Survival Benefit In Non-small Cell Lung Cancer Patients Research Articles

Prognostic value of cranial radiotherapy and optimal timing stratified by lung-molGPA for NSCLC patients with brain metastases.

The updated Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (lung-molGPA) index provide more accurate survival prediction for patients diagnose with advanced non-small cell lung cancer (NSCLC) with brain metastases (BM). Given that the value of cranial radiotherapy (CRT) is still controversial for NSCLC patients with BM, this retrospective study aimed to evaluate the value of CRT and optimal timing in NSCLC patients with initial BM after stratified with lung-molGPA index. This study screened NSCLC patients with initial BM in our cancer center from February 2012 to July 2018. The prognosis value of CRT and optimal timing was evaluated with Kaplan-Meier survival analysis and the patients were classified into lung-molGPA0-2 and lung-molGPA2.5-4 group. Upfront CRT was defined as received CRT within 3months after initial diagnosis and without BM progression, other CRT was classified into deferred CRT. Overall, 288 patients were enrolled in our study, 156 patients received CRT. The median follow-up time was 47months. In the entire cohort, the median PFS and OS were 9.2 and 17.0months, respectively. In the lung-molGPA2.5-4 group, CRT can bring significantly overall survival benefit for NSCLC patients with initial BM (HR: 0.48, 95% CI: 0.34-0.68, P < 0.0001), and the upfront CRT can further expand this survival benefits compared with deferred CRT (HR: 0.49, 95% CI: 0.27-0.89, P = 0.0026). But this phenomenon was not observed in lung-molGPA0-2 group patients. Upfront CRT could bring significantly overall survival benefit for these patients with lung-molGPA2.5-4 but not for patients with lung-molGPA0-2.

The efficacy and safety of immune checkpoint inhibitors for patients with EGFR-mutated non-small cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy: A systematic review and network meta-analysis.

Non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR)-mutated who progressed on EGFR tyrosine-kinase inhibitor (EGFR-TKI) therapy have limited therapeutic options. There is still no consensus on the role of immune checkpoint inhibitors (ICIs) in NSCLC with EGFR mutations. We did a network meta-analysis (NMA) with a systematic literature search on PubMed, Embase, Web of Science, and The Cochrane Library. We included all phase II and III randomized controlled trials (RCTs), non-randomized controlled trials (Non-RCTs), and retrospective studies. Progression-free survival (PFS) and overall survival (OS) were assessed through hazard ratios (HR). Objective response rate (ORR) and adverse events (AEs) were assessed through odds ratio (OR) and relative risk (RR), respectively. R software was used to compare the outcomes of different treatments by Bayesian NMA. We identified 1835 published results and 17 studies were included ultimately. A total of 2085 patients were included and accepted the following six treatments: ICIs plus chemotherapy (ICIs+Chemo), chemotherapy (Chemo), ICIs monotherapy (ICIs), ICIs plus chemotherapy and antiangiogenic therapy (ICIs+Chemo+Antiangio), antiangiogenic therapy plus chemotherapy (Antiangio+Chemo), ICIs plus antiangiogenic therapy (ICIs+Antiangio). ICIs+Chemo+Antiangio was associated with longer PFS and OS, as well as higher ORR (surface under the cumulative ranking curve [SUCRA], 96%, 90%, 91%). ICIs conferred the safety profile in terms of any-grade AEs, grade greater than or equal to 3 AEs and any grade leading to treatment discontinuation occurred AEs (SUCRA, 99%, 68%, 94%). ICIs+Chemo+Antiangio brings the greatest survival benefit in NSCLC patients with EGFR mutations who progressed on EGFR-TKI therapy, even for whom with baseline brain metastases. Compared with chemotherapy, ICIs has a low incidence of AEs and a benefit in OS.

Prognostic Factors and Survival Benefits of Antitumor Treatments for Advanced Non-Small Cell Lung Cancer Patients With Central Nervous System Metastasis With or Without Driver Genes: A Chinese Single-Center Cohort Study.

BackgroundThe prognosis of non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastasis is poor. The treatment for CNS metastasis could prolong the overall survival of NSCLC patients. We aimed to investigate the prognostic factors of Chinese NSCLC patients with CNS metastasis and the survival benefits of various treatments for CNS metastasis in NSCLC patients with or without driver genes.MethodsBased on the CAPTRA-Lung database, NSCLC patients with CNS metastasis admitted at the Peking Union Medical College Hospital between January 2010 and October 2018 were enrolled in the study. The prognostic factors were analyzed using univariate and multivariate Cox regression analyses.ResultsOverall, 418 patients were enrolled in the study. A total of 206 patients (49.3%) had CNS metastasis with positive driver genes, while 97 patients (23.2%) had negative driver genes. The median survival time after CNS metastasis was 20.8 months. In the multivariable analysis, an Eastern Cooperative Oncology Group performance status of ≥2 (hazard ratio [HR]: 1.750, 95% confidence interval [CI]: 1.184-2.588, P=0.005), number of CNS metastases ≥5 (HR: 1.448, 95% CI: 1.084 -1.934, P=0.012), and CNS metastasis developed during treatment (HR: 1.619, 95% CI: 1.232-2.129, P=0.001) were independent risk factors for poor survival. Lung adenocarcinoma (HR: 0.490, 95% CI: 0.279-0.861, P=0.013) and driver gene positivity (HR: 0.464, 95% CI: 0.302-0.715, P=0.001) were independent predictors of prolonged survival. Radiotherapy for CNS metastasis showed a survival benefit in NSCLC patients in the entire groups (HR: 0.472, 95% CI: 0.360-0.619, P <0.001), and in patients with positive driver genes.ConclusionPerformance status, number of CNS metastases, timing of CNS metastasis, histological subtype, and driver gene status are prognostic factors for NSCLC patients with CNS metastasis. Furthermore, radiotherapy improved the survival in NSCLC patients with CNS metastasis.

Anti-PD1/PDL1 IgG subclass distribution in ten cancer types and anti-PD1 IgG4 as biomarker for the long time survival in NSCLC with anti-PD1 therapy.

Antibodies targeting programmed cell death-1(PD1) and its ligand (PDL1) have revolutionized cancer therapy. However, little is known about the preexisted anti-PD1/PDL1 autoantibodies (AAbs) distribution in multiple cancer types, nor is their potential biomarker role for anti-PD1 therapy. Plasma anti-PD1/PDL1 AAb IgG and subclasses (IgG1-4) were detected by enzyme-linked immune sorbent assay (ELISA) in 190 cancer patients, covering 10 cancer types (lung, breast, esophageal, colorectal, liver, prostatic, cervical, ovarian, gastric cancers and lymphoma), the comprehensive correlation of AAbs with multiple clinical parameters was analyzed. We further tested these AAbs in 76 non-small cell lung cancer (NSCLC) samples receiving anti-PD1 therapy, the association of AAbs level with survival was analyzed and validated in an independent cohort (n = 32). Anti-PD1/PDL1 AAb IgG were globally detected in 10 types of cancer patients. IgG1 and IgG2 were the major subtypes for anti-PD1/PDL1 AAbs. Correlation analysis revealed a distinct landscape between various cancer types. The random forest model indicated that IgG4 subtype was mostly associated with cancer. In discovery cohort of 76 NSCLC patients, high anti-PD1 IgG4 was associated with a reduced overall survival (OS, p = 0.019), not progression-free survival (PFS,p = 0.088). The negative association of anti-PD1 IgG4 with OS was validated in 32 NSCLC patients (p = 0.032). This study reports for the first time the distribution of preexisted anti-PD1/PDL1 AAb IgG and subclasses across 10 cancer types. Moreover, the anti-PD1 AAb IgG4 subclass was identified to associate with OS, which may serve as a potential biomarker for anti-PD1 therapeutic survival benefit in NSCLC patients.

A clinical variable-based nomogram could predict the survival for advanced NSCLC patients receiving second-line atezolizumab.

ObjectiveA nomogram model based on clinical variables was conducted to predict the survival in patients with non‐small cell lung cancer (NSCLC) receiving second‐line atezolizumab.MethodsFour hundred and twenty‐four patients with NSCLC receiving atezolizumab from OAK study were regarded as the training cohort. Next, a nomogram model based on clinical variables in the training cohort was established to predict the survival of patients receiving atezolizumab. The concordance index, area under curve (AUC), and calibration plots were used to assess the performance of the nomogram model. In addition, 144 patients with NSCLC receiving atezolizumab from POPLAR study were regarded as the test cohort to validate the nomogram model. Using Kaplan–Meier and log‐rank test, we compared the survival difference between the high‐ and low‐risk groups, atezolizumab and docetaxel treatment groups, respectively.ResultsWe successfully constructed a nomogram model based on different variable scores for predicting the survival in NSCLC patients receiving atezolizumab using the training cohort. According to risk score, patients receiving atezolizumab were divided into the high‐ and low‐risk groups. Importantly, in the training cohort, patients had worse overall survival (OS) in high‐risk group compared with the low‐risk group (median survival: 252.3 vs. 556.9 days; p < 0.0001). As expected, in the test cohort, the high‐risk patients also showed a worse OS (median survival: 288.8 vs. 529.3 days, p = 0.0003). In addition, all the patients from the training and test cohorts could be found the OS benefit from atezolizumab compared with docetaxel (all, p < 0.05).ConclusionsThe clinical variable‐based nomogram model could predict the survival benefit for NSCLC patients receiving second‐line atezolizumab.

Potential impact of clinical trial (CT) participation on survival of patients with metastatic non-small cell lung cancer (NSCLC).

137 Background: Evidence is conflicting as to whether enrollment in therapeutic drug trials confers a survival benefit for NSCLC patients. We assessed the effect of CT participation on overall survival in a cohort of metastatic NSCLC patients treated at a single large academic center. Methods: We retrospectively revised medical records of patients with metastatic NSCLC diagnosed between 1/1/2007 and 12/31/2015 that received treatment at the Seattle Cancer Care Alliance. Eligibility criteria included receipt of ≥ 1 anti-cancer drug within 180 days of M1 diagnosis, no active second malignancy, and 60 day minimum survival. We abstracted patient sociodemographic characteristics, smoking history, ECOG score, tumor histology, EGFR and ALK status, presence of brain metastases, systemic treatment history up to 5 lines, drug trial enrollment, and trial characteristics. We obtained death dates from the Washington State cancer registry complemented by medical records, censoring patients that were alive at end of follow-up (3/7/2019). We used multivariate Cox regression to test whether enrollment in ≥ 1 CT was associated with overall survival. Results: Of 371 eligible patients (median age 63.9 years, 47% male, 94% non-squamous histology, 30% never-smokers, 58% ECOG 0-1, 20% EGFR positive and 8% ALK positive, and 27% brain metastases), 118 (32%) enrolled in ≥ 1 CT. Of CT enrollees: 19% enrolled in &gt; 1 CT, 89% in phase I/II trials, 15% in phase III trials, 26% in randomized trials, and 51% in trials of drugs later approved by the FDA. Median survival in CT enrollees was 838 days (95% CI 688, 1,021), as compared to 454 days in non-enrollees (95% CI 378, 511). After adjusting for sex, ECOG score, smoking, histology, EGFR and ALK status, and presence of brain metastases, CT enrollees had a 47% lower risk of death relative to non-enrollees (HR 0.53; 95% CI 0.13, 0.92; P = 0.002). Conclusions: Participation in therapeutic drug trials is associated with longer overall survival in advanced NSCLC. Besides supporting drug development, CT participation may directly benefit NSCLC patients by providing access to promising agents and/or enhanced supportive care.

Clinical and biological significance of erlotinib therapy after pemetrexed in non-small cell lung cancer with wild-type EGFR.

Pemetrexed is amulti-targeted anti-folate agent that confers favorable benefits to patients with non-small cell lung cancer (NSCLC). However, the optimal use including treatment schedule of pemetrexed and other drugs in clinical practice remains to be determined, particularly for NSCLC with wild-type epidermal growth factor receptor (EGFR). The present study investigated apotential therapeutic strategy for NSCLC patients with wild-type EGFR who were treated with pemetrexed. To identify factors associated with asurvival, medical record data from 130 patients were retrospectively reviewed, using the Kaplan-Meier method with log-rank test. Factors identified in the clinical analysis were further investigated within in vitro studies. Patients who underwent the treatment schedule of erlotinib at the time of progression after pemetrexed-based chemotherapy prolonged overall survival, compared to those treated with other schedules (p=0.010; hazard ratio, 0.418). This survival benefit was also observed in the treatment schedule of pemetrexed monotherapy and subsequent erlotinib (p=0.008; hazard ratio, 0.220). As atreatment at the time of progression after pemetrexed-based chemotherapy, erlotinib conferred asurvival benefit when compared to docetaxel (p=0.024; hazard ratio, 0.377). The cell growth assay confirmed that treatment with pemetrexed followed by erlotinib significantly inhibited proliferation of NSCLC cells regardless of EGFR mutation status. In conclusion, use of erlotinib at the time of progression after pemetrexed therapy confers asurvival benefit in NSCLC patients with wild-type EGFR. The result of this study provides an important clue to the optimal treatment schedule for NSCLC.

P7170, a novel inhibitor of mTORC1/mTORC2 and Activin receptor-like Kinase 1 (ALK1) inhibits the growth of non small cell lung cancer.

BackgroundLung cancer is the major cause of cancer-related deaths and many cases of Non Small Cell Lung Cancer (NSCLC), a common type of lung cancer, have frequent genetic/oncogenic activation of EGFR, KRAS, PIK3CA, BRAF, and others that drive tumor growth. Some patients though initially respond, but later develop resistance to erlotinib/gefitinib with no option except for cytotoxic therapy. Therefore, development of novel targeted therapeutics is imperative to provide improved survival benefit for NSCLC patients. The mTOR cell survival pathway is activated in naïve, or in response to targeted therapies in NSCLC.MethodsWe have discovered P7170, a small molecule inhibitor of mTORC1/mTORC2/ALK1 and investigated its antitumor efficacy using various in vitro and in vivo models of human NSCLC.ResultsP7170 inhibited the phosphorylation of AKT, S6 and 4EBP1 (substrates for mTORC2 and mTORC1) levels by 80-100% and growth of NSCLC cells. P7170 inhibited anchorage-independent colony formation of NSCLC patient tumor–derived cells subsistent of disease sub-types. The compound also induced apoptosis in NSCLC cell lines. P7170 at a well-tolerated daily dose of 20 mg/kg significantly inhibited the growth of NSCLC xenografts independent of different mutations (EGFR, KRAS, or PIK3CA) or sensitivity to erlotinib. Pharmacokinetic-pharmacodynamic (PK-PD) analysis showed sub-micro molar tumor concentrations along with mTORC1/C2 inhibition.ConclusionsOur results provide evidence of antitumor activity of P7170 in the erlotinib –sensitive and –insensitive models of NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-259) contains supplementary material, which is available to authorized users.

Abstract 3759: P7170, a novel inhibitor of phosphoinositide 3-kinase (PI3K)-mammalian target of Rapamycin (mTOR) and activin receptor-like kinase 1 (ALK1) as a new therapeutic option for Kras mutated non small cell lung cancer (NSCLC)

Abstract Major breakthroughs in targeted cancer treatment have been achieved in last decade, but still some patient populations such as Kras mutated non small cell lung cancer (NSCLC), have no therapeutic options other than cytotoxic therapies. Therefore, development of targeted therapeutics is warranted in order to provide improved survival benefit for NSCLC patients with Kras mutation. P7170 is a small molecule inhibitor of PI3K (IC50 = 2.2 nM) and mTOR (IC50 = 4.4 nM). It also inhibits ALK1 and DNA-PK, two important enzymes involved in angiogenesis and DNA repair with IC50 of 47 and 1.5 nM, respectively. The structure, other in vitro, and in vivo efficacy of P7170 has been reported in the accompanying abstract submitted for AACR 2012. P7170 inhibited PI3K-mTOR pathway proteins pAKT, pS6 and p4EBP1 by 90 to 100 % in Kras mutated NSCLC cell line (H460) in a western blot assay. P7170 also exhibited potent cytotoxicity activity against two Kras mutated NSCLC (H460 and A549) cell lines with IC50 values of 7 and 5 nM. P7170 inhibited anchorage independent colony formation of tumor cells isolated from 10 different human tumor xenografts derived from NSCLC patient's tumors (Seven out of 10 samples had wild type Kras, and three had mutations in Kras). Moreover, P7170 induced apoptosis in H460 cell lines by inducing PARP cleavage. More interestingly, P7170 inhibited pAKT and pS6 in a dose dependent fashion in stem-like cells isolated from tumor samples of a Kras mutated NSCLC patient. P7170 demonstrated significant (p&amp;lt;0.01) in vivo efficacy following oral administration, in NSCLC xenograft studies using Kras mutated H460 cancer cell line. P7170 treatment resulted in 66% tumor growth inhibition at a dose of 5 mg/kg, and stabilization of tumor growth (89% tumor growth inhibition) at a dose of 20 mg/kg. Evaluation of mechanism of action of P7170 in H460 xenografted tumors confirmed the inhibition of PI3K-mTOR (pAKT and p4EBP) and Ras-Raf (pERK) pathways. In addition, inhibition of ALK1 and DNA-PK activity with the treatment of P7170 was also confirmed in xenografts. Conclusion: P7170 by virtue of its unique profile represents an opportunity to deliver a first-in-class therapeutic option for patients saddled with Kras mutated non small cell lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3759. doi:1538-7445.AM2012-3759

Survival benefit of gefitinib treated non-small-cell lung cancer patients with exon 19 deletion mutations in epidermal growth factor receptor (EGFR), detected by a new sensitive PCR-based method

10614 Background: As for two common types of EGFR mutations, patients with exon 19 deletion mutations have longer survival than those with the L858R point mutations in exon 21 after treatment with EGFR inhibitors. We have developed a simple, polymerase chain reaction (PCR)-based method to detect exon 19 deletion mutations, and evaluated survival benefit of gefitinib treated patients with exon 19 deletion mutations versus patients without these mutations. Patients and methods: Tumor tissue was microdissected under stereoscopic microscopy from formalin-fixed paraffin-embedded sections, and DNA was extracted from tumor cells with DNeasy (Qiagen). Our method consisted of two different semi-nested PCRs with the deletion screening PCR and the common deletion specific PCR. All of the known deletions present in cell lines were detected by this method without direct sequencing. The result was validated by sequencing of exon 19. 73 non-small-cell lung cancer (NSCLC) Japanese patients treated with gefitinib were analyzed with this method. Study group consisted of 28 females (38%), 29 never smokers (40%) and 57 patients with adenocarcinoma (78%). Results: The PCR-based method detected mutations at mutant to wild type DNA copy ratio of 1/600, and in samples as small as 30 ng of purified DNA. Exon 19 deletion mutations were found in 25 (34%) patients. This method was more sensitive than conventional sequencing. The sequencing was performed in 19 patients with mutations and could not detect 3 deletions. Among 60 assessable patients 14 had overall response (23%). Objective response rates to gefitinib were observed in 7/21 patients with exon 19 deletion mutations (33%), and 7/39 patients without exon 19 deletion mutations (17%) (P = .211). Patients with exon 19 deletion mutations survived significantly longer than those without exon 19 deletion mutations (P = .017). Conclusions: The PCR-based method to detect exon 19 deletion mutations is cost effective and very sensitive, compared to previously described methods. We demonstrated survival benefit in NSCLC patients with exon 19 deletion mutations treated with gefitinib, and our PCR-based method is easily applicable for clinical use. No significant financial relationships to disclose.