Adjuvant Pembrolizumab in Patients with Stage IIIA/N2 Non-Small Cell Lung Cancer Completely Resected after Neoadjuvant Concurrent Chemoradiation: A Prospective, Open-Label, Single-Arm, Phase 2 Trial.

Purpose: Optimal treatment for stage IIIA/N2 non-small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT). Materials and Methods: In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to two years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39+PD-1+CD8+ T cells using fold changes in the percentage of proliferating Ki-67+ cells from days 1 to 7 of cycle 1 (Ki-67D7/D1). Results: Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), 9 (26%), and 4 (12%) had a tumor proportion score of <1%, 1-50%, and ≥50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a five-year DFS rate of 29%. The OS rate was 86% at two years and 76% at five years. Patients with tumor recurrence within six months had a significantly lower Ki-67D7/D1 among CD39+PD-1+CD8+ T cells than those without (p=0.036). No new safety signals were identified. Conclusion: Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.

Phase II study to determine the anti-tumor activity and safety of simlukafusp alfa (FAP-IL2v) combined with atezolizumab in esophageal cancer.

PURPOSE: Reported here are results from the esophageal squamous cell carcinoma (SCC) cohort of a Phase II, non-comparative, basket study, evaluating the anti-tumor activity and safety of FAP-IL2v plus atezolizumab in patients with advanced/metastatic solid tumors (NCT03386721). EXPERIMENTAL DESIGN: Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1; measurable metastatic, persistent, or recurrent esophageal SCC; progression on ≥1 prior therapy; and were checkpoint inhibitor naive. Patients received FAP-IL2v 10 mg plus atezolizumab 1200 mg intravenously every 3 weeks, or FAP-IL2v weekly for 4 weeks, then every 2 weeks, plus atezolizumab 840 mg intravenously every 2 weeks. Primary endpoint was investigator-assessed objective response rate (ORR). RESULTS: In the response-evaluable population (N=34), best confirmed ORR was 20.6% (95% confidence interval [CI]: 10.4-36.8) with a complete response (CR) seen in one patient and partial responses (PR) in six patients. Disease control rate was 44.1% (CR=2.9%; PR=17.6%; stable disease [SD]=23.5%) and median duration of response was 10.1 months (95% CI: 5.6-26.7). Median progression-free survival was 1.9 months (95% CI: 1.8-3.7). Analysis of response by PD-L1 expression (Ventana SP263) resulted in an ORR of 26.7 % for patients with PD-L1-positive tumors (tumor area positivity [TAP] cut-off ≥1%; n=15) and 7.1% for patients with PD-L1-negative tumors (TAP cut-off <1%; n=14). Overall, the treatment combination was tolerable and adverse events were consistent with the known safety profiles of each drug. CONCLUSIONS: FAP-IL2v plus atezolizumab demonstrated clinical activity and was tolerable in patients with previously treated esophageal SCC.

Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION.

BACKGROUND: Tepotinib, a MET inhibitor approved for the treatment of MET exon 14 (METex14) skipping NSCLC, demonstrated durable clinical activity in VISION (Cohort A + C; N = 313): objective response rate (ORR) 51.4% (95% CI: 45.8, 57.1); median duration of response (mDOR) 18.0 months (95% CI: 12.4, 46.4). We report outcomes in Asian patients from VISION (Cohort A + C) (cut-off: November 20, 2022). METHODS: Patients with advanced METex14 skipping NSCLC, detected by liquid or tissue biopsy, received tepotinib 500 mg (450 mg active moiety) once daily. PRIMARY ENDPOINT: objective response (RECIST 1.1) by independent review. Secondary endpoints included: DOR, progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: Across treatment lines in 106 Asian patients (39.6% female, 43.4% smoking history, 79.2% adenocarcinoma, 47.2% treatment-naive), ORR was 56.6% (95% CI: 46.6, 66.2), mDOR 18.5 months (10.4, ne), mPFS 13.8 months (10.8, 22.0), and mOS 25.5 months (19.3, 36.4). Consistent efficacy observed, regardless of baseline characteristics. HRQoL remained stable during treatment. Treatment-related adverse events (TRAEs) occurred in 95.3% of patients (39.6% Grade ≥3). Most common TRAEs: peripheral edema (62.3%), creatinine increase (38.7%). CONCLUSIONS: Tepotinib demonstrated robust and durable efficacy, with a manageable safety profile, in Asian patients with METex14 skipping NSCLC. CLINICAL TRIAL REGISTRATION: NCT02864992.

Analysis of Response and Progression Patterns of Tyrosine Kinase Inhibitors in Recurrent or Metastatic Adenoid Cystic Carcinoma: A Post Hoc Analysis of Two KCSG Phase II Trials.

Purpose: In this study, we evaluated 66 patients diagnosed with adenoid cystic carcinoma (ACC) enrolled in two Korean Cancer Study Group trials to investigate the response and progression patterns in recurrent and/or metastatic ACC treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). Materials and Methods: We evaluated 66 patients diagnosed with ACC who were enrolled in the Korean Cancer Study Group trials. The tumor measurements, clinical data, treatment outcomes, and progression patterns of therapy were analyzed. Results: In the 66 patients (53 receiving axitinib and 13 receiving nintedanib), the disease control rate was 61%, and 3 patients achieved partial response. The median follow-up, median progression-free survival (PFS), overall survival, and 6-month PFS rate were 27.6, 12.4, and 18.1 months and 62.1%, respectively. Among 42 patients who experienced progression, 27 (64.3%) showed target lesion progression. Bone metastasis was an independent poor prognostic factor. Conclusion: Overall, most patients demonstrated stable disease with prolonged PFS; however, prominent target lesion progression occurred in some patients. Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate.

Survival benefit in EGFR-wild and ALK negative NSCLC patients who participate in clinical trials compared to standard-of-care: Propensity-matched analysis.

OBJECTIVES: Advanced non-small cell lung cancer patients harboring EGFR mutation or ALK fusion have achieved significant survival benefit with targeted agents. In contrast, EGFR-wild type and ALK negative lung adenocarcinoma still have poor survival outcome. This study assessed the impact of participating in clinical trials on clinical outcomes in patients with EGFR-wild-type and ALK-negative lung adenocarcinoma. MATERIALS AND METHODS: This study included patients with advanced EGFR-wild-type and ALK-negative lung adenocarcinoma who received systemic treatment between March 2017 and June 2022. We compared clinical outcomes between patients who participated in clinical trials and those treated with standard-of-care (SOC) using propensity score matching (PSM). RESULTS: Overall, 1,686 patients with EGFR-wild-type and ALK-negative advanced lung adenocarcinoma were included in the final analysis. Of these, 1,380 (81.9 %) received SOC only and 306 (18.1 %) patients were enrolled in at least one clinical trial during their cancer journey. After PSM (1:1), 612 patients were matched to the SOC (n = 306) and clinical trial (n = 306) groups. Among those who participated in clinical trials, 27.8 % and 72.2 % were included in clinical trials involving targeted therapy and immunotherapy respectively. In the clinical trial group, more patients received targeted therapy (31.7 % vs. 5.5 %, p < 0.001) and immunotherapy (88.6 % vs. 62.8 %, p < 0.001) compared to the SOC group. The median overall survival was 17.1 months (95 % confidence interval [CI], 13.2-21.4) in the SOC group and 27.3 months (95 % CI, 22.1-32.4) in the clinical trial group (hazard ratio = 0.71, [95 % CI, 0.58-0.88, P = 0.002]). CONCLUSIONS: This study demonstrated that participating in clinical trials resulted in a survival benefit that reduced the risk of death by 29.6% compared to receiving SOC in EGFR-wild-type and ALK-negative lung adenocarcinoma.

Edoxaban for the treatment of hypercoagulability and cerebral thromboembolism associated with cancer: A randomized clinical trial of biomarker targets.

BACKGROUND: This study aimed compare efficacy of edoxaban and enoxaparin upon biomarkers of hypercoagulability in patients with cancer-related embolic stroke of undetermined source (ESUS). METHODS: In this open-label, randomized, pilot trial, patients with cancer-related ESUS within 30 days of diagnosis were randomly assigned (1:1) to receive edoxaban (60 mg once daily) or enoxaparin (1 mg/kg twice daily) for 90 days. The primary endpoint was interval change of serum D-dimer level between days 0 and 7. The secondary endpoints were microembolic signals detected by transcranial Doppler at 7 and 90 days, the modified Rankin scale score, and stroke recurrence during 90 days. Safety outcomes included major bleeding and all-cause death at 90 days. RESULTS: Of 303 patients with ischemic stroke and cancer, 40 fully met enrollment criteria and were randomized. Baseline D-dimer levels were numerically higher in the edoxaban group (22.9 ± 15.9 µg/mL vs 16.9 ± 16.9 µg/mL). D-dimer level change (%) between days 0 and 7 was similar in the two groups (53.2 ± 25.7 vs 52.2 ± 52.0; P = 0.11). Microembolic signals were detected in 41.1% and 43.8% at baseline, 41.2% and 42.9% at day 7, and 25.0% and 28.6% at day 90 in the edoxaban and enoxaparin groups, respectively. Non-significantly higher major bleeding (35.0% vs 10.0%, P = 0.06) and 90-day mortality (40.0% vs 25.0%, P = 0.31) were noted in the edoxaban group. CONCLUSION: Edoxaban and enoxaparin were comparable with respect to the biomarkers of hypercoagulability and cerebral thromboembolism. Larger trials are warranted to compare effects of edoxaban and enoxaparin upon recurrent stroke and major bleeding in patients with cancer-related ESUS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03570281 (https://clinicaltrials.gov/ct2/show/NCT03570281).

Durvalumab in combination with chemoradiotherapy for patients with unresectable stage III non-small-cell lung cancer: Results from the phase 1 CLOVER study.

INTRODUCTION: For patients with unresectable, stage III non-small-cell lung cancer (NSCLC), current standard of care is concurrent chemoradiotherapy (cCRT) followed by consolidation durvalumab. However, earlier initiation of durvalumab simultaneously with cCRT may increase antitumor activity relative to initiation after cCRT. The phase 1 CLOVER study (NCT03509012) evaluated durvalumab combined with cCRT in patients with advanced solid tumors; we report findings from the NSCLC cohort. METHODS: CLOVER comprised a dose-limiting toxicity (DLT) assessment part, followed by an expansion part. In the NSCLC cohort, patients with previously untreated, unresectable, stage III NSCLC were enrolled in three treatment arms: durvalumab every 4 weeks (Q4W) + cisplatin + etoposide + radiotherapy (Arm 1); durvalumab Q4W + carboplatin + paclitaxel + radiotherapy (Arm 2); or durvalumab Q4W + carboplatin or cisplatin + pemetrexed + radiotherapy (non-squamous histology only; Arm 3). Patients received durvalumab until disease progression or unacceptable toxicity. The primary endpoint was safety and tolerability. RESULTS: Sixty-four patients were enrolled: 21, 22, and 21 in Arms 1, 2, and 3, respectively. One patient in Arm 1 had DLT (grade 3 aspartate aminotransferase increase and grade 4 alanine aminotransferase increase); no DLTs were observed in Arms 2 or 3. Grade 3/4 adverse events occurred in 76.6 % of patients overall; the most common were neutropenia (51.6 %), leukopenia (20.3 %), and anemia (17.2 %). In a post-hoc analysis, 7.8 % of patients had grade 3 pneumonitis/radiation pneumonitis (grouped term) events. Overall, the objective response rate was 60.9 % (95 % confidence interval [CI], 47.9-72.9); median duration of response was 15.8 months (95 % CI, 9.0-not estimable [NE]). Median progression-free survival was 13.4 months (95 % CI, 8.8-20.1) and median overall survival was not reached (95 % CI, 21.9-NE). CONCLUSION: Durvalumab in combination with cCRT was well tolerated, with a manageable safety profile and showed encouraging antitumor activity in patients with unresectable, stage III NSCLC.

Predicting disease recurrence in limited disease small cell lung cancer using cell-free DNA-based mutation and fragmentome analyses.

Background: Limited disease (LD) small cell lung cancer (SCLC) treated with definitive concurrent chemoradiotherapy (CCRT) potentially experience disease recurrence. We investigated the feasibility of circulating-tumor DNA (ctDNA)-based genomic and fragmentome analyses to assess the risk of recurrence. Methods: Targeted sequencing was conducted using pre-treatment and on-treatment blood samples from definitive CCRT-treated patients with LD-SCLC (n=50). Based on 12-month recurrence-free survival (RFS), patients were categorized into persistent-response (PeR, n=29) and non-PeR (n=21) groups. Fragmentome analysis was conducted using ctDNA fragments of different lengths: P1 (100-155 bp) and P2 (160-180 bp). Results: Patients with TP53 (n=15) and RB1 (n=11) mutation in on-treatment samples demonstrated significantly shorter RFS than patients with wild-type (WT) (P=0.05, P=0.0014, respectively). Fragmentome analysis of all available on-treatment samples (n=26) revealed that the non-PeR group (n=10) had a significantly higher P1 range (P=0.003) and lower P2 range (P=0.002). The areas under the curves for P1, P2, and the fragmentation ratio (P1/P2) in distinguishing the PeR and non-PeR were 0.850, 0.725, and 0.900, respectively. Using optimal cut-off, longer RFSs were found with the low-fragmentation-ratio group than with the high-fragmentation-ratio group (not reached vs. 7.6 months, P=0.002). Patients with both WT RB1 and a low-fragmentation-ratio (n=10) showed better outcomes than patients with both mutated RB1 and a high-fragmentation-ratio (n=10; hazard ratio, 7.55; 95% confidence interval: 2.14-26.6; P=0.002). Conclusions: RB1 mutations and high fragmentation ratios correlated with early disease recurrence. Analyzing ctDNA could help in predicting early treatment failure and making clinical decisions for high-risk patients.

Comprehensive analysis of transcription factor-based molecular subtypes and their correlation to clinical outcomes in small-cell lung cancer.

BACKGROUND: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes. METHODS: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype. FINDINGS: IHC-based molecular subtyping, comprised of 90 limited-disease (35.7%) and 162 extensive-disease (64.3%), revealed a high incidence of ASCL1 subtype (IHC-A, 56.3%) followed by ASCL1/NEUROD1 co-expressed (IHC-AN, 17.9%), NEUROD1 (IHC-N, 12.3%), POU2F3 (IHC-P, 9.1%), triple-negative (IHC-TN, 4.4%) subtypes. IHC-based subtype showing high concordance with WTS-based subtyping and non-negative matrix factorization (NMF) clusterization method. IHC-AN subtype resembled IHC-A (rather than IHC-N) in terms of both gene expression profiles and clinical outcomes. Favourable median overall survival was observed in IHC-A (15.2 months) compared to IHC-N (8.0 months, adjusted HR 2.3, 95% CI 1.4-3.9, p = 0.002) and IHC-P (8.3 months, adjusted HR 1.7, 95% CI 0.9-3.2, p = 0.076). Inflamed tumours made up 25% of cases (including 53% of IHC-P, 26% of IHC-A, 17% of IHC-AN, but only 11% of IHC-N). Consistent with recent findings, inflamed tumours were more likely to benefit from first-line immunotherapy treatment than non-inflamed phenotype (p = 0.002). INTERPRETATION: This study provides fundamental data, including the incidence and basic demographics of molecular subtypes of SCLC using both IHC and WTS from a comparably large, real-world Asian/non-Western patient cohort, showing high concordance with the previous NMF-based SCLC model. In addition, we revealed underlying biological pathway activities, immunogenicity, and treatment outcomes based on molecular subtype, possibly related to the difference in clinical outcomes, including immunotherapy response. FUNDING: This work was supported by AstraZeneca, Future Medicine 2030 Project of the Samsung Medical Center [grant number SMX1240011], the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number 2020R1C1C1010626] and the 7th AstraZeneca-KHIDI (Korea Health Industry Development Institute) oncology research program.

Outcomes in biomarker-selected subgroups from the KESTREL study of durvalumab and tremelimumab in recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Selective biomarkers may improve outcomes in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitor therapy. We investigated three independent biomarkers for association with efficacy in the randomized, phase III KESTREL study (NCT02551159) of first-line durvalumab monotherapy or durvalumab plus tremelimumab versus the EXTREME regimen: programmed cell death ligand-1 (PD-L1) immunohistochemistry, blood tumor mutational burden (bTMB) via circulating tumor DNA, and neutrophil-to-lymphocyte ratio (NLR). METHODS: Tumor or blood samples from patients enrolled in the KESTREL study were analyzed for PD-L1, bTMB, and NLR. Associations with overall survival (OS) or objective response rates (ORRs) were evaluated based on prespecified cut-offs for PD-L1 (tumor cell [TC] ≥ 50%/immune cell ≥ 25% or TC ≥ 25%), bTMB (≥ 16 mutations [mut] per megabase [Mb]), and NLR (≤ 7). Ad hoc analyses of exploratory cut-offs were performed. RESULTS: Prespecified or exploratory cut-offs for PD-L1 did not enrich for ORR or OS for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME. In the bTMB ≥ 16 mut/Mb subgroup, OS hazard ratios (95% confidence interval) for durvalumab monotherapy and durvalumab plus tremelimumab versus EXTREME were 0.90 (0.48-1.72) and 0.69 (0.39-1.25), respectively. Complete response rates were 8.6% with durvalumab plus tremelimumab and 4.3% with EXTREME (≥ 16 mut/Mb subgroup). No improvement in OS was observed for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME at prespecified or exploratory NLR cut-offs. CONCLUSIONS: bTMB demonstrated potential utility for selecting patients with R/M HNSCC who benefited from durvalumab with or without tremelimumab versus EXTREME. Trial registration ClinicalTrials.gov identifier NCT02551159.

Combination of Dabrafenib and Trametinib in Patients with Metastatic BRAFV600E-Mutated Thyroid Cancer.

Purpose: BRAF mutations are detected in 30-80% of papillary thyroid cancer (PTC) cases. Dabrafenib and trametinib showed promising antitumor activity in patients with BRAFV600E-mutated metastatic melanoma and non-small cell lung cancer. This study aimed to evaluate the efficacy and safety of dabrafenib and trametinib in patients with metastatic BRAFV600E-mutated thyroid cancer. Materials and Methods: This was a retrospective study to evaluate the efficacy of dabrafenib and trametinib in patients with metastatic BRAFV600E-mutated PTC. The patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily at the Samsung Medical Center. This study evaluated the progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) overall survival (OS), and safety of dabrafenib and trametinib. Results: Between December 2019 and January 2022, 27 PTC patients including 8 patients with poorly differentiated or anaplastic transformation, received dabrafenib and trametinib. The median age was 73.0 years, and the median follow-up period was 19.8 months. The majority (81.5%) had undergone thyroidectomy, while 8 patients had received prior systemic treatments. ORR was 73.1%, with 19 partial responses, and DCR was 92.3%. Median PFS was 21.7 months, and median OS was 21.7 months. Treatment-related adverse events included generalized weakness (29.6%), fever (25.9%), and gastrointestinal problems (22.2%). Dose reduction due to adverse events was required in 81.5% of the patients. Conclusion: Dabrafenib and trametinib demonstrated a high ORR with promising PFS; however, most patients with BRAFV600E-mutated metastatic PTC required a dose reduction.

Lazertinib as a frontline treatment in patients with EGFR-mutated advanced non-small cell lung cancer: Long-term follow-up results from LASER201.

OBJECTIVE: This analysis of the first-line cohort of LASER201 study evaluated the efficacy and safety of lazertinib 240 mg as a frontline therapy for epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). METHODS: A total of 43 patients, with EGFR mutation-positive (Exon19Del, n = 24; L858R, n = 18; G719X, n = 1) locally advanced or metastatic NSCLC who had not previously received EGFR tyrosine kinase inhibitor (EGFR TKI) therapy, received once-daily lazertinib 240 mg. EGFR mutation status was confirmed by local or central testing. The primary endpoint was objective response rate (ORR) assessed by blinded independent central review. Secondary efficacy endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), tumor shrinkage, and overall survival (OS). RESULTS: At the primary data cut-off (DCO; January 8, 2021), the ORR was 70 % (95 % confidence interval [CI]: 56.0-83.5), DCR was 86 % (95 % CI: 75.7-96.4) and the median DoR was 23.5 (95 % CI: 12.5-not reached) months. The median PFS was 24.6 (95 % CI: 12.2-30.2) months. At the final DCO (March 30, 2023), the median OS was not estimable and the median follow-up duration for OS was 55.2 [95 % CI: 22.8-55.7] months. OS rates at 36 months and 54 months were 66 % (95 % CI: 47.5-79.3 %) and 55 % (95 % CI: 36.6-70.7 %), respectively. The most commonly reported TEAEs were rash (54 %), diarrhea (47 %), pruritus (35 %), and paresthesia (35 %). No drug-related rash or pruritus TEAEs of grade 3 or higher were reported. Diarrhea and paresthesia of grade 3 or higher were reported in 3 (7 %) and 1 (2 %) patients, respectively. CONCLUSION: This analysis demonstrated long-term clinical benefit with lazertinib 240 mg in patients with EGFR-mutated NSCLC who had not previously received EGFR TKIs. The safety profile for lazertinib was tolerable and consistent with that previously reported.

Machine learning model for circulating tumor DNA detection in chronic obstructive pulmonary disease patients with lung cancer.

Background: Patients with chronic obstructive pulmonary disease (COPD) have a high risk of developing lung cancer. Due to the high rates of complications from invasive diagnostic procedures in this population, detecting circulating tumor DNA (ctDNA) as a non-invasive method might be useful. However, clinical characteristics that are predictive of ctDNA mutation detection remain incompletely understood. This study aimed to investigate factors associated with ctDNA detection in COPD patients with lung cancer. Methods: Herein, 177 patients with COPD and lung cancer were prospectively recruited. Plasma ctDNA was genotyped using targeted deep sequencing. Comprehensive clinical variables were collected, including the emphysema index (EI), using chest computed tomography. Machine learning models were constructed to predict ctDNA detection. Results: At least one ctDNA mutation was detected in 54 (30.5%) patients. After adjustment for potential confounders, tumor stage, C-reactive protein (CRP) level, and milder emphysema were independently associated with ctDNA detection. An increase of 1% in the EI was associated with a 7% decrease in the odds of ctDNA detection (adjusted odds ratio =0.933; 95% confidence interval: 0.857-0.999; P=0.047). Machine learning models composed of multiple clinical factors predicted individuals with ctDNA mutations at high performance (AUC =0.774). Conclusions: ctDNA mutations were likely to be observed in COPD patients with lung cancer who had an advanced clinical stage, high CRP level, or milder emphysema. This was validated in machine learning models with high accuracy. Further prospective studies are required to validate the clinical utility of our findings.

A plain language summary of the PHAROS study: the combination of encorafenib and binimetinib for people with BRAF V600E-mutant metastatic non-small cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the results of a study called PHAROS. This study looked at combination treatment with encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®). This combination of medicines was studied in people with metastatic non-small-cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer. Metastatic means that the cancer has spread to other parts of the body. All people in this study had a type of NSCLC that has a change in a gene called BRAF termed a BRAF V600E mutation. A gene is a part of the DNA that has instructions for making things that your body needs to work, and the BRAF V600E mutation contributes to the growth of the lung cancer. WHAT WERE THE RESULTS?: In this study, 98 people with BRAF V600E-mutant metastatic NSCLC were treated with the combination of encorafenib and binimetinib (called encorafenib plus binimetinib in this summary). Before starting the study, 59 people had not received any treatment for their metastatic NSCLC, and 39 people had received previous anticancer treatment. At the time of this analysis, 44 (75%) out of 59 people who did not receive any treatment before taking encorafenib plus binimetinib had their tumors shrink or disappear. Eighteen (46%) out of 39 people who had received treatment before starting encorafenib plus binimetinib also had their tumors shrink or disappear. The most common side effects of encorafenib plus binimetinib were nausea, diarrhea, fatigue, and vomiting. WHAT DO THE RESULTS MEAN?: These results support the use of encorafenib plus binimetinib combination treatment as a new treatment option in people with BRAF V600E-mutant metastatic NSCLC. The side effects of encorafenib plus binimetinib in this study were similar to the side effects seen with encorafenib plus binimetinib in people with a type of skin cancer called metastatic melanoma.

STAR-121: A Phase III Randomized Study of Domvanalimab and Zimberelimab in Combination With Chemotherapy Versus Pembrolizumab With Chemotherapy in Untreated Metastatic Non-Small Cell Lung Cancer With No Actionable Gene Alterations.

INTRODUCTION: Dual inhibition with a T-cell immunoreceptor with immunoglobulin and ITIM domains plus programmed death (ligand)-1 (PD[L]-1) inhibitors, with or without chemotherapy, is an emerging therapeutic strategy in metastatic non-small cell lung cancer (mNSCLC). The STAR-121 (NCT05502237) phase III, global, randomized, open-label study will investigate first-line domvanalimab (anti-TIGIT) and zimberelimab (anti-PD-1) plus chemotherapy versus pembrolizumab plus chemotherapy in mNSCLC with no actionable gene alterations. PARTICIPANTS AND METHODS: Approximately 720 participants (≥18 years old) with untreated mNSCLC and no EGFR and ALK mutations will be randomized into 3 groups (A, B, or C) in a 4:4:1 ratio and stratified by baseline PD-L1 expression (tumor cells <50% vs. ≥50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia). Group A will receive domvanalimab 1200 mg plus zimberelimab 360 mg plus platinum-doublet chemotherapy (PT), group B will receive pembrolizumab 200 mg plus PT, and group C will receive zimberelimab 360 mg plus PT, every 3 weeks. Treatment will be administered until disease progression or intolerable toxicity. Dual primary endpoints are progression-free survival (by blinded independent central review [BICR]) and overall survival for group A versus B. Key secondary endpoints comprise overall response rate (by BICR), safety, and quality of life. Exploratory endpoints include efficacy and safety between groups A and C, pharmacokinetics, patient-reported outcomes, and biomarkers. CONCLUSION: Enrollment in the STAR-121 study commenced on October 12, 2022, and is currently ongoing with completion planned by September 2024. The study completion is expected by December 2027.

Immune checkpoint inhibitor use and the incidence of hepatitis B virus reactivation or immune-related hepatitis in non-small cell lung cancer patients with chronic hepatitis B.

BACKGROUND: The safety of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients in a real-world setting. METHODS: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (-)/hepatitis B core antibody immunoglobulin G (anti-HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune-related hepatitis, and jaundice. The secondary end points included other immune-related adverse events and efficacy. RESULTS: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune-related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune-related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons). CONCLUSIONS: In this large, real-world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.

Prognostic Value of Radiomic Analysis Using Pre- and Post-Treatment 18F-FDG-PET/CT in Patients with Laryngeal Cancer and Hypopharyngeal Cancer.

BACKGROUND: The prognostic value of conducting 18F-FDG PET/CT imaging has yielded different results in patients with laryngeal cancer and hypopharyngeal cancer, but these results are controversial, and there is a lack of dedicated studies on each type of cancer. This study aimed to evaluate whether combining radiomic analysis of pre- and post-treatment 18F-FDG PET/CT imaging features and clinical parameters has additional prognostic value in patients with laryngeal cancer and hypopharyngeal cancer. METHODS: From 2008 to 2016, data on patients diagnosed with cancer of the larynx and hypopharynx were retrospectively collected. The patients underwent pre- and post-treatment 18F-FDG PET/CT imaging. The values of ΔPre-Post PET were measured from the texture features. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select the most predictive features to formulate a Rad-score for both progression-free survival (PFS) and overall survival (OS). Kaplan-Meier curve analysis and Cox regression were employed to assess PFS and OS. Then, the concordance index (C-index) and calibration plot were used to evaluate the performance of the radiomics nomogram. RESULTS: Study data were collected for a total of 91 patients. The mean follow-up period was 71.5 mo. (8.4-147.3). The Rad-score was formulated based on the texture parameters and was significantly associated with both PFS (p = 0.024) and OS (p = 0.009). When predicting PFS, only the Rad-score demonstrated a significant association (HR 2.1509, 95% CI [1.100-4.207], p = 0.025). On the other hand, age (HR 1.116, 95% CI [1.041-1.197], p = 0.002) and Rad-score (HR 33.885, 95% CI [2.891-397.175], p = 0.005) exhibited associations with OS. The Rad-score value showed good discrimination when it was combined with clinical parameters in both PFS (C-index 0.802-0.889) and OS (C-index 0.860-0.958). The calibration plots also showed a good agreement between the observed and predicted survival probabilities. CONCLUSIONS: Combining clinical parameters with radiomics analysis of pre- and post-treatment 18F-FDG PET/CT parameters in patients with laryngeal cancer and hypopharyngeal cancer might have additional prognostic value.

Lazertinib versus Gefitinib as First-Line Treatment for EGFR-mutated Locally Advanced or Metastatic NSCLC: LASER301 Korean Subset.

PURPOSE: This subgroup analysis of the Korean subset of patients in the phase 3 LASER301 trial evaluated the efficacy and safety of lazertinib versus gefitinib as first-line therapy for epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with locally advanced or metastatic EGFRm NSCLC were randomized 1:1 to lazertinib (240 mg/day) or gefitinib (250 mg/day). The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: In total, 172 Korean patients were enrolled (lazertinib, n=87; gefitinib, n=85). Baseline characteristics were balanced between the treatment groups. One-third of patients had brain metastases (BM) at baseline. Median PFS was 20.8 months (95% confidence interval [CI], 16.7 to 26.1) for lazertinib and 9.6 months (95% CI, 8.2 to 12.3) for gefitinib (hazard ratio [HR], 0.41; 95% CI, 0.28 to 0.60). This was supported by PFS analysis based on blinded independent central review. Significant PFS benefit with lazertinib was consistently observed across predefined subgroups, including patients with BM (HR, 0.28; 95% CI, 0.15 to 0.53) and those with L858R mutations (HR, 0.36; 95% CI, 0.20 to 0.63). Lazertinib safety data were consistent with its previously reported safety profile. Common adverse events (AEs) in both groups included rash, pruritus, and diarrhoea. Numerically fewer severe AEs and severe treatment-related AEs occurred with lazertinib than gefitinib. CONCLUSION: Consistent with results for the overall LASER301 population, this analysis showed significant PFS benefit with lazertinib versus gefitinib with comparable safety in Korean patients with untreated EGFRm NSCLC, supporting lazertinib as a new potential treatment option for this patient population.

First-Line Alectinib vs. Brigatinib in Advanced Non-Small Cell Lung Cancer with ALK Rearrangement: Real-World Data.

PURPOSE: Alectinib and brigatinib are second-generation anaplastic lymphoma receptor tyrosine kinases (ALKs) that are widely used as first-line therapy for treating ALK-positive advanced non-small cell lung cancer (NSCLC). Given the lack of a head-to-head comparison of these drugs as first-line therapies, this retrospective observational study aimed to compare the real-world efficacy and safety of alectinib and brigatinib. MATERIALS AND METHODS: Patients who received alectinib or brigatinib as the first-line treatment for ALK-positive advanced NSCLC were evaluated for clinical outcomes of objective response rate (ORR), intracranial ORR, time to next treatment (TTNT), progression-free survival (PFS), overall survival (OS), and safety profiles. RESULTS: Of 208 patients who received either alectinib or brigatinib as a first-line treatment, 176 received alectinib and 32 received brigatinib. At the data cutoff point, the median follow-up duration was 16.5 months (95% confidence interval [CI], 14.7 to 18.3) in the brigatinib group and 27.5 months (95% CI, 24.6 to 30.4) in the alectinib group. The ORR was 92.5% with alectinib and 93.8% for brigatinib. The intracranial ORR rates were 92.7% (38/41) and 100% (10/10), respectively. The rate of PFS at 12 months was comparable between the alectinib group and the brigatinib groups (84.4% vs. 84.1%, p=0.64), and the median TTNT, PFS, and OS were not reached in either group. Treatment-related adverse events were usually mild, and treatment discontinuation due to adverse events was rare (alectinib 4.5% vs. brigatinib 6.25%). CONCLUSION: Alectinib and brigatinib had similar clinical benefits when used as the first-line treatment of NSCLC patients with ALK rearrangement in the real world.

A Phase II Trial of Nintedanib in Patients with Metastatic or Recurrent Head and Neck Squamous Cell Carcinoma: In-Depth Analysis of Nintedanib Arm from the KCSG HN 15-16 TRIUMPH Trial.

PURPOSE: Precision oncology approach for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) is necessary due to its dismal prognosis. We performed a genomic profile-based umbrella trial of patients with platinum-refractory HNSCC (KCSG-TRIUMPH). Here, we present an in-depth report of the the nintedanib arm (arm 3) of the current trial. MATERIALS AND METHODS: The TRIUMPH study was a multicenter, open-label, single-arm phase 2 trial, in which patients were assigned to treatment arms based on next-generation sequencing (NGS)-based, matching genomic profiles. Patients whose tumors harbor fibroblast growth factor receptor (FGFR) alteration were enrolled in the nintedanib arm (arm 3) as part of the TRIUMPH study. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression-free survival (PFS), safety, and biomarker analysis. RESULTS: Between October 2017 and August 2020, 207 were enrolled in the TRIUMPH study, and eight were enrolled in the nintedanib arm. ORR and disease control rate were 42.9% and 57.1%, respectively. The median PFS was 5.6 months and the median duration of response was 9.1 months. Median OS was 11.1 months. One patient maintained the partial response for 36 months. Overall, the toxicity profiles were manageable. CONCLUSION: Single-agent nintedanib has demonstrated significant efficacy in FGFR-mutated, recurrent or metastatic HNSCC patients, with tolerable toxicity profiles. The results from the study have provided the basis for routine NGS screening and FGFR-targeted therapy. Because of the small number of patients due to slow accrual in this study, further studies with a larger cohort are warranted for statistical power.