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

Strengths and challenges in current lung cancer care: Timeliness and diagnostic procedures in six Dutch hospitals

ObjectivesTimely diagnosis of lung cancer (LC) is crucial to achieve optimal patient care and outcome. Moreover, the number of procedures required to obtain a definitive diagnosis can have a large influence on the life expectancy of a patient. Here, adherence with existing Dutch guidelines for timeliness and type and number of invasive and imaging procedures was assessed. Materials and methods1096 patients with suspected LC were enrolled in this multicenter prospective study (NL9146). The overall survival, time from referral to the first appointment with the pulmonologist, time to diagnosis and treatment, and the number of imaging and invasive procedures were evaluated. Patients were divided into different diagnostic groupsearly- and advanced stage non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), large cell neuroendocrine carcinoma of the lung (LCNEC), patients without LC and patients without a definitive diagnosis. ResultsThe majority of patients (66 %) received a definitive diagnosis within 5 weeks, although the time to diagnosis of early-stage LC patients and patients without LC was significantly longer comparted to advanced stage LC. An increase in invasive procedures was seen for early-stage LC compared to advanced stage LC and for 13 % of the advanced stage non-squamous NSCLC patients up to three additional invasive procedures were performed solely to obtain sufficient material for NGS. For patients without a definitive diagnosis, 50 % did undergo at least one invasive procedure, while 11 % did not wish to undergo any invasive procedures. ConclusionThese insights could aid in improved LC diagnostics and efficient implementation of new techniques like liquid biopsy and artificial intelligence. This may lead to more timely LC care, a decreased number of invasive procedures, less variability between the diagnostic trajectory of different patients and aid in obtaining a definitive diagnosis for all patients.

Impact of prophylactic dexamethasone on the efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy in patients with advanced Non-Squamous Non-Small-Cell lung cancer

BackgroundBaseline corticosteroids exposure is associated with inferior clinical outcomes in patients with non-small-cell lung cancer (NSCLC) treated with programmed cell death-1 (PD-1) axis blockade. Dexamethasone is a potent corticosteroid used in the prevention of chemotherapy-associated adverse events (CAAEs). ObjectiveSince dexamethasone has immunosuppressive properties, this study attempted to elucidate its effects on the efficacy of immunotherapy plus chemotherapy in patients with non-squamous NSCLC. MethodsThe study retrospectively analyzed the medical records of 254 advanced non-squamous NSCLC patients who received front-line treatment with a PD-1 pathway inhibitor and platinum-based chemotherapy at three academic institutions. The average dosage of prophylactic dexamethasone per chemotherapy cycle was calculated. Patients were divided into three groups based on the dose of dexamethasone: High-d (≥24 mg), Moderate-d (12–24 mg), and Low-d (<12 mg). Spearman's rank correlation was used to assess the correlation between the dosage of dexamethasone and progression-free survival (PFS). Logistic regression was used to assess the correlation between dexamethasone dosage and the occurrence of immune related adverse effects (irAE). Univariate and multivariate Cox proportional hazards regression models were used to analyze the differences in survival among the different dexamethasone dosage groups. ResultThe dosage of prophylactic dexamethasone was not significantly correlated with PFS (Spearman’s rho = -0.103, P = 0.098). Results from the univariate [hazard ratio (HR)Low-d/High-d, 1.00; P = 0.997; HRModerate-d/High-d, 0.85; P = 0.438] and multivariate (HRLow-d/High-d, 0.71; P = 0.174; HRModerate-d/High-d, 0.87; P = 0.512) analyses showed no significant association between dexamethasone and PFS. Dexamethasone did not have significant effect on the objective response rate, disease control rate or overall survival. The toxicity profiles of irAE were similar across all three groups. ConclusionThe results of this study suggest that the use of prophylactic dexamethasone does not have an adverse effect on the clinical outcomes of non-squamous NSCLC patients treated with PD-1 blockade therapy and chemotherapy. Routine use of dexamethasone for preventing CAAEs should be recommended for patients undergoing combined immunotherapy and chemotherapy.

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

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

Integrated multi-dimensional deep neural network model improves prognosis prediction of advanced NSCLC patients receiving bevacizumab.

The addition of bevacizumab was found to be associated with prolonged survival whether in combination with chemotherapy, tyrosine kinase inhibitors or immune checkpoint inhibitors in the treatment landscape of advanced non-small cell lung cancer (NSCLC) patients. However, the biomarkers for efficacy of bevacizumab were still largely unknown. This study aimed to develop a deep learning model to provide individual assessment of survival in advanced NSCLC patients receiving bevacizumab. All data were retrospectively collected from a cohort of 272 radiological and pathological proven advanced non-squamous NSCLC patients. A novel multi-dimensional deep neural network (DNN) models were trained based on clinicopathological, inflammatory and radiomics features using DeepSurv and N-MTLR algorithm. And concordance index (C-index) and bier score was used to demonstrate the discriminatory and predictive capacity of the model. The integration of clinicopathologic, inflammatory and radiomics features representation was performed using DeepSurv and N-MTLR with the C-index of 0.712 and 0.701 in testing cohort. And Cox proportional hazard (CPH) and random survival forest (RSF) models were also developed after data pre-processing and feature selection with the C-index of 0.665 and 0.679 respectively. DeepSurv prognostic model, indicated with best performance, was used for individual prognosis prediction. And patients divided in high-risk group were significantly associated with inferior PFS (median PFS: 5.4 vs 13.1 months, P<0.0001) and OS (median OS: 16.4 vs 21.3 months, P<0.0001). The integration of clinicopathologic, inflammatory and radiomics features representation based on DeepSurv model exhibited superior predictive accuracy as non-invasive method to assist in patients counseling and guidance of optimal treatment strategies.

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

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

Impact of KRAS Mutations on Clinical Outcomes of Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Receiving Anti-PD-1/PD-L1 Therapy.

KRAS is the most frequently mutated gene in non-small cell lung cancer (NSCLC), however conflicting data are available on its role as a biomarker. The aim of our work was to investigate the impact of KRAS mutations on response and survival outcomes in advanced non-squamous NSCLC patients treated with immune checkpoint inhibitors alone or in combination with chemotherapy. We retrospectively identified 119 patients, most of whom (58%) were KRAS wild type. For each patient we evaluated overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). An exploratory analysis was performed among KRAS mutated patients to investigate the impact of specific KRAS mutations on response and survival outcomes. After a median follow-up of 10.3months, the median OS was 14.9months (95% confidence interval [CI] 7.6-22.7) in wild-type KRAS patients versus 14.7months (95% CI 8.0-19.5) in mutated KRAS patients (p = 0.529). No differences were detected between the two groups in terms of PFS and DCR. Patients with a KRAS G12C mutation reported survival and response outcomes that were not statistically different from those of patients with other KRAS mutations. Our data confirmed that KRAS mutational status is not associated with survival and response outcomes in advanced non-squamous NSCLC patients treated with immunotherapy alone or combined with chemotherapy.

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

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

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

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

Camrelizumab plus chemotherapy in advanced non-squamous non-small cell lung cancer: Treatment response, survival pattern, and safety.

Camrelizumab, a humanized monoclonal programmed cell death protein-1 antibody independently developed by China, is introduced as a treatment selection for non-small cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and safety of camrelizumab plus chemotherapy in treating advanced non-squamous NSCLC patients. This study retrospectively analysed 31 driver-gene-negative advanced non-squamous NSCLC patients who received a 21-day therapy cycle for four cycles of camrelizumab (intravenous injection, 200 mg/cycle) plus carboplatin and pemetrexed (CP) chemotherapy, followed by maintenance therapy using camrelizumab or pemetrexed or camrelizumab plus pemetrexed. Another 40 patients who underwent CP chemotherapy were retrieved as control group. The objective response rate (ORR) was elevated in camrelizumab plus CP group compared to CP group (58.1% vs. 32.5%, p=0.031), while disease control rate (DCR) was of no difference between those two groups (83.9% vs. 72.5%, p=0.255). Camrelizumab plus CP achieved a prolonged PFS compared with CP alone (median: 11.0 (95% CI: 9.1-12.9) months versus 7.2 (95% CI: 5.1-9.3) months, p=0.026), also realized an increasing OS trend (without statistical significance; 19.3 (95% CI: 15.4-23.2) months versus 15.1 (95% CI: 13.9-16.3) months, p=0.093). Further multivariate Cox's regression analysis exhibited that camrelizumab plus CP (vs. CP) independently related to prolonged PFS (p < 0.001) and OS (p=0.027). Moreover, the most common adverse events related to camrelizumab plus CP were fatigue (45.2%), peripheral neuropathy (35.5%), nausea and vomiting (35.5%); furthermore, most adverse events were controllable. Camrelizumab plus chemotherapy exhibits good efficacy and manageable adverse events in treating advanced non-squamous NSCLC patients.

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

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

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

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

EGFR-mutation testing and TKI treatment patterns in locally advanced and metastatic NSCLC in Norway – A nationwide retrospective cohort study

BackgroundTesting for epidermal growth factor receptor mutation (EGFRm) status is a prerequisite to identify eligible patients for tyrosine kinase inhibitors (TKI) treatment. However, EGFR testing of patients with non-small cell lung cancer (NSCLC) is suboptimal in many parts of the world. The aim of this study was to describe real-world EGFR testing practice, EGFRm prevalence, and subsequent TKI treatment patterns in Norway. Patients and methodsThis retrospective, observational, cohort study included all incident locally advanced and metastatic non-squamous NSCLC patients registered in the Norwegian Cancer Registry during 2010–2017. A cohort with follow-up through 2018 was formed with linkage to nationwide registries on comorbidities, prescribed drugs and causes-of-death. ResultsA total of 10,717 patients were included, of which 35% (3782) with locally advanced NSCLC and 65% (6935) with metastatic disease. Mean age at diagnosis was 71 years and 47% were female. EGFR testing among patients with metastatic NSCLC increased from 41% to >64% between 2010 and 2017, with a relative stable incidence of EGFRm+ (∼9%). More than 85% of EGFRm+ patients received TKI treatment. Patients with the most dismal prognosis (>80 age, comorbidities) and with diagnosis based on cytology/imaging were less likely to be tested. Differences in testing were observed between regions. ConclusionDespite increased test rates over the study period, in Norway, a significant proportion of patients with non-squamous metastatic NSCLC are still not tested for EGFR. To maximize the identification of eligible patients for targeted therapies, increased testing is recommended, regardless of age, comorbidity rate and place of residence.

Paclitaxel-bevacizumab combination in advanced non-squamous non-small-cell lung cancer (NSCLC): AVATAX, a retrospective multicentric study.

Introduction:Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel–bevacizumab combination (PB) as second- or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined.Methods:This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE).Results:From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19–82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in third-line (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2–9.6] and 10.8 [IQR: 5.3–19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI−): 7.0 [IQR: 4.2–11.0] versus 5.2 [IQR: 2.9–8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0–1. Only a performance status of 0–1 was associated with superior OS.Conclusion:PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.

Crizotinib efficacy in advanced non-squamous NSCLC patients with ALK or ROS1 rearrangement

In patients with advanced non-small cell lung cancer (NSCLC), comprehensive genetic diagnostics is currently carried out in order to qualify for molecularly targeted therapies and immunotherapy. The aim of the study was to assess the usefulness of the reverse transcriptase (RT-PCR) method in the diagnosis of gene rearrangements, the effectiveness of EGFR, ALK, ROS1, and PD-L1 inhibitors in first-line treatment in NSCLC patients. We enrolled 95 non-squamous NSCLC patients with known status of EGFR, ALK, ROS1, MET and RET genes and PD-L1 protein expression. We used the real time PCR, fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and RT-PCR techniques for determination of predictive factors. In patients with ALK and ROS1 genes alteration, the median overall survival was 34 months in crizotinib treated patients and 6 months in patients who received chemotherapy (HR = 0.266, p = 0.0056). The risk of death was lower in patients treated with molecularly targeted therapies or immunotherapy compared to patients with predictive factors without personalized treatment (HR = 0.265, 95% CI 0.116–0.606) and to patient without predictive factors who received chemotherapy (HR = 0.42, 95% CI 0.162–1.09). Diagnosis of predictive factors and implementation of personalized treatment are key to prolonging the survival in advanced NSCLC patients.

Canadian ROS proto-oncogene 1 study (CROS) for multi-institutional implementation of ROS1 testing in non-small cell lung cancer

Patients with non-small cell lung cancer (NSCLC) harboring ROS proto-oncogene 1 (ROS1) gene rearrangements show dramatic response to the tyrosine kinase inhibitor (TKI) crizotinib. Current best practice guidelines recommend that all advanced stage non-squamous NSCLC patients be also tested for ROS1 gene rearrangements. Several studies have suggested that ROS1 immunohistochemistry (IHC) using the D4D6 antibody may be used to screen for ROS1 fusion positive lung cancers, with assays showing high sensitivity but moderate to high specificity. A break apart fluorescence in situ hybridization (FISH) test is then used to confirm the presence of ROS1 gene rearrangement. The goal of Canadian ROS1 (CROS) study was to harmonize ROS1 laboratory developed testing (LDT) by using IHC and FISH assays to detect ROS1 rearranged lung cancers across Canadian pathology laboratories.Cell lines expressing different levels of ROS1 (high, low, none) were used to calibrate IHC protocols after which participating laboratories ran the calibrated protocols on a reference set of 24 NSCLC cases (9 ROS1 rearranged tumors and 15 ROS1 non-rearranged tumors as determined by FISH). Results were compared using a centralized readout. The stained slides were evaluated for the cellular localization of staining, intensity of staining, the presence of staining in non-tumor cells, the presence of non-specific staining (e.g. necrosis, extracellular mater, other) and the percent positive cells. H-score was also determined for each tumor.Analytical sensitivity and specificity harmonization was achieved by using low limit of detection (LOD) as either any positivity in the U118 cell line or H-score of 200 with the HCC78 cell line. An overall diagnostic sensitivity and specificity of up to 100% and 99% respectively was achieved for ROS1 IHC testing (relative to FISH) using an adjusted H-score readout on the reference cases.This study confirms that LDT ROS1 IHC assays can be highly sensitive and specific for detection of ROS1 rearrangements in NSCLC. As NSCLC can demonstrate ROS1 IHC positivity in FISH-negative cases, the degree of the specificity of the IHC assay, especially in highly sensitive protocols, is mostly dependent on the readout cut-off threshold. As ROS1 IHC is a screening assay for a rare rearrangements in NSCLC, we recommend adjustment of the readout threshold in order to balance specificity, rather than decreasing the overall analytical and diagnostic sensitivity of the protocols.

Anlotinib combined with pemetrexed and carboplatin as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC): ALTER L012.

e21040 Background: The anti-angiogenic drug bevacizumab combined with chemotherapy has achieved positive results in previous studies. In particular, the median progression-free survival (PFS) for EGFR-negative patients was increased to 8.3 months in the BEYOND study. Unlike bevacizumab, anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and PFS in advanced NSCLC patients. This exploratory study aims to establish the efficacy and safety of anlotinib in combination with pemetrexed and carboplatin as first-line treatment in advanced non-squamous NSCLC. Methods: This is a multi-center, single-arm clinical trial. Adults with treatment-naive, histologically confirmed stage IIIB-IV non-squamous NSCLC, ECOG 0-1, and without known sensitizing EGFR/ALK alterations are included. Patients received anlotinib (12 mg p.o., QD, d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m2, iv, d15-21, Q3W) + carboplatin (AUC = 5, iv, d15-21, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints were OS, objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Dec 2020, 40 patients were enrolled in six centers and 31 of them have received at least one tumor assessment. Median age was 62 (33, 75); 66.7% male, 11.1% brain metastasis. At data cutoff (Dec 31, 2020), patients were followed up for a median of 8.26 months. Median PFS was 10.5 months (95% CI: NE, NE); ORR was 67.7% (0 CR, 21 PR), DCR was 96.8% (0 CR, 21 PR, 9 SD) and median OS was NE. The most common Grade ≥ 3 AEs were hypertension 22.2%, neutropenia 19.44%, myelosuppression 11.1%, thrombocytopenia 8.33%, leukopenia 5.56%, hand-foot syndrome 5.56% and there were no Grade 5 toxicities. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin can significantly improve PFS and ORR compared to standard chemotherapy for treatment-naive non-squamous NSCLC patients. The combination was well tolerated, and the AEs were manageable. The follow-up time is not sufficient, and the OS outcomes need further evaluation. Clinical trial information: NCT03790228.

Validation of an immunohistochemical assay, CEACAM5 IHC 769, under development for use with the antibody-drug conjugate tusamitamab ravtansine (SAR408701).

e21030 Background: Despite recent advances in non-small cell lung cancer (NSCLC) treatment, a need remains for treatment options at disease progression. Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate of a humanized CEACAM5-specific monoclonal antibody linked to the maytansinoid DM4, a potent anti-tubulin agent. In a Phase 1/2 study, tusamitamab ravtansine showed promising antitumor activity in pretreated advanced non-squamous NSCLC (NSQ NSCLC) patients with high CEACAM5 expression, defined as ≥ 50% of the tumor cells per specimen with CEACAM5 positive staining at ≥ 2+ intensity (Gazzah A et al. J Clin Oncol 2020;38[15]: 9505). Sanofi and Agilent have partnered to develop an immunohistochemical (IHC) assay, CEACAM5 IHC 769, for detection of CEACAM5 protein in formalin-fixed paraffin-embedded (FFPE) NSQ NSCLC tissue using the EnVision FLEX visualization system on Dako Omnis. This assay is in development for the assessment of patients for whom tusamitamab ravtansine is being considered. Methods: CEACAM5 IHC 769 is a qualitative IHC assay using mouse monoclonal anti-CEACAM5 clone 769. Murine anti-CEACAM5 clone 769 is based on tusamitamab ravtansine, with the same specificity as the drug for CEACAM5. The clone was developed by Sanofi and used to evaluate CEACAM5 expression in a Phase 1/2 trial. The CEACAM5 IHC 769 scoring algorithm defines positive staining as any partial or complete tumor cell plasma membrane staining at ≥ 2+ intensity. Membrane staining may be linear or punctate. Staining may appear as complete or partial staining involving the basal, lateral, or basolateral aspects of the membrane, or as apical staining of the luminal aspect of the cell. CEACAM5 IHC 769 is being validated by Agilent Technologies for NSQ NSCLC at the cutoff of ≥ 50% at ≥ 2+ intensity. Internal studies included sensitivity, specificity, intra-block heterogeneity, observer precision, laboratory repeatability/precision, and robustness. Results: Sensitivity studies demonstrated detection across a dynamic range of CEACAM5 expression. Specificity studies indicated that the antibody is specific for CEACAM5. An intra-block heterogeneity study showed good overall diagnostic agreement for sections from the same tumor (point estimate ≥ 85%). Inter- and intra-observer precision, laboratory repeatability/precision, and robustness validation studies met acceptance criteria; the lower bound of the two-sided 95% confidence interval was ≥ 85% for positive, negative, and overall percent agreement. Conclusions: Internal validation studies demonstrated that CEACAM5 IHC 769 is sensitive, specific, precise, reproducible and robust in evaluating CEACAM5 expression in NSQ NSCLC tissue at the cutoff of ≥ 50% at ≥ 2+ intensity. CEACAM5 IHC 769 is being used for patient selection/stratification in ongoing Phase 2 and 3 clinical trials of tusamitamab ravtansine.

PD-1/PD-L1 inhibitors plus chemotherapy versus bevacizumab plus chemotherapy as first-line treatment for advanced nonsquamous non-small cell lung cancer: A Bayesian network meta-analysis of randomized controlled trials.

e21152 Background: Chemotherapy in combination with PD-1/PD-L1 inhibitor or bevacizumab have demonstrated superior efficacy to chemotherapy in the first-line treatment for non-squamous non-small-cell lung cancer (NS-NSCLC). However, there has been no randomized study comparing PD-1/PD-L1 inhibitors plus chemotherapy (immune-chemo) with bevacizumab plus chemotherapy (bev-chemo). Thus, we performed this network meta-analysis (NMA) to evaluate the comparative efficacy and safety of immune-chemo and bev-chemo as first-line treatment for NS-NSCLC. Methods: The randomized controlled trials (RCTs) were identified by searching PubMed, Embase, the Cochrane library, and conference abstracts until Oct 2020. Bayesian NMA with fixed effect consistency model was applied to estimate hazard ratio (HR) and Odds ratio (OR) with their 95% confidence intervals (CIs). The outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). Results: 15 RCTs involving 6541 advanced NS-NSCLC patients were eligible for analysis. For OS, immune-chemo (HR 0.70, 95% CI 0.64-0.79) and bev-chemo (0.87, 0.79-0.95) significantly prolonged survival compared with chemotherapy. For PFS, immune-chemo (0.58, 0.53-0.62) and bev-chemo (0.66, 0.61-0.71) were significantly superior to chemotherapy. For ORR, immune-chemo (2.42, 1.93-3.08) and bev-chemo (2.27, 1.75-2.92) were associated with better benefits than chemotherapy. However, immune-chemo (1.61, 1.08-2.35) and bev-chemo (1.83, 1.08-2.90) increased grade ≥3 TRATEs compared with chemotherapy. The results of Bayesian NMAs shown that immune-chemo (PFS: 0.88[0.80-0.97]; OS: 0.81[0.72-0.92]) was associated with better outcomes than bev-chemo, while there were no significant differences in ORR and the risk of grade ≥3 TRATEs (Table). Conclusions: Immune-chemo and bev-chemo are superior to chemotherapy in first-line treatment of NS-NSCLC. Immune-chemo could significantly improve clinical outcomes compared with bev-chemo without higher severe TRAEs. [Table: see text]

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.

Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) combined with bevacizumab for advanced non-squamous non-small-cell lung cancer patients with gradual progression on EGFR-TKI treatment: A cohort study.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve outcomes of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, acquired resistance inevitably emerges and remains a major challenge. The present study aimed to evaluate the efficacy of EGFR-TKIs plus bevacizumab in advanced non-squamous NSCLC patients with gradual progression on EGFR-TKIs.Advanced non-squamous EGFR-mutated NSCLC patients with gradual progression on EGFR-TKIs were administered bevacizumab while EGFR-TKIs were continued until disease progression occurred. Tumor lesions were assessed, and blood samples were collected at the start of the combination treatment and every 6 weeks until disease progression.Among the 15 included patients, there were no grade 3 or higher adverse events (AEs). Partial response (PR) and stable disease (SD) were achieved in 1 and 13 patients, respectively, with an objective response rate (ORR) of 6.7% and a disease control rate (DCR) of 93.3%. The median progression-free survival 2 (PFS2), defined as the time from the initiation of combination treatment to disease progression, was 5.0 (95% confidence interval [CI]: 4.0–6.0) months. Additionally, Spearman correlation analysis revealed that PFS2 was positively correlated with the serum vascular endothelial growth factor (VEGF) level at baseline (r = 0.7212, P = .0234). Patients with high baseline serum VEGF levels showed a better median PFS2 than those with low baseline serum VEGF levels (5.5 months vs 3.6 months, P = .0333).EGFR-TKIs plus bevacizumab led to a durable prolongation of PFS in non-squamous NSCLC patients with gradual progression on EGFR-TKIs. This therapeutic regimen was well tolerated and could be a promising strategy for these patients. Serum VEGF could be a potential biomarker to predict a subset of patients who are likely to benefit from EGFR-TKIs combined with bevacizumab.