Radiotherapy to reinvigorate immunotherapy activity after acquired resistance in metastatic non-small-cell lung cancer: A pooled analysis of two institutions prospective phase II single arm trials.

AIM: The current work aimed to investigate the clinical benefit of radiotherapy in patients with metastatic non-small cell lung cancer (NSCLC) developing acquired resistance to immune checkpoint inhibitors. METHOD: We report on a pooled, two-institution, phase II single-arm prospective cohort study. The study included patients with stage IV NSCLC who showed progression of one or more measurable lesions under anti-PD-(L)1 inhibition alone, after initially having achieved at least stable disease. Hypofractionated radiotherapy (hRT) of one to four metastases was performed, while one or more lesions were kept untreated. Following hRT, treatment with immune checkpoint inhibitors was continued unchanged until further evidence of tumor progression or unacceptable toxicity. Primary endpoint of the pooled analysis was progression-free survival (PFS), secondary endpoints included overall survival (OS) and toxicity. RESULTS: A total of 48 patients were enrolled: mean age was 67.1 ± 9.3 years, 50 % were male and 72.9 % were PD-L1 positive. Immunotherapy was in 95.8 % of patients the first or second line therapy at time of enrollment. hRT was performed to one (93.8 % of cases) or more lesions (median total dose: 27.5 Gy, median 6.5 Gy/fraction). Forty-five patients (93.8 %) were able to continue immunotherapy for a median of 6.2 months following hRT. Median PFS was 4.4 months, with 62.5 % disease control at three months and 37.5 % at six months. Median OS was 14.9 months. Severe adverse events (grade ≥ 2) were reported in 12 cases (25 %), of which none were radiotherapy-related and four were immunotherapy-related. Salvage therapy consisted of chemotherapy (48.8 %) or repeated irradiation (21.9 %). No further tumor treatment was performed in 29.3 % of patients. CONCLUSIONS: The current pooled analysis is a prospective evaluation of the role of radiation therapy for metastatic NSCLC in the setting of newly acquired immunotherapy resistance. Hypofractionated radiotherapy can support the outcome of immune checkpoint inhibitors and thus allow continuation of treatment for a relevant amount of time despite initial tumor progression.

Analysis of phase III clinical trials in metastatic NSCLC to assess the correlation between QoL results and survival outcomes.

BACKGROUND: In addition to improving survival outcomes, new oncology treatments should lead to amelioration of patients' quality of life (QoL). Herein, we examined whether QoL results correlated with PFS and OS outcomes in phase III randomized controlled trials (RCTs) investigating new systemic treatments in metastatic non-small cell lung cancer (NSCLC). METHODS: The systematic search of PubMed was conducted in October 2022. We identified 81 RCTs testing novel drugs in metastatic NSCLC and published in the English language in a PubMed-indexed journal between 2012 and 2021. Only trials reporting QoL results and at least one survival outcome between OS and PFS were selected. For each RCT, we assessed whether global QoL was "superior," "inferior," or with "non-statistically significant difference" in the experimental arm compared to the control arm. RESULTS: Experimental treatments led to superior QoL in 30 (37.0%) RCTs and inferior QoL in 3 (3.7%) RCTs. In the remaining 48 (59.3%) RCTs, a statistically significant difference between the experimental and control arms was not found. Of note, we found a statistically significant association between QoL and PFS improvements (X2 = 3.93, p = 0.0473). In more detail, this association was not significant in trials testing immunotherapy or chemotherapy. On the contrary, in RCTs testing target therapies, QoL results positively correlated with PFS outcomes (p = 0.0196). This association was even stronger in the 32 trials testing EGFR or ALK inhibitors (p = 0.0077). On the other hand, QoL results did not positively correlate with OS outcomes (X2 = 0.81, p = 0.368). Furthermore, we found that experimental treatments led to superior QoL in 27/57 (47.4%) trials with positive results and in 3/24 (12.5%) RCTs with negative results (p = 0.0028). Finally, we analyzed how QoL data were described in publications of RCTs in which QoL outcomes were not improved (n = 51). We found that a favorable description of QoL results was associated with sponsorship by industries (p = 0.0232). CONCLUSIONS: Our study reveals a positive association of QoL results with PFS outcomes in RCTs testing novel treatments in metastatic NSCLC. This association is particularly evident for target therapies. These findings further emphasize the relevance of an accurate assessment of QoL in RCTs in NSCLC.

Personal and clinical characteristics associated with immunotherapy effectiveness in stage IV non-small cell lung cancer.

Background: Immunotherapy response rates in metastatic non-small cell lung cancer (NSCLC) are low and survival varies significantly. Factors like age, sex, race, and histology may modulate immunotherapy response. Existing analyses are limited to clinical trials, with limited generalizability, and meta-analyses where adjustment for potential confounders cannot be performed. Here, we conduct a cohort study with patient-level analysis to explore how personal and clinical characteristics moderate chemoimmunotherapy effectiveness in metastatic NSCLC. Methods: Stage IV NSCLC patients diagnosed in 2015 were drawn from Surveillance Epidemiology, and End Results-Medicare linked data. Receipt of chemoimmunotherapy and overall survival (OS) were the primary predictor and outcome of interest respectively. Multivariable Cox-proportional hazards regression and propensity-score matching were performed to evaluate the effectiveness of immunotherapy addition to chemotherapy. Results: From a total of 1,471 patients, 349 (24%) received chemoimmunotherapy and 1,122 (76%) received chemotherapy alone. Survival was significantly better among those treated with chemoimmunotherapy compared to those receiving chemotherapy alone [adjusted hazard ratio (HRadj) =0.72, 95% confidence interval (CI): 0.63-0.83]. Males saw significantly better OS from chemoimmunotherapy (HRadj =0.62, 95% CI: 0.51-0.75) than females (HRadj =0.81, 95% CI: 0.65-1.01, Pinteraction=0.0557). After propensity-score matching, the effect of chemoimmunotherapy was borderline significant according to sex (Pinteraction =0.0414), but not age or histology. Conclusions: Males may benefit more from chemoimmunotherapy, but there is limited evidence suggesting age, histology, race, and comorbidities contribute to differences in effectiveness. Future research should elucidate who responds best to chemoimmunotherapy, and further analyses of characteristics like race can inform how to tailor different treatment regimens to distinct patient subpopulations.

A Prospective Study Comparing Dosimetry between Computed Tomography (CT) based Radiation Planning and Positron Emission Computed Tomography (PET-CT) based Radiation Planning in Treatment of Non-Metastatic Non Small Cell Lung Carcinoma.

BACKGROUND: To evaluate dosimetry between CT based radiation planning and PET-CT based radiation planning. MATERIAL & METHODS: Histologically proven 40 cases of locally advanced non-small cell carcinoma of lung were accrued for the prospective study. Contrast enhanced planning CT images and PET images were acquired. Target volume delineation, organs of interest & radiation planning were performed in Eclipse V 14.5 followed by dosimetric comparison among GTV, PTV and OARs. A p-value of <0.05 was considered significant. RESULTS: The mean of GTV were 141.18 ± 119.76 cc in CT and 115.54 ± 91.02 cc in PET-CT based and the difference was statistically significant (p=0.03). The mean of CTV were 313.91 ± 180.87 cc in CT and 260.81 ± 148.83 cc in PET-CT based and the difference was statistically significant (p=0.03). The contralateral lung mean dose was statistically very significant (p<0.01) among both the 3D-CRT plans which were 8.49 Gy in CECT based planning and 9.53 Gy in PET CT based planning. The heart mean dose was also statistically significant (p=0.03) among the plans which were 17.90 Gy in CECT based planning and 17.06 Gy in PET CT based planning. Mann-Whitney U test showed the CT based PTV D90 was 58.20 Gy vs 57.58 Gy in PET CT based planning (p=0.02). PTV V95 were also comparable in both of the plans (p=0.02). CONCLUSIONS: GTV measured using PET-CT, may be greater or lesser than the CECT-based GTV. PET-CT-based contouring is more accurate for identifying tumour margins and new lymph node volumes.

Efficacy and outcomes of ramucirumab and docetaxel in patients with metastatic non-small cell lung cancer after disease progression on immune checkpoint inhibitor therapy: Results of a monocentric, retrospective analysis.

Current first-line standard therapy for metastatic non-small cell lung cancer without driver mutations involves chemotherapy and immunotherapy combination. Prior to the advent of immune checkpoint inhibition, REVEL, a randomized phase III trial demonstrated improved progression-free and overall survival with ramucirumab and docetaxel (ram+doc) in patients who failed platinum-based first-line therapy. Long-term outcomes related to second-line ramucirumab and docetaxel after first-line immunotherapy exposure remain unknown. We analyzed outcomes for 35 patients from our center whom received ramucirumab and docetaxel following disease progression on chemotherapy and immunotherapy combination. Median progression-free survival among patients who received ram+doc after exposure to immunotherapy was 6.6 months (95% CI = 5.5 to 14.9 months; p<0.0001), and median overall survival was 20.9 months (95% CI = 13.4 months to infinity; p<0.0001). These outcomes suggest that there may a synergistic benefit to combining chemotherapy with anti-angiogenic therapy after immunotherapy exposure. Future analyses should be evaluated prospectively and among a larger patient subset.

Non-small cell lung cancer presenting as back cyst.

Cutaneous metastasis as the presenting sign of lung cancer is rare, with a poor prognosis and a life expectancy of 3 to 5 months. We present the complicated course of a 60-year-old woman with extensive metastatic non-small cell lung cancer that presented as a back cyst. Due to the benign appearance of the cyst and the difficulty discovering the location of the primary malignancy, diagnosis and treatment were delayed. Unfortunately, once aggressive treatment was initiated at the request of the patient, she died 2 weeks later. This case highlights the importance of recognizing cutaneous lesions as a sign of internal malignancy and emphasizes multidisciplinary discussion that focuses on the patient's quality of life.

NEPTUNE: Phase 3 Study of First-Line Durvalumab Plus Tremelimumab in Patients With Metastatic NSCLC.

INTRODUCTION: NEPTUNE, a phase 3, open-label study, evaluated first-line durvalumab plus tremelimumab versus chemotherapy in metastatic NSCLC (mNSCLC). METHODS: Eligible patients with EGFR and ALK wild-type mNSCLC were randomized (1:1) to first-line durvalumab (20 mg/kg every 4 weeks until progression) plus tremelimumab (1 mg/kg every 4 weeks for up to four doses) or standard chemotherapy. Randomization was stratified by tumor programmed death-ligand 1 expression (≥25% versus <25%), tumor histologic type, and smoking history. The amended primary end point was overall survival (OS) in patients with blood tumor mutational burden (bTMB) greater than or equal to 20 mutations per megabase (mut/Mb). Secondary end points included progression-free survival (PFS) in patients with bTMB greater than or equal to 20 mut/Mb and safety and tolerability in all treated patients. RESULTS: As of June 24, 2019, 823 patients were randomized (intention-to-treat [ITT]); 512 (62%) were bTMB-evaluable, with 129 of 512 (25%) having bTMB greater than or equal to 20 mut/Mb (durvalumab plus tremelimumab [n = 69]; chemotherapy [n = 60]). Baseline characteristics were balanced in the intention-to-treat. Among patients with bTMB greater than or equal to 20 mut/Mb, OS improvement with durvalumab plus tremelimumab versus chemotherapy did not reach statistical significance (hazard ratio 0.71 [95% confidence interval: 0.49-1.05; p = 0.081]; median OS, 11.7 versus 9.1 months); the hazard ratio for PFS was 0.77 (95% confidence interval, 0.51-1.15; median PFS, 4.2 versus 5.1 months). In the overall safety population, incidence of grade 3 or 4 treatment-related adverse events was 20.7% (durvalumab plus tremelimumab) and 33.6% (chemotherapy). CONCLUSIONS: NEPTUNE did not meet its primary end point of improved OS with durvalumab plus tremelimumab versus chemotherapy in patients with mNSCLC and bTMB greater than or equal to 20 mut/Mb. Despite the amended study design, with a resultant small primary analysis population, therapeutic activity was aligned with expectations based on mechanistic biology and previous studies.

Is ICI-based therapy better than chemotherapy for metastatic NSCLC patients who develop EGFR-TKI resistance? A real-world investigation.

Purpose: To evaluate the outcomes of immune checkpoint inhibitor (ICI)-based treatments versus classical chemotherapy for metastatic non-small cell lung cancer (NSCLC) patients who develop epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance and to explore the population that may benefit from ICI-based therapy. Materials and methods: All patients who had previously received EGFR-TKI therapy at two cancer centers in China and developed resistance to targeted therapies were included. Progression-free survival (PFS) and overall survival (OS) were utilized to evaluate the outcomes of the study cohort. Results: A total of 132 patients were included. The median follow-up time for this cohort was 21.7 months (IQR, 14.8-28.8 months), calculated from the date of EGFR-TKI resistance. The median PFS and OS were 4.9 months (IQR, 2.8-9.2) and 13.5 months (IQR, 6.6-26.5 months), respectively. Multivariate analysis showed that ICI-based therapy could significantly improve OS when compared to the classic chemotherapy (hazard ratio [HR], 0.55; 95% CI, 0.34-0.88; P = 0.01) after adjusting for variables such as gender, age, mutation status, and brain or liver metastasis status. The combined modality of ICI plus chemotherapy could offer a long-term OS benefit in most subgroups, such as young (<65 years) patients, and those without secondary T790M mutations or absence of liver and brain metastases, and the populations with good Eastern Cooperative Oncology Group (ECOG) scores. Conclusion: For patients presenting with EGFR-TKI resistance, ICI-based therapy could offer a more favorable survival than classical chemotherapy. The combination of ICI with chemotherapy may be the optimal modality for those with good ECOG PS scores.

Clinical and Economic Impact of Upfront Next-Generation Sequencing for Metastatic NSCLC in East Asia.

Introduction: Upfront next-generation sequencing (NGS) in patients with metastatic NSCLC has been associated with cost savings and shorter time-to-test results in the United States. Nevertheless, this may not apply in jurisdictions where the prevalence of patients with actionable mutations, cost of health care, and reimbursement models differ. Methods: A decision analytical model was built to compare sequential, panel, exclusionary, and upfront NGS testing in patients with metastatic NSCLC in Hong Kong. In sequential and panel testing, patients were tested for genomic alterations (GAs) with treatment followed by sequential or NGS. In exclusionary testing, EGFR and ALK were tested first, followed by NGS. For each modality, the mutation identified, time to receive testing results, and costs (2020 U.S. dollars) were estimated. Results: Exclusionary testing required the shortest time-to-results (1.6 wk) and was most cost saving. In the scenario where all patients used exclusionary testing, a cost saving of $4.6 million was expected relative to current practice, with 90.7% of actionable and 46.5% of nonactionable GAs detected; when all patients used NGS, it would be $2.9 million more expensive with a 100% GA detection rate. Results were sensitive to testing costs and the proportion of patients that continued testing. Conclusions: Exclusionary testing is the best option in terms of cost and time-to-results in Hong Kong. This finding may be applicable for other Asian countries; however, exclusionary testing does not capture all possible GAs. As more GAs become actionable and the cost of NGS declines, NGS may become a cost-saving option.

Stereotactic ablative radiotherapy for acquired resistance to EGFR therapy in metastatic non-small cell lung cancer.

The advent of targeted therapy has transformed the treatment paradigm and survival of patients with metastatic non-small cell lung cancer (NSCLC) with driver mutations. The development of acquired resistances during treatment with tyrosine kinase inhibitors (TKIs) impedes a prolonged survival in many patients. This fact is leading to the use of locally ablative therapies such as stereotactic ablative radiotherapy (SABR) to counter these resistances. SABR is a non-invasive treatment that can be delivered in multiple locations and has already proven effective in oligometastatic disease. Clinical evidence suggests that the combination of SABR with TKIs prolongs progression-free survival (PFS) in metastatic NSCLC patients with mutations in epidermal growth factor receptor (EGFR), with international guidelines recommending their use in unfavorable scenarios such as oligoprogressive disease. In this publication, we have reviewed the available evidence on EGFR-TKIs resistance mechanisms and the combination of SABR with TKI in metastatic NSCLC with EGFR mutations. We also describe the utility and clinical recommendations of this combination in oligometastatic and oligoprogressive disease.

Surgery for advanced-stage non-small cell lung cancer: lobectomy or sub-lobar resection?

BACKGROUND: Metastatic non-small cell lung cancer (NSCLC) has many comorbidities, such as chronic obstructive pulmonary disease, coronary heart disease, and older age-related comorbidities. A survival benefit was observed in such patients who underwent surgery for selected oligometastatic disease. However, to the best of our knowledge, there is no evidence to support whether lobectomy (compared with sub-lobar resection) would further prolong these patients' lives. METHODS: Patients with metastatic NSCLC who underwent primary tumor resection were identified from the Surveillance, Epidemiology, and End Results (SEER) database and then divided into lobectomy and sub-lobar resection groups. Propensity score matching (PSM, 1:1) was performed to match the baseline characteristics of the two groups. Cancer-specific survival (CSS) was estimated. RESULTS: In total, 24,268 patients with metastatic NSCLC were identified; 4,114 (16.95%) underwent primary tumor surgery, and of these, 2,045 (49.71%) underwent lobectomy and 1,766 (42.93%) underwent sub-lobar resection. After PSM, 644 patients in each group were included. Lobectomy was independently correlated with longer median CSS time [hazards ratio (HR): 0.70, 95% confidence interval (CI): 0.61-0.80, P<0.001]. The 1, 2, and 3-year survival rates after PSM also favored the lobectomy group. However, no significant survival difference was found for wedge resection and segmentectomy (HR: 0.96, 95% CI: 0.70-1.31, P=0.490). The 1-, 2-, and 3-year survival rates after PSM also exhibited no difference within the sub-lobar group. We explored whether lymph node dissection would provide additional survival benefits for stage IV NSCLC patients. According to the multivariate Cox analysis of the matched population, lymph node dissection was independently associated with better CSS (HR: 0.76, 95% CI: 0.66-0.88, P<0.001) and overall survival (OS) (HR: 0.74, 95% CI: 0.65-0.86, P<0.001). We confirmed this result in the different types of surgery and found that the lymph node dissection group consistently had better survival outcomes both in the lobectomy group and sub-lobar resection population. According to the subgroup analysis, with the exception of stage T4 and brain metastatic patients, all of the patient subtypes exhibited greater benefit from lobectomy than sub-lobar resection. CONCLUSIONS: Lobectomy has a greater survival benefit in metastatic NSCLC patients compared with sub-lobar resection when radical treatment of primary site was indicated.

The effect of itraconazole on the clinical outcomes of patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy: a randomized controlled study.

Itraconazole is an oral antifungal that has a been reported to have anticancer effect in non-small cell lung cancer (NSCLC) through inhibition of angiogenesis. The aim is to evaluate the effect of using itraconazole on the clinical outcome of metastatic NSCLC. This was a prospective randomized controlled open-label study conducted on 60 chemotherapy-naive metastatic NSCLC. Patients were simply randomized to either Control group who received platinum-based chemotherapy for a maximum of six cycles or Itraconazole group who received the same chemotherapy regimen in addition to itraconazole 200 mg daily for 21 days starting from day 1 in each cycle. Primary outcome was 1-year progression-free survival (PFS) while secondary outcomes included overall response rate (ORR), 1-year overall survival (OS) and tolerability. The two groups were comparable at baseline with no significant difference between groups regarding demographics and clinical characteristics. The ORR in Control group was 66.7% versus 90% in Itraconazole group (p value 0.028). There was a significant difference between groups regarding PFS where the mean 1-year PFS was 5.415 months in Control group versus 6.556 months in Itraconazole group (p value = 0.002). However, there was no significant difference between groups with respect to 1-year OS. All adverse effects reported were tolerable except for one patient who developed grade 2 cardiotoxicity in Itraconazole group requiring itraconazole discontinuation. Itraconazole use was beneficial in NSCLC in terms of 1-year PFS and ORR which was not reflected by improvement in 1-year OS.Clinical trial.gov registration number: NCT03664115, date of registration: September 10, 2018.

Impact of Radiotherapy on the Efficacy and Toxicity of anti-PD-1 Inhibitors in Metastatic NSCLC.

BACKGROUND: The impact of radiotherapy (RT) on the efficacy and toxicity of immune checkpoint inhibitors (ICIs) in patients with metastatic non-small-cell lung cancer (NSCLC) is unclear. MATERIALS AND METHODS: We identified patients with metastatic NSCLC treated with the anti-programmed death 1 antibodies nivolumab or pembrolizumab between January 2016 and May 2019 at 3 tertiary centers, who were also treated with palliative RT either during or within 3 months of starting anti-programmed death 1 treatment. Patient demographics, tumor characteristics, and treatment history were collected. Response rates, progression-free survival (PFS), and overall survival (OS) were analyzed and correlated with RT use. RESULTS: A total of 269 patients were identified, with a median follow-up of 19.4 months. The median age was 70 years (range, 35-90 years), and they were 63% male, 60% smokers, and 65% had adenocarcinoma histology. At the commencement of ICI treatment, the majority (86%) had ≥ 1 line of prior therapy and 34% had brain metastases. A total of 102 (38%) patients received RT within 3 months of starting ICI or subsequently during ICI treatment. Of patients that received RT, 86 (84%) received conventional hypofractionated RT, and, in the majority, 81 (79%) the intent of RT was symptom control. The use of RT did not increase grade 3/4 immune-related adverse events. The overall median PFS was 2.0 months (95% confidence interval, 1.3-2.6 months) and the median OS was 9.0 months (95% confidence interval, 6.4-9.5 months). There were no significant differences in median PFS (3.0 vs. 2.0 months; P = .515) and median OS (9.0 vs. 9.0 months; P = .917) in the patients who received RT versus those that did not. CONCLUSIONS: In patients with metastatic NSCLC, the addition of RT to ICI was not associated with increased toxicity or improved survival.

Massive Spondylectomy for Metastatic Spinal Cord Compression From Non-Small-Cell Lung Cancer With Local Failure After Radiotherapy.

STUDY DESIGN.: A retrospective multivariate analysis. OBJECTIVE.: To analyze clinical outcomes of surgical treatment and prognostic factors of local failure after stereotactic body radiation therapy (SBRT) in patients with spinal metastatic non-small-cell lung cancer (NSCLC). METHODS.: This study included patients with metastatic spinal cord compression (MSCC) from spinal NSCLC after radiotherapy who received massive spondylectomy for circumferential decompression of spinal cord and reconstruction of spinal stability in our center between May 2006 and February 2017. Neurological function was evaluated using the Frankel score. Overall survival (OS) was estimated by the Kaplan-Meier method. Factors with Pvalues ≤.1 were subjected to multivariate analysis for OS by proportional hazard analysis. Values of P<.05 were considered statistically significant. RESULTS.: The mean age of the 55 included patients (36 male and 19 female) was 57.76 ± 8.94 (median 58, range 36-77) years, with a mean postoperative OS of 14.98 ± 14.81 (median 10.0, range 1-84) months. Neurological function was improved in 46 (83.6%) of the 55 patients after surgery. Prognostic analysis suggested that preoperative frankel score (FS) score, visceral metastasis, D-dimer (D-D) level, and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for selected patients. CONCLUSIONS.: Massive spondylectomy could provide circumferential decompression and improve the neurological function of patients with MSCC from spinal NSCLC after radiotherapy. A preoperative FS score of C/D, no visceral metastasis, D-D <1000 µg/L, and NLR <5 are predictors of better prognosis.

Survival nomogram for patients with initially diagnosed metastatic non-small-cell lung cancer: a SEER-based study.

Aim: Prognosis of patients with metastatic non-small-cell lung cancer differ widely. Methods: All patients were randomly divided into training or validation cohort. Cox-regression analyses were conducted to select independent predictors. We built a nomogram by R code and evaluated the accuracy and the reliability of the model using C-index, calibration curves and decision curve analyses. We made a risk classification system based on the nomogram. Results: In the validation cohort, C-index was 0.729 and 0.738 for 1- and 2-year overall survival. Calibration plots and decision curve analyses presented great prognostic accuracy and clinical applicability. Its prognostic accuracy preceded the American Joint Committee on Cancer staging with evaluated integrated discrimination improvement. Conclusion: The model can be a practical tool in treatment decision and individual counseling.

Prognostic effect of VEGF gene variants in metastatic non-small-cell lung cancer patients.

INTRODUCTION: Clinical and pathological characteristics are still considered prognostic markers in metastatic non-small-cell lung cancer (NSCLC) patients but they cannot explain all interindividual variability. Tumoral angiogenesis mediated by the vascular endothelial growth factor (VEGF) is critical for the progression and metastasis of the disease. We aimed to investigate the prognostic role of genetic variants within the VEGF pathway in patients with metastatic NSCLC. MATERIALS AND METHODS: We prospectively included 170 patients with metastatic NSCLC treated with first-line platinum-based chemotherapy. A comprehensive panel of single-nucleotide polymorphisms (SNPs) in genes belonging to the VEGF pathway (VEGFA, VEGFR1/FLT1, VEGFR2/KDR, GRB2, ITGAV, KISS1, KRAS, PRKCE, HIF1α, MAP2K4, MAP2K6, and MAPK11) were genotyped in blood DNA samples. SNPs were evaluated for association with overall survival (OS) and progression-free survival (PFS). RESULTS: In multivariate analyses adjusted for patient characteristics, we found that VEGFA rs2010963 and VEGFR2 rs2071559 were significantly associated with OS [Hazard Ratio (HR) 0.7 (0.5-0.9); p = 0.026 and HR 1.5 (1.1-2.3); p = 0.025, respectively]. Additionally, ITGAV rs35251833 and MAPK11 rs2076139 were significantly associated with PFS [HR 2.5 (1.4-4.3; p = 0.002 and HR 0.6 (0.5-0.9); p = 0.013, respectively]. CONCLUSION: Our findings reinforce the potential clinical value of germline variants in VEGFA and VEGFR2 and show for the first time variants in ITGAV and MAPK11 as promising prognostic markers in metastatic NSCLC patients receiving platinum-based chemotherapy.

Pan-Asian adapted Clinical Practice Guidelines for the management of patients with metastatic non-small-cell lung cancer: a CSCO-ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS.

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.

Kinetic change of serum carcinoembryonic antigen can early predict progression in patients with metastatic non-small cell lung cancer during maintenance therapy with bevacizumab plus pemetrexed.

In this retrospective study, we investigated whether the kinetic change of serum carcinoembryonic antigen (CEA) levels can be an early indicator for the progression in metastatic non-small cell lung cancer (NSCLC) patients during maintenance therapy with bevacizumab plus pemetrexed. Ten patients diagnosed with metastatic lung adenocarcinoma who received a first-line therapy including bevacizumab-based chemotherapy and a following maintenance therapy including bevacizumab plus pemetrexed from June 2015 to October 2016 were recruited in this study. During the maintenance treatment, patients' CEA levels all elevated at or after the first cycle of maintenance treatment with a median CEA elevation-free survival time as 17.7 days, which was far more shorter than the median progression-free survival time evaluated by CT imaging specially for maintenance treatment (102.2 days). Before the disease progressed, the values of CEA increased steadily for several cycles with the response evaluation still as stable disease, indicating that the changes of CEA level would be earlier and more sensitive for detection of progression. The CEA kinetic was calculated with a mean of 9.6451 and a median of 8.0135, which sensitively reflected the increasing rate of CEA levels at an early stage. Our study showed that the kinetic change of CEA could be an early predictor for the progression in metastatic NSCLC patients during maintenance therapy.

A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non-small cell lung cancer.

AIM: The phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non-small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC. PATIENTS AND METHODS: A 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1-14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination. RESULTS: All 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a '14 days on, 7 days off' schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients. CONCLUSION: Combining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.