Many patients with oncogene-driven non–small-cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors experience limited sites of disease progression. This study investigated retrospectively ...the benefits of local ablative therapy (LAT) to central nervous system (CNS) and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively.
Patients with metastatic ALK+ NSCLC treated with crizotinib (n = 38) and EGFR-MT NSCLC treated with erlotinib (n = 27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression-free survival (PFS1), and site of first progression were recorded. A subset of patients with either nonleptomeningeal CNS and/or four sites or fewer of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same tyrosine kinase inhibitors. The subsequent median progression-free survival from the time of first progression (PFS2) and pattern of progression were recorded.
Median progression-free survival in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. Twenty-five of 51 patients (49%) who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, one with surgery) and continuation of the same targeted therapy. Post-LAT, 19 of 25 patients progressed again, with median PFS2 of 6.2 months.
Oncogene-addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with more than 6 months of additional disease control.
Background
Immune‐related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study aimed to evaluate whether the development of irAEs correlates with treatment response ...in advanced non‐small‐cell lung cancer (NSCLC).
Patients and Methods
We conducted a retrospective study of patients who received nivolumab monotherapy at Sendai Kousei Hospital (n = 70). The patients were categorized into two groups based on the incidence of irAEs: those with irAEs (irAE group) or those without (non‐irAE group). Treatment efficacy was evaluated in each group. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were determined.
Results
The objective response rate was 57% in the irAE group versus 12% in the non‐irAE group. Median progression‐free survival was 12.0 months in the irAE versus 3.6 months in the non‐irAE group. The incidence of both irAEs and pre‐existing antithyroid antibody was significantly higher in responders than in nonresponders. Multivariate analysis identified incidence of irAEs and pre‐existing antithyroid antibody as an independent predictor of treatment response.
Conclusion
Objective response rate and progression‐free survival were significantly better in the irAE than in the non‐irAE group in patients with advanced NSCLC treated with nivolumab monotherapy. The development of irAEs was associated with clinical efficacy, and the presence of pre‐existing antithyroid antibody might be correlated with treatment response to nivolumab monotherapy.
Implications for Practice
Immune‐related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study evaluted whether the development of irAEs correlates with treatment response in advanced non‐small‐cell lung cancer. Results showed that the objective response rate and progression‐free survival were significantly better in the patients who developed irAEs than in the patients who did not develop irAEs, and the incidence of irAEs and positivity for antithyroid antibody at pretreatment were independent predictors of treatment response of nivolumab monotherapy. Therefore, the development of irAEs predicts clinical benefit and suggests that cautious management of irAEs can lead to achieving maximum clinical benefit from nivolumab monotherapy.
摘要
背景。 免疫相关不良事件 (irAE) 经常发生在纳武单抗单药治疗中。本研究旨在评估 irAE 发生是否与晚期非小细胞肺癌 (NSCLC) 的治疗反应相关。
患者和方法。 我们对在 Sendai Kousei 医院 (n=70) 接受纳武单抗治疗的患者进行了一项回顾性研究。根据 irAE 发生率将患者分为两组:出现 irAE 患者组( irAE 组)或未出现 irAE 患者组(非‐irAE 组)。评估各组的治疗效果。将患者进一步分为应答者和无应答者,并确定治疗反应的预测因素。
结果。 irAE 组和非‐irAE 组的客观有效率分别为57%和12%。irAE 组和非‐irAE 组的中位无进展生存期分别为12.0个月和3.6个月。应答者的 irAE 和既往抗甲状腺抗体的发生率均显著高于无应答者。多因素分析发现,irAE 和既往抗甲状腺抗体的发生率是治疗反应的独立预测指标。
结论。 在接受纳武单抗单药治疗的晚期 NSCLC 患者中,irAE 组客观有效率和无进展生存期明显优于非‐irAE 组。irAE 的发生与临床疗效有关,而既往抗甲状腺抗体的存在可能与纳武单抗单药的治疗反应有关。
实践意义: 纳武单抗单药治疗频繁出现免疫相关不良事件 (irAE)。本研究评估了 irAE 进展与晚期非小细胞肺癌治疗反应是否相关。结果表明,客观有效率和无进展生存期在发生 irAE 的患者中明显好于未发生 irAE 的患者,治疗前 irAE 的发生率和抗甲状腺抗体的阳性率是纳武单抗单药治疗效果的独立预测指标。因此,通过 irAE 发生可以预测临床受益,并且表明,谨慎管理 irAE 可以使纳武单抗单药治疗获得最大临床受益。
This article reports the results of a study evaluating the development of immune‐related adverse events in patients who received nivolumab monotherapy to determine clinical benefit in patients with advanced non‐small cell lung cancer.
Lorlatinib is a novel, highly potent, brain‐penetrant, third‐generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad‐spectrum potency against most known resistance mutations that can ...develop during treatment with crizotinib and second‐generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100 mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid‐lowering agent. Prescription of supportive therapy should also consider the potential for drug‐drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100 mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK‐positive metastatic non‐small cell lung cancer previously treated with a second‐generation ALK TKI.
Implications for Practice
Despite the advancement of second‐generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK‐positive non‐small cell lung cancer. Lorlatinib is a potent, brain‐penetrant, third‐generation, macrocyclic ALK/ROS1 TKI, with broad‐spectrum potency against most known resistance mutations that can develop during treatment with existing first‐ and second‐generation ALK TKIs. This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.
摘要
劳拉替尼是一种新型、高效、具有脑渗透作用的第三代 ALK/ROS1 酪氨酸激酶抑制剂 (TKI)，对克唑替尼和第二代 ALK TKI 治疗期间可能发生的大多数已知耐药突变具有广谱效力。295 名患者每日服用一次 100 mg 推荐剂量的劳拉替尼，在此基础上确立了劳拉替尼的安全谱。劳拉替尼相关不良事件的严重程度主要为轻度至中度，最常报告的不良事件是高胆固醇血症 (82.4%)、高甘油三酯血症 (60.7%)、水肿 (51.2%)、周围神经病变 (43.7%) 和中枢神经系统影响 (39.7%)。由于因不良事件引起的永久停药的发生率较低，因此可通过调整剂量和/或标准支持性药物疗法来有效管理上述不良事件。大多数患者 (81.0%) 服用至少一种降脂药。支持疗法的处方还应考虑劳拉替尼通过特定 CYP450 酶的参与发生药物相互作用的可能性。本文总结了劳拉替尼 I 期研究者的临床经验，并通过对临床研究方案和数据库的讨论和回顾，就报告的罗拉替尼主要不良事件(包括高脂血症、中枢神经系统影响、体重增加、水肿、周围神经病变和胃肠影响)的管理提供了专家共识意见。总体而言，根据美国食品药品监督管理局最新的批准，我们认为，凭处方每天服用一次 100 mg 的劳拉替尼对治疗 ALK 阳性转移性非小细胞肺癌患者(之前接受过第二代 ALK TKI 治疗)具有出色的安全性。
实践意义:尽管第二代间变性淋巴瘤激酶 (ALK) 酪氨酸激酶抑制剂 (TKI) 取得了发展，但中枢神经系统转移出现耐药性和进展仍是 ALK 阳性非小细胞肺癌面临的重要临床问题。劳拉替尼是一种高效、具有脑渗透作用的第三代大环 ALK/ROS1 TKI，对现有第一代和第二代 ALK TKI 治疗期间可能发生的大多数已知耐药突变具有广谱效力。本文为报告的劳拉替尼主要不良反应的临床管理提供了
建议。
This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.
•EXPRESS evaluated real-world prevalence of PD-L1 expression in advanced NSCLC.•The PD-L1 IHC 22C3 pharmDx assay was used, with local testing across 18 countries.•Testing failure rate was low with ...PD-L1 evaluation across a large number of sites.•The prevalence of PD-L1 expression was similar across geographic regions.•53% of patients without EGFR/ALK aberrations had PD-L1 TPS ≥ 1% and 27% had TPS ≥ 50%.
: Tumor programmed death ligand 1 (PD-L1) expression is associated with improved clinical benefit from immunotherapies targeting the PD-1 pathway. We conducted a global, multicenter, retrospective observational study to determine real-world prevalence of tumor PD-L1 expression in patients with NSCLC.
: Patients ≥18 years with histologically confirmed stage IIIB/IV NSCLC and a tumor tissue block (≤5 years old) obtained before treatment were identified in 45 centers across 18 countries. Tumor samples from eligible patients were selected consecutively, when possible. PD-L1 expression was evaluated at each center using the PD-L1 IHC 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA).
: Of 2617 patients who met inclusion criteria, 2368 (90%) had PD-L1 data; 530 (22%) patients had PD-L1 TPS ≥ 50%, 1232 (52%) had PD-L1 TPS ≥ 1%, and 1136 (48%) had PD-L1 TPS < 1%. The most common reason for not having PD-L1 data (n = 249) was insufficient tumor cells (<100) on the slide (n = 170 6%). Percentages of patients with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively were: 22%/52% in Europe; 22%/53% in Asia Pacific; 21%/47% in the Americas, and 24%/55% in other countries. Prevalence of EGFR mutations (19%) and ALK alterations (3%) was consistent with prior reports from metastatic NSCLC studies. Among 1064 patients negative for both EGFR mutation and ALK alteration, the percentage with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively, were 27% and 53%.
: This is the largest real-world study in advanced NSCLC to date evaluating PD-L1 tumor expression using the 22C3 pharmDx kit. Testing failure rate was low with local evaluation of PD-L1 TPS across a large number of centers. Prevalence of PD-L1 TPS ≥ 50% and TPS ≥ 1% among patients with stage IIIB/IV NSCLC was similar across geographic regions and broadly consistent with central testing results from clinical trial screening populations.
Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations ...observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs). While the use of targeted therapies and immune checkpoint inhibitors (CPIs) has drastically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC) in recent years, historic attempts to target KRAS (both direct and indirect approaches) have had little success, and no KRAS-specific targeted therapies have been approved to date for patients in this molecular subset of NSCLC. With the discovery by Ostrem, Shokat, and colleagues of the switch II pocket on the surface of the active and inactive forms of KRAS, we now have an improved understanding of the complex interactions involved in the RAS family of signaling proteins which has led to the development of a number of promising direct KRASG12C inhibitors, such as sotorasib and adagrasib. In previously treated patients with KRASG12C-mutant NSCLC, clinical activity has been shown for both sotorasib and adagrasib monotherapy; these data suggest promising new treatment options are on the horizon. With the stage now set for a new era in the treatment of KRASG12C-mutated NSCLC, many questions remain to be answered in order to further elucidate the mechanisms of resistance, how best to use combination strategies, and if KRASG12C inhibitors will have suitable activity in earlier lines of therapy for patients with advanced/metastatic NSCLC.
•Better understanding of RAS signaling has led to the development of promising directly blocking compounds in KRAS-mutant tumors.•New drug candidates take advantage of the increased knowledge of the KRAS mutation complex and relevant protein structures.•Increasing evidence continues to demonstrate the genomic heterogeneity in KRAS-mutated NSCLC.•Current efforts include understanding and overcoming resistance after treatment with KRASG12C inhibitors.
Background
Evidence from cancer clinical trials can be difficult to generalize to real‐world patient populations, but can be complemented by real‐world evidence to optimize personalization of care. ...Further, real‐world usage patterns of programmed cell death protein 1 (PD‐1) inhibitors following approval can inform future studies of subpopulations underrepresented in clinical trials.
Materials and Methods
We performed a multicenter analysis using electronic health record data collected during routine care of patients treated in community cancer care clinics in the Flatiron Health network. Real‐world metastatic non‐small cell lung cancer (NSCLC) patients who received nivolumab or pembrolizumab in the metastatic setting (n = 1,344) were selected from a starting random sample of 55,969 NSCLC patients with two or more documented visits from January 1, 2011, through March 31, 2016. The primary study outcome measurement was demographic and treatment characteristics of the cohort.
Results
Median age at PD‐1 inhibitor initiation was 69 years (interquartile range 61–75). Patients were 56% male, 88% smokers, 65% nonsquamous histology, and 64% diagnosed at stage IV. Of 1,344 patients, 112 (8%) were tested for programmed death‐ligand 1 expression. Overall, 50% received nivolumab or pembrolizumab in the second line, with a substantial proportion of third and later line use that began to decline in Q4 2015.
Conclusion
During the year following U.S. regulatory approval of PD‐1 inhibitors for treatment of NSCLC, real‐world patients receiving nivolumab or pembrolizumab were older at treatment initiation and more had smoking history relative to clinical trial cohorts. Studies of outcomes in underrepresented subgroups are needed to inform real‐world treatment decisions.
Implications for Practice
Evidence gathered in conventional clinical trials used to assess safety and efficacy of new therapies is not necessarily generalizable to real‐world patients receiving these drugs following regulatory approval. Real‐world evidence derived from electronic health record data can yield complementary evidence to enable optimal clinical decisions. Examined here is a cohort of programmed cell death protein 1 inhibitor‐treated metastatic non‐small cell lung cancer patients in the first year following regulatory approval of these therapies in this indication. The analysis revealed how the real‐world cohort differed from the clinical trial cohorts, which will inform which patients are underrepresented and warrant additional studies.
This study evaluated real‐world usage patterns of the PD‐1 inhibitors nivolumab and pembrolizumab in metastatic non‐small cell lung cancer patients in the first year following regulatory approval of these therapies in this indication. The analysis revealed how the real‐world cohort differed from the clinical trial cohorts, which may inform the design of future studies to understand outcomes of underrepresented populations.
Background
Non‐small cell lung cancer (NSCLC) is one of the most common human malignancies and the leading cause of cancer‐related death. Over the past few decades, genomic alterations of cancer ...driver genes have been identified in NSCLC, and molecular testing and targeted therapies have become standard care for lung cancer patients. Here we studied the unique genomic profile of driver genes in Chinese patients with NSCLC by next‐generation sequencing (NGS) assay.
Materials and Methods
A total of 1,200 Chinese patients with NSCLC were enrolled in this study. The median age was 60 years (range: 26–89), and 83% cases were adenocarcinoma. NGS‐based genomic profiling of major lung cancer‐related genes was performed on formalin‐fixed paraffin‐embedded tumor samples and matched blood.
Results
Approximately 73.9% of patients with NSCLC harbored at least one actionable alteration recommended by the National Comprehensive Cancer Network guideline, including epidermal growth factor receptor (EGFR), ALK, ERBB2, MET, BRAF, RET, and ROS1. Twenty‐seven patients (2.2%) harbored inherited germline mutations of cancer susceptibility genes. The frequencies of EGFR genomic alterations (both mutations and amplification) and ALK rearrangement were identified as 50.1% and 7.8% in Chinese NSCLC populations, respectively, and significantly higher than the Western population. Fifty‐six distinct uncommon EGFR mutations other than L858R, exon19del, exon20ins, or T790M were identified in 18.9% of patients with EGFR‐mutant NSCLC. About 7.4% of patients harbored both sensitizing and uncommon mutations, and 11.6% of patients harbored only uncommon EGFR mutations. The uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. In patients <40 years of age, the ALK‐positive percentage was up to 28.2%. Moreover, 3.2% of ALK‐positive patients harbored multi ALK rearrangements, and seven new partner genes were identified.
Conclusion
More unique features of cancer driver genes in Chinese NSCLC were identified by next‐generation sequencing. These findings highlighted that NGS technology is more feasible and necessary than other molecular testing methods, and suggested that the special strategies are needed for drug development and targeted therapy for Chinese patients with NSCLC.
Implications for Practice
Molecular targeted therapy is now the standard first‐line treatment for patients with advanced non‐small cell lung cancer (NSCLC). Samples of 1,200 Chinese patients with NSCLC were analyzed through next‐generation sequencing to characterize the unique feature of uncommon EGFR mutations and ALK fusion. The results showed that 7.4% of EGFR‐mutant patients harbored both sensitizing and uncommon mutations and 11.6% harbored only uncommon mutations. Uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. ALK fusion was more common in younger patients, and the frequency decreased monotonically with age. 3.2% of ALK‐positive patients harbored multi ALK rearrangement, and seven new partner genes were identified.
Lung cancer is the most fatal malignancy in China. This study assessed genomic alterations of driver genes in a cohort of Chinese patients with non‐small cell lung cancer. This article reports the resulting analysis of germline mutations, EGFR variations, and ALK rearrangements, the most common and important driver genes in Chinese NSCLC population.
We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP experimental arm) and OS data with approximately 39.8 months of median follow-up with ...atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) versus bevacizumab-carboplatin-paclitaxel (BCP) in chemotherapy-naive patients with metastatic nonsquamous NSCLC in the phase 3 IMpower150 study (NCT02366143).
In this randomized, open-label study (N = 1202), coprimary end points included investigator-assessed progression-free survival and OS in intention-to-treat (ITT) wild-type (WT; no EGFR or ALK alterations) patients. Secondary and exploratory end points included OS in ITT and programmed death-ligand 1 (PD-L1) subgroups defined by the VENTANA SP142 and SP263 immunohistochemistry assays.
At the final analysis with ACP versus BCP (data cutoff: September 13, 2019; minimum follow-up: 32.4 mo), ACP had numerical, but not statistically significant, improvements in OS (ITT-WT: median OS = 19.0 versus 14.7 mo; hazard ratio = 0.84; 95% confidence interval: 0.71–1.00). OS benefit was sustained with ABCP versus BCP (ITT-WT: 19.5 versus 14.7 mo; hazard ratio = 0.80; 95% confidence interval: 0.67–0.95). Exploratory analyses in the SP142-defined PD-L1 subgroups revealed longer median OS with ABCP and ACP versus BCP in PD-L1–high and PD-L1–positive subgroups; in the PD-L1–negative subgroups, median OS was similar with ACP and ABCP versus BCP. Safety was consistent with that in earlier analyses (data cutoff: January 22, 2018).
At the final IMpower150 OS analysis, ACP had numerical, but not statistically significant, OS improvement versus BCP. Updated data with an additional 20 months of follow-up revealed continued OS improvement with ABCP versus BCP in all patients.
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