Advanced Non-squamous Non-squamous Non-small Cell Lung Cancer Patients Research Articles

Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study

BackgroundThis multicenter phase 2 trial evaluated the safety and efficacy of osimertinib and platinum-based chemotherapy (OPP) in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer (NSCLC). Patients and methodsPatients received osimertinib 80 mg once daily (QD), with either cisplatin 75 mg/m2 (arm A) or carboplatin (area under the curve [AUC] = 5; arm B), plus pemetrexed 500 mg/m2 for four cycles and maintenance therapy of osimertinib 80 mg QD with pemetrexed 500 mg/m2 every 3 weeks. The primary end-points were safety and objective response rate (ORR), and the secondary end-points were complete response rate (CRR), disease control rate (DCR), and progression-free survival (PFS). ResultsIn total, 67 patients (34 in arm A and 33 in arm B) were enrolled between July 2019 and February 2020. At the data cutoff (28th February 2022), 35 (52.2%) patients had discontinued the protocol treatment, including 10 (14.9%) due to adverse events. No treatment-related deaths occurred. In the full analysis set, the ORR, CRR, and DCR were 90.9% (95% confidence interval [CI], 84.0–97.8), 3.0% (0.0–7.2), and 97.0% (92.8–100.0), respectively. Based on updated survival data (data cutoff on August 31, 2022, median follow-up time: 33.4 months), the median PFS was 31.0 months (95% CI, 26.8 months–not reached) and median overall survival was not reached. ConclusionsThis is the first study to show that OPP has excellent efficacy with acceptable toxicity in previously untreated EGFR-mutated advanced non-squamous NSCLC patients.

Effect of EGFR amplification on the prognosis of EGFR-mutated advanced non–small-cell lung cancer patients: a prospective observational study

BackgroundEpidermal growth factor receptor (EGFR) amplification refers to the copy number increase of EGFR gene, and is often identified as a “bypass” way of Epidermal growth factor receptor Tyrosine kinase inhibitors (EGFR-TKI) resistance. We aimed to explore the effect of EGFR amplification on EGFR mutation treatment-naive advanced non-squamous non-small cell lung cancer (NSCLC) patients.MethodsWe conducted a prospective observational study in single center, enrolling advanced non-squamous NSCLC patients receiving Tyrosine kinase inhibitors (TKIs) between March 3, 2019, and February 1, 2022. Next-generation sequencing (NGS) was used to detect genetic alterations in tumor tissue samples. Progression-free survival (PFS) curves were performed using the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate factors affecting the efficacy of TKIs.ResultsA total of 117 treatment-naive advanced NSCLC patients were identified in this study. EGFR amplification was found in 22 of 117 (18.8%) patients with EGFR mutations. Of 22 patients with EGFR amplification, 10 patients harbored EGFR 19 del, 11 patients with 21-L858R. The median follow-up time was 22.47 months. The median PFS of the patients with or without EGFR amplification was 8.25 months and 10.67 months, respectively (log-rank test, P = 0.63). In multivariate analysis, EGFR amplification was not an independent prognosis factor for the patients receiving first-line TKIs [HR = 1.38, 95%CI (0.73–2.58), P = 0.321]. Subgroup analysis revealed that EGFR amplification is a risk factor for progression in the brain metastasis population. [HR = 2.28, 95%CI (1.01, 5.14), P = 0.047].ConclusionEGFR amplification is not an independent prognosis factor for PFS in advanced non-squamous NSCLC patients receiving first-line TKIs. However, it is an independent risk factor for PFS in the brain metastasis population.

Up-front mutation detection in circulating tumor DNA by droplet digital PCR has added diagnostic value in lung cancer

Identification of actionable mutations in advanced stage non-squamous non-small-cell lung cancer (NSCLC) patients is recommended by guidelines as it enables treatment with targeted therapies. In current practice, mutations are identified by next-generation sequencing of tumor DNA (tDNA-NGS), which requires tissue biopsies of sufficient quality. Alternatively, circulating tumor DNA (ctDNA) could be used for mutation analysis. This prospective, multicenter study establishes the diagnostic value of ctDNA analysis by droplet digital PCR (ctDNA-ddPCR) in patients with primary lung cancer.CtDNA from 458 primary lung cancer patients was analyzed using a panel of multiplex ddPCRs for EGFR (Ex19Del, G719S, L858R, L861Q and S768I), KRAS G12/G13 and BRAF V600 mutations. For 142 of 175 advanced stage non-squamous NSCLC patients tDNA-NGS results were available to compare to ctDNA-ddPCR. tDNA-NGS identified 98 mutations, of which ctDNA-ddPCR found 53 mutations (54%), including 32 of 45 (71%) targetable driver mutations. In 2 of these 142 patients, a mutation was found by ctDNA-ddPCR only. In 33 advanced stage patients lacking tDNA-NGS results, ctDNA-ddPCR detected 15 additional mutations, of which 7 targetable.Overall, ctDNA-ddPCR detected 70 mutations and tDNA-NGS 98 mutations in 175 advanced NSCLC patients. Using an up-front ctDNA-ddPCR strategy, followed by tDNA-NGS only if ctDNA-ddPCR analysis is negative, increases the number of mutations found from 98 to 115 (17%). At the same time, up-front ctDNA-ddPCR reduces tDNA-NGS analyses by 40%, decreasing the need to perform (additional) biopsies.

Phase II study of carboplatin/nab-paclitaxel/atezolizumab combination therapy for advanced nonsquamous non–small cell lung cancer patients with impaired renal function: RESTART trial

Background First-line treatment of nonsquamous non–small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with immune checkpoint inhibitors (ICIs). However, phase III studies of combinations of cytotoxic chemotherapy and ICIs have included only patients with maintained organ function, not those with renal impairment.MethodsCytotoxic chemotherapy–naïve advanced nonsquamous NSCLC patients aged 20 years or older with impaired renal function (creatinine clearance of 15 to 45 mL/min) are prospectively registered in this single-arm phase II study and receive combination therapy with carboplatin, nanoparticle albumin-bound (nab-) paclitaxel, and atezolizumab. Individuals with known genetic driver alterations including those affecting EGFR, ALK, ROS1, BRAF, MET, RET, and NTRK are excluded. We plan to enroll 40 patients over 2 years at 32 oncology facilities in Japan. The primary end point is confirmed objective response rate.DiscussionIf the study demonstrates efficacy and safety of carboplatin/nab-paclitaxel/atezolizumab, then this combination regimen may become a treatment option even for nonsquamous NSCLC patients with impaired renal function.Trial registrationRegistered with Japan Registry for Clinical Trials on 25 February 2021 (jRCTs071200102).

Cost-Effectiveness of Bevacizumab Biosimilar LY01008 Combined With Chemotherapy as First-Line Treatment for Chinese Patients With Advanced or Recurrent Nonsquamous Non-Small Cell Lung Cancer.

Objective: To investigate whether LY01008, a locally developed bevacizumab biosimilar agent, is appropriate for widespread use among Chinese advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC) patients, our current study was designed to evaluate the cost-effectiveness of first-line LY01008 combined with platinum-doublet chemotherapy versus chemotherapy alone from the perspective of the Chinese healthcare system. Material and Methods: This economic evaluation designed a Markov model to compare the healthcare cost and quality-adjusted life-year (QALY) of first-line LY01008 combined with chemotherapy versus first-line chemotherapy. Transition probabilities, including disease progression, survival, and adverse event (AE)-related discontinuation of first-line treatment, were estimated using data from the clinical trials. Costs and health utilities were derived from local databases, hospitals, and published literature. Our base case analysis and scenario analysis focused on the cost-effectiveness of chemotherapy combined with a clinical trial dosage (15 mg/kg every 3-week cycle) and a real-world dosage (7.5 mg/kg every 3-week cycle) of LY01008, respectively. Results: In the base case analysis, first-line LY01008 combined with chemotherapy was associated with an increase of 0.48 QALYs in effectiveness and an increase of CNY 189,988 (US$ 26,240) in healthcare costs compared with first-line chemotherapy, resulting an incremental cost-effectiveness ratio (ICER) of CNY 375,425 (US$ 54,430)/QALY. In the scenario analysis, first-line LY01008 combined with chemotherapy was associated with a mean healthcare cost of CNY 265,060 (US$ 38,429), resulting an ICER of CNY 221,579 (US$ 32,125/QALY) between first-line LY01008 combined with chemotherapy versus first-line chemotherapy. The parameters that determine the cost of LY01008 have the greatest impact on the cost-effectiveness results. Conclusion: From the perspective of the Chinese healthcare system, first-line LY01008 at a real-world dosage combined with chemotherapy is likely to represent a cost-effective strategy compared with first-line chemotherapy alone for Chinese advanced or recurrent nonsquamous NSCLC patients.

Combined Immunotherapy with Chemotherapy versus Bevacizumab with Chemotherapy in First-Line Treatment of Driver-Gene-Negative Non-Squamous Non-Small Cell Lung Cancer: An Updated Systematic Review and Network Meta-Analysis.

Background: A network meta-analysis was conducted to summarize randomized control trials and updated results to evaluate the efficacy and safety profiles of existing first-line therapies for advanced non-squamous non-small cell lung cancer (NSCLC) patients without known driver gene mutations. Patients and Methods: Eligible studies were identified following a systematic search of the Cochrane Library, PubMed, Embase, Web of Science, Wanfang Data, and the China Knowledge Resource Integrated Database from January 2000 to December 2021. Results: Nineteen trials involving 8176 patients with driver-gene-negative advanced non-squamous NSCLC were included. For patients with driver-gene-negative advanced NSCLC, immunotherapy + chemotherapy (IC) significantly prolonged overall survival (OS) (hazard ratio (HR), 0.80; 95% confidence intervals (CI): 0.67–0.95) and progression-free survival (PFS) (HR, 0.68; 95% CI: 0.53–0.86) compared with bevacizumab + chemotherapy (BC), with a similar objective response rate and incidence of ≥3 treatment-related adverse events (TRAEs) (risk ratios (RR), 0.98; 95% CI: 0.79–1.21/RR, 0.89; 95% CI: 0.61–1.28; respectively) compared with BC. IC yielded a superior PFS rate (HR, 1.59; 95% CI: 1.05–2.38) compared to BC in the subgroup of patients < 65 years old. Conclusions: Currently, IC is a more efficient first-line therapy for driver-gene-negative advanced non-squamous NSCLC patients, with prolonged PFS and OS, as well as a comparatively lower risk of ≥3 TRAEs compared to BC.

Efficacy and safety of pemetrexed maintenance chemotherapy for advanced non-small cell lung cancer in a real-world setting.

BackgroundPemetrexed maintenance therapy offers a survival benefit in patients with nonprogressive advanced nonsquamous non-small cell lung cancer (NSCLC) with good tolerability. This study was designed to analyze the efficacy and safety of pemetrexed maintenance chemotherapy in advanced nonsquamous NSCLC patients in a real-world setting.MethodsThe response rate (RR) and adverse events in 71 nonsquamous NSCLC patients treated with pemetrexed-based chemotherapy were observed until disease progression or unacceptable toxicities. Measures of survival were analyzed during follow-up.ResultsOf 69 efficacy-evaluable patients, the objective response rate (ORR) was 46.4% and the disease control rate (DCR) was 98.6%. ORR showed no significant difference between patients who received pemetrexed as first-line therapy and those who received pemetrexed as second-line or higher treatment. The median treatment cycle for all patients was 8. The median progression-free survival (PFS) was 9.5 months (m) and median overall survival (OS) was 30.5 m. The univariate and multivariate analyses showed that the number of chemotherapy cycles was an independent factor for PFS. The most common adverse reactions were grade 1 to 2 hematologic toxicities, gastrointestinal reactions, and liver enzyme abnormalities. Only 1 patient experienced a grade 3 gastrointestinal event.ConclusionsPemetrexed maintenance chemotherapy can improve PFS in patients with advanced nonsquamous NSCLC with good tolerability.

Prospective Evaluation of Single Nucleotide Variants by Two Different Technologies in Paraffin Samples of Advanced Non-Small Cell Lung Cancer Patients

Targeted therapies are a new paradigm in lung cancer management. Next-generation sequencing (NGS) techniques have allowed for simultaneous testing of several genes in a rapid and efficient manner; however, there are other molecular diagnostic tools such as the nCounter® Vantage 3D single nucleotide variants (SNVs) solid tumour panel which also offer important benefits regarding sample input and time-to-response, making them very attractive for daily clinical use. This study aimed to test the performance of the Vantage panel in the routine workup of advanced non-squamous non-small cell lung cancer (NSCLC) patients and to validate and compare its outputs with the Oncomine Solid Tumor (OST) panel DNA kit, the standard technique in our institution. Two parallel multiplexed approaches were performed based on DNA NGS and direct digital detection of DNA with nCounter® technology to evaluate SNVs. A total of 42 advanced non-squamous NSCLC patients were prospectively included in the study. Overall, 95% of samples were successfully characterized by both technologies. The Vantage panel accounted for a sensitivity of 95% and a specificity of 82%. In terms of predictive values, the probability of truly presenting the SNV variant when it is detected by the nCounter panel was 82%, whereas the probability of not presenting the SNV variant when it is not detected by the platform was 95%. Finally, Cohen’s Kappa coefficient was 0.76, indicating a substantial correlation grade between OST and Vantage panels. Our results make nCounter an analytically sensitive, practical and cost-effective tool.

Combination of apatinib and docetaxel in treating advanced non-squamous non-small cell lung cancer patients with wild-type EGFR: a multi-center, phase II trial.

BackgroundThis trial aimed to investigate the treatment response, survival profiles and treatment-related adverse events (AEs) of apatinib plus docetaxel in advanced non-squamous non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR).MethodsThirty advanced non-squamous NSCLC patients with wild-type EGFR were recruited in this multi-center, phase II trial. All patients received apatinib (orally 500 mg, once daily until disease progression, intolerable toxicity, or death) plus docetaxel (intravenously 60 mg/m2 at day 1 every 3 weeks for 4–6 cycles). The treatment response, progression-free survival (PFS), overall survival (OS) and treatment-related AEs were evaluated.ResultsOne patient lacked response and survival assessment due to early lost follow-up, therefore, 29 patients were included in response and survival analysis. There was no (0.0%) patient achieved complete remission, 8 (27.6%) patients achieved partial remission, 20 (69%) patients with stable disease, and 1 (3.4%) patient with progressive disease, resulting in objective response rate and disease control rate of 27.6% and 96.6%, respectively. According to the survival data, median PFS was 5.3 months (95% CI: 3.6–6.9 months) and median OS was 9.6 months (95% CI: 6.33–12.9 months). For safety, totally 30 patients were included in the analysis. Common non-hematologic AEs included hypertension (66.7%), hand-foot syndrome (40.0%), proteinuria (36.7%); common hematologic AEs included leukopenia (26.7%), thrombocytopenia (23.3%), neutropenia (16.7%). Notably, majority of AEs were at grade 1–2, and the overall AEs were tolerable.ConclusionsApatinib plus docetaxel is an effective and tolerable treatment option for advanced non-squamous NSCLC with wild-type EGFR.

Usefulness of Two Independent DNA and RNA Tissue-Based Multiplex Assays for the Routine Care of Advanced NSCLC Patients.

Personalized medicine is nowadays a paradigm in lung cancer management, offering important benefits to patients. This study aimed to test the feasibility and utility of embedding two multiplexed genomic platforms as the routine workup of advanced non-squamous non-small cell lung cancer (NSCLC) patients. Two parallel multiplexed approaches were performed based on DNA sequencing and direct digital detection of RNA with nCounter® technology to evaluate gene mutations and fusions. The results were used to guide genotype-directed therapies and patient outcomes were collected. A total of 224 advanced non-squamous NSCLC patients were prospectively included in the study. Overall, 85% of samples were successfully characterized at DNA and RNA levels and oncogenic drivers were found in 68% of patients, with KRAS, EGFR, METΔex14, BRAF, and ALK being the most frequent (31%, 19%, 5%, 4%, and 4%, respectively). Among all patients with complete genotyping results and follow-up data (n = 156), the median overall survival (OS) was 1.90 years (confidence interval (CI) 95% 1.69–2.10) for individuals harbouring an actionable driver treated with a matched therapy, compared with 0.59 years (CI 95% 0.39–0.79) in those not eligible for any targeted therapy and 0.61 years (CI 95% 0.12–1.10) in patients with no drivers identified (p < 0.001). Integrating DNA and RNA multiplexing technologies into the routine molecular testing of advanced NSCLC patients is feasible and useful and highlights the necessity of widespread integrating comprehensive molecular diagnosis into lung cancer care.

P2.04-09 Immune-Related Adverse Events in Advanced Non-Squamous NSCLC Patients Treated with Upfront Checkpoint Inhibitors Combination

Immune-related adverse events (IRAE) are a unique set of adverse events caused by checkpoint inhibitors due to enhanced activation of the immune system. IRAEs can virtually affect any organ system and have been responsible for significant morbidity, treatment delay, treatment discontinuation, and even death. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of IRAEs when checkpoint inhibitors were utilized as first-line in combination with chemotherapies in non-squamous non-small cell lung cancer (NSCLC) patients. We systematically conducted a literature search using PUBMED, MEDLINE, EMBASE databases and meeting abstracts from inception through March 2019. Phase 3 RCTs that mention IRAEs as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q -statistic. Random effects model was applied. 2785 patients with advanced non-squamous NSCLC from 5 RCTs (Keynote – 021,189, IMpower – 130, 132 and 150) were eligible. The study arm used standard chemotherapy regimens in combination with pembrolizumab or atezolizumab while control arm utilized only standard chemotherapy regimens. The randomization ratio was 2:1 in IMpower-130 and Keynote-189 studies and 1:1 in other studies. The RR of all-grade side effects were as follows: hypothyroidism, 3.82 (95% CI: 2.14 – 6.80, p < 0.0001); hyperthyroidism, 2.58 (95% CI: 1.32– 5.04; p = 0.005); pneumonitis, 2.62 (95% CI: 1.58– 4.32; p = 0.0002); hepatitis, 3.75 (95% CI: 1.23 – 11.50, p = 0.02); colitis, 4.82 (95% CI: 1.67– 13.90; p = 0.004); and pancreatitis, 2.35 (95% CI: 0.75–7.41; p =0.14). The RR of high-grade side effects were as follows: hypothyroidism, 2.93 (95% CI: 0.62 – 13.74, p = 0.17); hyperthyroidism, 2.32 (95% CI: 0.37– 14.71; p = 0.37); pneumonitis, 1.65 (95% CI: 0.80– 3.41; p = 0.18); hepatitis, 4.14 (95% CI: 1.05 – 16.33, p = 0.04); colitis, 3.31 (95% CI: 1.02– 10.77; p = 0.05); and pancreatitis, 1.44 (95% CI: 0.29– 7.13; p = 0.65). Patients on combined chemoimmunotherapy experienced a significant increase in all grades of hepatitis and colitis with a relative risk of 4.14 for grade 3 and 4 hepatitis. They also contributed to all-grade hypothyroidism, hyperthyroidism and pneumonitis. These toxicities have significant impact on patients’ quality of life, ultimately affecting patients’ compliance. A timely intervention with proper supportive care is necessary.

Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced nonsquamous non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).

125 Background: RCTs have tested the role of adding immunotherapy to standard therapy in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in the first-line setting. We conducted a systematic review and meta-analysis of RCTs to assess the efficacy and toxicity of adding immunotherapy in this patient population. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line standard therapy +/- immunotherapy in patients with advanced non-squamous NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥grade 3). Heterogeneity was assessed with Cochrane Q-statistic. Random effects were used due to significant heterogeneity among studies. Results: Three phase 2 &amp; 3 RCTs (Keynote – 021,189 and IMpower – 150) including 1431 patients with advanced non-squamous NSCLC patients were included in the analysis. Keynote 021 &amp; 189 trials did not allow patients with EGFR or ALK mutations, while IMpower 150 trial allowed EGFR or ALK mutations. The study arm used standard regimens in combination with pembrolizumab or atezolizumab while control arm used only standard regimens. The pooled HR for PFS was 0.57 (95% CI: 0.5-0.65; P=0.00001), the pooled HR for OS was 0.61 (95% CI: 0.43-0.87; P=0.006), and the pooled RR for ORR was 1.83 (95 CI: 1.13-2.95; P=0.01). The pooled RRs for all-grade AEs and high-grade AEs were 1 (95% CI: 0.99-1.02; P=0.48) and 1.11 (95% CI: 0.97-1.28; P=0.14), respectively. Conclusions: Pooled data showed significant improvement in PFS, OS &amp; ORR with chemo-immunotherapy compared to the standard treatment regimen for the first-line treatment of advanced non-squamous NSCLC. There was no increase in the risk of all-grade and high-grade AEs.

Pemetrexed and carboplatin combination therapy followed by pemetrexed maintenance in Japanese patients with non-squamous non-small cell lung cancer: A subgroup analysis of elderly patients.

The combination of pemetrexed and carboplatin is commonly used for the treatment of advanced non-squamous non-small cell lung cancer (NSCLC), mainly because it is comparatively effective and less toxic than other platinum-doublet therapies. Using the JMII (JACAL) study, we report the efficacy and safety of this treatment followed by pemetrexed maintenance in the elderly population (≥70 years of age). The JMII study was a multicenter, post-marketing study that assessed the efficacy and safety of carboplatin (AUC6) and pemetrexed (500 mg/m2, given on Day 1 of a 21-day cycle, 4 cycles) followed by pemetrexed (500 mg/m2) maintenance in advanced non-squamous NSCLC patients (n = 109). Retrospective subgroup analyses were performed in elderly patients aged ≥70. The study includes younger (<70 years, n = 84) and elderly (≥70 years, n = 25) patients who received induction therapy. Median progression-free survival and overall survival from the start of the induction phase were 5.2 (95% CI: 3.5, 8.2) and 16.8 (95% CI: 10.3, NC) months for the elderly patients compared with 5.8 (95% CI: 4.3, 7.4) and 20.5 (95% CI: 16.7, NC) months for the younger patients, respectively. Grade 3/4 hematologic toxicities were more frequent in the elderly patients. Non-hematologic toxicities in the elderly patients were comparable to those in younger patients. Dose reduction was more common in the elderly (44% vs 23%), due to hematologic toxicities. There was no difference in efficacy (evaluated by progression-free survival) between elderly and younger patients. Although grade 3/4 hematologic toxicities were frequently observed in the elderly patients, they were easily managed with dose adjustment.

Efficacy and Safety of Bevacizumab Combined with Chemotherapy as Second-line or Later-line Treatment in Advanced Nonsquamous Non-small Cell Lung Cancer

背景与目的贝伐珠单抗联合含铂双药化疗被推荐为无驱动基因的晚期非鳞非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的一线治疗方案，但此方案用于二线及以上非鳞NSCLC的研究并不普遍。本研究拟探讨二线及以上应用贝伐珠单抗联合化疗治疗晚期非鳞NSCLC的疗效和安全性。方法回顾性分析郑州大学附属肿瘤医院2014年1月-2017年6月间一线治疗进展后应用贝伐珠单抗的晚期非鳞NSCLC患者的临床资料，采用Kaplan-Meier法、Log-rank检验和Cox模型进行统计分析。结果这项研究共纳入62例患者，总体的客观缓解率（objective response rate, ORR）为32.2%，疾病控制率（disease control rate, DCR）为96.8%。中位无进展生存期（progression-free survival, PFS）为6.4个月（95%CI: 6.05-6.83），中位总生存期（overall survival, OS）为20.4个月（95%CI: 12.98-27.76）。在亚组分析中，脑转移患者与无脑转移患者的中位PFS差异无统计学意义（6.2个月vs 6.4个月，P=0.052）。贝伐珠单抗的应用周期（> 6个或≤6个）是PFS的独立影响因素（P=0.004）。最常见的不良反应有白细胞减少、乏力、恶心、血小板减少和高血压。结论二线及以上应用贝伐珠单抗联合化疗治疗晚期非鳞NSCLC的疗效显著且安全性良好。

Current Smoking has a Detrimental Effect on Survival for Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) negative Advanced non-squamous Non-small Cell Lung Cancer (NSCLC) Patients Treated with Pemetrexed Continuation Maintenance

Objectives: The aim of this study is to investigate the predictive value of smoking history on treatment outcomes of pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC patients without EGFR mutations and ALK rearrangements.Methods: 71 consecutive EGFR and ALK negative advanced non-squamous NSCLC patients who had received pemetrexed continuation maintenance therapy at least two cycles were retrospectively analyzed in our single center. The enrolled patients were categorized into two groups as never-/former light smokers and current smokers according to their smoking history.Results: In the 71 non-squamous NSCLC patients, 30 (42.3%) were never-/former light smokers and 41 (57.7%) were current smokers. The objective response rate (ORR) of never-/former light smokers was significantly higher than that of current smokers (26.7% vs. 7.3%, p = 0.026). Never-/former light smokers showed significantly longer progression free survival (PFS) (6.6 [95% CI 5.3-7.9] months vs. 5.1 [95% CI 3.5-6.7] months; HR: 0.557, 95% CI 0.339-0.915, p = 0.021) and overall survival (OS) (17.3 [95% CI 14.4-20.2] months vs. 15.7 [95% CI 12.0-19.4] months; HR: 0.578, 95% CI 0.338-0.986, p = 0.044) than current smokers. Multivariate analysis identified smoking history was an independent predictive factor for PFS and OS.Conclusions: Current smoking is an independent negative predictive factor of outcomes for pemetrexed continuation maintenance therapy in advanced non-squamous NSCLC patients without EGFR mutations and ALK rearrangements.

24h-gene variation effect of combined bevacizumab/erlotinib in advanced non-squamous non-small cell lung cancer using exon array blood profiling

BackgroundThe SAKK 19/05 trial investigated the safety and efficacy of the combined targeted therapy bevacizumab and erlotinib (BE) in unselected patients with advanced non-squamous non-small cell lung cancer (NSCLC). Although activating EGFR mutations were the strongest predictors of the response to BE, some patients not harboring driver mutations could benefit from the combined therapy. The identification of predictive biomarkers before or short after initiation of therapy is therefore paramount for proper patient selection, especially among EGFR wild-types. The first aim of this study was to investigate the early change in blood gene expression in unselected patients with advanced non-squamous NSCLC treated by BE. The second aim was to assess the predictive value of blood gene expression levels at baseline and 24h after BE therapy.MethodsBlood samples from 43 advanced non-squamous NSCLC patients taken at baseline and 24h after initiation of therapy were profiled using Affymetrix’ exon arrays. The 24h gene dysregulation was investigated in the light of gene functional annotations using gene set enrichment analysis. The predictive value of blood gene expression levels was assessed and validated using an independent dataset.ResultsSignificant gene dysregulations associated with the 24h-effect of BE were detected from blood-based whole-genome profiling. BE had a direct effect on “Pathways in cancer”, by significantly down-regulating genes involved in cytokine–cytokine receptor interaction, MAPK signaling pathway and mTOR signaling pathway. These pathways contribute to phenomena of evasion of apoptosis, proliferation and sustained angiogenesis. Other signaling pathways specifically reflecting the mechanisms of action of erlotinib and the anti-angiogenesis effect of bevacizumab were activated. The magnitude of change of the most dysregulated genes at 24h did not have a predictive value regarding the patients’ response to BE. However, predictive markers were identified from the gene expression levels at 24h regarding time to progression under BE.ConclusionsThe 24h-effect of the combined targeted therapy BE could be accurately monitored in advanced non-squamous NSCLC blood samples using whole-genome exon arrays. Putative predictive markers at 24h could reflect patients’ response to BE after adjusting for their mutational status.Trial registration ClinicalTrials.gov: NCT00354549

431P First-line treatment of advanced nonsquamous non-small cell lung cancer (NSCLC) in China in the era of precision medicine

Background Over 40% of advanced nonsquamous NSCLC patients in China have an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion and would benefit from treatment with EGFR or ALK tyrosine kinase inhibitors (TKIs), which are associated with significantly higher response rates and longer progression-free survival. We analysed first-line treatment according to gene aberration test status in advanced nonsquamous NSCLC patients in China (CTONG- 1506). Methods Our survey of 12 tertiary hospitals in China included advanced nonsquamous NSCLC patients admitted for first-line anti-cancer treatment from August 2015 to March 2016. Data extracted from medical charts for analysis were patient demographics, tumor histologic type, gene aberration test status and results (if performed), and first-line anti-cancer treatment regimen. Results The gene aberration test rate for patients (N = 932; median age, 59 years; male, 56%) with advanced nonsquamous NSCLC was 71% and varied with hospital location (Beijing, Shanghai, Guangzhou vs other locations) and type (general vs specialist), and patient residence (urban vs rural). Although 67% of patients with EGFR mutations (mainly in exons 19 or 21; n = 280) received first-line EGFR TKIs, 31% received first- line chemotherapy (chemo.; Table). Most patients with ALK fusions received first-line chemotherapy (56%) or ALK TKIs (35%); 3 patients had co-existing EGFR mutations and received first-line EGFR TKIs (Table). Nearly all patients with negative or unknown gene aberration status (96%) received first-line chemotherapy (Table), of which pemetrexed (66%, 367/554) was the predominant nonplatinum chemotherapy- backbone agent.Tabled 1Table: 431PGene aberrationn (%)PositiveNegative/UnknownEGFRALKROSIN = 309N = 48N = 1N = 574TKIs207 (67)20 (42)115 (3)EGFR2053015ALK11710VEGFR1000Chemo.a95 (31)27 (56)0554 (96)TKIs 1 Chemo.7 (2)1 (2)05 (1)EGFR7002nonEGFR0103 Open table in a new tab aIncluding bevacizumab-triplet Conclusions Results from our survey of tertiary hospitals in China suggest that first- line treatment of advanced nonsquamous NSCLC patients is mostly aligned with the presence or absence of gene aberrations. Clinical trial indentification Chinese Thoracic Oncology Group (CTONG) study number 1506 Legal entity responsible for the study Lilly Suzhou Pharmaceutical Co. Ltd., China Funding: Lilly Suzhou Pharmaceutical Co. Ltd., China Disclosure Q. Shi, L.L. Yang, P.H. Zhang: Employee of Lilly Suzhou Pharmaceutical Co., China. Y-L. Wu: Honoraria: F. Hoffmann-La Roche, Eli Lilly, AstraZeneca, Pfizer. All other authors have declared no conflicts of interest.

Long-term survival in advanced non-squamous NSCLC patients treated with first-line bevacizumab-based therapy.

First-line bevacizumab-based therapies have been shown to improve clinical outcomes in patients with non-squamous non-small-cell lung cancer (NSCLC). We aimed to descriptively analyse patients with non-squamous NSCLC who received a long-term period of maintenance bevacizumab. This retrospective study included 104 patients who had already reached a progression-free survival (PFS) of at least 9months. Median overall survival and PFS were 30.7 and 15.1months, respectively. The overall response rate was 83%. Weight loss ≤5%, ECOG PS=0, or low number of metastatic sites seem to be predictive factors of good evolution. The incidence of bevacizumab-related adverse events appeared to be similar as the previous studies. Our findings show that there is a long-term survivor group whom the administration of bevacizumab resulted in a relevant prolongation of response without new safety signals. Due to the population heterogeneity, it was not possible to identify the standardised predictive factors.

Efficacy of pemetrexed plus platinum doublet chemotherapy as first-line treatment for advanced nonsquamous non-small-cell-lung cancer: a systematic review and meta-analysis.

PurposeTo assess the efficacy of pemetrexed plus platinum doublet chemotherapy as first-line treatment for advanced nonsquamous non-small-cell lung cancer (NSCLC) through a trial-level meta-analysis.MethodsTrials published between 1990 and 2015 were identified by an electronic search of public databases (Medline, Embase, and Cochrane Library). All clinical studies were independently identified by two authors. Demographic data, treatment regimens, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were extracted and analyzed using comprehensive meta-analysis software (version 2.0).ResultsA total of 2,551 patients with advanced nonsquamous NSCLC from ten trials were included for analysis: 1,565 patients were treated with pemetrexed plus platinum doublet chemotherapy and 986 with platinum plus other first-line chemotherapy. Pooled ORR for pemetrexed plus platinum chemotherapy was 37.8% (95% confidence interval [CI]: 31.7%–44.3%), with median PFS and OS of 5.7 and 16.05 months, respectively. When compared to other platinum-based doublet chemotherapies, the use of pemetrexed plus platinum chemotherapy significantly improved OS (hazard ratio [HR] =0.86, 95% CI: 0.77–0.97, P=0.01) but not PFS (HR =0.90, 95% CI: 0.80–1.01, P=0.084) in advanced nonsquamous NSCLC patients.ConclusionPemetrexed plus platinum doublet regimen is an efficacious treatment for advanced nonsquamous NSCLC patients. Our findings support the use of pemetrexed plus platinum doublet regimen as first-line treatment in advanced nonsquamous NSCLC patients because of its potential survival benefits.

Full-dose pemetrexed plus cisplatin combined with concurrent thoracic radiotherapy for previously untreated advanced nonsquamous non-small cell lung cancer.

Compared with other platinum-based doublet chemotherapy, pemetrexed plus platinum is more effective and tolerable as the first-line treatment for nonsquamous non-small cell lung cancer (NSCLC). Thus, we examined the feasibility of using thoracic radiotherapy combined with concurrent full-dose pemetrexed as the first-line treatment for advanced nonsquamous NSCLC patients. From January 2009 to July 2012, 41 patients with stage IIIB or IV nonsquamous NSCLC were treated with full-dose pemetrexed plus cisplatin as the first-line chemotherapy combined with concurrent thoracic radiotherapy, with or without radiotherapy for metastases. The status of mutations in the epidermal growth factor receptor was unknown before the treatment, and no tyrosine-kinase inhibitor and cytotoxic drug maintenance therapy were administered to the patients after the chemotherapy. The median follow-up duration was 26.3 months (range, 5.8-57.5 months). Twenty-one patients had stage IIIB disease (19 with stage N3-IIIB). Of the 20 patients with stage IV disease, 16 had oligometastases (≤5) and four had polymetastases. The median number of chemotherapy cycles was 4. The median radiation dose was 60 Gy. Thirty-six patients received radical doses of radiotherapy. Toxicities were highly tolerated. The median progression-free survival was 12 months and the median overall survival was 32 months. The 1-, 2-, and 3-year overall survival rates were 87.5, 67.1, and 43.4%, respectively. As the first-line treatment for selected patients with advanced nonsquamous NSCLC, thoracic radiotherapy combined with concurrent full-dose pemetrexed plus cisplatin was safe and highly tolerable. In addition, the survival rate was encouraging. Prospective clinical trials are needed to verify the results.