Publications by authors named "Chia-Chi Lin"

165 Publications

Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Oncol 2021 Jul 5. Epub 2021 Jul 5.

Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: Patients with radioiodine-refractory differentiated thyroid cancer (DTC) previously treated with vascular endothelial growth factor receptor (VEGFR)-targeted therapy have aggressive disease and no available standard of care. The aim of this study was to evaluate the tyrosine kinase inhibitor cabozantinib in this patient population.

Methods: In this global, randomised, double-blind, placebo-controlled, phase 3 trial, patients aged 16 years and older with radioiodine-refractory DTC (papillary or follicular and their variants) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to oral cabozantinib (60 mg once daily) or matching placebo, stratified by previous lenvatinib treatment and age. The randomisation scheme used stratified permuted blocks of block size six and an interactive voice-web response system; both patients and investigators were masked to study treatment. Patients must have received previous lenvatinib or sorafenib and progressed during or after treatment with up to two VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib on disease progression confirmed by blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (confirmed response per Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) in the first 100 randomly assigned patients (objective response rate intention-to-treat [OITT] population) and progression-free survival (time to earlier of disease progression per RECIST version 1.1 or death) in all patients (intention-to-treat [ITT] population), both assessed by BIRC. This report presents the primary objective response rate analysis and a concurrent preplanned interim progression-free survival analysis. The study is registered with ClinicalTrials.gov, NCT03690388, and is no longer enrolling patients.

Findings: Between Feb 27, 2019, and Aug 18, 2020, 227 patients were assessed for eligibility, of whom 187 were enrolled from 164 clinics in 25 countries and randomly assigned to cabozantinib (n=125) or placebo (n=62). At data cutoff (Aug 19, 2020) for the primary objective response rate and interim progression-free survival analyses, median follow-up was 6·2 months (IQR 3·4-9·2) for the ITT population and 8·9 months (7·1-10·5) for the OITT population. An objective response in the OITT population was achieved in ten (15%; 99% CI 5·8-29·3) of 67 patients in the cabozantinib group versus 0 (0%; 0-14·8) of 33 in the placebo (p=0·028) but did not meet the prespecified significance level (α=0·01). At interim analysis, the primary endpoint of progression-free survival was met in the ITT population; cabozantinib showed significant improvement in progression-free survival over placebo: median not reached (96% CI 5·7-not estimable [NE]) versus 1·9 months (1·8-3·6); hazard ratio 0·22 (96% CI 0·13-0·36; p<0·0001). Grade 3 or 4 adverse events occurred in 71 (57%) of 125 patients receiving cabozantinib and 16 (26%) of 62 receiving placebo, the most frequent of which were palmar-plantar erythrodysaesthesia (13 [10%] vs 0), hypertension (11 [9%] vs 2 [3%]), and fatigue (ten [8%] vs 0). Serious treatment-related adverse events occurred in 20 (16%) of 125 patients in the cabozantinib group and one (2%) of 62 in the placebo group. There were no treatment-related deaths.

Interpretation: Our results show that cabozantinib significantly prolongs progression-free survival and might provide a new treatment option for patients with radioiodine-refractory DTC who have no available standard of care.

Funding: Exelixis.
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http://dx.doi.org/10.1016/S1470-2045(21)00332-6DOI Listing
July 2021

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma.

Cancer Immunol Immunother 2021 Jul 3. Epub 2021 Jul 3.

START Madrid-FJD, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain.

Background: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016).

Patients And Methods: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments.

Results: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1-617) and 71 days (range, 1-490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1-24.5) in the HNSCC cohort and 19% (90% CI, 9.2-32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7-4.7) and 1.9 months (95% CI, 1.7-3.7) in the HNSCC and NSCLC cohorts.

Conclusions: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing.
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http://dx.doi.org/10.1007/s00262-021-02973-wDOI Listing
July 2021

Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study.

Lancet Diabetes Endocrinol 2021 Aug 9;9(8):491-501. Epub 2021 Jun 9.

Earle A Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.

Background: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers.

Methods: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis.

Findings: Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion-positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event.

Interpretation: Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer.

Funding: Blueprint Medicines.
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http://dx.doi.org/10.1016/S2213-8587(21)00120-0DOI Listing
August 2021

Moving Beyond 3+3: The Future of Clinical Trial Design.

Am Soc Clin Oncol Educ Book 2021 Jun;41:e133-e144

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

Misgivings have been raised about the operating characteristics of the canonical 3+3 dose-escalation phase I clinical trial design. Yet, the traditional 3+3 design is still the most commonly used. Although it has been implied that adhering to this design is due to a stubborn reluctance to adopt change despite other designs performing better in hypothetical computer-generated simulation models, the continued adherence to 3+3 dose-escalation phase I strategies is more likely because these designs perform the best in the real world, pinpointing the correct dose and important side effects with an acceptable degree of precision. Beyond statistical simulations, there are little data to refute the supposed shortcomings ascribed to the 3+3 method. Even so, to address the unique nuances of gene- and immune-targeted compounds, a variety of inventive phase 1 trial designs have been suggested. Strategies for developing these therapies have launched first-in-human studies devised to acquire a breadth of patient data that far exceed the size of a typical phase I design and blur the distinction between dose selection and efficacy evaluation. Recent phase I trials of promising cancer therapies assessed objective tumor response and durability at various doses and schedules as well as incorporated multiple expansion cohorts spanning a variety of histology or biomarker-defined tumor subtypes, sometimes resulting in U.S. Food and Drug Administration approval after phase I. This article reviews recent innovations in phase I design from the perspective of multiple stakeholders and provides recommendations for future trials.
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http://dx.doi.org/10.1200/EDBK_319783DOI Listing
June 2021

Exposure-Response Relationships in Patients With HER2-Positive Metastatic Breast Cancer and Other Solid Tumors Treated With Trastuzumab Deruxtecan.

Clin Pharmacol Ther 2021 May 17. Epub 2021 May 17.

Daiichi Sankyo, Inc., Basking Ridge, New Jersey, USA.

Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate composed of a novel enzyme-cleavable linker and membrane-permeable topoisomerase I inhibitor payload. T-DXd has been approved for HER2-positive metastatic breast cancer and for HER2-positive metastatic gastric cancer. The approval in breast cancer was based on results from the DESTINY-Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials. Here, we present dose justification for the approved 5.4 mg/kg every-3-weeks (Q3W) dose based on exposure-efficacy evaluated in patients with HER2-positive breast cancer (N = 337) from these 2 trials. Exposure-safety was assessed in patients with all tumor types (N = 639, n = 512 with breast cancer) across 5 trials, including J101 and DESTINY-Breast01. T-DXd doses ranged from 0.8-8.0 mg/kg Q3W; most patients received 5.4 (n = 312) or 6.4 mg/kg (n = 291). For each end point, multivariate logistic or Cox regression analysis was performed using various exposure metrics of T-DXd and released drug. A statistically significant association was observed between intact T-DXd area under the concentration-time curve (AUC) and confirmed objective response rate (ORR; P = 0.028). No significant exposure-response relationships were observed between intact T-DXd or released drug and duration of response or progression-free survival; however, follow-up was limited. All evaluated safety end points demonstrated a significant (P < 0.05) relationship with either intact T-DXd or released drug, with higher adverse event (AE) rates projected at higher exposures. Dose-response projections suggested an increase in ORR (67.5% vs. 62.9%) and toxicity (e.g., grade ≥ 3 all-cause treatment-emergent AEs: 61% vs. 54%) with T-DXd 6.4 vs. 5.4 mg/kg. Results demonstrate the benefit-risk profile at different doses and guide clinicians in the use of the 5.4-mg/kg Q3W dose in patients with HER2-positive metastatic breast cancer.
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http://dx.doi.org/10.1002/cpt.2291DOI Listing
May 2021

Phase I/Ib Clinical Trial of Sabatolimab, an Anti-TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti-PD-1 Antibody, in Advanced Solid Tumors.

Clin Cancer Res 2021 Jul 21;27(13):3620-3629. Epub 2021 Apr 21.

MD Anderson Cancer Center, Houston, Texas.

Purpose: Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.

Patients And Methods: Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W.

Results: Enrolled patients ( = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab ( = 133) or sabatolimab plus spartalizumab ( = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12-27 months) in colorectal cancer ( = 2), non-small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3-positive staining, including one patient with NSCLC who received prior PD-1 therapy.

Conclusions: Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4746DOI Listing
July 2021

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFβ and PD-L1, in Patients with Esophageal Squamous Cell Carcinoma: Results from a Phase 1 Cohort in Asia.

Target Oncol 2021 Jul 11;16(4):447-459. Epub 2021 Apr 11.

National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: Patients with esophageal squamous cell carcinoma (SCC) have limited treatment options. Blocking transforming growth factor-β (TGFβ), which can be overexpressed in these tumors, may enhance responses to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] inhibitors. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFβ receptor II (TGFβRII) (a TGFβ "trap") fused to a human IgG1 monoclonal antibody blocking PD-L1.

Objective: The objective of this study was to investigate the safety and efficacy of bintrafusp alfa in Asian patients with pretreated, PD-L1-unselected esophageal SCC.

Patients And Methods: In a phase 1 study, Asian patients with pretreated esophageal SCC received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was safety/tolerability with a goal of exploring clinical activity.

Results: By the database cutoff of August 24, 2018, 30 patients (76.7% had two or more prior anticancer regimens) received bintrafusp alfa for a median of 6.1 weeks; two remained on treatment. Nineteen patients (63.3%) had treatment-related adverse events, seven (23.3%) with grade 3/4 events, and there were no treatment-related deaths. The confirmed objective response rate (ORR) per independent review was 10.0% (95% confidence interval [CI] 2.1-26.5); responses lasted 2.8-8.3 + months. All responses occurred in immune-excluded tumors. Investigator-assessed confirmed ORR was 20.0% (95% CI 7.7-38.6). Median overall survival was 11.9 months (95% CI 5.7-not reached).

Conclusions: Bintrafusp alfa demonstrated a manageable safety profile and efficacy in Asian patients with pretreated esophageal SCC.

Clinical Trials Registration: NCT02699515.
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http://dx.doi.org/10.1007/s11523-021-00810-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266718PMC
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 Apr 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

Overcoming the impact of the COVID-19 pandemic on oncology early phase trials and drug development in Asia-Experiences and perspectives of the Asian Oncology Early Phase 1 Consortium.

Asia Pac J Clin Oncol 2021 Aug 27;17(4):388-395. Epub 2021 Jan 27.

Experimental Cancer Therapeutics Unit, Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

Aim: The significance and prioritization of early phase oncology trial continuation during a global pandemic is unknown. This study reported the outcomes, multiple challenges, and broad recommendations associated with the impact of the novel coronavirus disease 2019 (COVID-19) on oncology early phase 1 trials-and on drug development in Asia-based on the experiences and perspectives of Asian oncology phase 1 centers.

Methods: Between March and April 2020 during the initial period of outbreak, the impact of COVID-19 across oncology phase 1 sites in five Asian countries-China (Hong Kong), Japan, South Korea, Taiwan, and Singapore-was retrospectively analyzed.

Results: There was no trial termination or treatment discontinuation in all five countries. Although the most common impact was new patient enrollment being placed on hold, which was based on pharmaceutical sponsors' decision-making, the situation varied per site. Most sites had no restrictions in place that would limit their ability to fully comply with the requirements of conducting the early phase studies. The number of protocol deviations during the pandemic was largely dependent on domestic transportation status during the outbreak rather than the ability of the clinical trial centers.

Conclusion: Determining the risk to benefits ratio of patients with cancer who are enrolled in early phase 1 clinical trials under the unusual circumstances of a global pandemic is important. Specific guidance or guidelines on the conduct of early phase 1 clinical trials during public health emergencies that are based on the recent lessons learned is urgently required.
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http://dx.doi.org/10.1111/ajco.13510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014030PMC
August 2021

Thienoisoindigo (TII)-Based Quinoidal Small Molecules for High-Performance n-Type Organic Field Effect Transistors.

Adv Sci (Weinh) 2020 Jan 20;8(1):2002930. Epub 2020 Nov 20.

Department of Chemistry and the Materials Research Center Northwestern University Evanston IL 60208 USA.

A novel quinoidal thienoisoindigo (TII)-containing small molecule family with dicyanomethylene end-capping units and various alkyl chains is synthesized as n-type organic small molecules for solution-processable organic field effect transistors (OFETs). The molecular structure of the 2-hexyldecyl substituted derivative, , is determined via single-crystal X-ray diffraction and shows that the core is planar and exhibits molecular layers stacked in a "face-to-face" arrangement with short core intermolecular distances of 3.28 Å. The very planar core structure, shortest intermolecular N···H distance (2.52 Å), existence of an intramolecular non-bonded contact between sulfur and oxygen atom (S···O) of 2.80 Å, and a very low-lying LUMO energy level of -4.16 eV suggest that molecules should be electron transporting semiconductors. The physical, thermal, and electrochemical properties as well as OFET performance and thin film morphologies of these new s are systematically studied. Thus, air-processed OFETs exhibit an electron mobility up to 2.54 cm V s with a current ON/OFF ratio of 10-10, which is the first demonstration of TII-based small molecules exhibiting unipolar electron transport characteristics and enhanced ambient stability. These results indicate that construction of quinoidal molecule from TII moiety is a successful approach to enhance n-type charge transport characteristics.
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http://dx.doi.org/10.1002/advs.202002930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788596PMC
January 2020

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors.

Oncologist 2021 05 24;26(5):e863-e873. Epub 2020 Dec 24.

University Hospital Essen, University of Duisburg-Essen, Germany.

Background: Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib.

Materials, And Methods: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288.

Results: In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases.

Conclusion: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury.

Implications For Practice: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.
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http://dx.doi.org/10.1002/onco.13629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100574PMC
May 2021

A Solution Processable Dithioalkyl Dithienothiophene (DSDTT) Based Small Molecule and Its Blends for High Performance Organic Field Effect Transistors.

ACS Nano 2021 Jan 30;15(1):727-738. Epub 2020 Nov 30.

Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.

The 3,5-dithiooctyl dithienothiophene based small molecular semiconductor (), end functionalized with fused dithienothiophene () units, was synthesized and characterized for organic field effect transistors (OFET). The thermal, optical, electrochemical, and computed electronic structural properties of were investigated and contrasted. The single crystal structure of reveals the presence of intramolecular locks between S(alkyl)···S(thiophene), with a very short S-S distance of 3.10 Å, and a planar core. When measured in an OFET device compound exhibits a hole mobility of 3.19 cm V s, when the semiconductor layer is processed by a solution-shearing deposition method and using environmentally acceptable anisole as the solvent. This is the highest value reported to date for an all-thiophene based molecular semiconductor. In addition, solution-processed small molecule/insulating polymer (/PαMS) blend films and devices were investigated. Morphological analysis reveals a nanoscopic vertical phase separation with the PαMS layer preferentially contacting the dielectric and located on top of the stack. The OFET based on the blend comprising 50% weight of exhibits a hole mobility of 2.44 cm V s and a very smaller threshold voltage shift under gate bias stress.
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http://dx.doi.org/10.1021/acsnano.0c07003DOI Listing
January 2021

Phase I Dose-Escalation Study of SCB01A, a Microtubule Inhibitor with Vascular Disrupting Activity, in Patients with Advanced Solid Tumors.

Oncologist 2021 04 18;26(4):e567-e579. Epub 2020 Dec 18.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Lessons Learned: SCB01A is a novel microtubule inhibitor with vascular disrupting activity. This first-in-human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity. SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

Background: SCB01A, a novel microtubule inhibitor, has vascular disrupting activity.

Methods: In this phase I dose-escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m to the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). SCB01A-induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.

Results: Treatment-related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m cohort; grade 3 gastric hemorrhage in the 6.5 mg/m cohort; grade 2 thromboembolic event in the 24 mg/m cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m cohort. The MTD was 24 mg/m , and average half-life was ~2.5 hours. The area under the curve-dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A-induced neurotoxicity was reversible in vitro.

Conclusion: The MTD of SCB01A was 24 mg/m every 21 days; it is safe and tolerable in patients with solid tumors.
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http://dx.doi.org/10.1002/onco.13612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018321PMC
April 2021

Safety and Clinical Activity of a New Anti-PD-L1 Antibody as Monotherapy or Combined with Targeted Therapy in Advanced Solid Tumors: The PACT Phase Ia/Ib Trial.

Clin Cancer Res 2021 Mar 23;27(5):1267-1277. Epub 2020 Nov 23.

Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.

Purpose: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334).

Patients And Methods: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy ( = 15) or combined with ramucirumab ( = 10), abemaciclib ( = 24), or merestinib ( = 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety.

Results: Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months.

Conclusions: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2821DOI Listing
March 2021

Safety and Preliminary Efficacy of Ramucirumab in Combination with FOLFOX4 in Patients with Advanced Hepatocellular Carcinoma: A Nonrandomized, Open-Label, Phase Ib Study.

Oncologist 2020 12 31;25(12):e1921-e1929. Epub 2020 Oct 31.

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

Lessons Learned: The combination of ramucirumab (8 mg/kg intravenous, day 1 every 2 weeks) and FOLFOX4 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC) was not sufficiently tolerated. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with HCC. Dose modification and patient selection should be considered for the future development of ramucirumab plus FOLFOX chemotherapy for advanced HCC.

Background: The objective of this study was to investigate the safety, preliminary efficacy, pharmacokinetics, and immunogenicity of ramucirumab plus FOLFOX4 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC).

Methods: Patients received ramucirumab (8 mg/kg) intravenously (IV) on day 1, followed by FOLFOX4 (oxaliplatin 85 mg/m IV on day 1, folinic acid 200 mg/m IV, bolus fluorouracil [5-FU] 400 mg/m , and a continuous infusion of 5-FU 600 mg/m over 22 hours, on days 1 and 2) every 2 weeks. The primary endpoint was to assess the safety and tolerability of the combination therapy.

Results: Eight patients (6 men, 2 women) were treated; all eight patients experienced at least one treatment-emergent adverse event (TEAE) of grade ≥3. Dose-limiting toxicities occurred in three patients (37.5%): hepatic hemorrhage (grade 4), blood bilirubin increased (grade 3), and febrile neutropenia (grade 3). Two patients discontinued study because of hepatic hemorrhage (grade 4) and blood bilirubin increase (grade 3). Six deaths occurred due to progressive disease, and no deaths due to TEAEs.

Conclusion: There were no unexpected safety findings with ramucirumab plus FOLFOX4 based on the known safety and toxicity of this regimen. The combination was not sufficiently tolerated in patients with advanced HCC at the specified dose and schedule.
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http://dx.doi.org/10.1002/onco.13550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108062PMC
December 2020

Ramucirumab and durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: An open-label, phase Ia/b study (JVDJ).

Eur J Cancer 2020 09 19;137:272-284. Epub 2020 Aug 19.

National Taiwan University Hospital, Taipei, Taiwan.

Background: Emerging evidence supports combining immune checkpoint inhibitors (ICIs) with conventional or targeted therapies to enhance ICI antitumour activity and broaden the spectrum of patients who respond to ICIs. Here, we present the safety and preliminary efficacy of ramucirumab, an anti-VEGFR2 IgG1, plus durvalumab, an anti-PD-L1 IgG1, in previously treated patients with advanced non-small-cell lung cancer (NSCLC), gastric/gastro-oesophageal junction adenocarcinoma (gastric/GEJ), or hepatocellular carcinoma (HCC).

Patients And Methods: A 25-centre, phase Ia/b single-arm, non-randomised, multi-cohort study was undertaken in patients with advanced/metastatic disease, Eastern Cooperative Oncology Group performance status, 0-1, progression on prior therapy, no prior ramucirumab or immunotherapy and any PD-L1 status. Patients received ramucirumab (10 mg/kg) plus durvalumab (1125 mg) intravenously Q3W (NSCLC), or ramucirumab (8 mg/kg) plus durvalumab (750 mg) Q2W (gastric/GEJ, HCC).

Results: Phase Ia treatment was found safe for phase Ib expansion; final enrolment was NSCLC (n = 28), gastric/GEJ (n = 29), HCC (n = 28). Grade ≥3 treatment-related adverse events occurred in 32.1%, 37.9% and 42.9% of patients, respectively. The most common were fatigue (35.7%), hypertension (34.5%) and diarrhoea (28.6%), respectively. Two patients died owing to an adverse event; one was treatment-related (hepatitis acute, HCC cohort). Objective response rate was 11% for NSCLC and HCC and 21% for gastric/GEJ. Median progression-free survival and overall survival were, respectively, 2.7 and 11 months in NSCLC; 2.6 and 12.4 months in gastric/GEJ; 4.4 and 10.7 months in HCC, with more prolonged survival in patients with high PD-L1 expression.

Conclusion: Ramucirumab/durvalumab exhibited manageable safety. The combination showed antitumour activity in all cohorts, particularly in patients with high PD-L1 expression.
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http://dx.doi.org/10.1016/j.ejca.2020.06.007DOI Listing
September 2020

Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors.

J Immunother Cancer 2020 06;8(1)

Linear Clinical Research, Nedlands, Western Australia, Australia.

Background: The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.

Methods: Patients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab's safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.

Results: Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1-2 severity; anemia (4.9%) was the most common grade 3-4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.

Conclusions: Tislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.

Trial Registration Number: NCT02407990.
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http://dx.doi.org/10.1136/jitc-2019-000453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295442PMC
June 2020

An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer.

Thyroid 2020 09 29;30(9):1254-1262. Epub 2020 Jul 29.

Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided  = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test:  = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test -value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.
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http://dx.doi.org/10.1089/thy.2019.0269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482116PMC
September 2020

Open-label, phase IIa study of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma.

Eur J Cancer 2020 08 10;135:31-38. Epub 2020 Jun 10.

Department of Urology and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China.

Purpose: This study (NCT02083354) assessed the efficacy and safety of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma.

Method: Overall, 77 patients of East Asian origin (including 61 from Mainland China) with unresectable or metastatic BRAF V600-mutant cutaneous melanoma were enrolled. Prior treatment was allowed except with BRAF/MEK inhibitors. Patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end-point was objective response rate (ORR) using Response Evaluation Criteria in Solid Tumours 1.1. Secondary end-points were duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetics and safety.

Results: At data cutoff (February 23, 2018; median follow-up, 8.3 months), treatment was ongoing in 36 patients (47%). The median age was 52 years; 32% of patients had elevated lactate dehydrogenase, and 84% had received prior systemic therapy. ORR was 61% (95% confidence interval: 49.2-72.0), with four patients (5%) achieving complete response. Median DOR and PFS were 11.3 and 7.9 months, respectively. Median OS was not reached. The most common adverse event (AE) of any grade was pyrexia (56%). Grade ≥III AEs occurred in 29 patients (38%). The most common grade ≥III AEs were pyrexia (8%) and anaemia (6%). AEs led to permanent discontinuation in five patients (6.5%). Mean C for dabrafenib and trametinib was 3560 and 11.5 ng/mL (day 1) and 2680 and 27.1 ng/mL (day 15), respectively.

Conclusion: These results support the efficacy and tolerability of dabrafenib in combination with trametinib in East Asian patients with unresectable or metastatic BRAF V600-mutant cutaneous melanoma.
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http://dx.doi.org/10.1016/j.ejca.2020.04.044DOI Listing
August 2020

Endoscopic ultrasound ablation in a patient with multiple metastatic pancreatic tumors from adrenocorticotropic hormone-producing thymic neuroendocrine neoplasm.

Dig Endosc 2021 Mar 18;33(3):458-463. Epub 2020 Aug 18.

Departments of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Adrenocorticotropic hormone (ACTH)-producing neuroendocrine neoplasm (NEN) of the thymus is rare. Lymph nodes and bones are the most common metastatic sites. Most cases present with florid Cushing's syndrome (CS). Here, we reported a 58-year-old woman, who presented with intermittent flush and weight loss. Imaging studies revealed tumors in the mediastinum, pancreas, and bones. Contrast-enhanced harmonic endoscopic ultrasound (EUS) of the pancreatic tumors showed heterogeneous and hyperenhancing characteristics. EUS elastography revealed a heterogeneous stiff pattern. EUS-fine needle biopsy to the pancreatic lesion confirmed the NEN nature. Serum ACTH and cortisol levels were abnormally high. Immunohistochemical staining of the thymic and pancreatic specimens was positive for ACTH. However, the patient did not have obvious CS appearance. The patient underwent surgery, radiation, EUS-guided ethanol injection, and anti-cancer medications, but the disease still progressed. The patient died from infection 16 months after NEN was diagnosed. In conclusion, the pancreas can be a metastatic site for ACTH-producing thymic NEN. EUS-associated procedures can help in the diagnosis and treatment of pancreatic metastatic NEN.
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http://dx.doi.org/10.1111/den.13752DOI Listing
March 2021

Association of Programmed Death-Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinoma Receiving Crizotinib.

Oncologist 2020 08 13;25(8):702-711. Epub 2020 May 13.

Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Background: Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib.

Materials And Methods: PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments.

Results: A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD-L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression-free survival (PFS) was better in tumors with negative PD-L1 expression (ORR/PFS in PD-L1 0% vs. 1%-49% vs. 50%-100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD-L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160-0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD-L1 expression.

Conclusion: Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib.

Implications For Practice: Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small-molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD-L1 expression was also associated with worse response rate and shorter progression-free survival of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD-L1 compared with long variants (V1, V2, and V6). Testing PD-L1 before initiating crizotinib for ALK-positive lung cancer could be a simple method to provide important prognostic information.
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http://dx.doi.org/10.1634/theoncologist.2020-0088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418350PMC
August 2020

PD-1 Blockade in Anaplastic Thyroid Carcinoma.

J Clin Oncol 2020 08 4;38(23):2620-2627. Epub 2020 May 4.

Oregon Health & Science University, Portland, OR.

Purpose: Anaplastic thyroid carcinoma is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options for patients with -wild type disease. As part of a phase I/II study in patients with advanced/metastatic solid tumors, patients with anaplastic thyroid carcinoma were treated with spartalizumab, a humanized monoclonal antibody against the programmed death-1 (PD-1) receptor.

Methods: We enrolled patients with locally advanced and/or metastatic anaplastic thyroid carcinoma in a phase II cohort of the study. Patients received 400 mg spartalizumab intravenously, once every 4 weeks. The overall response rate was determined according to RECIST v1.1.

Results: Forty-two patients were enrolled. Adverse events were consistent with those previously observed with PD-1 blockade. Most common treatment-related adverse events were diarrhea (12%), pruritus (12%), fatigue (7%), and pyrexia (7%). The overall response rate was 19%, including three patients with a complete response and five with a partial response. Most patients had baseline tumor biopsies positive for PD-L1 expression (n = 28/40 evaluable), and response rates were higher in PD-L1-positive (8/28; 29%) versus PD-L1-negative (0/12; 0%) patients. The highest rate of response was observed in the subset of patients with PD-L1 ≥ 50% (6/17; 35%). Responses were seen in both -nonmutant and -mutant patients and were durable, with a 1-year survival of 52.1% in the PD-L1-positive population.

Conclusion: To our knowledge, this is the first clinical trial to show responsiveness of anaplastic thyroid carcinoma to PD-1 blockade.
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http://dx.doi.org/10.1200/JCO.19.02727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476256PMC
August 2020

An International Real-World Analysis of the Efficacy and Safety of Lorlatinib Through Early or Expanded Access Programs in Patients With Tyrosine Kinase Inhibitor-Refractory ALK-Positive or ROS1-Positive NSCLC.

J Thorac Oncol 2020 09 28;15(9):1484-1496. Epub 2020 Apr 28.

Department of Hematology-Oncology, National University Cancer Institute, Singapore.

Introduction: Lorlatinib, a next-generation central nervous system-penetrant ALK/ROS1 tyrosine kinase inhibitor (TKI), is approved to treat TKI-refractory ALK-positive (ALK+) NSCLC based on results from a phase 2 study.

Methods: A real-world analysis was performed on ALK+ or ROS1-positive (ROS1+) patients with NSCLC enrolled in lorlatinib early or expanded access programs in Hong Kong, Singapore, South Korea, Taiwan, Thailand, and the United States.

Results: A total of 95 patients with NSCLC (76 ALK+ and 19 ROS1+) were analyzed. Among ALK+ patients treated with less than two previous TKIs, two or more previous TKIs, and three or more previous TKIs, the objective response rates (ORR) and median progression-free survival (mPFS) were 42% (95% confidence interval [CI]: 26-59; n = 38) and not reached (NR) (95% CI: 4.5-NR; n = 45), 35% (95% CI: 22-49; n = 55) and 11.2 months (95% CI: 4.5-NR; n = 66), and 18% (95% CI: 4-43; n = 17) and 6.5 months (95% CI: 3.5-11.6; n = 21), respectively. The ORRs and mPFSs were 13% (95% CI: 0-53; n = 8) and 9.2 months (95% CI: 3.3-NR; n = 9) for patients treated with one second-generation ALK TKI as the only ALK TKI received. For ROS1+ patients, ORRs and mPFSs were 41% (95% CI: 18-67; n = 17) and 11.9 months (95% CI: 6.4-NR; n = 19). The intracranial ORRs were 35% (95% CI: 22-49) and 55% (95% CI: 23-83) for 52 ALK+ and 11 ROS1+ patients. mPFS was 9.3 months (95% CI: 1.0-NR; n = 13) for patients with leptomeningeal carcinomatosis. No new safety signals were noted.

Conclusion: Lorlatinib exhibited meaningful activity in TKI-refractory ALK+ or ROS1+ patients with NSCLC enrolled in early or expanded access programs.
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http://dx.doi.org/10.1016/j.jtho.2020.04.019DOI Listing
September 2020

Impact of lorlatinib on patient-reported outcomes in patients with advanced ALK-positive or ROS1-positive non-small cell lung cancer.

Lung Cancer 2020 06 10;144:10-19. Epub 2020 Mar 10.

University of Colorado, Aurora, CO, USA. Electronic address:

Objectives: To evaluate patient-reported outcomes (PROs) from a phase 1/2 study (NCT01970865) in patients with anaplastic lymphoma kinase (ALK)- or ROS1-positive advanced non-small cell lung cancer (NSCLC) treated with lorlatinib 100 mg once daily.

Materials And Methods: PRO measures, including global quality of life (QoL), functioning domains and symptoms, were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the 13-item Lung Cancer (QLQ-LC13) module. Mean changes of absolute scores from baseline were assessed. Percentages of patients showing improvement, stability or worsening on each scale were reported, with a change of ≥10 points considered clinically meaningful (CM).

Results: 255 patients completed baseline and ≥1 post-baseline PRO assessment. Most patients had CM improvement (42.4 %) or stable (38.0 %) scores for global QoL. Functioning domains with the greatest proportion of patients with improved scores were role (37.6 %) and emotional (36.9 %); only one domain had more patients showing worsening than improving function (cognitive [24.3 % vs 22.4 %]). Most patients showed improved or stable scores for disease-related symptoms. No QLQ-C30 symptom domains had more patients worsening than improving. Symptoms on the QLQ-C30 scale with the greatest proportion of patients with improved scores were fatigue (49.4 %) and insomnia (46.3 %). Four QLQ-LC13 domains had more patients worsening than improving (two most affected were peripheral neuropathy [37.3 % vs 13.7 %] and alopecia [19.2 % vs 13.3 %]). Symptoms on the QLQ-LC13 scale with the greatest proportion of patients with improved scores were cough (42.7 %) and pain in other parts (32.9 %).

Conclusions: Lorlatinib treatment showed CM improvement from baseline in global QOL that was maintained over time. Additionally, there were improvements in physical, emotional, social, and role functioning. Improvements were shown in appetite loss and key symptoms such as pain, dyspnea, cough and fatigue; a worsening in peripheral neuropathy was noted.
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http://dx.doi.org/10.1016/j.lungcan.2020.02.011DOI Listing
June 2020

A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti-PD-1 antibody, in patients with advanced solid tumors.

J Immunother Cancer 2020 03;8(1)

Sarah Cannon Research Institute, Nashville, Tennessee, USA.

Background: Spartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.

Methods: In the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).

Results: Patients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.

Conclusions: Spartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types.

Trial Registration Number: NCT02404441.
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http://dx.doi.org/10.1136/jitc-2020-000530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073791PMC
March 2020

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial.

J Thorac Oncol 2020 07 13;15(7):1210-1222. Epub 2020 Mar 13.

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

Introduction: The safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β) receptor II (a TGF-β "trap") fused to a human immunoglobulin G1 antibody blocking programmed death-ligand 1 (PD-L1), was evaluated in patients with advanced NSCLC.

Methods: This expansion cohort of NCT02517398, an ongoing, phase 1, open-label trial, includes 80 patients with advanced NSCLC that progressed after platinum doublet therapy or after platinum-based adjuvant or neoadjuvant treatment and those who also have not received previous immunotherapy. Patients were randomized at a one-to-one ratio to receive either bintrafusp alfa 500 mg or the recommended phase 2 dosage of 1200 mg every 2 weeks. The primary end point was the best overall response (by Response Evaluation Criteria in Solid Tumors 1.1 as adjudicated by independent review committee) and was assessed by the objective response rate (ORR).

Results: A total of 80 patients were randomized to receive bintrafusp alfa 500 or 1200 mg (n = 40 each). Median follow-up was 51.9 weeks (IQR, 19.6-74.0). The ORR in all patients was 21.3% (17 of 80). The ORR was 17.5% (seven of 40) and 25.0% (10 of 40) for the 500 mg dose and the 1200 mg dose (recommended phase 2 dose), respectively. At the 1200 mg dose, patients with PD-L1-positive and PD-L1-high (≥80% expression on tumor cells) had ORRs of 36.0% (10 of 27) and 85.7% (six of seven), respectively. Treatment-related adverse events occurred in 55 of the 80 patients (69%) and were graded as greater than or equal to 3 in 23 of the 80 patients (29%). Of the 80 patients, eight (10%) had a treatment-related adverse event that led to treatment discontinuation; no treatment-related deaths occurred.

Conclusions: Bintrafusp alfa had encouraging efficacy and manageable tolerability in patients with NSCLC previously treated with platinum.
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http://dx.doi.org/10.1016/j.jtho.2020.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210474PMC
July 2020

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours.

Br J Cancer 2020 04 12;122(9):1324-1332. Epub 2020 Mar 12.

Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S. Rd., Taipei, Taiwan.

Background: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers.

Methods: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD.

Results: Study 1280.1 involved 61 patients (part I: xentuzumab 10-1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10-3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD.

Conclusions: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity.

Clinical Trial Registration: NCT01403974; NCT01317420.
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http://dx.doi.org/10.1038/s41416-020-0774-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188670PMC
April 2020

Phase I Dose-Escalation and -Expansion Study of Telisotuzumab (ABT-700), an Anti-c-Met Antibody, in Patients with Advanced Solid Tumors.

Mol Cancer Ther 2020 05 3;19(5):1210-1217. Epub 2020 Mar 3.

Virginia G. Piper Cancer Center, Scottsdale Healthcare, Scottsdale, Arizona.

This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5-25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, = 15; dose expansion, = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia ( = 9, 20.0%) and fatigue ( = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with -amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors ( = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with -amplified advanced solid tumors.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0529DOI Listing
May 2020

Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials.

Lancet Oncol 2020 02 11;21(2):261-270. Epub 2019 Dec 11.

Ignyta, San Diego, CA, USA.

Background: Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC.

Methods: We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).

Findings: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64-88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4-20·2). Median duration of response was 24·6 months (95% CI 11·4-34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred.

Interpretation: Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC.

Funding: Ignyta/F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(19)30690-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811790PMC
February 2020

Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts.

Cancer Sci 2020 Feb 30;111(2):536-547. Epub 2019 Dec 30.

State Key Laboratory of Translational Oncology, Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Hong Kong, China.

Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, C >EC (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).
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http://dx.doi.org/10.1111/cas.14254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004521PMC
February 2020