the most common all-grade toxicity (100%). Major grade III/IV toxicities were mucositis (28%), anemia (28%), neutropenia (16%), HFS (16%), diarrhea (12%), thrombocytopenia (8%) and renal dysfunction (8%). Two patients had hemoptysis related deaths. Cabozantinib dose escalation was feasible in 20% patients, interruption was needed in 28% and discontinuation in 12%. Conclusions: The combination of pemetrexed, carboplatin, and cabozantinib showed encouraging antitumor activity in KRAS-mutant NSCLC achieving numerically superior ORR and PFS to historical controls for standard chemo-immunotherapy with acceptable toxicity and safety. This real-world study suggests that adding anti-angiogenic/MET-targeted therapy to chemotherapy is a viable therapeutic strategy for KRAS-mutant patients, warranting validation in larger prospective trials.