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Relevant Articles About Research and Clinical Trials in Lung Cancer

RELATED :SCLC (Small Cell Lung Cancer):NSCLC (Non-Small Cell Lung Cancer)

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NSCLC (Non-Small Cell Lung Cancer)Biological: BNT116Biological: CemiplimabCarboplatinDocetaxelPaclitaxelRecruitingGermanyHungaryPolandSpainTurkeyUnited States 0NCT05142189Phase 1LuCa-MERIT-1
Clinical Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced Non-small Cell Lung Cancer

Clinical Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced Non-small Cell Lung Cancer

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CT Radiomics for Lung Cancer: Predicting Ki-67 Expression

KEY TAKEAWAYS

  • The study aimed to assess radiomics’ accuracy in predicting Ki-67 expression in lung cancer via systematic review and meta-analysis.
  • CT radiomics showed potential for predicting Ki-67 in lung cancer, urging enhanced accuracy research for less invasive diagnostic integration.

Radiomics, a burgeoning discipline, offers a hopeful pathway for precise prognostication of biomarkers across various solid cancers. Lung cancer persists as a prominent worldwide health concern, significantly impacting cancer fatality rates. Precise evaluation of Ki-67, a marker indicative of cellular proliferation, holds paramount importance in gauging tumor aggressiveness and treatment efficacy, notably in non-small cell lung cancer (NSCLC).

Xinmin Luo and the team aimed to identify radiomics studies predicting Ki-67 expression in lung cancer, while assessing their quality through QUADAS-2 and RQS tools. 

The study employed systematic review and meta-analysis methodologies, adhering to PRISMA-DTA guidelines. Two authors independently conducted literature searches until September 23, 2023, across PubMed, Embase, and Web of Science databases. The objective was to identify radiomics studies predicting Ki-67 expression in lung cancer. Quality assessment utilized both QUADAS-2 and RQS tools. Statistical analysis, conducted with STATA 14.2, including evaluation of sensitivity, specificity, heterogeneity, and diagnostic values.

About 10  retrospective studies revealed promising diagnostic performance of computed tomography (CT) scan-based radiomics in predicting Ki-67 expression in lung cancer. In the training cohorts, pooled sensitivity, specificity, and area under the curve (AUC) were 0.78, 0.81, and 0.85, respectively. In validation cohorts, these values were 0.78, 0.70, and 0.81. Quality assessment using QUADAS-2 and RQS indicated generally acceptable study quality. Heterogeneity in training cohorts, attributed to factors such as contrast-enhanced CT scans and specific Ki-67 thresholds, was noted. Notably, publication bias was detected in the training cohort, suggesting a tendency for positive results to be published over non-significant or negative results. Hence, there’s an encouragement for journals to publish negative findings also.

The study found that CT-based radiomics showed potential for predicting Ki-67 expression in lung cancer. While the findings indicate promise for clinical application, further research should focus on improving diagnostic precision. This may lead to the integration of radiomics approaches as a less invasive option compared to current methods such as biopsy and surgery for assessing Ki-67 expression. The funding for this study was provided by the Scientific Research Project of Sichuan Provincial Primary Health Development Research Center (No. SWFZ22-C-65).

Source: https://pubmed.ncbi.nlm.nih.gov/38384802/ 

Luo X, Zheng R, Zhang J, et al. (2024) ‘’CT-based radiomics for predicting Ki-67 expression in lung cancer: a systematic review and meta-analysis.’’ https://doi.org/10.3389/fonc.2024.1329801.

ML Predicts Immunotherapy Efficacy in SCLC

KEY TAKEAWAYS

  • The study aimed to create a predictive biomarker for immunotherapy efficacy via ML analysis of the TIME.
  • Spatial analysis of the TIME using ML predicted immunotherapy efficacy in SCLC patients, affirming its role as a biomarker.

The tumor immune microenvironment (TIME) holds promise as an immunotherapy biomarker in small-cell lung cancer (SCLC), but its assessment presents significant challenges.

Ryota Shibak and the team aimed to devise a predictive biomarker for immunotherapy effectiveness by employing machine learning (ML) to analyze the TIME. 

The biomarker analysis was conducted in extensive-stage SCLC patients undergoing chemoimmunotherapy as first-line treatment. The model was trained to forecast 1-year progression-free survival (PFS) using pathological images (H&E, PD-L1) and double immunohistochemical assay (CD8, FoxP3) alongside patient data. The primary outcome was ML models’ mean area under the curve (AUC) in predicting 1-year PFS.

The study analyzed 100,544 patches of pathological images from 78 patients. The mean AUC values for patient information, pathological images, and combined models were 0.789 (range 0.571-0.982), 0.782 (range 0.750-0.911), and 0.868 (range 0.786-0.929), respectively. Patients in the high efficacy group had longer PFS compared to the low efficacy group in all three models (patient information model: HR 0.468, 95% CI [0.287 to 0.762]; pathological image model: HR 0.334, 95% CI [0.117 to 0.628]; combined model: HR 0.353, 95% CI [0.195 to 0.637]). 

The ML analysis of the TIME showed superior accuracy compared to human count evaluations (AUC of human count: CD8-positive lymphocyte: 0.681, FoxP3-positive lymphocytes: 0.626, PD-L1 score: 0.567). 

The results showed that ML-based spatial analysis of the TIME accurately forecasted immunotherapy efficacy in SCLC patients, affirming its utility as an immunotherapy biomarker. Research was funded by Chugai Pharmaceutical.

Source: https://pubmed.ncbi.nlm.nih.gov/38360040/

Shibaki R, Fujimoto D, Nozawa T, et al. (2024) ‘’Machine learning analysis of pathological images to predict 1-year progression-free survival of immunotherapy in patients with small-cell lung cancer .’’ DOI: 10.1136/jitc-2023-007987

TP53 and STK11 Co-mutation in NSCLC

KEY TAKEAWAYS

  • The study aimed to investigate the impact of TP53 co-mutations on the TIME and clinical responses to ICIs in a subset of STK11mut NSCLC.
  • Researchers noticed that STK11mut NSCLC subgroup with TP53 co-mutation can inform strategic patient selection for innovative ICIs-based combination therapies.

Non-small-cell lung cancer (NSCLC) with STK11mut exhibits suboptimal responses to immune checkpoint inhibitors (ICIs). Utilizing multiomics, Abdul Rafeh Naqash and his team aimed to investigate a distinct subset of STK11mut NSCLC characterized by an enriched inflamed tumor immune microenvironment (TIME) and concurrent TP53 comutations, offering insights into refining patient selection for effective ICI-based strategies.

Researchers performed an inclusive analysis of (N = 16,896) NSCLC tumors through next-generation sequencing (DNA-Seq/592 genes), with a subset of (n = 5,034) tumors undergoing gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11mut NSCLC was derived from a pan-immune analysis. Tumor immune cell content was determined using the microenvironment cell population (MCP) counter on transcriptome profiles. Progression-free survival (PFS) modeling utilized ICI data from POPLAR/OAK (n = 34) and Rizvi et al study (n = 49), while a separate ICI-treated cohort from Dana-Farber Cancer Institute (DFCI, n = 53) assessed time to treatment failure (TTF) and tumor RECIST response for STK11mutTP53mut versus STK11mutTP53wt NSCLC.

About 12.6% of NSCLC tumors exhibited STK11mut, with tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high proportions at 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of STK11mut (n = 463) tumors identified a STING-high cluster, notably enriched in TP53mut NSCLC (P < .01). Compared to STK11mutTP53wt, STK11mutTP53mut tumors displayed higher CD8+T cells and natural killer cells (P < .01), elevated TMB (P < .001), and increased neoantigen load (P < .001). These tumors exhibited enhanced expression of MYC and HIF-1A (P < .01), along with higher expression of glycolysis/glutamine metabolism genes (P < .01). Meta-analysis of OAK/POPLAR and Rizvi et al’s data suggested a trend toward improved PFS in STK11mutTP53mut patients. In the DFCI cohort, compared to STK11mutTP53wt, STK11mutTP53mut tumors demonstrated higher objective response rates (42.9% v 16.7%; P = .04) and longer TTF (14.5 vs. 4.5 months, P adj = .054) with ICIs.

The study concluded that STK11mut NSCLC with TP53 co-mutation represents a distinctive subgroup characterized by an immunologically active TIME and metabolic reprogramming. These unique properties suggest the potential for strategic exploitation in guiding patient selection for innovative ICI-based combination approaches.

The study is sponsored by Novartis (Inst)

Source: https://pubmed.ncbi.nlm.nih.gov/38330261/

Naqash AR, Floudas CS, Aber E,et al. (2024). “Influence of TP53 Comutation on the Tumor Immune Microenvironment and Clinical Outcomes With Immune Checkpoint Inhibitors in STK11-Mutant Non-Small-Cell Lung Cancer.” JCO Precis Oncol. 2024 Feb;8:e2300371. doi: 10.1200/PO.23.00371. PMID: 38330261; PMCID: PMC10860998.

Ningetinib + Gefitinib Feasible for EGFR-mutant NSCLC

Ningetinib + Gefitinib Feasible for EGFR-mutant NSCLC

KEY TAKEAWAYS

  • The study aimed to assess the effectiveness and safety of ningetinib + gefitinib in EGFR-mutant NSCLC patients and determine if MET/AXL levels influence response.
  • The primary endpoints were tolerability and ORR.
  • The results demonstrated that targeting MET, AXL, and EGFR together shows promise for a specific group of EGFR-mutant NSCLC patients.

Dysregulations of MET and AXL contribute to acquired resistance to EGFR-TKIs in non-small cell lung cancer (NSCLC). However, there is a lack of consensus regarding the ideal definition of MET/AXL dysregulations in EGFR-mutant NSCLC.

Shen Zhao and the team spearheaded the study that aimed to assess the efficacy and tolerability of ningetinib, a MET/AXL inhibitor, in combination with gefitinib for EGFR-mutant NSCLC. Additionally, they aimed to evaluate the clinical significance of MET/AXL dysregulations using various definitions.

The study employed dose-escalation and dose expansion, participants were administered ningetinib at doses of 30 mg, 40 mg, or 60 mg along with gefitinib at 250 mg once daily. The primary endpoints were evaluating tolerability during dose escalation and assessing the objective response rate (ORR) during dose expansion. MET/AXL status was determined through fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). 

Among the 108 enrolled patients, the prevalence of MET focal amplification, MET polysomy, MET overexpression, AXL amplification, and AXL overexpression stands at 18.1%, 5.6%, 55.8%, 8.1%, and 45.3%, respectively. 6.8% of patients exhibit concurrent MET amplification and AXL overexpression. Notably, tumors with MET amplification showcase an ORR of 30.8%, while those with MET polysomy register a 0% ORR. The ORR for tumors with MET overexpression, AXL amplification, and AXL overexpression is 24.1%, 20%, and 27.6%, respectively.

For patients with concurrent MET amplification and AXL overexpression, the combination of ningetinib plus gefitinib demonstrates an ORR of 80%, a disease control rate (DCR) of 100%, and a median progression-free survival (PFS) of 4.7 months. Moreover, higher MET copy numbers and elevated AXL expression correlate with an increased likelihood of response. Biomarker analyses revealed that MET focal amplification and overexpression synergistically predict clinical benefit from MET inhibition. Conversely, AXL dysregulations, when defined by an arbitrary threshold, may attenuate the efficacy of AXL blockade.

This study illustrated the viability of employing a combined blockade targeting MET, AXL, and EGFR as a viable strategy for a specific subset of EGFR-mutant NSCLC.  

Source: https://www.lungcancerjournal.info/article/S0169-5002(24)00001-1/abstract#%20 

Zhao S, Ma Y, Liu L, et al. (2024) ‘’Ningetinib plus gefitinib in EGFR-mutant non-small-cell lung cancer with MET and AXL dysregulations: A phase 1b clinical trial and biomarker analysis.’’ https://doi.org/10.1016/j.lungcan.2024.107468.

Pembro Monotherapy: Safety Overview in Cancer

KEY TAKEAWAYS

  • The study aimed to investigate the expanded safety profile of pembro, beyond its labeled indications.
  • Researchers noticed a consistent safety profile of pembro across various indications in this pooled analysis of 31 clinical trials.

Pembrolizumab (pembro), known for its manageable safety in melanoma and non-small cell lung cancer trials (2799 patients (pts), underwent a comprehensive safety assessment. Julie R. Brahmer and her team aimed to evaluate the safety of pembro in a broader population of pts from 31 advanced cancer clinical trials across 19 cancer types.

Researchers performed an inclusive safety analysis on pts administered pembro, considering various dosing regimens (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). The evaluation encompassed adverse events (AEs), immune-mediated AEs, and infusion reactions in pts who received at least one dose of the medication.

About 8937 pts from 31 pembro monotherapy trials were included in the safety analysis, with a median of seven administrations (range: 1-59) and a median treatment duration of 4.1 months (range: 0.03-40.1). AEs occurred in 96.6% of pts, with Grade 3-5 AEs in 50.6%. Pembro discontinuation due to AEs occurred in 12.7%, resulting in death in 5.9%. Immune-mediated AEs and infusion reactions were observed in 23.7% pts (4.6% experienced multiple immune-mediated AEs/infusion reactions) leading to pembro discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3%, with serious cases in 6.0% of pts. The median time to onset of immune-mediated AEs was 85 days (range: 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% with lower steroid doses.

The study concluded that pembro demonstrates a consistently favorable safety profile across diverse indications based on the comprehensive analysis of 31 clinical trials.

The study is sponsored by Merck Sharp & Dohme LLC  and  was also supported by the National Cancer Institute, USA      

Source: https://pubmed.ncbi.nlm.nih.gov/38295556/

Brahmer JR, Long GV, Hamid O,  et al. (2024). “Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients.” Eur J Cancer. 2024 Mar;199:113530. doi: 10.1016/j.ejca.2024.113530. Epub 2024 Jan 11. PMID: 38295556.

Zeno Shows Promise in NRG1+ NSCLC: ENRGy Study

KEY TAKEAWAYS

  • The eNRGy phase 2 trial aimed to investigate the efficacy of Zeno in NRG1 fusion-positive NSCLC pts
  • The primary endpoint was to determine ORR, and the secondary endpoints were to determine DOR and safety.
  • Researchers noticed robust and durable efficacy of Zeno in advanced NRG1+ NSCLC pts.

NRG1 fusions are rare oncogenic drivers in non-small cell lung cancer (NSCLC) and various solid tumors, initiating HER2/HER3 heterodimerization and oncogenic transformation. The bispecific antibody Zenocutuzumab (Zeno) (MCLA-128; Zeno) targets HER3-mediated NRG1 signaling in NRG1+ cancers. Currently under evaluation in the pivotal phase 2 eNRGy study and Early Access Program (EAP), Zeno holds potential as a therapeutic intervention.

Dong-Wan Kim and his team aimed to assess the updated data on Zeno in advanced NRG1+ NSCLC.

Researchers conducted an inclusive analysis involving patients (pts) with advanced NRG1+ NSCLC identified through NGS, irrespective of prior standard therapy candidacy. Inclusion criteria comprised age ≥ 18 years, ECOG PS ≤ 2, and measurable or evaluable disease according to (RECIST v1.1). Zeno (750 mg IV Q2W) was administered until disease progression or unacceptable toxicity. Tumor imaging occurred Q8W, with the primary endpoint being investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints encompassed duration of response (DOR) and safety.

About 85 pts with NRG1+ NSCLC (78 eNRGy/7 EAP) were enrolled by February 01, 2023. The efficacy analysis included 65 pts who received ≥ 1 dose of Zeno and were enrolled by August 01, 2022, ensuring ≥ 6 months of follow-up and meeting primary efficacy criteria. Median age was 64 years (range 32–86), 65% female, and 29%/63%/5% with ECOG PS 0/1/2 (missing 2 pts). Predominantly Asian (52%) or White (37%), 77% had visceral metastases, 98% adenocarcinoma histology, and 1 pt had non-measurable disease. CD74 (52%) and SLC3A2 (23%) were common fusion partners.

Patients received a median of 2 prior systemic therapies (range 0-6), 78% with platinum-based chemotherapy; 12% were treatment-naïve. In 64 pts with measurable disease, confirmed ORR was 34% (22/64; 95% CI 23-47). 78% (50/64) had target lesion reduction. Median DOR was 12.9 months with ongoing responses in 11/22 (50%) pts. Kaplan-Meier estimate of the 6-month DOR rate was 79%. Among 85 pts treated, Grade ≥ 3 individual adverse events(AEs) occurred in < 4% of pts. No patient discontinued Zeno for a treatment-related AE.

The study concluded that Zeno demonstrates robust and enduring efficacy in advanced NRG1+ NSCLC, accompanied by a well-tolerated safety profile, underscoring its potential as a promising therapeutic option for this patient population.

The study is sponsored by Merus N.V.

Source: https://cslide.ctimeetingtech.com/asia2023/attendee/confcal/show/session/78

Clinical Trial: https://clinicaltrials.gov/study/NCT02912949

Kim D W, Goto K, Schram A, et al. (2023). “Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC).” Presented at ESMO ASIA 2023 (Abstract 595P).

S+T With ET in 1L Advanced SCLC

KEY TAKEAWAYS

  • The phase I/II trial aimed to present updated results on long-term efficacy and safety of S+T and EP regimen for SCLC patients.
  • The primary endpoints were RP2D of S and PFS.
  • The results showed promising efficacy and tolerable toxicity in 1L advanced SCLC, potentially offering a novel therapeutic option, particularly for patients without liver or bone metastases.

In small cell lung cancer (SCLC), Surufatinib (S), a novel small-molecule inhibitor targeting VEGFR1-3, FGFR1, and CSF-1R, along with toripalimab (T), an anti-PD-1 antibody, has shown promising efficacy in phase 2 trials for patients who have failed first-line chemotherapy. Building upon previous findings, preliminary results from NCT04996771 indicated encouraging efficacy of S plus T in combination with etoposide plus cisplatin (EP) as a first-line regimen for SCLC.

Here, Wen Feng Fang and the team presented an updated result from the study showcasing the encouraging efficacy of S plus T in combination with EP as a first-line regimen for SCLC. 

The study followed  a 3+3 dose-escalation phase (Phase Ib) and a dose expansion phase (Phase II), enrolled patients aged ≥18 years with histologically confirmed advanced SCLC and an ECOG PS of 0-1, possessing at least one measurable lesion. Eligible patients with treated, stable, asymptomatic brain metastases were included. In Phase Ib, Surufatinib (S) was administered orally at doses ranging from 150mg to 250mg once daily every 3 weeks (Q3W), in combination with a fixed dose of T (200mg intravenously on day 1, Q3W) and EP every 3 weeks (Q3W). Maintenance therapy with S plus T was administered after 4 cycles.

The primary endpoints were the recommended phase 2 dose (RP2D) of S and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.

About 39 patients were enrolled in the study. The median age was 64 years, with 82.1% being male, and 59.0% having an ECOG PS of 1. Additionally, 89.7% of patients were categorized as TNM stage IV. Liver, bone, and brain metastases were present in 33.3%, 30.8%, and 12.8% of patients, respectively. The recommended phase 2 dose (RP2D) of S was determined to be 200mg orally once daily every 3 weeks (Q3W). Among patients with at least one post-baseline tumor assessment (n=35), the median PFS was 6.0 months (95% CI 4.7, 7.3). 

Patients without liver metastases had significantly longer PFS compared to those with liver metastases (5.7 months vs 8.4 months, p=0.0169), as did patients without bone metastases compared to those with bone metastases (5.7 months vs 8.4 months, P=0.0198). The ORR was 97.1%, and the DCR was 100%. The most common (≥10%) grade ≥3 treatment-emergent adverse events (TEAEs) were neutrophil count decreased (31.6%), white blood cell count decreased (23.7%), and platelet count decreased (10.5%).

The combination of S plus T with ET demonstrated promising efficacy and manageable toxicity in first-line treatment for advanced SCLC, particularly benefiting patients without liver or bone metastases, suggesting a potential novel therapeutic approach. Research was funded by Sun Yat-sen University.

Source: https://cslide.ctimeetingtech.com/immuno23hybrid/attendee/confcal/show/session/34

Clinical Trial: https://clinicaltrials.gov/study/NCT04996771

Fang WF et al. (2023) ‘‘Surufatinib plus toripalimab combined with etoposide (E) and cisplatin (P) in patients (pts) with advanced naive small cell lung cancer (SCLC) -Updated results of a phase ?b/? Trial.’’ Presented at ESMO IO 2023 (124P).

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