In an interim analysis of a trial involving 296 patients with
ALK
-positive non–small-cell lung cancer, lorlatinib, an anaplastic lymphoma kinase inhibitor, was superior to crizotinib in response (in ...76% vs. 58%), 12-month progression-free survival (78% vs. 39%), and intracranial disease response (82% vs. 23%). Altered lipid levels were the major toxic effect associated with lorlatinib.
The ALK inhibitor crizotinib as first-line therapy was associated with a significantly better response rate, longer progression-free survival, and greater improvement in quality of life measures than ...standard chemotherapy in patients with
ALK
-positive lung cancer.
Rearrangements of the anaplastic lymphoma kinase (
ALK
) gene are present in 3 to 5% of non–small-cell lung cancers (NSCLCs).
1
,
2
They define a distinct subgroup of NSCLC that typically occurs in younger patients who have never smoked or have a history of light smoking and that has adenocarcinoma histologic characteristics.
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–
5
Crizotinib is an oral small-molecule tyrosine kinase inhibitor of ALK, MET, and ROS1 kinases.
6
In phase 1 and 2 studies, crizotinib treatment resulted in objective tumor responses in approximately 60% of patients with
ALK
-positive NSCLC and in progression-free survival of 7 to 10 months.
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–
9
In . . .
AZD9291, an irreversible inhibitor of epidermal growth factor receptor, was associated with tumor responses in the majority of patients with advanced non–small-cell lung cancer in whom T790M-mediated ...drug resistance to other EGFR tyrosine kinase inhibitors had developed.
Somatic mutations in the gene encoding epidermal growth factor receptor (
EGFR
) are detected in approximately 30 to 40% of non–small-cell lung cancers (NSCLCs) from Asian patients and in 10% of NSCLCs from white patients.
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–
3
EGFR
mutations lead to constitutive activation of EGFR signaling and oncogenic transformation both in vitro and in vivo.
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,
5
Cancers with
EGFR
mutations (
EGFR-
mutated cancers) depend on EGFR signaling for growth and survival and are often sensitive to treatment with EGFR tyrosine kinase inhibitors.
6
Among patients with advanced
EGFR-
mutated NSCLC, treatment with EGFR tyrosine kinase inhibitors (e.g., gefitinib, erlotinib, and . . .
Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons ...that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD <3%). Overall, our results support the hypothesis that identification of a preexisting and stable adaptive immune response as defined by mRNA expression pattern is reproducible and sufficient to predict clinical outcome, regardless of the type of cancer or the PD1 therapeutic antibody administered to patients.
.
Among patients with lung cancer that expressed programmed death ligand 1, the anti–PD-L1 antibody atezolizumab was compared with chemotherapy in a randomized trial. In the subgroup with the highest ...PD-L1 expression, the median overall survival was 20.2 months with atezolizumab and 13.1 months with chemotherapy.
In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in ...patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680).
Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis.
As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio HR, 0.56; 95% CI, 0.45 to 0.70). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups.
First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.
Purpose The phase III PROFILE 1014 trial compared crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) -positive advanced nonsquamous non-small-cell ...lung cancer. Here, we report the final overall survival (OS) results. Patients and Methods Patients were randomly assigned to receive oral crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m
plus cisplatin 75 mg/m
or carboplatin (area under the concentration-time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Results Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053; two-sided P = .0978). Median OS was not reached (NR) with crizotinib (95% CI, 45.8 months to NR) and 47.5 months with chemotherapy (95% CI, 32.2 months to NR). Survival probability at 4 years was 56.6% (95% CI, 48.3% to 64.1%) with crizotinib and 49.1% (95% CI, 40.5% to 57.1%) with chemotherapy. After crossover adjustment, there was an improvement in OS that favored crizotinib (hazard ratio, 0.346; 95% bootstrap CI, 0.081 to 0.718). The longest OS was observed in crizotinib-treated patients who received a subsequent ALK tyrosine kinase inhibitor. No new safety signals were identified. Conclusion The final analysis of the PROFILE 1014 study provides a new benchmark for OS in patients with ALK-rearranged non-small-cell lung cancer and highlights the benefit of crizotinib for prolonging survival in this patient population.
Although pembrolizumab has appeared to be more effective than chemotherapy in patients with lung cancer whose tumors had at least 50% PD-L1–positive cells, nivolumab was not as effective as ...chemotherapy in patients with lung cancer whose tumors had PD-L1 expression of at least 5%.
For the past two decades, platinum-based combination chemotherapy has been the standard-of-care, first-line treatment for patients with advanced non–small-cell lung cancer (NSCLC) without mutations that were sensitive to targeted therapy.
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,
2
However, chemotherapy has provided only a moderate benefit, with a limited safety profile. In phase 3 clinical trials, the median progression-free survival with platinum-based chemotherapy was 4 to 6 months, and the median overall survival was 10 to 13 months.
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8
In two phase 3 trials, nivolumab, a programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, resulted in significantly longer overall survival than docetaxel among patients with metastatic NSCLC who had . . .
In a randomized trial involving patients with
ALK
-rearranged lung cancer, brigatinib was associated with longer progression-free survival and more activity against central nervous system disease ...than crizotinib.
Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase ...inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
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