Background: Several clinical trials have demonstrated the efficacy and safety of osimertinib in advanced nonsmall-cell lung cancer (NSCLC). However, there is significant unexplained variability in treatment outcome.Methods: Observational prospective cohort of 22 pre-treated patients with stage IV NSCLC harboring the epidermal growth factor receptor (EGFR) p.T790M resistance mutation and who were treated with osimertinib. Three hundred and twenty-six serial plasma samples were collected and analyzed by digital PCR (dPCR) and next-generation sequencing (NGS). Results:The median progression-free survival (PFS), since the start of osimertinib, was 8.9 [interquartile range (IQR): 4.6-18.0] months. The median treatment durations of sequential gefitinib + osimertinib, afatinib + osimertinib and erlotinib + osimertinib treatments were 30.1, 24.6 and 21.1 months, respectively. The p.T790M mutation was detected in 19 (86%) pre-treatment blood samples. Undetectable levels of the original EGFR-sensitizing mutation after 3 months of treatment were associated with superior PFS (HR: 0.2, 95% CI: 0.05-0.7). Likewise, re-emergence of the original EGFR mutation, alone or together with the p.T790M mutation was significantly associated with shorter PFS (HR: 8.8, 95% CI: 1.1-70.7 and HR: 5.9, 95% CI: 1.2-27.9, respectively). Blood-based monitoring revealed three molecular patterns upon progression to osimertinib: sensitizing+/T790M+/C797S+, sensitizing+/T790M+/C797S-, and sensitizing+/T790M-/ C797S-. Median time to progression in patients showing the triplet pattern (sensitizing+/T790M+/C797S+) was 12.27 months compared with 4.87 months in patients in whom only the original EGFR sensitizing was detected, and 2.17 months in patients showing the duplet pattern (sensitizing+/T790M+). Finally, we found that mutations in exon 545 of the PIK3CA gene were the most frequent alteration detected upon disease progression in patients without acquired EGFR-resistance mutations.Conclusions: Different molecular patterns identified by plasma genotyping may be of prognostic significance, suggesting that the use of liquid biopsy is a valuable approach for tumor monitoring.
Despite impressive and durable responses, non-small cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase inhibitors (ALK-Is) ultimately progress due to development of resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next-generation sequencing (NGS) upon disease progression. We collected26 plasma and two cerebrospinal fluid samples from 24 advanced ALK-positive NSCLC patients at disease progression to an ALK-I. These samples were analyzed by NGS and digital PCR. A tool to retrieve variants at the ALK locus was developed (VALK tool).We identified at least one resistance mutation in the ALK locus in ten (38.5%) plasma samples; the G1269A and G1202R mutations were the most prevalent among patients progressing to first-and secondgeneration ALK-Is, respectively. Overall, 61 somatic mutations were detected in 14 genes: TP53, ALK,
Background: KRAS is mutated in w30% of non-small-cell lung cancer (NSCLC) but it has also been identified as one of the mechanisms underlying resistance to tyrosine kinase inhibitors (TKIs) in EGFR-positive NSCLC patients. Novel KRAS inhibitors targeting KRAS p.G12C mutation have been developed recently with promising results. The proportion of EGFR-positive NSCLC tumours harbouring the KRAS p.G12C mutation upon disease progression is completely unexplored. Materials and methods: Plasma samples from 512 EGFR-positive advanced NSCLC patients progressing on a first firstline treatment with a TKI were collected. The presence of KRAS p.G12C mutation was assessed by digital PCR. Results: Overall, KRAS p.G12C mutation was detected in 1.17% of the samples (n ¼ 6). In two of these cases, we could confirm that the KRAS p.G12C mutation was not present in the pre-treatment plasma samples, supporting its role as an acquired resistance mutation. According to our data, KRAS G12C patients showed similar clinicopathological characteristics to those of the rest of the study cohort and no statistically significant associations between any clinical features and the presence of the mutation were found. However, two out of six KRAS G12C tumours harboured less common EGFR driver mutations (p.G719X/p.L861Q). All KRAS G12C patients tested negative for the presence of p.T790M resistance mutation. Conclusions: The KRAS p.G12C mutation is detected in 1% of EGFR-positive NSCLC patients who progress on a first line with a TKI. All KRAS G12C patients were negative for the presence of the p.T790M mutation and they did not show any distinctive clinical feature.
Background ALK rearrangements are present in 5% of nonsmall cell lung cancer (NSCLC) tumors and identify patients who can benefit from ALK inhibitors. ALK fusions testing using liquid biopsies, although challenging, can expand the therapeutic options for ALK-positive NSCLC patients considerably. RNA inside extracellular vesicles (EVs) is protected from RNases and other environmental factors, constituting a promising source for noninvasive fusion transcript detection. Methods EVs from H3122 and H2228 cell lines, harboring EML4-ALK variant 1 (E13; A20) and variant 3 (E6a/b; A20), respectively, were successfully isolated by sequential centrifugation of cell culture supernatants. EVs were also isolated from plasma samples of 16 ALK-positive NSCLC patients collected before treatment initiation. Results Purified EVs from cell cultures were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and flow cytometry. Western blot and confocal microscopy confirmed the expression of EV-specific markers as well as the expression of EML4-ALK-fusion proteins in EV fractions from H3122 and H2228 cell lines. In addition, RNA from EV fractions derived from cell culture was analyzed by digital PCR (dPCR) and ALK-fusion transcripts were clearly detected. Similarly, plasma-derived EVs were characterized by NTA, flow cytometry, and the ExoView platform, the last showing that EV-specific markers captured EV populations containing ALK-fusion protein. Finally, ALK fusions were identified in 50% (8/16) of plasma EV-enriched fractions by dPCR, confirming the presence of fusion transcripts in EV fractions. Conclusions ALK-fusion transcripts can be detected in EV-enriched fractions. These results set the stage for the development of EV-based noninvasive ALK testing.
disease progression occurred. Treatment was changed to alectinib 600 mg twice daily, leading to a complete response in May 2020 (Figure 2). Conclusion:CNS often represents the unique site of disease progression in patients receiving crizotinib, supporting a primary pharmacokinetic failure due to poor blood-brain barrier penetration. As illustrated by our case, local therapies followed by maintenance crizotinib may prolong progression-free survival (PFS). After crizotinib failure and/or among patients with CNS metastatic disease, alectinib demonstrates a high response rate and longer PFS, which is also consistent with our observational findings.
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