AZD9291 is an oral, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI), which specifically targets both sensitizing and resistant T790M ...mutations. This compound has shown outstanding activity, in a phase I/II (AURA) trial. However, despite impressive tumor responses in T790M-positive patients, acquired resistance to this drug limits the benefit of this compound. Mutations at the EGFR C797 codon, located within the kinase-binding site, were very recently reported to be a potential mechanism of resistance to AZD9291 in T790M-positive patients.
To identify potential mechanisms of resistance to AZD9291, we report here on two patients with resistant biopsy specimens that had been treated with AZD9291.
We identified in two distinct cases, HER2 and MET amplification by FISH and CGH as a potential mechanism of acquired resistance to third-generation EGFR-TKI. Interestingly, this event occurred with complete loss of the T790M mutation. In one case, we observed a different molecular status at two biopsy sites (the T790M mutation at the primary site and wild-type T790M at the metastatic site with different pathways of acquired resistance to AZD9291).
Our observations suggest that T790M-positive and wild-type T790M clones may coexist at baseline. AZD9291 efficiently suppresses the growth of T790M-positive cells, but a population of wild-type T790M cells at baseline will mediate the development of resistance, here via a by-pass pathway activating either HER2 or MET.
Immune checkpoint inhibitors are an important tool in the therapeutic strategy against metastatic non–small cell lung cancer (NSCLC); however, radiological evaluation is challenging due to the ...emergence of atypical patterns of responses. Several evaluation criteria have been proposed, such as the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, immune -related RECIST (irRECIST) and iRECIST, but have not been systematically compared in a homogeneous population.
We conducted a monocentric retrospective analysis of consecutive advanced NSCLC patients treated with an anti–programmed cell death-1 or anti–program death-ligand 1. Response patterns and the discordance between RECIST 1.1, irRECIST and iRECIST guidelines were described, and associations of response patterns and clinical outcome were explored.
Overall, 160 patients treated between February 2013 and October 2016 were included. Atypical responses were observed in 20 patients (13%), including eight pseudoprogressions (PsPDs) (5%) and 12 dissociated responses (8%). Thirteen of the 20 patients demonstrated clinical benefit. Per the RECIST 1.1, 37 patients (23%) showed an objective response or stable disease, and 123 patients (77%) exhibited progression. Eighty progressive patients were assessable for irRECIST and iRECIST: 15 patients were assessed differently; however, only three (3.8%) mismatches with a theoretical impact on the therapeutic decision were identified. Patients with PsPD or dissociated response had higher overall survival than patients with true progression.
Atypical responses (PsPD/dissociated response) occurred in 13% of NSCLC patients under immune checkpoint inhibitors. Based on survival analyses, the RECIST 1.1 evaluation underestimated the benefit of immune checkpoint inhibitors in 11% of the progressive patients. Immune-related RECIST and iRECIST identified these unconventional responses, with a 3.8% discrepancy rate.
•Non–small cell lung cancer patients under immune checkpoint inhibitor may experience atypical responses.•Conventional Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, are insufficient for capturing pseudoprogression.•The RECIST 1.1 criteria may have underestimated the benefit of immune checkpoint inhibitors.•The immune-related RECIST (irRECIST) and iRECIST are able to capture unconventional responses.•The iRECIST provided highly concordant response assessment compared with irRECIST.
•This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing oncogene-addicted mNSCLC.•ESMO-MCBS scores are given to describe the levels of evidence for treatment ...choices.•ESCAT scores are given to describe the evidence level for genomic alterations as biomarkers for using targeted therapies.•Recommendations are based on available scientific data and the authors’ collective expert opinion.•In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach.
Non-small-cell lung cancer (NSCLC) harbouring HER2 alterations is now considered a distinct molecular subtype. The activation of HER2 in NSCLC occurs via three mechanisms, i.e. gene mutation (1%-4% ...of cases), gene amplification (2%-5%) and protein overexpression (2%-30%), with different prognostic and predictive outcomes. So far, non-selective tyrosine kinase inhibitors (TKIs) have shown a minor benefit in HER2-mutant NSCLC patients with objective response rates (ORRs) ranging from 0% to 19%. Trastuzumab-based chemotherapy was not found to be superior to chemotherapy alone median progression-free survival (PFS) 6.1 versus 7 months, respectively and dual HER2 antibody blockade with trastuzumab and pertuzumab had limited efficacy (ORR 13%-21%). In contrast, novel more selective HER2 TKIs such as poziotinib and pyrotinib have shown a promising activity in HER2-mutant pre-treated NSCLC patients, with response rates up to 38% and 44%, respectively. The most encouraging data come from phase II studies that evaluated the antibody–drug conjugates (ADCs) ado-trastuzumab–emtansine and trastuzumab–deruxtecan in patients with HER2-mutant NSCLC, with response rates of 50% and 62%, respectively. These agents are bringing hope to the management of HER2-altered NSCLC. Moreover, a paradigm shift from monotherapies towards combinations of agents with distinct mechanisms of action, such as ADCs with irreversible TKIs or immune checkpoint inhibitors, is already taking place and will change the therapeutic landscape of HER2-driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with HER2 molecular alterations.
•Activation of Her2 in NSCLC occurs via gene mutation, amplification or protein overexpression.•Selective Her2 TKIs like poziotinib and pyrotinib induced responses in up to 44% of pre-treated Her2-mutant NSCLC patients.•ADCs trastuzumab–emtansine and trastuzumab–deruxtecan showed impressive response rates in 62% of Her2-mutant NSCLC patients.•Ongoing studies evaluating combination strategies may help improve the therapeutic landscape in Her2-dependent NSCLC.
•This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing non-oncogene-addicted mNSCLC.•ESMO-MCBS scores are given to describe the levels of evidence for ...treatment choices.•ESCAT scores are given to describe the evidence level for genomic alterations as biomarkers for using targeted therapies.•Recommendations are based on available scientific data and the authors’ collective expert opinion.•In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach.
In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer ...(NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression.
Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan–Meier-estimated medians).
In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%–24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups HR, 95% confidence interval (CI); medians: TC ≥25% (0.41, 0.26–0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43–0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33–0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48–1.11; 10.7 versus 5.6 months), 1%–24% 0.49, 0.30–0.80; not reached (NR) versus 9.0 months, and unknown (0.59, 0.42–0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30–0.83; NR versus 21.1 months), <25% (0.89, 0.63–1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41–0.83; NR versus 29.6 months), 1%–24% (0.67, 0.41–1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43–0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71–1.84; 33.1 versus 45.6 months). Safety was similar across subgroups.
PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.
•Tumour tissue acquisition (pre-chemoradiotherapy) and tumour cell (TC) PD-L1 expression testing were not mandated.•However, outcomes were assessed based on PD-L1 expression in subgroups defined by pre-specified and post hoc TC cut-offs.•Treatment benefit with durvalumab, versus placebo, was observed irrespective of PD-L1 expression in terms of PFS.•OS improvement was demonstrated overall and across all subgroups, apart from the post hoc TC <1% subgroup.•Limitations (few events and baseline imbalances) and a wide CI for OS HR (includes 1) prevent robust conclusions for TC <1%.
Small cell lung cancer (SCLC) is an aggressive malignancy accounting for 15% of all diagnosed cases of lung cancer. After >15 years without any clinically relevant therapeutic advances, ...extensive-disease SCLC has become the second thoracic malignancy for which immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm to improve overall survival. Today, atezolizumab or durvalumab in combination with platinum-etoposide chemotherapy is considered the new standard of care in the first-line setting in SCLC. However, the magnitude of benefit with this immune-chemotherapy strategy in SCLC is more modest than that observed in metastatic non-small-cell lung cancer patients. The immunosuppressive phenotype of SCLC plays an important role in hampering ICI efficacy and may explain the differences in outcomes between these two types of lung cancer. In this review, we provide a summary of recent therapeutic advances in SCLC in light of ICIs, as well as current challenges of this strategy in patients who are elderly, have poor performance status or brain metastases. We also address future perspectives of immunotherapeutic strategies currently in clinical development for these patients.
•ICIs have shifted the treatment paradigm to improve overall survival in advanced SCLC.•The magnitude of immune-chemotherapy strategy is still modest. The immunosuppressive phenotype of SCLC hamper ICI efficacy.•Efficacy of this new SoC in some subgroups of patients is challenging as well as new immunotherapeutic strategies.
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of metastatic non-small-cell lung cancer (NSCLC) ...was published in 2016. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Chinese Society of Clinical Oncology (CSCO) to convene a special guidelines meeting immediately after the Chinese Thoracic Oncology Group Annual Meeting 2018, in Guangzhou, China. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic NSCLC cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic NSCLC representing the oncological societies of China (CSCO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the six participating Asian countries. During the review process, the updated ESMO 2018 Clinical Practice Guidelines for metastatic NSCLC were released and were also considered, during the final stages of the development of the Pan-Asian adapted Clinical Practice Guidelines.
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