Publications by authors named "Byoung Chul Cho"

257 Publications

Cardiac Safety Assessment of Lazertinib: Findings From Patients With Mutation-Positive Advanced NSCLC and Preclinical Studies.

JTO Clin Res Rep 2021 Oct 8;2(10):100224. Epub 2021 Sep 8.

Yuhan R&D Institute, Yuhan Corporation, Yongin, Republic of Korea.

Introduction: Lazertinib is a potent, irreversible, brain-penetrant, mutant-selective, and wild-type-sparing third-generation EGFR tyrosine kinase inhibitor (TKI), creating a wide therapeutic index. Cardiovascular adverse events (AEs), including QT prolongation, decreased left ventricular ejection fraction (LVEF), and heart failure, have emerged as potential AEs with certain EGFR TKI therapies.

Methods: Cardiac safety of lazertinib was evaluated in TKI-tolerant adults with mutation-positive locally advanced or metastatic NSCLC receiving lazertinib (20-320 mg/d). QT intervals corrected with Fridericia's formula (QTcF) prolongation, time-matched concentration-QTcF relationship, change of LVEF, and cardiac failure-associated AEs were evaluated. The clinical findings were supplemented by the following three preclinical studies: an in vitro hERG inhibition assay, an ex vivo isolated perfused rabbit heart study, and an in vivo telemetry-instrumented beagle dog study.

Results: Preclinical evaluation revealed little to no physiological effect on the basis of electrocardiogram, electrophysiological, proarrhythmic, and hemodynamic parameters. Clinical evaluation of 181 patients revealed no clinically relevant QTcF prolongation by centralized electrocardiogram in any patient and at any dose level. The predicted magnitude of QTcF value increase at maximum steady-state plasma concentration for the therapeutic dose of lazertinib (240 mg/d) was 2.2 msec (upper bound of the two-sided 90% confidence interval: 3.6 msec). No patient had clinically relevant LVEF decrease (i.e., minimum postbaseline LVEF value of <50% and a maximum decrease in LVEF value from baseline of ≥10 percentage points). Cardiac failure-associated AE occurred in one patient (grade 2 decreased LVEF) and resolved without any dose modifications.

Conclusions: Our first-in-human study, together with preclinical data, indicates that lazertinib is not associated with increased cardiac risk.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501499PMC
October 2021

Phase 1b Open-Label Trial of Afatinib Plus Xentuzumab (BI 836845) in Patients With Mutation-Positive NSCLC After Progression on EGFR Tyrosine Kinase Inhibitors.

JTO Clin Res Rep 2021 Sep 10;2(9):100206. Epub 2021 Jul 10.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Introduction: Insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. This phase 1 trial (NCT02191891) investigated the combination of xentuzumab (an insulin-like growth factor-ligand neutralizing monoclonal antibody) and afatinib (an EGFR TKI) in patients with previously treated mutation-positive NSCLC.

Methods: The trial comprised dose escalation (part A) and expansion (part B). Patients had advanced or metastatic NSCLC that had progressed on EGFR TKI monotherapy or platinum-based chemotherapy (nonadenocarcinoma only, part A) or irreversible EGFR TKI monotherapy (part B). Absence of T790M mutation was required in part B. Part A used a 3 + 3 design, with a starting dose of xentuzumab 1000 mg/wk (intravenous) and afatinib 30 mg/d (oral). Primary endpoints were the maximum tolerated dose of the combination (part A) and objective response (part B).

Results: A total of 16 patients each were treated in parts A and B. Maximum tolerated dose was xentuzumab 1000 mg/wk plus afatinib 40 mg/d. No patients in part B had an objective response, but 10 had stable disease (median [range] duration of disease control: 2.3 [0.8-10.9] mo). The most common drug-related adverse events were diarrhea (75 %), paronychia (69 %), and rash (69 %) in part A and diarrhea (31 %), rash (19 %), paronychia (19 %), and fatigue (19 %) in part B.

Conclusions: There were no new safety issues; xentuzumab and afatinib could be safely coadministered. Nevertheless, the combination revealed only modest activity in patients with mutation-positive, T790M-negative NSCLC after progression on afatinib.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474216PMC
September 2021

Brief Report: Heterogeneity of Acquired Resistance Mechanisms to Osimertinib and Savolitinib.

JTO Clin Res Rep 2021 Jun 30;2(6):100180. Epub 2021 Apr 30.

Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.

Introduction: amplification is a frequently observed mechanism of resistance to osimertinib, and coinhibition strategy of MET and EGFR revealed promising results in recent clinical trials. Nevertheless, acquired resistance mechanisms to combined EGFR and MET inhibition are poorly understood. In this study, we investigated the mechanisms of acquired resistance to osimertinib and savolitinib by using pretreatment and post-treatment tissue analysis.

Methods: Whole-exome sequencing was performed in -mutant, -amplified patients who received osimertinib and savolitinib using tissues obtained both before and after therapy. All patients achieved partial response or durable stable disease to osimertinib and savolitinib before developing acquired resistance.

Results: After progression on osimertinib and savolitinib, whole-exome analysis revealed -dependent mechanisms of resistance, such as acquired p.D1246H mutation, p.Y1230C mutation, and copy number gain. As for -independent mechanisms, development of mutation and amplification and copy number gains in amplifications in , , and were observed. Patient 2 harbored an acquired p.H1047R mutation in which resistance could be overcome with combination of PI3K inhibitor and osimertinib in the patient-derived xenograft model.

Conclusions: Our study reveals that acquired resistance to savolitinib plus osimertinib can occur from both MET-dependent and MET-independent mechanisms.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474358PMC
June 2021

Efficacy and safety of atezolizumab, in combination with etoposide and carboplatin regimen, in the first-line treatment of extensive-stage small-cell lung cancer: a single-center experience.

Cancer Immunol Immunother 2021 Sep 27. Epub 2021 Sep 27.

Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Yonsei-ro 50-1, Seodaemun-gu, Seoul, 03722, Korea.

Background: Patients with small-cell lung cancer (SCLC) have a dismal prognosis with limited overall survival (OS) despite a high response rate to chemotherapy. Recently, immune checkpoint inhibitors, combined with chemotherapy, as the first-line treatment for extensive-stage (ES)-SCLC have shown improvement in clinical outcomes.

Patients And Methods: Real-world data from 68 Korean ES-SCLC patients, treated with atezolizumab, etoposide, and carboplatin at Yonsei Cancer Center between June 2019 and November 2020, were retrospectively analyzed to determine safety and efficacy using Cox regression analysis.

Results: The median follow-up was 11.6 months. The median progression-free survival was 4.6 months (95% confidence interval [CI] 4.0-5.2), and the median OS was 12.0 months (95% CI 7.4-16.6). Baseline bone metastasis, immune-related adverse events (IRAEs), and elevated LDH were related to OS (hazard ratio 2.18, 0.33, and 4.64; P = 0.05, 0.02, and 0.003, respectively). Among the 42 patients with disease progression, liver metastasis progression and baseline bone metastasis were associated with inferior OS, but without statistical significance (hazard ratio 2.47 and 1.97; P = 0.25 and 0.26, respectively). Overall, 61 (89.7%) patients experienced treatment-related adverse events (TRAEs), with hematologic toxicities as the most common grade 3-4 TRAEs. Twenty-two (32.4%) patients experienced IRAEs, with skin rash as the most common, and five (7.4%) patients had grade-3 IRAEs (pneumonitis, hyperglycemia, and aspartate aminotransferase elevation).

Conclusion: Atezolizumab, combined with etoposide and carboplatin, showed efficacy and safety in our real-world data. Further studies are needed to predict the response to immunotherapy in SCLC.
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http://dx.doi.org/10.1007/s00262-021-03052-wDOI Listing
September 2021

A phase II study of poziotinib in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

Cancer Med 2021 Oct 16;10(20):7012-7020. Epub 2021 Sep 16.

Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Cancer Centre, Seoul, Republic of Korea.

Background: In phase I studies, poziotinib has shown meaningful efficacy against various types of cancers. This phase 2 study aimed to investigate the efficacy and safety of poziotinib in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M-HNSCC).

Methods: Overall, 49 patients were enrolled (median age, 62 years; age range, 21-78 years). Patients received a median of two prior treatments including chemotherapy and others and received 12 mg poziotinib orally once daily as part of a 28-day cycle. The primary endpoint was objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Targeted capture sequencing was performed using available tissues to identify translational biomarkers related to clinical response.

Results: ORR was 22.4%, median PFS was 4.0 months (95% confidence interval [CI], 1.8-6.2 months), and median OS was 7.6 months (95% CI, 4.4-10.8 months). The most common treatment-related adverse events were acneiform rash (85%) and mucositis (77%). A grade 3 or higher adverse event was acneiform rash (3%). Targeted capture sequencing was performed in 30 tissue samples. TP53 and PIK3CA were the most frequently mutated genes (43%), followed by CCND1 (33%) and EGFR (30%). Mutations in ERBB2, ERBB3, and ERBB4, which are HER family genes, were observed in 17%, 13%, and 10% samples, respectively. There was no difference in the frequency of somatic mutations in the HER family genes between the clinically benefitted and non-benefitted groups.

Conclusion: Compared to other pan-HER inhibitors, poziotinib showed clinically meaningful efficacy in heavily treated R/M-HNSCC.

Clinical Trial Registration Number: NCT02216916.
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http://dx.doi.org/10.1002/cam4.4231DOI Listing
October 2021

Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study.

Lancet 2021 08;398(10302):759-771

National Cancer Center Hospital, Tokyo, Japan.

Background: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer.

Methods: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment.

Findings: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group.

Interpretation: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S0140-6736(21)01234-4DOI Listing
August 2021

Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD).

Clin Lung Cancer 2021 Jun 25. Epub 2021 Jun 25.

UC Davis Comprehensive Cancer Center, Sacramento, CA, USA.

Introduction: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments.

Methods: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety.

Conclusions: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves.
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http://dx.doi.org/10.1016/j.cllc.2021.06.006DOI Listing
June 2021

Anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody quavonlimab in combination with pembrolizumab: Safety and efficacy from a phase I study in previously treated extensive-stage small cell lung cancer.

Lung Cancer 2021 09 18;159:162-170. Epub 2021 Jul 18.

Chaim Sheba Medical Center at Tel HaShomer, Derech Sheba 2, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel. Electronic address:

Objectives: This first-in-human phase I study (NCT03179436) investigated anti-cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti-programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab + pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥ 3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non-small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy.

Materials And Methods: Patients with stage III/IV SCLC received quavonlimab 75 mg Q6W plus pembrolizumab 200 mg Q3W for ≤ 2 years. Primary endpoints were safety and tolerability; ORRs as assessed by blinded independent central review per Response Evaluation Criteria In Solid Tumorsv1.1 was a secondary endpoint. Progression-free survival (PFS), overall survival (OS), and the correlation of response with PD-L1 expression were exploratory endpoints.

Results: Forty patients with extensive-stage SCLC received treatment; median follow-up was 13 months. Dose-limiting toxicity occurred in 4 patients (10%). TRAEs occurred in 80% of patients; grade 3 events occurred in 33% of patients and no grade 4/5 events were reported. Confirmed ORRs (95% CI) were 18% (7-33) among all patients, 7% (<1-34) for PD-L1-positive tumors (n = 14), and 19% (5-42) for PD-L1-negative tumors (n = 21). Response duration ranged from 2.9 to 19.1+ months. Median PFS was 2.0 months; 6-month PFS rate was 26%. Median OS was 11.0 months; 6-month OS rate was 66%.

Conclusions: Encouraging antitumor activity was observed with quavonlimab + pembrolizumab in patients with extensive-stage SCLC; responses were observed in PD-L1-positive and PD-L1-negative tumors. The combination was tolerable with manageable toxicities.
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http://dx.doi.org/10.1016/j.lungcan.2021.07.009DOI Listing
September 2021

Analyses of CNS Response to Osimertinib in Patients with T790M-Positive Advanced NSCLC from ASTRIS Korean Subset, Open-Label Real-World Study.

Cancers (Basel) 2021 Jul 22;13(15). Epub 2021 Jul 22.

Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

Up to 40% of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) may develop central nervous system (CNS) metastases throughout their disease. Moreover, the first- and second-generation EGFR-tyrosine kinase inhibitors have limited efficacy because of their poor blood-brain barrier permeability. Therefore, we conducted preplanned analyses of ASTRIS, a clinical study of the third-generation EGFR-TKI osimertinib to demonstrate its potential role in intracranial response efficacies. We retrospectively examined 89 NSCLC patients with brain evaluation who were not amenable to curative surgery or radiotherapy and received osimertinib upon confirmation of the presence of the T790M mutation. We collected the information regarding patients' baseline characteristics, baseline intracranial status, including leptomeningeal metastases (LM), and intracranial responses measured by Response Evaluation Criteria in Solid Tumors version 1.1, using independent central review. The median age was 60 years, and 69.7% of the patients were female. Sixty-five patients (73.0%) had brain metastases (BM) at baseline and nineteen patients (23.5%) had additional LM. Among patients with brain metastases, 24 (36.9%) had ≥1 measurable brain metastases and 16 were evaluated for the objective response. In the CNS evaluable for response set, the intracranial objective response rate (cORR) and disease control rate (cDCR) were 62.5% (95% confidence interval (CI), 38.3-82.6%) and 93.8% (95% CI, 74.3-99.3%), respectively. The median intracranial progression-free survival (cPFS) was 13.0 (95% CI, 7.21-18.8) months, including patients with measurable and non-measurable BM or LM. Our cORR, cDCR, and cPFS were comparable to those observed in previous clinical trials. The outcome of this study helps to demonstrate the potential role of intracranial efficacies of osimertinib 80 mg administration in T790M-positive advanced NSCLC with/without BM or LM.
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http://dx.doi.org/10.3390/cancers13153681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345213PMC
July 2021

Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study.

J Clin Oncol 2021 Oct 2;39(30):3391-3402. Epub 2021 Aug 2.

Janssen R&D, Spring House, PA.

Purpose: Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor () exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site.

Methods: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5.

Results: In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively.

Conclusion: Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with Exon20ins mutations after progression on platinum-based chemotherapy.
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http://dx.doi.org/10.1200/JCO.21.00662DOI Listing
October 2021

Distinct Characteristics and Clinical Outcomes to Predict the Emergence of Amplification in Patients with Non-Small Cell Lung Cancer Who Developed Resistance after Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

Cancers (Basel) 2021 Jun 21;13(12). Epub 2021 Jun 21.

Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

Objectives: Patients with epidermal growth factor receptor () mutant non-small cell lung cancer (NSCLC) ultimately acquire resistance to tyrosine kinase inhibitors (TKIs) during treatment. In 5-22% of these patients, resistance is mediated by aberrant mesenchymal epithelial transition factor () gene amplification. Here, we evaluated the emergence of amplification after EGFR-TKI treatment failure based on clinical parameters.

Materials And Methods: We retrospectively analyzed 186 patients with advanced -mutant NSCLC for amplification status by in situ hybridization (ISH) assay after EGFR-TKI failure. We collected information including baseline patient characteristics, metastatic locations and generation, line, and progression-free survival (PFS) of EGFR-TKI used before evaluation. Multivariate logistic regression analysis was conducted to evaluate associations between amplification status and clinical variables.

Results: Regarding baseline mutations, exon 19 deletion was predominant (57.5%), followed by L858R mutation (37.1%). The proportions of ISH assays performed after first/second-generation and third-generation TKI failure were 66.7% and 33.1%, respectively. The median PFS for the most recent EGFR-TKI treatment was shorter in amplification-positive patients than in amplification-negative patients (median PFS 7.0 vs. 10.4 months, = 0.004). Multivariate logistic regression demonstrated that a history of smoking, short PFS on the most recent TKI, and less intracranial progression were associated with a high probability of amplification (all < 0.05).

Conclusions: Our results demonstrated the distinct clinical characteristics of patients with amplification-positive NSCLC after EGFR-TKI therapy. Our clinical prediction can aid physicians in selecting patients eligible for amplification screening and therapeutic targeting.
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http://dx.doi.org/10.3390/cancers13123096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234556PMC
June 2021

Clinical decision support algorithm based on machine learning to assess the clinical response to anti-programmed death-1 therapy in patients with non-small-cell lung cancer.

Eur J Cancer 2021 Aug 26;153:179-189. Epub 2021 Jun 26.

Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Objective: Anti-programmed death (PD)-1 therapy confers sustainable clinical benefits for patients with non-small-cell lung cancer (NSCLC), but only some patients respond to the treatment. Various clinical characteristics, including the PD-ligand 1 (PD-L1) level, are related to the anti-PD-1 response; however, none of these can independently serve as predictive biomarkers. Herein, we established a machine learning (ML)-based clinical decision support algorithm to predict the anti-PD-1 response by comprehensively combining the clinical information.

Materials And Methods: We collected clinical data, including patient characteristics, mutations and laboratory findings, from the electronic medical records of 142 patients with NSCLC treated with anti-PD-1 therapy; these were analysed for the clinical outcome as the discovery set. Nineteen clinically meaningful features were used in supervised ML algorithms, including LightGBM, XGBoost, multilayer neural network, ridge regression and linear discriminant analysis, to predict anti-PD-1 responses. Based on each ML algorithm's prediction performance, the optimal ML was selected and validated in an independent validation set of PD-1 inhibitor-treated patients.

Results: Several factors, including PD-L1 expression, tumour burden and neutrophil-to-lymphocyte ratio, could independently predict the anti-PD-1 response in the discovery set. ML platforms based on the LightGBM algorithm using 19 clinical features showed more significant prediction performance (area under the curve [AUC] 0.788) than on individual clinical features and traditional multivariate logistic regression (AUC 0.759).

Conclusion: Collectively, our LightGBM algorithm offers a clinical decision support model to predict the anti-PD-1 response in patients with NSCLC.
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http://dx.doi.org/10.1016/j.ejca.2021.05.019DOI Listing
August 2021

The promise of bispecific antibodies: Clinical applications and challenges.

Cancer Treat Rev 2021 Sep 4;99:102240. Epub 2021 Jun 4.

Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea. Electronic address:

The development of cancer therapies using monoclonal antibodies has been successful during the last 30 years. Recently much progress was achieved with technologies involving bispecific and multi-specific antibodies. Bispecific antibodies (BsAbs) are antibodies that bind two distinct epitopes, and a large number of potential clinical applications of BsAbs have been described. Here we review mechanism of action, clinical development and future challenges of BsAbs which could be a serve as a valuable arsenal in cancer patients.
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http://dx.doi.org/10.1016/j.ctrv.2021.102240DOI Listing
September 2021

Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study.

Lancet Oncol 2021 07 9;22(7):959-969. Epub 2021 Jun 9.

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC.

Methods: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis.

Findings: Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population.

Interpretation: Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC.

Funding: Blueprint Medicines.
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http://dx.doi.org/10.1016/S1470-2045(21)00247-3DOI Listing
July 2021

Intracranial Efficacy of Selpercatinib in Fusion-Positive Non-Small Cell Lung Cancers on the LIBRETTO-001 Trial.

Clin Cancer Res 2021 Aug 4;27(15):4160-4167. Epub 2021 Jun 4.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for fusion-positive non-small cell lung cancers (NSCLC).

Patients And Methods: In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced -altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed.

Results: Eighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0-10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60-95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, = 38), median duration of intracranial response was not reached (95% CI, 9.3-NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9-NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population.

Conclusions: Selpercatinib has robust and durable intracranial efficacy in patients with fusion-positive NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447251PMC
August 2021

Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma.

Clin Cancer Res 2021 Aug 3;27(15):4397-4409. Epub 2021 Jun 3.

Division of Medical Oncology, Yonsei University College of Medicine, Yonsei Cancer Center, Seoul, Korea.

Purpose: Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.

Experimental Design: Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing ( = 12). Organoids were analyzed by whole-exome sequencing ( = 61) and RNA sequencing ( = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.

Results: PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non-small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an exon 19 deletion and a G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against exon 20 insertions and pralsetinib against fusions.

Conclusions: We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-5026DOI Listing
August 2021

Real-World Treatment Patterns and Clinical Outcomes in Patients With Stage III NSCLC: Results of KINDLE, a Multicountry Observational Study.

J Thorac Oncol 2021 10 26;16(10):1733-1744. Epub 2021 May 26.

Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea.

Introduction: Stage III NSCLC is a heterogeneous disease requiring a multimodal management approach. We conducted a real-world, global study to characterize patients, treatment patterns, and their associated clinical outcomes for stage III NSCLC.

Methods: KINDLE was a retrospective study in patients with stage III NSCLC (American Joint Committee on Cancer, seventh edition) diagnosed between January 2013 and December 2017, with at least 9 months of documented follow-up since index diagnosis. In addition to descriptive statistics, Kaplan-Meier methodology evaluated survival estimates; two-sided 95% confidence interval was computed. Cox proportional hazards model was used for univariate and multivariate analyses.

Results: A total of 3151 patients from more than 100 centers across 19 countries from Asia, Middle East, Africa, and Latin America were enrolled. Median age was 63.0 years (range: 21.0-92.0); 76.5% were males, 69.2% had a smoking history, 53.7% had adenocarcinoma, and 21.4% underwent curative resection. Of greater than 25 treatment regimens, concurrent chemoradiotherapy was the most common (29.4%). The overall median progression-free survival (95% confidence interval) and median overall survival (mOS) were 12.5 months (12.06-13.14) and 34.9 months (32.00-38.01), respectively. Significant associations (p < 0.05) were observed for median progression-free survival and mOS with respect to sex, region, smoking status, stage, histology, and Eastern Cooperative Oncology Group status. In univariate and multivariate analyses, younger age, stage IIIA, better Eastern Cooperative Oncology Group status, concurrent chemoradiotherapy, and surgery as initial therapy predicted better mOS.

Conclusions: KINDLE reveals the diversity in treatment practices and outcomes in stage III NSCLC in a real-world setting in the preimmuno-oncology era. There is a high unmet medical need, necessitating novel approaches to optimize outcomes.
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http://dx.doi.org/10.1016/j.jtho.2021.05.003DOI Listing
October 2021

Five Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel for Previously Treated, Programmed Death-Ligand 1-Positive Advanced NSCLC.

J Thorac Oncol 2021 10 26;16(10):1718-1732. Epub 2021 May 26.

The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Introduction: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% and ≥1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study.

Methods: Patients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis.

Results: A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0‒77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44‒0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61‒0.80) with PD-L1 TPS ≥1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS ≥50% and 15.6% versus 6.5% with PD-L1 TPS ≥1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (∼5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (≥175 mutations per exome) was associated with improved outcomes with pembrolizumab.

Conclusions: Pembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting.
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http://dx.doi.org/10.1016/j.jtho.2021.05.001DOI Listing
October 2021

Sequencing of MET Inhibitors in Lung Cancer: Have We Met the Target?

J Thorac Oncol 2021 05;16(5):709-711

Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2021.02.017DOI Listing
May 2021

DGG-100629 inhibits lung cancer growth by suppressing the NFATc1/DDIAS/STAT3 pathway.

Exp Mol Med 2021 Apr 15;53(4):643-653. Epub 2021 Apr 15.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) promotes the progression of lung cancer and hepatocellular carcinoma through the regulation of multiple pathways. We screened a chemical library for anticancer agent(s) capable of inhibiting DDIAS transcription. DGG-100629 was found to suppress lung cancer cell growth through the inhibition of DDIAS expression. DGG-100629 induced c-Jun NH(2)-terminal kinase (JNK) activation and inhibited NFATc1 nuclear translocation. Treatment with SP600125 (a JNK inhibitor) or knockdown of JNK1 restored DDIAS expression and reversed DGG-100629-induced cell death. In addition, DGG-100629 suppressed the signal transducer and activator of transcription (STAT3) signaling pathway. DDIAS or STAT3 overexpression restored lung cancer cell growth in the presence of DGG-100629. In a xenograft assay, DGG-100629 inhibited tumor growth by reducing the level of phosphorylated STAT3 and the expression of STAT3 target genes. Moreover, DGG-100629 inhibited the growth of lung cancer patient-derived gefitinib-resistant cells expressing NFATc1 and DDIAS. Our findings emphasize the potential of DDIAS blockade as a therapeutic approach and suggest a novel strategy for the treatment of gefitinib-resistant lung cancer.
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http://dx.doi.org/10.1038/s12276-021-00601-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102629PMC
April 2021

Rovalpituzumab Tesirine as a Maintenance Therapy After First-Line Platinum-Based Chemotherapy in Patients With Extensive-Stage-SCLC: Results From the Phase 3 MERU Study.

J Thorac Oncol 2021 09 3;16(9):1570-1581. Epub 2021 Apr 3.

Department of Oncology, Sheba Medical Center, Ramat Gan, Israel; Sackler Medical School, Tel-Aviv University, Tel-Aviv, Israel.

Introduction: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, an atypical Notch ligand expressed in SCLC tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive-stage-SCLC after platinum-based chemotherapy.

Methods: MERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression after four cycles of platinum-based, front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (every 6 wk, omitted every third cycle). Primary efficacy end points were progression-free survival (PFS) evaluated by the Central Radiographic Assessment Committee and overall survival (OS) in patients with DLL3-high tumors.

Results: Median age of all randomized patients (N = 748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84-1.36) favoring the placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 mo, hazard ratio = 0.48, p < 0.001). Any-grade adverse events (≥20%) in the Rova-T arm were pleural effusion (27%), decreased appetite (27%), peripheral edema (26%), photosensitivity reaction (25%), fatigue (25%), nausea (22%), and dyspnea (21%).

Conclusions: Because of the lack of survival benefit in the Rova-T arm, the study did not meet its primary end point and was terminated early. As a result, the Central Radiographic Assessment Committee evaluation of PFS was not performed. The frequency of grade greater than or equal to 3 and drug-related toxicities were higher with Rova-T versus placebo. Rova-T was associated with unique toxicities, such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the population with extensive-stage-SCLC.
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http://dx.doi.org/10.1016/j.jtho.2021.03.012DOI Listing
September 2021

Intracranial failure after hippocampal-avoidance prophylactic cranial irradiation in limited-stage small-cell lung cancer patients.

Sci Rep 2021 04 1;11(1):7435. Epub 2021 Apr 1.

Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

We evaluated intracranial failure after hippocampus-avoidance-prophylactic cranial irradiation (HA-PCI) for limited-stage small-cell lung cancer (SCLC). Data of 106 patients who received PCI with 25 Gy were retrospectively reviewed. The patients were divided into two groups based on whether they underwent HA-PCI: the HA-PCI group (n = 48) and the conventional PCI (C-PCI) group (n = 58). Twenty-one patients experienced intracranial failure: 11 and 10 patients in the C-PCI and HA-PCI groups, respectively. Using the log-rank test, the intracranial failure rate was not significantly different between the groups (p = 0.215). No clinical factor was significantly associated with intracranial failure in multivariate Cox regression analysis, but HA-PCI tended to be associated with increased incidence of intracranial failure (HR 2.87, 95% CI 0.86-9.58, p = 0.087). Among patients who received HA-PCI, two developed peri-hippocampal recurrence. A higher thoracic radiotherapy dose (≥ 60 Gy) was significantly associated with DFS (HR 0.52, p = 0.048) and OS (HR 0.35, p = 0.003). However, HA-PCI was associated with neither DFS nor OS. Although HA-PCI may be associated with an increased risk of intracranial failure, HA-PCI did not impair disease control or survival. Future prospective randomized trials are needed to reach a definite conclusion.
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http://dx.doi.org/10.1038/s41598-021-86851-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016941PMC
April 2021

Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC).

Clin Lung Cancer 2021 07 19;22(4):301-312.e8. Epub 2021 Feb 19.

Division of Hematology/Oncology, Columbia University Medical Center, New York, NY.

Background: The phase 3 MYSTIC study of durvalumab ± tremelimumab versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC) patients with tumor cell (TC) programmed cell death ligand 1 (PD-L1) expression ≥ 25% did not meet its primary endpoints. We report patient-reported outcomes (PROs).

Patients And Methods: Treatment-naïve patients were randomized (1:1:1) to durvalumab, durvalumab + tremelimumab, or chemotherapy. PROs were assessed in patients with PD-L1 TC ≥ 25% using EORTC Quality of Life Questionnaire (QLQ)-C30/LC13. Changes from baseline (12 months) for prespecified PRO endpoints of interest were analyzed by mixed model for repeated measures (MMRM) and time to deterioration (TTD) by stratified log-rank tests.

Results: There were no between-arm differences in baseline PROs (N = 488). Between-arm differences in MMRM-adjusted mean changes from baseline favored at least one of the durvalumab-containing arms versus chemotherapy (nominal P < .01) for C30 fatigue: durvalumab (-9.5; 99% confidence interval [CI], -17.0 to -2.0), durvalumab + tremelimumab (-11.7; 99% CI, -19.4 to -4.1); and for C30 appetite loss: durvalumab (-11.9; 99% CI, -21.1 to -2.7). TTD was longer with at least one of the durvalumab-containing arms versus chemotherapy (nominal P < .01) for global health status/quality of life: durvalumab (hazard ratio [HR] = 0.7; 95% CI, 0.5-1.0), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-1.0); and for physical functioning: durvalumab (HR = 0.6; 95% CI, 0.4-0.8), durvalumab + tremelimumab (HR = 0.6; 95% CI, 0.5-0.9) (both C30); as well as for the key symptoms of dyspnea: durvalumab (HR = 0.6; 95% CI, 0.5-0.9), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-1.0) (both LC13); fatigue: durvalumab + tremelimumab (HR = 0.6; 95% CI, 0.4-0.8); and appetite loss: durvalumab (HR = 0.5; 95% CI, 0.4-0.7), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-0.9) (both C30).

Conclusion: Durvalumab ± tremelimumab versus chemotherapy reduced symptom burden and improved TTD of PROs, suggesting it had no detrimental effects on quality of life in metastatic NSCLC patients.
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http://dx.doi.org/10.1016/j.cllc.2021.02.010DOI Listing
July 2021

Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic Fusion-Positive Non-Small-Cell Lung Cancer.

J Clin Oncol 2021 04 1;39(11):1253-1263. Epub 2021 Mar 1.

Aix Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France.

Purpose: Genetic rearrangements of the tyrosine receptor kinase ROS proto-oncogene 1 () are oncogenic drivers in non-small-cell lung cancer (NSCLC). We report the results of an updated integrated analysis of three phase I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2) of the ROS1 tyrosine kinase inhibitor, entrectinib, in fusion-positive NSCLC.

Methods: The efficacy-evaluable population included adults with locally advanced or metastatic fusion-positive NSCLC with or without CNS metastases who received entrectinib ≥ 600 mg orally once per day. Co-primary end points were objective response rate (ORR) assessed by blinded independent central review and duration of response (DoR). Secondary end points included progression-free survival (PFS), overall survival (OS), intracranial ORR, intracranial DoR, intracranial PFS, and safety.

Results: In total, 161 patients with a follow-up of ≥ 6 months were evaluable. The median treatment duration was 10.7 months (IQR, 6.4-17.7). The ORR was 67.1% (n = 108, 95% CI, 59.3 to 74.3), and responses were durable (12-month DoR rate, 63%, median DoR 15.7 months). The 12-month PFS rate was 55% (median PFS 15.7 months), and the 12-month OS rate was 81% (median OS not estimable). In 24 patients with measurable baseline CNS metastases by blinded independent central review, the intracranial ORR was 79.2% (n = 19; 95% CI, 57.9 to 92.9), the median intracranial PFS was 12.0 months (95% CI, 6.2 to 19.3), and the median intracranial DoR was 12.9 months (12-month rate, 55%). The safety profile in this updated analysis was similar to that reported in the primary analysis, and no new safety signals were found.

Conclusion: Entrectinib continued to demonstrate a high level of clinical benefit for patients with fusion-positive NSCLC, including patients with CNS metastases.
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http://dx.doi.org/10.1200/JCO.20.03025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078299PMC
April 2021

Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study.

J Thorac Oncol 2021 09 16;16(9):1547-1558. Epub 2021 Feb 16.

Thoracic Oncology Department, Asklepios Fachkliniken München-Gauting, Gauting, Germany.

Introduction: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated.

Methods: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS).

Results: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6-7.3) in the Rova-T arm and 8.6 months (7.7-10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports.

Conclusions: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.
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http://dx.doi.org/10.1016/j.jtho.2021.02.009DOI Listing
September 2021

KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma.

Future Oncol 2021 Apr 3;17(10):1143-1153. Epub 2021 Feb 3.

Department of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA 02215-5450, USA.

Despite curative-intent treatment, most patients with locally advanced esophageal cancer will experience disease recurrence or locoregional progression, highlighting the need for new therapies. Current guidelines recommend definitive chemoradiotherapy in patients ineligible for surgical resection, but survival outcomes are poor. Pembrolizumab is well tolerated and provides promising antitumor activity in patients with previously treated, advanced, unresectable esophageal/esophagogastric junction cancer. Combining pembrolizumab with chemoradiotherapy may further improve outcomes in the first-line setting. Here, we describe the design and rationale for the double-blind, Phase III, placebo-controlled, randomized KEYNOTE-975 trial investigating pembrolizumab in combination with definitive chemoradiotherapy as first-line treatment in patients with locally advanced, unresectable esophageal/gastroesophageal junction cancer. Overall survival and event-free survival are the dual primary end points. NCT04210115 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927908PMC
April 2021

Olmutinib in T790M-positive non-small cell lung cancer after failure of first-line epidermal growth factor receptor-tyrosine kinase inhibitor therapy: A global, phase 2 study.

Cancer 2021 May 12;127(9):1407-1416. Epub 2021 Jan 12.

Hanmi Pharmaceutical Company, Ltd, Seoul, Republic of Korea.

Background: In this open-label, international phase 2 study, the authors assessed the efficacy and safety of olmutinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had a confirmed T790M mutation and disease progression on previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

Methods: Patients aged ≥20 years received once-daily oral olmutinib 800 mg continuously in 21-day cycles. The primary endpoint was the objective response rate (patients who had a confirmed best overall response of a complete or partial response), assessed by central review. Secondary endpoints included the disease control rate, the duration of objective response, progression-free survival, and overall survival. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).

Results: Overall, 162 patients (median age, 63 years; women, >60%) were enrolled from 68 sites in 9 countries. At the time of database cutoff, 23.5% of enrolled patients remained on treatment. The median treatment duration was 6.5 months (range, 0.03-21.68 months). Overall, 46.3% of patients (95% CI, 38.4%-54.3%) had a confirmed objective response (all partial responses). The best overall response (the objective response rate regardless of confirmation) was 51.9% (84 patients; 95% CI, 43.9%-59.8%). The confirmed disease control rate for all patients was 86.4% (95% CI, 80.2%-91.3%). The median duration of objective response was 12.7 months (95% CI, 8.3-15.4 months). Estimated median progression-free survival was 9.4 months (95% CI, 6.9-12.3 months), and estimated median overall survival was 19.7 months (95% CI, 15.1 months to not reached). All patients experienced treatment-emergent adverse events, and 71.6% of patients had grade ≥3 treatment-emergent adverse events.

Conclusions: Olmutinib has meaningful clinical activity and a manageable safety profile in patients with T790M-positive non-small cell lung cancer who received previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.
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http://dx.doi.org/10.1002/cncr.33385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247868PMC
May 2021

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies.

J Immunother Cancer 2020 12;8(2)

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β 'trap') fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa.

Methods: In these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety.

Results: As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred.

Conclusion: Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.
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http://dx.doi.org/10.1136/jitc-2020-001395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745517PMC
December 2020

The feasibility and safety of radical esophagectomy in patients receiving neoadjuvant chemoradiotherapy with pembrolizumab for esophageal squamous cell carcinoma.

J Thorac Dis 2020 Nov;12(11):6426-6434

Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.

Background: Immune checkpoint inhibitors have been tried for several thoracic malignancies; however, their application as a neoadjuvant therapy in esophageal squamous cell carcinoma (ESCC) has not been studied. We evaluated the feasibility and safety of esophagectomy and total lymphadenectomy after neoadjuvant chemoradiation therapy with pembrolizumab.

Methods: Between 2017 and 2018, 38 patients who received the neoadjuvant therapy followed by radical esophagectomy and total lymphadenectomy for ESCC were analyzed. Twenty-two patients received conventional neoadjuvant chemoradiation therapy (Group 1), and sixteen patients received neoadjuvant chemoradiation therapy with pembrolizumab in clinical trial (Group 2). Two groups were compared retrospectively.

Results: The basic characteristics of age, clinical stage, location and methods of operation were not different between the two groups. The pathologic stages were higher in Group 2, but the difference was not statistically significant. The operative outcomes, i.e., operation time, blood loss, and numbers of dissected lymph nodes in the thorax, neck, and abdomen were comparable. Complications, including pulmonary complications and anastomotic leakage, were also comparable. The rate of recurrent laryngeal nerve palsy was also comparable between the two groups (31.8% 18.8%, P=0.469). Operative mortalities developed in 2 patients [0 2 (12.5%), P=0.171] due to acute respiratory distress syndrome (ARDS).

Conclusions: Radical esophagectomy for esophageal squamous cell carcinoma after neoadjuvant chemoradiation therapy with pembrolizumab may not increase the operative risk or reduce the quality of radical dissection including lymphadenectomy. The risk of ARDS after neoadjuvant neoadjuvant chemoradiation therapy with pembrolizumab has to be studied in the further analysis.
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http://dx.doi.org/10.21037/jtd-20-1088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711420PMC
November 2020

Author Correction: NOVA1 induction by inflammation and NOVA1 suppression by epigenetic regulation in head and neck squamous cell carcinoma.

Sci Rep 2020 Nov 30;10(1):21299. Epub 2020 Nov 30.

Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, South Korea.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-77481-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704637PMC
November 2020
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