FP12.09 Molecular Insight into NADIM Clinical Trial: Potential Immune Biomarkers of Pathological Response for NSCLC Patients.

AbstractSeveral clinical trials have shown the safety and effectiveness of PD-1/PD-L1 inhibitors in neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC). However, 18–83% patients can benefit from it. In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden, copy number alteration (CNA, including copy number gain and loss) burden with the pathologic response to neoadjuvant PD-1 blockade and investigate the changes in the tumor immune microenvironment (TIME) during neoadjuvant immunotherapy in NSCLC. Pre-immunotherapy treatment tumor samples from twenty-nine NSCLC patients who received neoadjuvant immunotherapy with sintilimab, an anti-PD-1 drug, were subjected to targeted DNA sequencing and PD-L1 immunochemistry staining. The pathological response was positively correlated with tumor proportion score (TPS) of PD-L1 and negatively correlated with copy number gain (CNgain) burden. Of note, the combination of CNgain burden and TPS can better stratify major pathological response (MPR) patients than did CNgain or TPS alone. Whereas, TMB showed a limited correlation with pathological regression. Additionally, PD-1 blockade led to an increase in CD8+PD-1−T cells which was clinically relevant to MPR as evaluated by multiplex immunofluorescence. A significant reduction in CD19+ cells was observed in the Non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC. Together, our study provides new data for the correlation of PD-L1 expression and genomic factors with drug response in neoadjuvant immunotherapy settings in NSCLC. The changes of TIME may provide novel insight into the immune responses to neoadjuvant anti-PD-1 therapy.

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Clinical Trial for Evaluating Efficacy and Safety of PDR001 in Concurrent Plus Consolidation Versus Consolidation Only in Addition to Standard Chemoradiotherapy in Unresectable Stage III NSCLC Patients (PASTURE)

Case Medical Research ◽

10.31525/ct1-nct03945227 ◽

2019 ◽

Author(s):

Keyword(s):

Clinical Trial ◽

Stage Iii ◽

Efficacy And Safety ◽

Unresectable Stage ◽

Stage Iii Nsclc ◽

Nsclc Patients

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P60.02 Insight Into Intestinal Microbiome in NSCLC Patients: More Personalized Immunotherapy in the Crosshairs

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.961 ◽

2021 ◽

Vol 16 (3) ◽

pp. S541

Author(s):

A. Grenda ◽

E. Iwan ◽

P. Krawczyk ◽

M. Słomiany-Szwarc ◽

A. Bomba ◽

...

Keyword(s):

Intestinal Microbiome ◽

Nsclc Patients ◽

Insight Into

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P60.11 TCR Repertoire Predicts Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemoimmunotherapy from NADIM Trial

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.970 ◽

2021 ◽

Vol 16 (3) ◽

pp. S545-S546

Author(s):

M. Casarrubios ◽

E. Nadal ◽

A. Cruz-Bermudez ◽

A. Insa ◽

R. Laza Briviesca ◽

...

Keyword(s):

Pathological Response ◽

Tcr Repertoire ◽

Nsclc Patients

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Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06307-3 ◽

2021 ◽

Author(s):

Foluso O. Ademuyiwa ◽

Ina Chen ◽

Jingqin Luo ◽

Mothaffar F. Rimawi ◽

Ian S. Hagemann ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Pathological Response

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Camrelizumab plus chemotherapy as neoadjuvant therapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC-ESCC2019): A multicenter, open-label, single-arm, phase 2 study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4028 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4028-4028

Author(s):

Jingpei Li ◽

Jun Liu ◽

Zhuoyi Li ◽

Fei Cui ◽

Yuan Zeng ◽

...

Keyword(s):

Clinical Trial ◽

Squamous Cell Carcinoma ◽

Neoadjuvant Chemotherapy ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Primary Tumor ◽

Pathologic Response ◽

Pathological Response ◽

Phase 2 ◽

Phase 2 Study

4028 Background: Despite multidisciplinary therapies, prognosis of pts with resectable esophageal squamous cell carcinoma (ESCC) remains poor. Combining PD-1 blockade to neoadjuvant chemotherapy might be a feasible and effective strategy. Camrelizumab (an anti-PD-1 antibody) was approved for advanced or metastatic ESCC in the second-line setting and showed improved anti-tumor activity and survival benefit when combined with chemotherapy in multiple advanced tumors. Methods: In this NIC-ESCC2019 phase 2 study, histologically or cytologically confirmed ESCC pts (stage II-IVA) were enrolled to receive two cycles of neoadjuvant chemoimmunotherapy (NIC) with camrelizumab (200 mg on day 1) plus nab-paclitaxel (260 mg/m² in total on day 1 and day 8) and cisplatin (75 mg/m² in total on days 1-3) of each 21-day cycle, followed by esophagectomy. The primary endpoint was complete pathologic response (CPR) rate in the primary tumor. Besides, we also explored the relationship between the tumor genomic profile or primary-tumor microenvironment and the pathological response. Results: Between Jan 17, 2020 and Dec 8, 2020, 56 pts were enrolled. 51 pts underwent surgical resection, and all had complete tumor resection. CPR was achieved in 18 (35.3%; 95% CI, 21.7%-48.9%) pts; 12 (23.5%) pts had major pathologic response (MPR), and 21 (41.2%) had incomplete pathological response (IPR). Of note, 16 (31.4%) pts achieved CPR in both primary tumor and lymph nodes. The objective response rate was 66.7% (95% CI, 40.0-70.4). No in-hospital mortality occurred. The most common treatment-related adverse events (TRAEs) were decreased WBC (20 [36%] of 56 pts), vomiting (19 [34%]), and alopecia (18 [32%]). Grade 3 TRAEs only occurred in 6 (11%) pts, and there were no grade 4 or 5 TRAEs. The most common immune-related AEs included grade 1-2 rash maculo-papular (7 [13%]) and reactive cutaneous capillary endothelial proliferation (5 [9%]). Presence of mutations in CREBBP and KMT2D at treatment-naïve time-point was correlated with non-response group (IPR and stable disease) (CREBBP, p = 0.046; KMT2D, p = 0.047). Among the immune populations, CD8+, CD8+PD-1+ and CD8+PD-L1+ T cells increased significantly after two doses of NIC, especially in the CPR+MPR group (CD8+, p = 0.013; CD8+PD-1+, p < 0.001; CD8+PD-L1+, p = 0.068). Conclusions: The addition of camrelizumab to neoadjuvant chemotherapy in ESCC demonstrated promising efficacy with acceptable toxicity, supporting the further investigation in a randomized phase 3 clinical trial. Clinical trial information: NCT04225364. [Table: see text]

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Integration of proteomic and clinical data for the prediction of response to immune checkpoint inhibitor therapy in non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21110 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21110-e21110

Author(s):

Yuval Shaked ◽

Michal Harel ◽

Coren Lahav ◽

Eyal Jacob ◽

Itamar Sela ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trial ◽

Host Response ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Resistance Mechanisms ◽

Small Cell ◽

Plasma Samples ◽

Small Cell Lung ◽

Nsclc Patients

e21110 Background: Immune checkpoint inhibitor (ICI) therapy represents one of the most promising cancer treatments to date. However, despite unprecedented rates of durable response, only a small proportion of patients benefits from this approach. Major efforts are therefore required to characterize treatment resistance mechanisms, as well as to identify reliable biomarkers for response. We have previously shown that in response to various types of cancer therapy, including ICIs, the host may induce pro-tumorigenic processes that can promote therapy resistance. Here we examined systemic host-response proteomic profiles in non-small cell lung cancer (NSCLC) patients, aiming to discover biomarkers for response to ICI therapy and to unravel underlying resistance mechanisms. Methods: As part of our ongoing PROPHETIC clinical trial (NCT04056247), plasma samples were obtained at baseline (T0) and early-on treatment (T1; following the first treatment) from 120 NSCLC patients receiving ICI therapy. Proteomic profiling of the plasma samples was performed using proximity-extension assay (PEA) technology; validation was carried out for a fraction of the samples using ELISA-based arrays. To identify a proteomic signature that predicts clinical outcome, machine learning algorithms were applied following a random separation of the cohort into a discovery set and a validation set. Results: A proteomic signature predictive of response to treatment was identified and validated. Bioinformatic analysis identified potential mechanisms of resistance based on differentially expressed proteins associated with pro-tumorigenic biological processes. Statistical analysis of the clinical data identified multiple novel differential clinical parameters between responders and non-responders, either at baseline or by comparing T0 to T1, which may suggest host-mediated effects. Conclusions: Our study demonstrates the potential clinical utility of analyzing the host response to ICI therapy, in particular for the discovery of novel predictive biomarkers for NSCLC patient stratification. Clinical trial information: NCT04056247.

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21040 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21040-e21040

Author(s):

Qiming Wang ◽

Xiuli Yang ◽

Tianjiang Ma ◽

Qiumin Yang ◽

Chenghui Zhang ◽

...

Keyword(s):

Clinical Trial ◽

Kinase Inhibitor ◽

Objective Response ◽

Progression Free Survival ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Treatment Naïve ◽

Nsclc Patients ◽

First Line Treatment

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.

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The combination of EGFR-TKIs and anlotinib as a first-line therapy for EGFR-mutant advanced non-small cell lung cancer: A multicenter, single-arm, phase II clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9030 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9030-9030

Author(s):

Zhiyong He ◽

Jinghui Lin ◽

Yueming He ◽

Jing Zhang ◽

Dongyong Yang ◽

...

Keyword(s):

Clinical Trial ◽

Adverse Events ◽

Advanced Nsclc ◽

De Novo ◽

Egfr Mutations ◽

Treatment Naïve ◽

Pre Treatment ◽

Egfr Mutant ◽

Nsclc Patients ◽

Egfr Tkis

9030 Background: Currently,EGFR-TKIs are widely accepted as the standard treatment for EGFR- mutant advanced non-small-cell lung cancer (NSCLC); however, acquired resistance is inevitable. Combination therapy is considered as a strategy to overcome the resistance to EGFR-TKIs. Anlotinib, a novel multi-targeting, small-molecule TKI, has shown active to suppress tumor angiogenesis and growth. However, there is still a lack of evidence supporting the use of EGFR-TKIs in combination with anlotinib for the treatment of NSCLC until now. A multi-center, single-arm, phase II clinical trial was therefore designed to examine the efficacy and safety of EGFR-TKIs combined with anlotinib for treatment-naïve, advanced NSCLC patients, and unravel the possible mechanisms. Methods: This study was conducted in 14 research centers in Fujian, China. The main eligibility criteria were stage IV or relapsed nonsquamous NSCLC with EGFR mutations (exon 19 deletion,, and L858R), ECOG score 0-2,and age 20 to 75 years and no previous systemic treatment. Patients with asymptomatic brain metastases were admitted.Eligible patients were given gefitinib (250 mg QD) or icotinib (125 mg TID) in combination with anlotinib (10 mg per day, on days 1‒14; 21 days per cycle) until disease progression. The primary endpoint is progression-free survival (PFS) and safety, and the secondary endpoint is overall survival (OS), objective response rate (ORR) and disease control rate (DCR).Peripheral blood was sampled pre-treatment, once every two months during treatment and after disease progression, and T790M mutation was detected in plasma ctDNA using a droplet digital PCR (ddPCR) assay. Results: Of 60 patients enrolled (August 2, 2018 to May 28, 2020). As of February 1, 2021, 37 patients (61.7%) experienced PFS events and 10 (16.7%) died. The ORR was 78.3%, and the DCR was100%.Median PFS was 13.0 months (95%CI,10.7-15.3).The 5 most common treatment-related adverse events included rash (63.3%), fatigue (55.0%), hypertension (48.3%), diarrhea (33.3%) and hand-foot syndrome (30.0%), and grade 3 adverse events included hypertension (5.0%), rash (1.67%), hypertriglyceridemia (1.67%), vomiting (1.67%) and elevated ALT (1.67%); no grade 4 adverse events or drug-related deaths were observed. Peripheral blood samples were collected from 36 patients pre-treatment, and 30.6% were identified with low-frequency de novo T790M mutations, with the mutation-allele frequency (MAF) ranging from 0.01% to 0.28%. Conclusions: The combination of the first-generation EGFR-TKIs and anlotinib shows impressive ORR and DCR, and acceptable toxicity in treatment-naïve advanced NSCLC patients with activating EGFR mutations, and we observed a high proportion of patients harboring de novo EGFR T790M mutations in this study. Clinical trial information: NCT03720873.

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