Wild-type ALK Research Articles

Clinical Outcomes of Maintenance Durvalumab After Definitive Concurrent Chemoradiotherapy in Unresectable Locally Advanced Stage III NSCLC According to EGFR and ALK Status: Korean Cancer Study Group LU-22-18

IntroductionThe role of maintenance durvalumab after definitive concurrent chemoradiotherapy (CCRT) in unresectable locally advanced NSCLC with EGFR mutation or ALK translocation remains unclear. We compared the effectiveness of durvalumab maintenance therapy in groups with EGFR/ALK wild-type versus those with EGFR or ALK mutations. MethodsIn this retrospective multicenter observational study, patients with locally advanced NSCLC without progression after CCRT followed by maintenance durvalumab and available molecular test results (EGFR and ALK) were eligible. The primary objective was to compare progression-free survival (PFS) between EGFR/ALK wild-type and EGFR or ALK mutant NSCLC. Secondary objectives include overall survival according to EGFR or ALK mutation and programmed death-ligand 1 (PD-L1) expression. ResultsAmong 339 patients, 279 had wild-type EGFR/ALK, 41 had EGFR mutations and 19 had ALK translocations. The median age was 68 years with 276 male individuals (81.4%) and 63 female individuals (18.6%), 165 (49.3%) had adenocarcinoma, 149 (44.5%) had squamous cell carcinoma, and 21 (6.3%) had other histologic types, 120 (35.4%) had stage IIIA, 168 (49.6%) stage IIIB, and 51 (15.0%) had stage IIIC. Most of the patients (n = 288, 85%) achieved partial response to CCRT, two (0.6%) had a complete response, and 49 patients (14.4%) had stable disease. Excluding four patients with unknown PD-L1 tumor proportion score (TPS), 16 (4.8%) had a PD-L1 TPS of 0, 168 (50.1%) had 1 to 49, and 151 (45.1%) had 50 or higher. The median PFS was 21.4 months (95% confidence interval [CI]: 17.3–25.3) for the EGFR/ALK wild-type group and 21.0 months (95% CI: 15.7–not available [NA]) for the EGFR or ALK mutant group with no significant difference (p = 0.74). Significant differences occurred in PFS on the basis of PD-L1 expression with values of 13.6 (95% CI: 10.5–NA), 18.7 (95% CI: 15.1–26.9), and 24.7 (95% CI: 20.7–NA) months for TPS of 0, 1–49, and 50 or higher, respectively (p = 0.02). ConclusionsDurvalumab maintenance therapy after definitive CCRT in unresectable locally advanced NSCLC patients with EGFR or ALK mutation demonstrates comparable clinical outcomes to those with wild-type EGFR/ALK when PD-L1 expression is present.

Association of human leukocyte antigen (HLA) status with immune checkpoint inhibitor (ICI) pneumonitis in patients with non-small cell lung cancer (NSCLC).

8620 Background: Pneumonitis is a potentially serious complication occurring in 5-20% of lung cancer patients receiving ICI. The genetic risk factors for ICI pneumonitis are unclear. Given the association between HLA genetic variants and autoimmune diseases, we hypothesized that certain HLA genetic variants are associated with risk of ICI pneumonitis. Methods: Patients with advanced EGFR/ ALK wild type, PD-L1 tumor proportion score ≥50% NSCLC who received ICI were enrolled from year 2019 to 2022. Germline HLA typing was performed on buccal swab specimens using the Alltype Fastplex assay. Clinicopathological characteristics, treatment courses and survival outcomes were retrospectively collated. The primary endpoint was the correlation of common HLA variants (present in >30% of subjects) to the risk of ICI pneumonitis. Results: 42 patients (all Chinese, 36 male, 33 current/former smokers) were enrolled. Median age was 71 years old (range 51-91). 34, 6, 1 and 1 patients had adenocarcinoma, NSCLC not otherwise specified, squamous cell carcinoma and large cell neuroendocrine carcinoma respectively. Majority (33/42, 79%) received pembrolizumab monotherapy while 9 (21%) patients received pembrolizumab plus chemotherapy. Median follow up time was 27.8 months. At data cutoff, 28 (67%) patients received ICI for more than 1 year and 10 (24%) patients stopped ICI after completion of 2-year course of treatment. Seven (17%) patients developed pneumonitis, of which 3 were grade 2 and 4 were grade 3 in severity. Median time to development of pneumonitis was 6.9 months (range 0.3-25.2). Demographic characteristics were similar between patients who did or did not experience pneumonitis. In the entire cohort, twenty-two (52%) patients harbored the class II DPB1*02 allele. This allele was significantly associated with development of ICI pneumonitis. All 7 patients who had ICI pneumonitis harbored the DPB1*02 allele. The incidence of pneumonitis in patients harboring the DPB1*02 allele was 32% compared to 0% in those without this allele (p=0.009). Patients who experienced pneumonitis had worse survival rates than those without (p=0.03), but expression of DPB1*02 allele was not associated with inferior survival outcomes. Conclusions: Our results suggested that expression of DPB1*02 allele may be associated with development of ICI pneumonitis. A larger case-control study is ongoing to validate this association. [Table: see text]

EVOLVE-Lung02: A phase 3 study of first-line (1L) volrustomig plus chemotherapy (CT) versus pembrolizumab plus CT in metastatic non-small-cell lung cancer (mNSCLC) with PD-L1 tumor cell (TC) expression <50%.

TPS8652 Background: Immunotherapies targetingprogrammed cell death-1 (PD-1) and its ligand PD-L1 have transformed 1L mNSCLC. However, in a subset of patients (pts) with PD-L1-low or PD-L1-negative disease (i.e. PD-L1 TC expression <50% or <1%, respectively), anti-PD-(L)1 therapies, with or without CT, are associated with shorter overall survival (OS) than in pts with PD-L1-high disease. Dual inhibition of PD-1 and CTLA-4 is often undertaken in PD-L1-low, and especially PD-L1-negative, mNSCLC to address the poorer prognosis in these pts. Although combination therapy using lower doses of CTLA-4 inhibitors has shown benefit in this setting, toxicity at higher doses has limited the clinical utility of this approach. Volrustomig (MEDI5752) is a monovalent, PD-1/CTLA-4 bispecific, humanized IgG1 monoclonal antibody engineered to specifically inhibit PD-1, with increased CTLA-4 blockade on PD-1+ activated T cells compared to PD-1– resting peripheral T cells. This mode of action may facilitate enhanced CTLA-4 inhibition at tolerable doses beyond those achievable with current PD-1/CTLA-4 combinations. Data from the first-in-human phase 1/2 study (NCT03530397) showed encouraging antitumor activity and acceptable tolerability with 1L volrustomig plus carboplatin/pemetrexed (CP) in NSCLC, particularly in pts with PD-L1 TC <1%. The phase 3, two-arm, parallel-group, randomized, multicenter, open-label eVOLVE-Lung02 study (NCT05984277) is designed to evaluate the efficacy of 1L volrustomig plus CT versus pembrolizumab plus CT in mNSCLC pts with PD-L1 TC <50%. Methods: Eligibility criteria include age ≥18 years; ECOG performance status 0 or 1; histologically or cytologically documented squamous (sq) or non-squamous (non-sq) stage IV NSCLC with PD-L1 TC expression <50%; wild-type EGFR, ALK, or ROS1; and no prior systemic therapy for mNSCLC. Approximately 900 pts will be randomized 1:1 to receive histology-specific CT (sq, paclitaxel plus carboplatin; non-sq, CP with pemetrexed maintenance at investigator discretion) in combination with either volrustomig or pembrolizumab (200 mg) every 3 weeks (Q3W) for 4 cycles; after this volrustomig or pembrolizumab will be administered Q3W until completion of 24 months of treatment or disease progression, or other discontinuation criteria are met. Randomization will be stratified according to histology (sq vs non-sq), PD-L1 (<1% vs 1–49%), smoking (never vs former/current), and region (Asia vs rest of world). Primary endpoints are progression-free survival (PFS) per RECIST v1.1 and OS in the PD-L1 TC <1% population. Secondary endpoints include PFS and OS in all randomized pts (PD-L1 TC <50%), overall response rate, duration of response, PFS2, safety and tolerability, patient-reported outcomes, pharmacokinetics, and immunogenicity. Enrollment is ongoing. Clinical trial information: NCT05984277 .

PEOPLE (NTC03447678), a phase II trial to test pembrolizumab as first-line treatment in patients with advanced NSCLC with PD-L1

BackgroundChemoimmunotherapy represents the standard of care for patients with advanced non-small cell lung cancer (NSCLC) and programmed death-ligand 1 (PD-L1) <50%. Although single-agent pembrolizumab has also demonstrated some activity in...

Acquired L1196M ALK mutation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma during alectinib administration.

Acquired L1196M ALK mutation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma during alectinib administration.

Association Between EGFR and ALK Mutation Status on Patient-Reported Symptoms After Palliative Radiation for Bone Pain in NSCLC

IntroductionAfter palliative radiotherapy for bone metastases from NSCLC, up to 30% of patients may derive no symptomatic benefit, and there are a lack of biological predictors for this. The purpose was to investigate whether EGFR and ALK genetic rearrangements were associated with greater rates of pain response to palliative radiotherapy. MethodsPatients were identified from a prospectively collected patient-reported outcomes database for all patients with lung cancer treated with conventional palliative radiotherapy for bone metastases from 2013 to 2016 in the province of British Columbia. Patients were divided on the basis of mutational status into the following: EGFR and ALK wild type (WT), EGFR mutation present (EGFR+), or ALK mutation present (ALK+). Patient-reported outcomes of global pain severity were collected before and after radiotherapy and on an ordinal scale of 0 to 4, with 0 representing no bone pain and 4 representing the maximal possible bone pain. The primary outcome was the rate of partial pain response (any improvement in score), and the secondary outcome was the rate of complete pain response (final pain score of 0). Stepwise, multivariable logistic analysis was used to compare response rates between treatment courses for different mutational statuses. ResultsThe final cohort consisted of 388 treatment courses for 329 unique patients. For the WT, EGFR+, and ALK+ groups, there were 180, 63, and nine treatment courses, respectively. There were 92 patients with no ALK and EGFR testing. The most common treatment fractionations were 8 Gy in one fraction (188 of 388) and 20 Gy in five fractions (160 of 388), and use of multifraction radiotherapy did not differ between mutation status groups (p = 0.3). Partial pain response rates were as follows: WT 63%, EGFR+ 75%, and ALK+ 78%. On multivariable analysis, rates of partial response were higher for EGFR+ (OR = 5.4, p < 0.001) and for ALK+ (OR = 12.8, p = 0.008) in comparison to WT. Complete response rates were as follows: WT 20.5%, EGFR+ 35%, and ALK+ 67%. On multivariable analysis, complete response was not significantly increased in EGFR+ compared with WT (OR = 1.6, p = 0.127). ALK+ mutation status was associated with a higher rate of complete response compared with WT (OR = 5.2, p = 0.031). ConclusionsThere was an association between EGFR+ and ALK+ tumors and increased rates of partial pain response to palliative radiotherapy.

PEOPLE (NTC03447678), a phase II trial to test pembrolizumab as first-line treatment in patients with advanced NSCLC with PD-L1 &lt; 50%: A multiomics approach.

9051 Background: Chemo-immunotherapy is the standard of care for patients with advanced NSCLC and PD-L1 &lt; 50%. Efficacy has been reported in this setting with single agent pembrolizumab, but no reliable biomarkers yet exist for selecting patients likely to respond to single agent immunotherapy. The aim of this trial was to identify potential new immune biomarkers associated with PFS in NSCLC patients with PD-L1 &lt; 50% treated with first line pembrolizumab. Methods: Advanced EGFR and ALK wild type treatment-naïve NSCLC patients with PD-L1 &lt; 50% were enrolled. Gene expression profile was performed using nCounter PanCancer IO 360 Panel (Nanostring) on baseline tissue. Circulating immune profiling was performed by determination of absolute cell counts with multiparametric flow cytometry on freshly isolated whole blood samples at baseline and at first radiological evaluation. Gut bacterial taxonomic abundance was obtained by shotgun metagenomic sequencing of stool sample at baseline. Pembrolizumab was administered at 200 mg flat dose every 3 weeks until 35 cycles, disease progression or unacceptable toxicity. Omics data was analyzed with sequential univariate Cox Proportional Hazards regression predicting PFS, with Benjamini-Hochberg multiple comparisons correction. Biological features significant with univariate analysis were analyzed with multivariate Least Absolute Shrinkage and Selection Operator (LASSO). Results: From May 2018 to October 2020 65 patients were enrolled. Main characteristics were: male 67.6%, smokers 87.7%, PD-L1 positive 70.8%. Median follow up and PFS were 26.4 and 2.9 months, respectively. Gene expression profile was performed in 48 patients, microbiome in 54 patients and circulating immune profiling in 56 patients at baseline and in 46 patients at first radiologic evaluation. LASSO multivariate analysis with optimal lambda of 0.28 showed high expression levels of IRF9 and COMP genes was associated with an unfavorable PFS (HR 3.03, 1.52 – 6.02, p = 0.08 and HR 1.22, 1.08 – 1.37, corrected p = 0.06, respectively). High expression levels of CD244 (HR 0.74, 0.62- 0.67, p = 0.05), PTPRC (HR 0.55, 0.38 – 0.81, p = 0.098), KLRB1 (HR 0.76, 0.66 – 0.89, p = 0.05) in tissue samples and NK cells/CD56dimCD16+ (HR 0.56, 0.41 – 0.76, p = 0.006) in peripheral blood at baseline and non classical CD14dim CD16+ monocytes (HR 0.52, 0.36 – 0.75, p = 0.004), eosinophils (CD 15+CD16-) (HR 0.62, 0.44 – 0.89, p = 0.003) lymphocytes (HR 0.28, 0.15 – 0.5, p &lt; 0.001) in peripheral blood after first radiologic evaluation were associated to a favorable PFS. No microbiome features were selected by LASSO. Conclusions: To the best of our knowledge, this is the first prospective trial in NSCLC with PD-L1 &lt; 50% performed with a multi-omic approach able to identify immune cell subsets and expression levels of genes associated to PFS under first line treatment with pembrolizumab. Clinical trial information: NTC03447678.

PEOPLE (NTC03447678), a phase II trial of first-line, single-agent pembrolizumab in advanced NSCLC with low PD-L1: Clinical outcomes and association with circulating immune biomarkers.

9033 Background: In advanced NSCLC (aNSCLC) with PD-L1 &lt; 50% chemo-immunotherapy is the standard of care. Although the activity of single agent pembrolizumab was reported, no biomarkers have been identified able to select patients who mostly benefit. The trial aimed to identify immune biomarkers associated with PFS in aNSCLC patients with PD-L1 levels &lt; 50% treated with first-line pembrolizumab. Here we reported for the first time the clinical outcomes of the trial and circulating immune profiling (CIP) biomarkers correlated to PFS. Methods: This phase II trial was conducted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan. Eligible patients were previously untreated stage IIIB-IV NSCLC, EGFR and ALK wild type with PD-L1 &lt; 50%, PS 0-2. PD-L1 was assessed with 22-C3 antibody (Dako). Patients received pembrolizumab 200 mg every 3 weeks until 35 cycles, disease progression or unacceptable toxicity. The primary endpoint was the association of immune biomarkers with PFS. OS, ORR, DCR, DoR and safety were secondary endpoints. CIP was performed by determination of absolute cell counts for 36 innate and adaptive immunity subsets through multiparametric flow cytometry on freshly isolated whole blood samples at baseline. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyse CIP variables and their correlation with clinical endpoints. Results: From May 2018 to October 2020, of 87 screened, 65 patients were enrolled. The median age was 70.9 years, most patients were male (67.7%), smoker (87.7%), non-squamous (83.1%), PDL1 + (70.8%). 12 patients (18.5%) had PS 2. During a median follow-up of 26.4 months (mo), 51 radiological progressions, 46 deaths and 60 PFS events were observed. The median PFS was 2.9 mo (95%CI 1.8 - 5.6) and the median OS was 12.1 mo (95%CI 8.7 - 17.1). The ORR was 24.1% (2 complete and 12 partial responses), DCR was 53.4% and median DoR was 14.5 mo (95%CI 6.4 - 24.9). Drug related G3-G4 adverse events were: 2 hyponatremia, 2 lipase increased, 1 pneumonitis. Out of 7 CIP clusters identified, 2 were statistically significant at multivariable analysis on 57 patients. Higher baseline counts of 8 subsets within these two clusters were associated with better PFS (HR values range: 0.88-0.98; p values range: 0.001- 0.016). The significant subsets included lymphocytes (cells expressing CD3, or CD19 or CD56, but lacking granulocyte and monocyte markers) and main NK subsets (including CD56dim CD16+, CD56dim CD16- and HLA-DR+ NK cells). Conclusions: This trial confirmed that pembrolizumab as first-line single agent is safe and active also in a subgroup of aNSCLC patients with PD-L1 &lt; 50%. CIP biomarkers can be useful to identify patients with a favourable outcome, thus avoiding the adding toxicity of chemotherapy. Clinical trial information: NTC03447678.

An individual nomogram can reliably predict tumor spread through air spaces in non-small-cell lung cancer

BackgroundTumor spread through air spaces (STAS) has been shown to adversely affect the prognosis of lung cancer. The correlation between clinicopathological and genetic features and STAS remains unclear.MethodWe retrospectively reviewed 3075 NSCLC patients between2017-2019. We evaluated the relationship between STAS and patients’ clinicopathological and molecular features. The chi-square test was performed to compare categorical variables. Univariate analysis and multivariate logistic regression analysis were performed to investigate the association of clinical factors with STAS. A nomogram was formulated to predict the presence of STAS.ResultsSTAS was identified in 617 of 3075 patients (20.07%). STAS was significantly related to sex (p < 0.001), smoking (p < 0.001), CEA (p < 0.001), differentiation (p < 0.001), histopathological type (p < 0.001), lymphatic vessel invasion (p < 0.001), pleural invasion (p < 0.001), T stage (p < 0.001), N stage (p < 0.001), M stage (p < 0.001), and TNM stage (p < 0.001). STAS was frequently found in tumors with wild-type EGFR (p < 0.001), KRAS mutations (p < 0.001), ALK rearrangements (p < 0.001) or ROS1 rearrangements (p < 0.001). For programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1), STAS was associated with PD-L1 expression level in tumor cells (p < 0.001) or stromal cells (p < 0.001), while PD-1 only in stromal cells (p < 0.001). Multivariable analyses demonstrated significant correlations between STAS and CEA level (p < 0.001), pathological grade (p < 0.001), lymphatic vessel invasion (p < 0.001), pleural invasion (p = 0.001), and TNM stage (p = 0.002). A nomogram was formulated based on the results of the multivariable analysis.ConclusionsTumor STAS was associated with several invasive clinicopathological features. A nomogram was established to predict the presence of STAS in patients with NSCLC.

104P Exploring the real-world impact of COVID-19 on first line (1L) treatment and management of EGFR-wild type (EGFR-WT) and ALK-wild type (ALK-WT) metastatic non-small cell lung cancer (mNSCLC) across Europe

The COVID-19 pandemic has led to worldwide disruptions in healthcare. This study aimed to explore the impact of COVID-19 on 1L treatment and management of patients (pts) with EGFR-WT and ALK-WT mNSCLC.

Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial

For patients with resectable, early-stage non-small-cell lung cancer (NSCLC), surgery is the primary treatment; however, 5-year survival rates remain poor. Postoperative adjuvant platinum-doublet chemotherapy is associated with a statistically significant but modest improvement in survival of ∼5% at 5 years and is widely accepted as standard of care in patients with resectable, Stage II-III NSCLC. Neoadjuvant chemotherapy has been associated with similar improvements in overall survival to adjuvant therapy in this setting. Durvalumab, a high-affinity PD-L1 inhibitor, has become the standard of care for patients with unresectable, Stage III NSCLC following chemoradiotherapy based on improved progression-free and overall survival in the phase III PACIFIC trial. AEGEAN is a phase III, double-blind, placebo-controlled, international study that will assess pathological and clinical outcomes of durvalumab plus chemotherapy prior to surgery, followed by durvalumab monotherapy after surgery in adults with resectable, Stage II-III NSCLC. Approximately 800 patients will be randomized (1:1) to receive durvalumab or placebo every 3 weeks (q3w) alongside platinum-based chemotherapy (≤4 cycles) prior to surgery, followed by durvalumab or placebo monotherapy q4w, for an additional 12 cycles post surgery, stratified by disease stage (IASLC 8th Edition, Stage II vs. Stage III) and PD-L1 tumor cell expression levels (<1% vs. ≥1%). Primary endpoints include pathological complete response and event-free survival for patients with wild-type EGFR and ALK. Key secondary efficacy endpoints include major pathologic response, disease-free survival and overall survival.

Selected Articles from This Issue

In this First Disclosure, Murray and colleagues describe TPX-0131, a compact macrocyclic ALK inhibitor designed to fit completely in the ATP-binding pocket and inhibit both wild-typ. ALK and drug-resistance mutations. Using a combination of biochemical, cellular, and in vivo preclinical assessments, TPX-0131 was shown to a CNS-penetrant molecule that potently inhibits wild-type ALK and a broad array of clinically relevant ALK mutants that limit the utility of previous generations of ALK inhibitors such as solvent front, gatekeeper, hinge region, and compound mutations. TPX-0131 currently is being evaluated in a phase 1/2 clinical study of TKI-pretreated patients with ALK+ NSCLC (NCT04849273).This First Disclosure describes the lead selection and preclinical research supporting the development of SENTI-101, a novel allogeneic cell therapy preclinical product candidate for the treatment of peritoneal carcinomatosis, including advanced ovarian cancer. SENTI-101 uses mesenchymal stromal cells innate capacity to traffic and localize to solid tumors to deliver two potent immune stimulatory cytokines (IL-12 and IL-21) to the tumor microenvironment. Studies conducted by Senti Bio demonstrate that, with this approach, scientists safely turned “cold” tumors “hot” resulting in long term anti-tumor immunity and rendered them susceptible to checkpoint inhibition. SENTI-101 demonstrates anti-tumor activity and proposes a cell modality that may address an unmet need for patients with ovarian cancer.Tumor hypoxia is a barrier to radiotherapy. It has been reported that DNAp. inhibition preferentially sensitizes tumor cells to radiation under hypoxia in vitro. However, whether DNAPK inhibition sensitizes hypoxic tumor cells to radiation in vivo has not been reported. In this study, Jiang et al show that transient DNAPK inhibition by a novel selective DNAPK inhibitor, NU5455 favorably compromises the repair of radiation-induced DNA DSBs in chronically hypoxic tumor cells in vivo, suggesting that DNAPK inhibition may preferentially sensitizes chronically hypoxic tumor cells to radiotherapy, which could form the basis for clinical trials investigating the impact of DNAPK inhibitors in radioresistant hypoxic tumors.Therapy-resistant leukemic stem cells can lead to the relapse of acute myeloid leukemia. In this study, Lee and colleagues target these residual cancer cells using mucin domain 3 (TIM-3) targeted chimeric antigen receptor (CAR) T cells. TIM-3 was selected due to its high expression on AML blasts and leukemic stem cells and its low expression on normal hematopoietic cells. Phage display was used to determine a TIM-3 antibody suitable for expression on the CAR T cells, which were subsequently tested on murine models and primary AML blasts. Although the consequences of TIM-3 targeting require further investigation, the authors demonstrate favorable anti-tumor activity by TIM-3 CAR T cells.

1363TiP A phase I/II study of TPX-0131, a novel oral ALK tyrosine kinase inhibitor, in patients with ALK+ advanced/metastatic NSCLC

TPX-0131 is a next-generation ALK tyrosine kinase inhibitor (TKI) designed to overcome a broad array of mutations that can limit the effectiveness of previous generation ALK TKIs. In cellular assays, TPX-0131 potently inhibits wild-type ALK (IC50 = 0.4 nM) and many clinically observed resistance mutations, including the G1202R solvent front mutation (IC50 = 0.2 nM), L1196M gatekeeper mutation (IC50 = 0.5 nM) and multiple compound mutations (IC50 < 1 nM). In vivo studies show brain tissue penetration.

PD-L1 Expression and Comprehensive Molecular Profiling Predict Survival in Nonsmall Cell Lung Cancer: A Real-World Study of a Large Chinese Cohort

BackgroundProgrammed death ligand 1 (PD-L1) expression is the current standard biomarker used to predict non-smallcell lung cancer (NSCLC) response to immunotherapy. Gene expression signatures also seem to be related to the response to immunotherapy. Understanding the clinical and prognostic impact of molecular phenotype and tumor features on PD-L1 expression in NSCLC patients may improve the prediction of immunotherapy response. Materials and MethodsA total of 819 consecutive surgically resected NSCLC specimens from one institution were analyzed in our study. We determined PD-L1 expression by immunohistochemistry (IHC) using the 22C3 clone and the molecular phenotype by targeted next-generation sequencing with a 68-gene panel. ResultsHigh PD-L1 expression was significantly associated with wild-type EGFR (P < .001), KRAS mutation (P < .001), ROS1 rearrangement (P < .001), ALK rearrangement (P = .007), RET rearrangement (P = .041) and MET gene alterations (P = .003). Mutations in TP53 and Rb1 were also significantly associated with high PD-L1 expression (both P < .001). High PD-L1 expression was significantly associated with EGFR co-mutation with tumor suppressor genes such as TP53, Rb1, while EGFR mutation alone was not associated with high PD-L1 expression. Poor survival appeared to be linked to high PD-L1 expression or PD-L1 negative expression with concomitant mutations of tumor suppressor genes, especially multiple tumor suppressor genes. ConclusionPD-L1 expression is highly correlated with major driver and suppressor gene alterations. High PD-L1 expression and patients with negative PD-L1 expression harboring suppressor gene mutation are associated with poor prognosis in patients with NSCLC.

Abstract 1469: TPX-0131, a potent inhibitor of wild type ALK and a broad spectrum of both single and compound ALK resistance mutations

Abstract Three generations of ALK inhibitors are approved for the treatment of ALK+ NSCLC but their efficacy is often limited by ALK resistance mutations. The solvent front mutation G1202R and gatekeeper mutation L1196M are major resistance mechanisms to the first two generations of inhibitors. Patients treated with second generation inhibitors are reported to progress with multiple mutations on separate alleles (mutations in trans). In contrast, 35 - 48% of patients treated with lorlatinib progress with multiple mutations on the same allele (compound mutations, mutations in cis). TPX-0131 is an ALK inhibitor with a compact macrocyclic structure designed to bind completely within the ATP binding boundary and overcome a spectrum of single and compound ALK resistant mutations. TPX-0131 was profiled against previous generations of ALK inhibitors both in vitro and in vivo. In biochemical assays, TPX-0131 potently inhibits (IC50 &amp;lt;10 nM) wild type (WT) ALK and 26 ALK mutations (single and compound). Cell proliferation assays of WT, single mutations, and compound mutations were used to evaluate TPX-0131 relative to previous generations of ALK inhibitions (crizotinib, alectinib, brigatinib, ceritinib, lorlatinib). TPX-0131 is more potent against WT EML4-ALK (IC50 = 0.4 nM) than previous generations of ALK inhibitors (2-fold, lorlatinib; 10 - 30-fold, second generation inhibitors; &amp;gt;100-fold, crizotinib). TPX-0131 potently inhibits EML4-ALK harboring a G1202R solvent front mutation (IC50 = 0.2 nM) which is &amp;gt;100-fold more potent than previous generations of ALK inhibitors. TPX-0131 potently inhibits ALK harboring a gatekeeper mutation (IC50 = 0.5 nM) and is &amp;gt;10-fold more potent than previous generations of ALK inhibitors. TPX-0131 potently inhibits ALK with a L1198F hinge area mutation (IC50 = 0.2 nM) which is 87 - 3000-fold more potent than previous generations of ALK inhibitors. TPX-0131 is the most potent inhibitor against nine EML4-ALK double and triple compound mutations (6 with IC50 &amp;lt; 1 nM, 3 with IC50 1.6 - 14.9 nM). Evaluation of ALK phosphorylation as a pharmacodynamic marker in tumors showed potent ALK inhibition by TPX-0131 that correlated with TPX-0131 exposure. In Ba/F3 cell-derived xenograft tumor models with EML4-ALK mutations, TPX-0131 (2, 5, 10 mg/kg BID) demonstrated robust anti-tumor activity in the G1202R model (64%, 120%, 200% TGI), G1202R/L1198F model (complete regression, all doses), and G1202R/L1196M model (44%, 83% and 200% TGI). In contrast, lorlatinib (5 mg/kg BID) caused 31% TGI in the G1202R/L1198F model and did not have statistically significant TGI in the G1202R/L1196M model. Taken together, TPX-0131 is a next generation ALK inhibitor that has preclinical potency against WT ALK as well as a broad spectrum of acquired resistance mutations, especially compound mutations, which currently lack any effective ALK inhibitor therapy. Citation Format: Brion W. Murray, Dayong Zhai, Wei Deng, Evan Rogers, Xin Zhang, Jane Ung, Vivian Nguyen, Han Zhang, Maria Barrera, Ana Parra, Jessica Cowell, Dong Lee, Herve Aloysius. TPX-0131, a potent inhibitor of wild type ALK and a broad spectrum of both single and compound ALK resistance mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1469.

P75.01 Activity of Brigatinib in Alectinib-Resistant ALK-Positive NSCLC According to ALK Plasma Mutation Status From J-ALTA Trial

Brigatinib is a selective and potent ALK tyrosine kinase inhibitor (TKI) with preclinical activity against wild-type ALK and a broad spectrum of ALK secondary mutants, known to confer clinical resistance to crizotinib, ceritinib, and alectinib. Brigatinib has shown promising efficacy in Japanese patients with ALK+ NSCLC previously treated with alectinib in a phase 2 trial (J-ALTA). As an exploratory correlative analysis, we examined the relationship of ALK mutation status with brigatinib treatment outcome by NGS analysis of cell free DNA (cfDNA) using plasma specimens at baseline prior to brigatinib treatment (baseline [BL]) in ALK+ NSCLC patients who progressed on alectinib or other ALK TKIs and enrolled in this study.

Clinicopathological and molecular characteristics associated with PD-L1 expression in non-small cell lung cancer: a large-scale, multi-center, real-worldstudy in China.

The study aimed to evaluate the clinicopathological and molecular profiles associated with programmed death ligand 1 (PD-L1) expression in non-small cell lung cell (NSCLC) in a large-scale, multi-center, real-world Chinese cohort. A total of 6295 NSCLC specimens from six centers in China were analyzed by PD-L1 (22C3) assay. PD-L1 expression in tumor cells (TCs) was classified as negative (TPS expression in < 1% of TCs), low (TPS in 1-49% of TCs), or high (TPS in ≥ 50% of TCs). The status of EGFR mutation was determined by reverse transcription polymerase chain reaction or next-generation sequencing, and ALK and ROS1 translocation was analyzed by immunohistochemistry and fluorescence in situ hybridization. Associations of PD-L1 expression with clinicopathological features and driver mutations were analyzed. Positive PD-L1 expression was more frequently seen in squamous cell carcinoma (SCC) and other histological types of NSCLC compared to adenocarcinoma (AC). In AC, PD-L1 expression was associated with gender, histological type, metastatic status, and pathological features of lymphovascular invasion and visceral pleural invasion. Solid and micropapillary subtypes of AC were more likely to have positive PD-L1 expression compared to other subtypes. PD-L1 was more highly expressed in biopsy samples than in resected samples, and in metastatic samples compared with primary tissues. PD-L1 expression was significantly associated with wild-type EGFR and ALK translocations. PD-L1 expression in NSCLC is linked to histological type, pathological features, and driver mutation status, which has meaningful implications for clinical practice.

Association between Genetic Mutations and Risk of Venous Thromboembolism in Patients with Solid Tumor Malignancies: A Systematic Review and Meta-Analysis

Title: Association between genetic mutations and risk of venous thromboembolism in patients with solid tumor malignancies: A systematic review and meta-analysis. Introduction: Venous thromboembolisms (VTE) is a frequent complication in cancer patients with an overall incidence of approximately 20% and is associated with significant morbidity, mortality, and burden on the health care system [1]. VTE risk varies according to tumor type and it is possible that certain genetic mutations may promote hypercoagulability resulting in a prothrombotic state. We have studied the association between genetic mutations and risk of VTE in patients with melanoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colon, gastric and ovarian cancers. Aim: To evaluate the association of genetic mutations in melanoma, lung (SCLC, NSCLC), colon, gastric and ovarian cancer with the risk of venous thromboembolism. Search strategy: We conducted a systematic literature search in MEDLINE and EMBASE electronic databases from inception to May 2020 using a combination of the following subject headings and text words: gene mutation, genetic polymorphism, oncogenes, tumor-related genes, proto-oncogenes, oncoproteins, venous thromboembolism, venous thrombosis, pulmonary embolism, lung neoplasms (SCLC, NSCLC), gastrointestinal neoplasms, ovarian neoplasms, colorectal neoplasms, and melanoma. Selection criteria: We included studies presenting data on genetic mutations with &amp;gt; 5% prevalence in our population of interest [adult patients with melanoma, lung (SCLC, NSCLC), colon, gastric and ovarian cancer]. Studies with thrombosis events given, but not listed according to the mutation status of patients were excluded. Retrospective and prospective cohort studies, case-control studies and randomized clinical trials (RCTs) were included. Data collection and analysis: General descriptors for the patients in each study were collected, as well as number of patients with wildtype or mutated genes of interest that developed thrombosis. Fixed and random effects models were used to generate pooled adjusted ratios with 95% confidence intervals using data for thrombosis events in patients with mutated and wildtype driver genes of interest. The quality of the studies: Study qualities were assessed using Jadad score for randomized controlled trials and the Newcastle-Ottawa Scale for case-control and cohort studies. Main results: Of 616 eligible articles, we included 31 articles based on our inclusion criteria and 10 were included in the meta-analysis. In patients with lung cancer with EGFR, KRAS and ALK mutations the relative risk (RR) of VTE was 1.006 (40.084-11.150, P=0.965), 1.034 (0.514-2.081, P=0.925) and 1.571 (1.314-1.878, P&amp;lt;0.001) respectively using the fixed-effects model. Using the random-effects model, the RR of VTE in patients with lung cancer and EGFR, KRAS and ALK was 1.058 (0.632-1.768, P=0.831), 1.086 (0.504-2.343, P=0.833) and 1.667 (1.303-2.131, P&amp;lt;0.001), respectively. In patients with colon cancer and KRAS mutation the RR of VTE was 1.38 (1.368-33.942, P=0.017) using a fixed-effects model and 1.319 (0.794-2.191, P=0.285) using a random-effects model. Conclusion: In patients with lung cancer, those bearing ALK rearrangements carried a significantly higher relative risk of developing thrombosis than those with wild-type ALK. In patients with colon cancer, relative risk of VTE increased significantly in patients who had KRAS mutations than KRAS wild type. Disclosures No relevant conflicts of interest to declare.

Comprehensive analysis of spread through air spaces in lung adenocarcinoma and squamous cell carcinoma using the 8th edition AJCC/UICC staging system

BackgroundThis study aimed to comprehensively investigate the effect of spread through air spaces (STAS) on clinicopathologic features, molecular characteristics, immunohistochemical expression, and prognosis in lung adenocarcinomas (ADC) and squamous cell carcinomas (SQCC) based on the 8th edition AJCC/UICC staging system.MethodsIn total, 303 ADC and 121 SQCC cases were assessed retrospectively. Immunohistochemical staining was performed for E-cadherin, vimentin, Ki67, survivin, Bcl-2, and Bim. Correlations between STAS and other parameters were analyzed statistically.ResultsSTAS was observed in 183 (60.4%) ADC and 39 (32.2%) SQCC cases. In ADC, the presence of STAS was associated with wild-type EGFR, ALK and ROS1 rearrangements, low E-cadherin expression, and high vimentin and Ki67 expression. In SQCC, STAS was associated with low E-cadherin expression and high vimentin and survivin expression. Based on univariate analysis, STAS was associated with significantly shorter disease-free survival (DFS) and overall survival (OS) in ADC. In SQCC, STAS tended to be associated with shorter OS. By multivariate analysis, STAS was an independent poor prognostic factor in ADC for DFS but not OS. Stratified analysis showed that STAS was correlated with shorter DFS for stage I, II, IA, IB, and IIA ADC based on univariate analysis and was an independent risk factor for DFS in stage I ADC cases based on multivariate analysis.ConclusionsOur findings revealed that STAS is an independent negative prognostic factor for stage I ADC using the new 8th edition AJCC/UICC staging system. Stage I patients with STAS should be followed up more closely and might need different treatment strategies.

Abstract C027: A Phase I, dose finding study of BI 754111, an anti-LAG-3 antibody, in combination with BI 754091, an anti-PD-1 antibody, in patients with advanced solid tumors: preliminary results from the microsatellite stable (MSS) metastatic colorectal cancer (mCRC) cohort

Abstract Background: Inhibition of the PD-1 pathway is an effective immunotherapeutic approach in a subset of patients with various solid tumors and hematologic malignancies. Blockade of the PD-1 pathway leads to overexpression of other checkpoint receptors, including LAG3, potentially providing an escape pathway for tumor cells. LAG-3 signaling contributes to immune cell exhaustion, preventing T-cell proliferation. Dual blockade of PD-1 and LAG-3 has the potential to synergistically restore T-cell functionality and therefore enhance antitumor immune responses. This Phase I trial is evaluating the combination of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), and BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. Methods: This open-label, Phase I study is being conducted in two parts. Part 1 (dose-escalation) enrolled patients with advanced solid tumors; no dose limiting toxicities were reported and BI 754111 600 mg intravenous (iv) every 3 weeks (q3w) in combination with BI 754091 (240 mg iv q3w) was selected for further assessment in part 2 (dose expansion). In part 2, patients are being enrolled in 4 cohorts: 1) anti-PD-(L)1 pretreated non-small cell lung cancer (NSCLC) that progressed after having achieved benefit on previous PD-(L)1; 2) previously treated (anti-PD-[L]1 naïve) MSS mCRC; 3) anti-PD-(L)1 pretreated TMB &amp;gt;10 and/or MSI-h and/or dMMR solid tumors; 4) treatment-naive NSCLC with EGFR and ALK wild type tumors. Primary endpoint for the expansion cohorts is objective response. Safety and pharmacokinetics of the combination were secondary endpoints. The mCRC cohort is fully recruited; other cohorts are open to recruitment. This abstract presents data from the MSS CRC cohort. Results. 40 patients with MSS mCRC were enrolled (27 male [67.5%]; median age 56.5 years [range 25–85]; median of 3.0 prior regimens [range 1–10]) and received BI 754111 600 mg q3w in combination with BI 754091 240 mg q3w. Treatment-related AEs (TRAEs) were reported in 18 patients (45%); most commonly infusion-related reactions (10.0%), myalgia (10.0%), hypothyroidism (7.5%), diarrhea (7.5%) and arthralgia (7.5%). Grade 3/4 TRAEs occurred in 4 patients (grade 3 colitis, grade 3 maculo-papular rash, grade 4 diabetic ketoacidosis [n=2]). Treatment-emergent immune-related AEs occurred in 9 patients; of these, 4 had grade 3/4 events (colitis and maculo-papular rash [grade 3] and diabetic ketoacidosis [grade 4; n=2]). To date, 2 (5%) patients achieved a partial response, and 12 (30%) achieved stable disease. Updates will be presented. Conclusion. BI 754111 + BI 754091 was well-tolerated and showed preliminary activity in patients with previously treated MSS mCRC. Assessment of the combination in other cohorts is ongoing. Citation Format: Johanna Bendell, Susanna V Ulahannan, Quincy Chu, Manish Patel, Ben George, Renee Landsberg, Mabrouk Elgadi, Christine Duffy, Ralph Graeser, Wenbo Tang, Michael Merger, Miaomiao Ge, Melissa Johnson. A Phase I, dose finding study of BI 754111, an anti-LAG-3 antibody, in combination with BI 754091, an anti-PD-1 antibody, in patients with advanced solid tumors: preliminary results from the microsatellite stable (MSS) metastatic colorectal cancer (mCRC) cohort [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C027. doi:10.1158/1535-7163.TARG-19-C027