Although KRAS-activating mutations represent the most common oncogenic driver in non-small cell lung cancer (NSCLC), various attempts to inhibit KRAS failed in the past decade. KRAS mutations are associated with a poor prognosis and a poor response to standard therapeutic regimen. The recent development of new therapeutic agents (i.e., adagrasib, sotorasib) that target specifically KRAS G12C in its GDP-bound state has evidenced an unprecedented success in the treatment of this subgroup of patients. Despite providing pre-clinical and clinical efficacy, several mechanisms of acquired resistance to KRAS G12C inhibitors have been reported. In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of KRAS G12C seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting KRAS G12C and promising approaches of combined therapy to overcome acquired resistance to KRAS G12C inhibitors.

Tumor genomic profiling has a dramatic impact on the selection of targeted treatment and for the identification of resistance mechanisms at the time of progression. Solid tissue biopsies are sometimes challenging, and liquid biopsies are used as a non-invasive alternative when tissue is limiting. The clinical relevance of tumor genotyping through analysis of ctDNA is now widely recognized at all steps of the clinical evaluation process in metastatic non-small cell lung cancer (NSCLC) patients. ctDNA analysis through liquid biopsy has recently gained increasing attention as well in the management of early and locally advanced, not oncogene-addicted, NSCLC. Its potential applications in early disease detection and the response evaluation to radical treatments are promising. The aim of this review is to summarize the landscape of liquid biopsies in clinical practice and also to provide an overview of the potential perspectives of development focusing on early detection and screening, the assessment of minimal residual disease, and its potential role in predicting response to immunotherapy. In addition to available studies demonstrating the clinical relevance of liquid biopsies, there is a need for standardization and well-designed clinical trials to demonstrate its clinical utility.

The response to immunotherapy has been little investigated in overweight and obese cancer patients. We evaluated the relationships between BMI, toxicity, and survival in patients treated by immunotherapy for metastatic cancer. We included metastatic cancer patients treated by immunotherapy between January 2017 and June 2020 at the Centre Léon Bérard. In total, 272 patients were included: 64% men and 36% women, with a median age of 61.4 years. BMI ≥ 25 in 34.2% and 50% had non-small cell lung cancer (n = 136). Most received monotherapy, with nivolumab in 41.9% and pembrolizumab in 37.9%. Toxicity, mostly dysthyroiditis, occurred in 41%. Median overall survival (OS), estimated by Kaplan–Meier analysis, was significantly longer for patients with a BMI ≥ 25 than for those with a BMI < 25 (24.8 versus 13.7 months HR = 0.63; 95% CI 0.44–0.92, p = 0.015), and for patients experiencing toxicity than for those without toxicity (NR versus 7.8 months, HR = 0.22; 95% CI 0.15–0.33, p < 0.001). Adjusted OS was associated with toxicity, and the occurrence of toxicity was associated with sex and histological features but not with BMI. Thus, being overweight and experiencing toxicity was associated with longer overall survival in patients treated by immunotherapy. More attention should be paid to body composition in the care of cancer patients.

Genomic profiling is a major component for first-line treatment decisions in patients with non-small cell lung cancer (NSCLC) and the timeliness of biomarker testing is essential to improve time to treatment initiation (TTI) or avoid inappropriate treatment. The phase III LIBELULE trial (NCT03721120) included patients with radiological suspicion of advanced lung cancer. They were randomized (1:1), the control arm receiving diagnostic procedures according to each center's practice and the liquid biopsy arm with additional testing performed at the first visit using the InVisionFirst®-Lung assay. Treatment initiation and type were defined according to ESMO guidelines. Primary endpoint was the time from randomization to initiation of appropriate treatment based on informative genomic and pathological results in the intention-to-treat population. 319 patients were enrolled (LB: 161; control: 158). Median age was 68 years, 28.8% were non-smokers, 18.1% had PS≥2 and 56.7% had adenocarcinoma. In LB arm, 81% of patients had circulating tumor DNA findings. The mean TTI was not significantly reduced (LB: 29.0 days (d); control 34d (p=0.26)). Sensitivity analyses showed a shorter TTI in patients from the LB arm who received systemic treatment (LB: 29.1d; control: 38.8d, p=0.01), in patients with advanced non-squamous NSCLC (LB: 29.5d; control: 40.3d, p=0.01), and in patients with first-line targetable alterations (LB: 21d; control 37.4d) (p=0.004). Time to contributory genomic results was significantly reduced (LB: 17.9d; control 25.6d, p<0.001). Early liquid biopsy testing did not significantly shorten the TTI in unselected patients referred for suspected advanced lung cancer. Nevertheless, it could reduce the TTI in patients eligible for systemic treatment, particularly for those with actionable alterations.