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

P75.02 Non-Squamous NSCLC Patients Harbored STK11 or KEAP1 Mutation Showed Insensitivity to any Treatment Including Immunotherapy

The objective of this study was mainly to analyze the prognostic effect for patients with non-squamous non-small cell lung cancer (NSCLC) harbored STK11 or KEAP1 mutation received chemotherapy and PD1/PD-L1 inhibitors. The data from OAK and POPLAR clinical trials was firstly applied to analyze the relationship between STK11 or KEAP1 mutation and PD-L1 expression and blood tumor mutation burden (bTMB) for patients with non-squamous NSCLC; Then, the overall survival (OS) difference was compared between the patients who received atezolizumab or docetaxel harbored STK11 or KEAP1 mutation and none. Importantly, the OS difference of patients between STK11 or KEAP1 mutation and none was further confirmed using public database from the cBioPortal platform. Most STK11 (7.33% vs.1.57%) or KEAP1 (10.76% vs. 8.46%) mutation was found in non-squamous NSCLC patients comparing with squamous NSCLC. Interestingly, only 0.96% STK11 mutation and 1.92% KEAP1 mutation occurred in EGFR mutated non-squamous NSCLC patients. Compared with wild-type, higher bTMB were found in patients harbored STK11 or KEAP1 mutation (both, P < 0.001), while PD-L1 expression was higher (25% VS. 14.54%) in KEAP1 mutated patients and lower (7.89% VS. 15.9%) in STK11 mutated patients. Importantly, we found that non-squamous NSCLC patients harbored STK11 or KEAP1 mutations had worse OS no matter treated with atezolizumab monotherapy or docetaxel (all, P < 0.001). Moreover, these mutated patients could not benefit from atezolizumab compared with docetaxel (all, P > 0.05). Similarly, in further analysis of cBioPortal data, we also found that STK11 or KEAP1 mutated non-squamous NSCLC patients who received PD1/PD-L1 inhibitors or other treatment had worse survival than wild-type (all, P < 0.05). Non-squamous NSCLC patients harbored STK11 or KEAP1 mutation were not sensitive to any treatment, suggesting they may be a special subtype.

Efficacy and safety of first-line treatments with immune checkpoint inhibitors plus chemotherapy for non-squamous non-small cell lung cancer: a meta-analysis and indirect comparison.

Recently, several clinical studies have evaluated the first-line use of immune checkpoint inhibitors (ICIs) combined with platinum-doublet chemotherapy in patients with non-squamous non-small cell lung cancer (NSCLC), however, the differences in safety and efficacy between the various types of ICIs still require investigation. In this study, we evaluated the efficacy and safety of the first-line use of ICIs combined with platinum-doublet chemotherapy in patients with non-squamous NSCLC by meta-analysis and indirect comparison. Literature searches were performed using PubMed, the Cochrane Library, Embase, China Knowledge Resource Integrated Database, and Wanfang Data to identify all relevant randomized clinical trials for non-squamous NSCLC after 2010. Overall survival (OS), progression-free survival (PFS), and adverse effects (AEs) were pooled for meta-analysis and indirect comparison. Subgroup analyses were conducted to examine the factors associated with PFS. The meta-analysis showed that the additional use of ICIs could significantly improve PFS and OS. The indirect comparison showed no significant difference in pembrolizumab + chemotherapy and atezolizumab + chemotherapy in the reducing of disease progression, while a significant difference in restricted mean survival time (RMST) was found between pembrolizumab + chemotherapy compared with atezolizumab + chemotherapy. A significant increase in grade ≥3 AEs was observed with the additional use of atezolizumab combined with chemotherapy. Subgroups including PD-1 status [high (>50%), intermediate (1-49%), and negative (<1%) expression], sex (male and female), smoking status (current or former smoker, and never smoked), liver metastases (with and without), age (>65 and ≤65) and Eastern Cooperative Oncology Group (ECOG) score (ECOG=0 and ECOG=1) were all associated with better PFS. This meta-analysis confirmed the treatment effects of ICIs combined with chemotherapy for non-squamous NSCLC. The pembrolizumab combination group had a greater RMST benefit compared with the atezolizumab combination group. Furthermore, our study also demonstrated a PFS advantage for non-squamous NSCLC using ICIs combined with chemotherapy irrespective of programmed death-ligand 1 (PD-L1) expression level, smoking status, liver metastasis status, sex, age and ECOG score. Due to the significant increase in AEs (> grade 3), more attention should be paid to the additional use of atezolizumab.

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.

A Randomized Phase III Study of Pembrolizumab Versus Pembrolizumab-Carboplatin-Pemetrexed for Locally Advanced or Metastatic Nonsquamous Non-small-cell Lung Cancer with PD-L1 50% or more (LAPLACE-50): Study Protocol

BackgroundPembrolizumab monotherapy or immune checkpoint inhibitor with platinum and pemetrexed combination chemotherapy are the standard therapies for patients with nonsquamous non–small-cell lung cancer (NSCLC) with programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≥ 50%. However, there are no data on the comparative effectiveness of the 2 regimens in patients with nonsquamous NSCLC with PD-L1 TPS ≥ 50%. Patients and MethodsThis randomized, multicenter, phase III trial (LAPLACE-50, jRCTs031200078) was designed to compare the efficacy and safety of pembrolizumab with pembrolizumab-carboplatin-pemetrexed combination in patients with nonsquamous NSCLC with PD-L1 TPS ≥ 50%. Patients are eligible for enrollment if they are at least 20 years old; have pathologically confirmed locally advanced/metastatic nonsquamous NSCLC without sensitizing epidermal growth factor receptor or anaplastic lymphoma kinase mutations; have not received previous systemic therapy for metastatic disease; have an Eastern Cooperative Oncology Group performance status of 0 or 1; and have at least 1 measurable lesion. Patients will be excluded if they have symptomatic central nervous system metastases, interstitial pneumonitis, active autoimmune disease, or are on systemic immunosuppressive treatment. The patients will be randomized 1:1 to pembrolizumab (200 mg) or pembrolizumab (200 mg) plus carboplatin (area under the curve 5) plus pemetrexed (500 mg/m2) on day 1 of each 21-day treatment cycle. The primary endpoint is progression-free survival. The recruitment phase began in August 2020 and will enroll 290 patients. ConclusionIf the primary endpoint is achieved, pembrolizumab could be the first choice for first-line treatment in patients with nonsquamous NSCLC with PD-L1 TPS ≥ 50%.

Survival analysis for non-squamous NSCLC patients harbored STK11 or KEAP1 mutation receiving atezolizumab

ObjectiveTo analyze the prognostic effect for patients with non-squamous non-small cell lung cancer (NSCLC) harbored STK11 or KEAP1 (STK11/KEAP1) mutations receiving atezolizumab and docetaxel. MethodsData from OAK and POPLAR clinical trials was firstly applied to analyze genomic alteration frequency and the correlation between STK11/KEAP1 mutations and blood-based tumor mutational burden (bTMB)/PD-L1 expression. Univariate and multivariate Cox regression hazard models were preformed to analyze the influence of prognostic factors on survival. Survival difference was compared by Kaplan-Meier and log-rank test. ResultsMost STK11/KEAP1 mutations (7.33 %/10.76 %) were found in non-squamous NSCLC compared with squamous lung cancer. Interestingly, only 1.56 % STK11 mutation or 3.13 % KEAP1 mutation occurred in EGFR mutant non-squamous NSCLC. Compared with wild type, patients with STK11/KEAP1 mutations had higher bTMB (both, P < 0.001). Moreover, compared with wild type, patients harbored KEAP1 mutation had higher PD-L1 expression (TC3/IC3: 25.00 % vs. 14.54 %), while patients harbored STK11 mutation had lower PD-L1 expression (TC3/IC3: 7.89 % vs. 15.90 %). Univariate and multivariate analyses revealed that STK11/KEAP1 mutations were independent and significant prognostic factors on overall survival (OS) (both, P < 0.05) and progression-free survival (PFS) (both, P < 0.05). Importantly, patients harbored STK11/KEAP1 mutations had a relatively worse OS than wild type both in those receiving atezolizumab and docetaxel (all, P < 0.05). In addition, for STK11 mutant subset, atezolizumab did not improve OS compared with docetaxel (HR = 0.669; 95 %CI: 0.380–1.179; P = 0.669); while cox-regression analysis showed the improved survival of patients with KEAP1 mutation who receiving atezolizumab compared with docetaxel (HR = 0.610; 95 %CI: 0.384−0.969; P = 0.036). ConclusionCompared with wild type, non-squamous NSCLC patients with STK11/KEAP1 mutations may not benefit more from both atezolizumab and docetaxel. However, patients with mere KEAP1 mutations and without STK11 mutations may have a better response to atezolizumab than docetaxel.

Randomized phase II trial of uracil/tegafur and cisplatin versus pemetrexed and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-squamous non-small cell lung cancer: NJLCG1001

BackgroundThe optimal regimen for concurrent chemoradiotherapy (CCRT) of locally advanced non-squamous non-small cell lung cancer (NSCLC) was not definitive. We conducted randomized phase II study, NJLCG0601, and chemoradiotherapy with uracil/tegafur (UFT) and cisplatin achieved promising efficacy without severe toxicities. Here, we evaluated between this regimen and pemetrexed plus cisplatin in chemoradiotherapy for stage III non-squamous NSCLC.MethodsPatients with inoperable stage III non-squamous NSCLC were randomly assigned in a 1:1 ratio to UFT 400 mg/m2 on days 1–14 and 29–42, and cisplatin 80 mg/m2 on days 8 and 36 (UP), or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on days 1, 22, and 43 (PP). Involved-field radiotherapy (IFRT) underwent from day 1 to a total dose of 66 Gy in 33 fractions. Consolidation chemotherapy after CCRT was prohibited for this study. The primary endpoint was defined as 2-year overall survival (OS). This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000003948).ResultsFrom November 2010 to June 2017, 86 patients were entered from 11 institutions. Median follow-up was 54 months. Of the 85 eligible patients, the 2-year OS rate was 78.6% (95% CI, 62.8–88.3%) in UP and 85.5% (95% CI, 70.5–93.2%) in PP. Median PFS and OS was 12.3 and 64.2 months in UP, 26.2 months and not reached in PP, respectively. Grade 3/4 febrile neutropenia was more frequent in the UP group (14.0% vs. 2.0%).ConclusionsBoth UP and PP with IFRT achieved the expected 2-year OS. PP engendered more favorable OS and PFS compared to UP in terms.

Equivalent efficacy study of QL1101 and bevacizumab on untreated advanced non-squamous non-small cell lung cancer patients: a phase 3 randomized, double-blind clinical trial.

Objective:This phase 3 study aimed to test equivalence in efficacy and safety for QL1101, a bevacizumab analogue in Chinese patients with untreated locally advanced non-squamous non-small cell lung cancer (NSCLC).Methods:Eligible patients were randomly assigned 1:1 to receive carboplatin and paclitaxel in combination with either QL1101 or bevacizumab, 15 mg/kg every 3-week for 6 cycles. This was followed by maintenance treatment with single agent QL1101 every 3-week. The primary end-point was objective response rate (ORR), with secondary end-points being progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs).Results:Of 675 patients, 535 eligible patients were randomized to the QL1101 group (n = 269) and bevacizumab group (n = 266). ORRs were 52.8% and 56.8%, respectively, for the QL1101 and bevacizumab groups, with an ORR hazard ratio 0.93 (95% confidence interval: 0.8–0131.1). The PFS, OS, DCR, and AEs were comparable between the 2 groups, which remained the same after stratification according to epidermal growth factor receptor mutation or smoking history.Conclusions:QL1101 showed similar efficacy and safety profiles as compared to bevacizumab among Chinese patients with untreated locally advanced non-squamous NSCLC.

Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial

Immunotherapy combined with chemotherapy has been shown to be efficacious as treatment for advanced non-squamous non-small-cell lung cancer (NSCLC) without targetable genetic aberrations; however, there is scarce evidence of the effectiveness of the combinations in the Asian population. We evaluated camrelizumab plus chemotherapy against non-squamous NSCLC in China. We did a randomised, open-label, multicentre, phase 3 trial (CameL) in 52 hospitals in China for patients with non-squamous NSCLC without EGFR and ALK alteration. Eligible patients were aged 18-70 years and had no previous systemic chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (version 1.1). Patients were randomly assigned (1:1) to receive 4-6 cycles of carboplatin (area under curve 5 mg/mL per min) plus pemetrexed (500 mg/m2) with or without camrelizumab (200 mg) every 3 weeks, followed by maintenance therapy with camrelizumab plus pemetrexed or pemetrexed alone. Medication was administered intravenously on day 1 of each 3-week treatment cycle. Randomisation was done using a centralised interactive web-response system with the block size randomly generated as four or six and stratified by sex and smoking history. The two primary endpoints were progression-free survival per blinded independent central review, in all patients and in patients who were PD-L1 positive. Primary analysis was done in the full analysis set that included all randomly assigned patients who received at least one dose of the study treatment. Herein, due to the primary endpoint being met at the interim analysis, we reported the findings of prespecified interim analysis, which only included confirmatory statistical testing for progression-free survival in all patients. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT03134872 (follow-up is ongoing). Between May 12, 2017, and June 6, 2018, of the 419 patients who were randomly assigned, seven did not receive assigned treatment and 412 received either camrelizumab plus chemotherapy (n=205) or chemotherapy alone (n=207). At interim analysis, median follow-up duration was 11·9 months (IQR 9·0-14·9). Progression-free survival in this interim analysis was significantly prolonged with camrelizumab plus chemotherapy than with chemotherapy alone (median 11·3 months [95% CI 9·6-15·4] vs 8·3 months [6·0-9·7]; hazard ratio 0·60 [0·45-0·79]; one-sided p=0·0001). Most common grade 3 or worse treatment-related adverse events were decreased neutrophil count (78 [38%] patients in the camrelizumab plus chemotherapy group vs 63 [30%] patients in the chemotherapy alone group), decreased white blood cell count (40 [20%] vs 30 [14%]), anaemia (38 [19%] vs 23 [11%]), and decreased platelet count (34 [17%] vs 24 [12%]). Serious treatment-related adverse events occurred in 74 (36%) patients in the camrelizumab plus chemotherapy group and 27 (13%) patients in the chemotherapy alone group. The primary endpoint was met at the interim analysis, showing a statistically significant and clinically meaningful improvement in progression-free survival with camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in all patients, supporting camrelizumab plus carboplatin and pemetrexed as a first-line treatment option for Chinese patients with advanced non-squamous NSCLC without EGFR and ALK alterations. The trial is being continued to collect long-term outcomes in all patients and carry out confirmatory statistical testing for progression-free survival in the PD-L1-positive population. Jiangsu Hengrui Medicine.

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.

Factors associated with overall survival in a population-based cohort of non- squamous NSCLC patients from northern New Zealand: A comparative analysis by EGFR mutation status

BackgroundPrevious studies have reported inconsistent results regarding the effect of epidermal growth factor receptor (EGFR) mutations on overall survival in patients with non-squamous non-small-cell lung cancer (NSCLC). This study assesses the effect of EGFR mutation on overall survival, and how the effects of other survival predictors differ by EGFR mutation status. MethodsThe study used a population- based cohort of 1534 non-squamous NSCLC patients diagnosed in northern New Zealand between 1st February 2010 and 31st July 2017. Cox regression survival analyses were used to explore the associations between clinicopathological factors and overall survival by EGFR mutation status. The factors included were age at diagnosis, sex, ethnicity, smoking status, performance status, metastasis status and tumour site. ResultsIn this cohort, 20% had anEGFR mutation. The median overall survival times were 0.8 years and 2.79 years in EGFR-mutation-negative and -positive groups, respectively (p < 0.0001). Metastasis at diagnosis showed large effects on overall survival in both EGFR-mutation- negative (hazard ratio (HR) = 3.6) and mutation-positive (HR = 3.3) groups. In subgroup analyses by mutation status and metastasis, females had lower survival only if they were mutation-positive; Māori had lower survival (than European New Zealanders) only if the disease was metastatic, and tumour site had significant effects only in patients without metastasis. Age, performance status and smoking status showed consistent effects in all subgroups. ConclusionEGFR mutation status and metastasis are the main predictors for overall survival in non-squamous NSCLC patients. The effects of sex, ethnicity and tumour site vary depending on EGFR mutation and metastasis status.

The optimal timing and courses of bevacizumab added to chemotherapy for non-squamous non-small cell lung cancer: revelations from the real-world experience in a single Chinese cancer center.

BackgroundBevacizumab combined with platinum-based chemotherapy has been approved in the first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC) without driver genes, but this regimen for second-line or later-line treatment of non-squamous NSCLC remains to be further tested. Our study aimed to provide data on the safety and effectiveness of bevacizumab (Bev)-containing chemotherapy in different-line settings for patients with NSCLC in the Chinese real-world clinical routine practice and to explore predictors for progression-free survival (PFS) and overall survival (OS).MethodsWe reviewed the medical records of 194 patients with non-squamous NSCLC who received Bev plus chemotherapy as the first-, second- or third- or later-line treatment between December 2009 and January 2020 at Fudan University, Shanghai Cancer Center. Clinical characteristics, treatment history, clinical evaluation, and adverse effects of each patient were deeply analyzed. PFS and OS were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were conducted to find predictors of longer PFS and OS.ResultsOne hundred ninety-four patients were enrolled in this study, including 102 (52.6%), 58 (29.9%) and 34 (17.5%) patients received Bev in combination with the first-line chemotherapy (Bev + Che1), second-line chemotherapy (Bev + Che2) and third-/later-line chemotherapy (Bev + Che3), respectively. Administration of Bev in combination with the first-line chemotherapy and >6 courses were independent predictors of significantly prolonged PFS. Whereas, patients older than 65 years or with ECOG PS ≥2 may not benefit more from Bev added to the first-line chemotherapy compared to second-/later-line chemotherapy. PFS of patients received treatment with/without chemotherapy as maintenance therapy showed no significant difference (P=0.354) in >6 courses Bev cohort. As for OS, Bev plus the first-line chemotherapy and number of metastatic sites <3 were independent predictors. The most common adverse effects (AE) were leukopenia, neutropenia, hypertension, and proteinuria. Twenty patients suffered from AE ≥ Grade 3.ConclusionsBev, in combination with the front-line chemotherapy, is proven beneficial for survival well-tolerated.

Does Pemetrexed Work in Targetable, Nonsquamous Non-Small-Cell Lung Cancer? A Narrative Review.

Simple SummaryThe chemotherapy agent pemetrexed is currently considered in combination with other therapies for the treatment of advanced nonsquamous non-small-cell lung cancer (NSCLC) in patients negative for gene mutations/rearrangements. The aim of this review was to highlight data from clinical studies with pemetrexed in patients with advanced nonsquamous NSCLC positive for gene mutations/rearrangements. The results of the review suggest that pemetrexed could be a treatment option in patients with advanced nonsquamous NSCLC positive for certain gene mutations/rearrangements.Pemetrexed is currently mainly considered for the treatment of advanced nonsquamous non-small-cell lung cancer (NSCLC) negative for gene mutations/rearrangements (wild-type disease (WTD)). This narrative review aimed to highlight the role of pemetrexed in the treatment of onco-driven nonsquamous advanced NSCLC by reviewing published clinical studies. For epidermal growth factor receptor (EGFR) mutations, patient survival following first-line pemetrexed–platinum was longer than for WTD. Later-line pemetrexed-based treatment after tyrosine kinase inhibitor (TKI) failure provided greater benefits than non-pemetrexed regimens. First- and later-line pemetrexed-based therapy also provided survival benefits in patients with anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearrangements. In patients with rearranged during transfection (RET) proto-oncogene rearrangements, survival with pemetrexed was similar to that in ALK- and ROS1-positive patients and longer than that in patients with Kirsten rat sarcoma (KRAS) virus proto-oncogene mutations or WTD, although the available studies were limited. For Erb-b2 receptor tyrosine kinase 2 (ERRB2) mutations, first-line pemetrexed showed outcomes similar to those for EGFR and KRAS alterations. Data on pemetrexed in patients with KRAS mutations or MNNG HOS-transforming (MET) expression were limited. Pemetrexed could be an option for first- and second-line treatment for TKI failure in nonsquamous advanced NSCLC with select targetable driver mutations.

Randomized phase III trial comparing switch-maintenance pemetrexed with observation followed by pemetrexed at progression in advanced NSCLC

Objectives: Two phase III trials show that maintenance pemetrexed therapy after platinum-doublet chemotherapy prolongs overall survival (OS) and progression free survival (PFS) in advanced non-squamous non-small-cell lung cancer (NSCLC). However, few patients in the control arms received pemetrexed at progression in these trials, performance status (PS) two patients were ineligible and few of the participants were elderly. Thus, we designed this study comparing immediate switch-maintenance pemetrexed therapy with pemetrexed at progression after platinum-doublet chemotherapy.Methods: Patients with stage IIIB/IV non-squamous NSCLC, ≥18 years, PS 0–2, and non-progression after four courses of carboplatin/vinorelbine were randomized to receive immediate maintenance pemetrexed therapy or observation followed by pemetrexed at progression. The primary endpoint was OS, secondary endpoints were PFS, toxicity and health related quality of life (HRQoL).Results: 105 patients were randomized between May 2014 and September 2017. Median age was 67 years, 36% were >70 years, 9% had PS 2, 91% stage IV and 47% were women. In the observation arm, 73% received pemetrexed at progression. Patients in the maintenance arm had a numerically longer OS (median 12.0 vs. 10.0 months; p = .10) and a statistically significant longer PFS (median 3.1 vs. 1.9 months; p < .01). In multivariable analyses adjusting for baseline characteristics, there was a trend toward improved OS (HR 0.65, 95% CI 0.42–1.01); p = .05), and a significantly improved PFS (HR 0.53, 95% CI 0.35–0.80; p < .01). There were no significant differences in toxicity or HRQoL between the treatment arms.Conclusion: There was a trend toward prolonged OS and significantly longer PFS from switch- maintenance pemetrexed therapy when 73% of patients in the control arm received pemetrexed at progression. ClinicalTrials.gov Identifier: NCT02004184

Open-label, multicenter, randomized phase II study on docetaxel plus bevacizumab or pemetrexed plus bevacizumab for treatment of elderly (aged ≥75 years) patients with previously untreated advanced non-squamous non-small cell lung cancer: TORG1323.

BackgroundThe effectiveness of bevacizumab monotherapy in elderly patients with non-squamous non-small cell lung cancer (NSCLC) is unclear. The efficacy of the combinations for elderly patients was explored.MethodsUntreated patients (≥75 years; performance status 0–1) with stage IIIB, IV, or recurrent non-squamous NSCLC were included. Patients with epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) gene rearrangements were eligible even if they received tyrosine kinase inhibitors. Patients were randomized 1:1 to receive docetaxel (50 mg/m2) (DB) or pemetrexed (500 mg/m2) (PB) with bevacizumab (15 m/kg). The primary endpoint was progression-free survival (PFS). Treatment was administered every 3 weeks until disease progression or unacceptable toxicity.ResultsOverall, 103 patients (DB: n=51; PB: n=52) were enrolled. In the DB and PB arms, median ages [range] were 78 [75–88] and 79 [75–94] years, respectively; median PFS were 6.1 and 4.6 months, respectively [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.66–1.61]; and response rates were 43%, and 40%, respectively (P=0.840). Grade ≥3 leukopenia, neutropenia, and fatigue incidences were significantly higher in the DB arm. Febrile neutropenia incidence did not differ significantly (16% vs. 12%, P=0.578). One patient in the PB arm died from a ruptured abdominal aortic aneurysm. Quality of life (QoL) analysis revealed less deterioration in the PB arm.ConclusionsIn previously untreated elderly patients with non-squamous NSCLC, PB shows feasibility, better QoL, and promising efficacy in terms of PFS, and an objective response rate for further analysis (UMIN000012786).

Randomized phase III study of first-line pembrolizumab plus pemetrexed/platinum followed by pembrolizumab and maintenance olaparib versus pemetrexed in patients with metastatic nonsquamous non-small cell lung cancer (NSCLC): KEYLYNK-006.

TPS9632 Background: First-line treatment with pembrolizumab + pemetrexed/platinum improved clinical outcomes in patients with advanced nonsquamous NSCLC in KEYNOTE-021 and KEYNOTE-189. Poly(ADP-ribose) polymerase inhibitors (PARPi), including olaparib, have been shown to upregulate PD-L1 expression in preclinical studies, and preliminary evidence suggests potential therapeutic benefit and acceptable safety with PARPi plus anti–PD-(L)1 therapy. KEYLYNK-006 (NCT03976323) evaluates first-line pembrolizumab + pemetrexed/platinum followed by pembrolizumab + olaparib vs pembrolizumab + pemetrexed in patients with metastatic nonsquamous NSCLC. Methods: This phase III, randomized, open-label trial enrolls patients aged ≥18 years with histologically/cytologically confirmed treatment-naive, metastatic, nonsquamous NSCLC. Patients (target n = 792) receive induction pembrolizumab 200 mg + pemetrexed 500 mg/m2 + carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 Q3W for 4 cycles. Patients with PR/CR or SD are randomized (target n = 618) 1:1 to pembrolizumab 200 mg Q3W (31 cycles) + maintenance olaparib 300 mg twice daily or pembrolizumab + pemetrexed 500 mg/m2 Q3W stratified by ECOG PS (0 vs 1), PD-L1 tumor proportion score (&lt;50% vs ≥50%), and response (CR/PR vs SD). Tumor imaging per RECIST version 1.1 (≤5 per organ; maximum 10 total lesions) by central review (BICR) is performed at baseline and Q6W until 60 weeks after randomization, then Q9W until disease progression, start of new cancer therapy, study withdrawal, or death. Primary endpoints are PFS (RECIST 1.1 by BICR) and OS estimated by the Kaplan-Meier method, stratified log-rank test, and Cox proportional hazard model with Efron’s method of tie handling. Secondary endpoints are safety and quality of life; ORR and duration of response are exploratory endpoints. AEs are monitored throughout the study until 30 days after the last dose of treatment (90 days for serious AEs) and graded using NCI CTCAE, version 4.0. The study began enrolling in June 2019. Clinical trial information: NCT03976323 .

STK11/LKB1 revisited: A prognostic rather than predictive biomarker for immune checkpoint inhibitor in EGFR/ALKWT nonsquamous non-small cell lung cancer (NSCLC).

e21548 Background: Previous retrospective studies identified the mutation of serine/threonine-protein kinase (STK11, also known as Liver Kinase B1 [LKB1]) as predictor to the benefit from immune checkpoint inhibitor (ICI) in KRAS-mutant lung adenocarcinoma. This conclusion was drawn from merely the patients receiving ICI, lacking the indispensable control group undergoing chemotherapy. Therefore, we hereby revisit the impact of STK11 mutation in both immunotherapeutic and chemotherapeutic cohorts, in addition to TCGA database as a control cohort representing prognosis. Methods: 6 immunotherapeutic cohorts involving 807 patient-level data (Van Allen, Rizvi-34, Rizvi-240, MSKCC-75, MSKCC-350, and POPLAR/OAK-atezolizumab), 1 chemotherapeutic cohort (POPLAR/OAK-docetaxel, n = 244), and TCGA database (n = 485) were included to comprehensively re-examine the questionably predictive effect of STK11 mutation on the benefit from immunotherapy in patients with EGFR/ALKWT non-squamous NSCLC. Results: In the 6 immunotherapeutic cohorts, STK11 mutation was associated with shorter progression-free survival (PFS, HR = 1.54, 95%CI 1.17-2.03, P = 0.002) and overall survival (OS, HR = 1.57, 95%CI 1.16-2.11, P = 0.003), but no statistically lower overall response rate (ORR, RR = 0.71, 95%CI 0.39-1.28, P = 0.251). Similarly, in the patients receiving docetaxel, worse ORR and PFS at borderline level and significantly reduced OS (HR = 1.82, 95%CI 1.18-2.80, P = 0.006) were observed. Specifically, in the POPLAR/OAK cohort retrieved from two randomized controlled trials comparing atezolizumab and docetaxel, STK11 mutation and treatment choice separately impacted on OS, but the interaction between these two variables was barely profound (HR 1.10, 95%CI 0.60-2.01, P = 0.766), indicating the prognostic, but not predictive utility of STK11 mutation. Furthermore, in TCGA database, STK11 mutation was linked with poorer prognosis, with the similar hazard ratio in immunotherapeutic cohorts. Conclusions: Genomic abberation of STK11 remarkably worsens prognosis among 6 immunotherapeutic cohorts, 1 chemotherapeutic cohort, and TCGA database, demonstrating the prognostic, but not predictive utility of STK11 mutation in patients with EGFR/ALKWT non-squamous NSCLC.

A phase I study of ADXS-503 alone and in combination with pembrolizumab in subjects with metastatic squamous or non-squamous non-small cell lung cancer (NSCLC).

e21682 Background: ADXS-503 (A503) is an off-the-shelf, attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit potent T cell responses against 22 tumor antigens commonly found in NSCLC (i.e., 11 hotspot mutations and 11 tumor-associated antigens, TAAs). Pembrolizumab (Pembro) is a programed death receptor-1 (PD-1)- blocking antibody with proven efficacy in NSCLC. A503 and Pembro have complementary mechanisms of immune activation and reversal of immune tolerance. Methods: This is a phase I study of A503 ± Pembro in patients (pts) with metastatic squamous or non-squamous NSCLC. Dose escalation with A503 alone has been tested at two dose levels (i.e., 1 and 5 x108 CFU) in Part A in pts refractory or intolerant to prior systemic therapy. In dose escalation Part B, A503 is being evaluated at the same dose levels (DLs) in combination with Pembro in pts with disease progression on Pembro. Part C will be a dose expansion cohort with A503 + Pembro as first-line treatment in the metastatic setting. A503 ± Pembro (200 mg) will be infused intravenously every 3 weeks until disease progression or limiting toxicity. Main endpoints include safety, tolerability and immune-correlative data. Results: Nine patients have been treated: 7 with A503-alone in Part A and two pts with A503+ Pembro in Part B-DL1. No pts in Part A experienced dose-limiting toxicities at the 2 DLs tested. Two Grade 3 adverse events occurred in one pt related to the infusion: hypertension and flu-like syndrome. A transient and manageable SAE (Grade 2 acute kidney injury) was possibly related to A503 alone at 5 x108 CFU. A503+ Pembro have been well tolerated in 2 pts in Part B-DL1. Four pts achieved a best overall response of stable disease, three in Part A and one in Part B. A503 alone induced immune responses in pts so far evaluated in Part A. Conclusions: ADXS-503 alone has demonstrated a manageable safety profile and immune responses in Part A. The 1x108 CFU was identified as the recommended phase II dose. Dose escalation with A503+ Pembro is ongoing and dose expansion in first line treatment is due to start shortly. Clinical trial information: NCT03847519.

Phase I dose escalation study of immunoconjugate L-DOS47 in combination with pemetrexed/carboplatin in non-squamous non-small cell lung cancer (NSCLC) patients.

e21680 Background: L-DOS47, a cancer therapeutic designed to exploit the acidic tumour extracellular environment, consists of urease conjugated to an anti-CEACAM6 camelid monoclonal antibody. The antibody serves as a targeting agent to deliver urease to tumor sites, while the urease enzyme converts urea, an abundant natural metabolite, into ammonia and generates a local pH increase. The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells. An additive cytotoxic effect of L-DOS47 and pemetrexed/carboplatin has been observed against the A549 human lung adenocarcinoma cell line. L-DOS47 has been shown in a previous phase I clinical trial to be safe and well tolerated at doses up to 13.55 µg/kg. The current phase I study was designed to define the maximum tolerated dose of L-DOS47 in combination with pemetrexed/carboplatin. Methods: Stage IV (TNM M1a and M1b) histologically confirmed non-squamous NSCLC patients (aged ≥18 yrs, ECOG PS ≤1) received up to four cycles of L-DOS47 in combination with standard of care doses of pemetrexed/carboplatin. L-DOS47 was administered weekly over 21 days in each treatment cycle. Seven planned dosing cohorts (0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 μg/kg) employed a standard 3+3 design for the first two and the last two cohorts, and an accelerated 1 + 2 design for the middle three cohorts. Dose levels of L-DOS47 were escalated following a review of safety data by the Trial Steering Committee. Results: Fourteen (14) patients were enrolled across 6 dosing cohorts before recruitment was halted. Median age was 65.1 years, with 50.0% male and 78.6% Caucasian. 57.1% of patients had an ECOG score of 0, and 42.9% had an ECOG score of 1. The maximum tolerated dose (MTD) could not be determined as none of the patients experienced a dose limiting toxicity (DLT). 50.0% of patients experienced at least one treatment emergent adverse event (TEAE) assessed as study drug-related, with 14.3% of patients experiencing at least one grade 3/4 drug-related toxicity. Of 12 patients evaluable for efficacy, 5 patients (41.7%) had a partial response (PR), 4 patients (33.3%) experienced stable disease (SD) and 3 patients (25.0%) had progressive disease (PD). The objective response rate is 41.7%. The clinical benefit rate is 75.0%. Conclusions: L-DOS47, in combination with pemetrexed/carboplatin, appears to be well tolerated with promising anti-tumor activity against non-squamous NSCLC. Clinical trial information: NCT02309892.

A model comparing the value of broad next-gen sequencing (NGS)-based testing to single gene testing (SGT) in patients with nonsquamous non-small cell lung cancer (NSCLC) in the United States.

9529 Background: Patients (pts) with nonsquamous (ns) NSCLC should be tested for actionable driver oncogenes (ADOs), and highly effective treatments (tx) may be available for these pts. Although EGFR and ALK single gene testing (SGT) is relatively common (&gt;80%) in the US, testing for less common ADOs is rare. Unidentified pts with ADOs have survival comparable to pts without alterations. We interrogate plausible testing configurations and discuss their implications for the US population. Methods: Simulation was used to evaluate various levels of testing with SGT or NGS on the basis of life years gained (LYG) as well as cost per LYG. Expected prevalence of ADOs among nsNSCLC pts as well as the survival distribution of pts in the presence versus absence of an ADO tx strategy were calibrated based on current literature. Survival duration for each simulated pt was generated from Weibull distributions fit to statistical estimates of median and 5-year survival. With appropriate match between ADO and targeted tx, the Weibull distribution offered a median additional 2 years of life. ADOs included in NGS: EGFR, ALK, ROS1, BRAF, RET, MET, NTRK. SGT: EGFR and ALK. Results: Each incremental 10% increase in NGS instead of SGT produces 2630 additional LYG and a cost savings per LYG between -$49 to -$109. At the current 80% testing rate, replacing SGT with NGS would result in an additional 21,019 LYG with reduced cost per LYG of -$599. Increasing testing from 80% to 100% of eligible pts would increase LYG by 15,017 over the current state. If 100% of eligible pts were tested with NGS and every identified pt received tx, the cost per LYG of this strategy would be $16,641.57. Conclusions: In a hypothetical model where highly effective tx is available to all identified pts with ADOs, broad NGS testing compared to SGT for EGFR/ALK leads to large gains in life years at reduced cost per LYG compared to SGT, supporting universal NGS testing of all advanced nsNSCLC pts. Conversely, lower levels of testing or only testing for common ADOs (as is the current state) result in large numbers of pts being unidentified and not experiencing these benefits. [Table: see text]

PIT-1: Randomized phase II trail of pemetrexed-cisplatin plus bevacizumab or concurrent thoracic radiation therapy followed by surgery in stage IIIA (N2) nonsquamous non-small cell lung cancer.

9014 Background: PIT-1 (Personized Induction Therapy-1) is a multicenter, open-label, randomized phase II study using selection design of platinum doublet chemotherapy plus angiogenesis inhibitor or concurrent thoracic radiation therapy (TRT) as induction therapy followed by surgery in patients with stage IIIA (N2) nonsquamous non-small cell lung cancer (NSCLC) to investigate the efficacy and safety of these treatment strategies. Methods: Patients with stage IIIA (pathologically proven N2) nonsquamous NSCLC randomly received (1:1) induction therapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) plus bevacizumab (15 mg/kg) intravenously every 3 weeks for three cycles (arm A) or concurrent TRT (45 Gy in 25 fractions) (arm B) followed by surgery. The primary endpoint was 2-year progression-free survival (PFS) rate and key secondary endpoints included overall survival (OS), the objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the pathological complete remission (pCR) rate, feasibility and toxicity. Results: Eighty-eight patients were randomly assigned (each arm, n = 44) between October 2013 and June 2017 and 82 (arm A, n = 42; arm B, n = 40) were treated. Patient demographics were balanced between the two arms. The percentage of patients who received induction therapy followed by surgery was 88.1% (37/42) in arm A and 92.5% (37/40) in arm B. The complete resection rate was 81.1% (30/37) in arm A, and 91.9% (34/37) in arm B. The 2-year PFS rate was 36.8% (95% CI: 22.4-51.2) in arm A, and 50.0% (95% CI: 33.8-64.2) in arm B. The 2-year OS rate was 80.5% (95% CI: 64.7-89.7) in arm A, and 80.0% (95% CI: 64.0-89.5) in arm B. The ORR was 50.0% (21/42) in arm A and 60.0% (24/40) in arm B. The pCR rate was 8.1% (3/37) in arm A and 10.8% (4/37) in arm B. Grade 3 or 4 toxicities occurred during induction therapy in 35.7% of the patients in arm A and 22.5% of the patients in arm B. Grade 3 or 4 surgical complications occurred in 21.4% of the patients in arm A and 20.0% of the patients in arm B. Although no fatal toxicity was observed during induction therapy in either arm, two patients in arm A died after surgery due to bronchopleural fistula. Conclusions: The 2-year PFS rate in arm B was higher than that in arm A. Fatal surgical complications were only observed in arm A. Therefore, we chose pemetrexed-cisplatin plus concurrent thoracic radiation therapy as the investigational induction treatment strategy for a future phase III study. Clinical trial information: 000011941.