The Clinical Significance of RAS, PIK3CA, and PTEN Mutations in Non-Small Cell Lung Cancer Using Cell-Free DNA

Mutations in the EGFR gene downstream signaling pathways may cause receptor-independent pathway activation, making tumors unresponsive to EGFR inhibitors. However, the clinical significance of RAS, PIK3CA or PTEN mutations in NSCLC is unclear. In this study, patients who were initially diagnosed with NSCLC or experienced recurrence after surgical resection were enrolled, and blood samples was collected. Ultra-deep sequencing analysis of cfDNA using Ion AmpliSeq Cancer Hotspot Panel v2 with Proton platforms was conducted. RAS/PIK3CA/PTEN mutations were frequently detected in cfDNA in stage IV NSCLC (58.1%), and a high proportion of the patients (47.8%) with mutations had bone metastases at diagnosis. The frequency of RAS/PIK3CA/PTEN mutations in patients with activating EGFR mutation was 61.7%. The median PFS for EGFR-TKIs was 15.1 months in patients without RAS/PIK3CA/PTEN mutations, and 19.9 months in patients with mutations (p = 0.549). For patients with activating EGFR mutations, the overall survival was longer in patients without RAS/PIK3CA/PTEN mutations (53.8 months vs. 27.4 months). For the multivariate analysis, RAS/PIK3CA/PTEN mutations were independent predictors of poor prognosis in patients with activating EGFR mutations. In conclusion, RAS, PIK3CA and PTEN mutations do not hamper EGFR-TKI treatment outcome; however, they predict a poor OS when activating EGFR mutations coexist.

A phase III, open-label, randomized study of atezolizumab in combination with carboplatin + paclitaxel + bevacizumab compared with pemetrexed + cisplatin or carboplatin with stage IV non-squamous non-small cell lung cancer (NSCLC) with activating EGFR mutation or ALK translocation (ATLAS Trial).

TPS9636 Background: In patients with activating EGFR mutations and ALK fusion, target specific tyrosine kinase inhibitor (TKI) showed significant survival improvement compared to the cytotoxic chemotherapy. However, the questions remain which combination strategy will be the best option for the patients who have failed from TKI. Especially, the role of an immune checkpoint inhibitor (ICI) in this population is still unclear. This study is designed and conducted based on the recent subgroup analyses from the IMpower 150 study which showed the positive clinical outcomes of atezolizumab combined with VEGF inhibitor and conventional cytotoxic chemotherapy in EGFR mutation and ALK translocation. Methods: This study is the phase III, open-label, multicenter study of atezolizumab in combination with bevacizumab + carboplatin + paclitaxel (ABCP, Arm A) compared with pemetrexed + cisplatin or carboplatin (Arm B). The study population will be randomized to either Arm A (n = 152) or Arm B (n = 72) based on two stratification factors, EGFR vs. ALK and presence of brain metastases. In Arm A, patients will be treated with 4 or 6 cycles of ABCP followed by maintenance atezolizumab and bevacizumab every three weeks. In Arm B, pemetrexed maintenance therapy will be applied every three weeks after 4 or 6 cycles of pemetrexed + cisplatin or carboplatin. As key inclusion criteria, the patients must be diagnosed with stage IV non-squamous non-small cell lung cancer with either activating EGFR mutation or ALK translocation. All the patients need to be cytotoxic chemotherapy naïve and must have experienced disease progression to treatment with at least one EGFR or ALK TKI. If the patients have T790M mutation after 1st or 2nd generation EGFR TKI, second line 3rd generation EGFR TKI treatment is mandatory. The number of T790M positive patients is restricted to under 30% of the entire study population. The primary endpoint is progression-free survival and the major secondary endpoints are overall survival, objective response rate and duration of response. A total of 228 subjects will be enrolled to detect a hazard ratio of 0.67. The first subject received treatment in Aug. 2019 and 19 patients receive the treatment. This study is opened in 3 sites and expected to be opened at 18 sites in South Korea. The time point for the primary analyses is Q3. 2022. Clinical trial information: NCT03991403 .

In vitro model for resistance in oncogene-dependent tumors at the limit of radiological detectability

In solid tumors, the response to targeted therapy is typically short-lived, as therapy-resistant mutants can quickly expand during therapy. Here we analyze the spectrum of such resistance mutations coexisting in a large population of cancer cells. We use an iterative scheme of artificial evolution to amplify and isolate different resistance mechanisms. As a proof of concept, we apply our scheme to PC-9 cells, a human non-small cell lung cancer cell line with an activating EGFR mutation. The mechanisms we find comprise the well-known gatekeeper-mutation T790M in EGFR, a mutation in NRAS, the amplification of MET-ligand HGF, as well as induction of AKT-mTOR signaling. In this model, a combination of four drugs targeting these mechanisms prevents not only the expansion of resistant cells, but also inhibits the growth of drug-tolerant cells, which can otherwise act as a reservoir for further resistance mutations. These data suggest that a finite number of drugs specifically acting on individual resistant clones may be able to control resistance in oncogenically driven lung cancer.