Publications by authors named "Taofeek K Owonikoko"

168 Publications

Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451.

J Clin Oncol 2021 Apr 8;39(12):1349-1359. Epub 2021 Mar 8.

Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

Purpose: In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC.

Methods: Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested.

Results: Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab versus placebo (hazard ratio [HR], 0.92; 95% CI, 0.75 to 1.12; = .37; median, 9.2 9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI, 0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI, 0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS benefit with nivolumab plus ipilimumab was observed in patients with tumor mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4 treatment-related adverse events were nivolumab plus ipilimumab (52.2%), nivolumab (11.5%), and placebo (8.4%).

Conclusion: Maintenance therapy with nivolumab plus ipilimumab did not prolong OS for patients with ED-SCLC who did not progress on first-line chemotherapy. There were no new safety signals.
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http://dx.doi.org/10.1200/JCO.20.02212DOI Listing
April 2021

Downregulation of death receptor 4 is tightly associated with positive response of EGFR mutant lung cancer to EGFR-targeted therapy and improved prognosis.

Theranostics 2021 15;11(8):3964-3980. Epub 2021 Feb 15.

Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, USA.

Death receptor 4 (DR4), a cell surface receptor, mediates apoptosis or induces inflammatory cytokine secretion upon binding to its ligand depending on cell contexts. Its prognostic impact in lung cancer and connection between EGFR-targeted therapy and DR4 modulation has not been reported and thus was the focus of this study. Intracellular protein alterations were measured by Western blotting. Cell surface protein was detected with antibody staining and flow cytometry. mRNA expression was monitored with qRT-PCR. Gene transactivation was analyzed with promoter reporter assay. Drug dynamic effects were evaluated using xenografts. Gene modulations were achieved with gene overexpression and knockdown. Proteins in human archived tissues were stained with immunohistochemistry. EGFR inhibitors (e.g., osimertinib) decreased DR4 levels only in EGFR mutant NSCLC cells and tumors, being tightly associated with induction of apoptosis. This modulation was lost once cells became resistant to these inhibitors. Increased levels of DR4 were detected in cell lines with acquired osimertinib resistance and in NSCLC tissues relapsed from EGFR-targeted therapy. DR4 knockdown induced apoptosis and augmented apoptosis when combined with osimertinib in both sensitive and resistant cell lines, whereas enforced DR4 expression significantly attenuated osimertinib-induced apoptosis. Mechanistically, osimertinib induced MARCH8-mediated DR4 proteasomal degradation and suppressed MEK/ERK/AP-1-dependent DR4 transcription, resulting in DR4 downregulation. Moreover, we found that DR4 positive expression in human lung adenocarcinoma was significantly associated with poor patient survival. Collectively, we suggest that DR4 downregulation is coupled to therapeutic efficacy of EGFR-targeted therapy and predicts improved prognosis, revealing a previously undiscovered connection between EGFR-targeted therapy and DR4 modulation.
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http://dx.doi.org/10.7150/thno.54824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914351PMC
February 2021

Erratum: GSK3 is required for rapalogs to induce degradation of some oncogenic proteins and to suppress cancer cell growth.

Oncotarget 2021 Feb 2;12(3):251-252. Epub 2021 Feb 2.

Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.

[This corrects the article DOI: 10.18632/oncotarget.3291.].
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http://dx.doi.org/10.18632/oncotarget.27752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869579PMC
February 2021

Impact of lung metastases on overall survival in the phase 3 SELECT study of lenvatinib in patients with radioiodine-refractory differentiated thyroid cancer.

Eur J Cancer 2021 Apr 19;147:51-57. Epub 2021 Feb 19.

Massachusetts General Hospital Cancer Center, Boston, MA, USA.

Background: Lung metastases may worsen overall survival (OS) in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). We investigated (post hoc) the impact of lung metastases on survival in SELECT (a phase 3 study).

Patients And Methods: 392 patients with RR-DTC were randomised 2:1 to lenvatinib 24 mg daily (n = 261) or placebo (n = 131). Placebo-treated patients could crossover to open-label lenvatinib following progression. Patients were grouped by size of baseline lung metastases. Safety/efficacy outcomes, collated by these lung-metastases subgroups, were generated.

Results: Lenvatinib-treated population distributions per baseline lung metastases subgroup were any lung metastases (target/nontarget lesions; n = 226), and by maximum size of target lung lesions ≥1.0 cm (n = 199), ≥1.5 cm (n = 150), ≥2.0 cm (n = 94) and <2.0 cm (n = 105). In patients with any lung metastases, no statistically significant difference in OS was observed between treatment arms (HR: 0.76; 95% CI: 0.57-1.01; P = 0.0549). Median OS for lung metastases of ≥1.0 cm was 44.7 months (lenvatinib) versus 33.1 months (placebo) (HR: 0.63; 95% CI: 0.47-0.85; P = 0.0025). OS was significantly prolonged with lenvatinib versus placebo among patients with lung metastases of ≥1.0 cm, ≥1.5 cm, ≥2.0 cm and <2.0 cm; median OS was shorter in the ≥2.0 cm subgroup (lenvatinib: 34.7 months) versus other subgroups (lenvatinib: 44.1-49.2 months). Multivariate analysis demonstrated lenvatinib significantly prolonged OS in patients with lung metastases of ≥1.0 cm after adjustment for baseline characteristics.

Conclusions: Lenvatinib treatment resulted in longer OS in patients with lung metastases of ≥1.0 cm versus placebo (even with the 89% crossover rate). Early initiation of lenvatinib may improve outcomes in patients with RR-DTC and lung metastases of ≥1.0 cm.

Source Study Registration: ClinicalTrials.Gov Identifier: NCT01321554.
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http://dx.doi.org/10.1016/j.ejca.2020.12.032DOI Listing
April 2021

Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer.

Cancer Chemother Pharmacol 2021 May 17;87(5):689-700. Epub 2021 Feb 17.

G1 Therapeutics, Inc., Research Triangle Park, NC, USA.

Purpose: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC).

Methods: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection.

Results: Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m dose would induce a 40-50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03.

Conclusion: Integrated PK/PD, safety, and efficacy data support 240 mg/m as the RP2D for trilaciclib. CLINICALTRIALS.

Gov Identifiers: NCT02243150; NCT02499770; NCT02514447.
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http://dx.doi.org/10.1007/s00280-021-04239-9DOI Listing
May 2021

Phase 2 Study of Talazoparib in Patients With Homologous Recombination Repair-Deficient Squamous Cell Lung Cancer: Lung-MAP Substudy S1400G.

Clin Lung Cancer 2021 Jan 10. Epub 2021 Jan 10.

UC Davis Comprehensive Cancer Center, Sacramento, CA.

Purpose: This signal finding study (S1400G) was designed to evaluate the efficacy of talazoparib in advanced stage squamous cell lung cancer harboring homologous recombination repair deficiency.

Patients And Methods: The full eligible population (FEP) had tumors with a deleterious mutation in any of the study-defined homologous recombination repair genes and without prior exposure to a PARP inhibitor. The primary analysis population (PAP) is a subset of FEP with alteration in ATM, ATR, BRCA1, BRCA2, or PALB2. Treatment consisted of talazoparib 1 mg daily continuously in 21-day cycles. A 2-stage design with exact 93% power and 1-sided 0.07 type I error required enrollment of 40 patients in the PAP in order to rule out an overall response rate (ORR) of 15% or less if the true ORR is ≥ 35%.

Results: The study enrolled 47 patients in the FEP, of whom 24 were in the PAP. The median age for the FEP was 66.7 years; 83% were male and 85% white. ORR in the PAP was 4% (95% confidence interval [CI], 0, 21) with disease control rate of 54% (95% CI, 33, 74). Median progression-free survival and overall survival were 2.4 months (95% CI, 1.5-2.8) and 5.2 months (95% CI, 4.0-10), respectively. In the FEP, ORR was 11% (95% CI, 3.6, 23), the disease control rate was 51% (95% CI, 36, 66), and the median duration of response was 1.8 months (95% CI, 1.3, 4.2). Median progression-free and overall survival were 2.5 months and 5.7 months, respectively.

Conclusions: S1400G failed to show sufficient level of efficacy for single agent talazoparib in a biomarker defined subset of squamous lung cancer with homologous recombination repair deficiency.
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http://dx.doi.org/10.1016/j.cllc.2021.01.001DOI Listing
January 2021

Durvalumab and tremelimumab with or without stereotactic body radiation therapy in relapsed small cell lung cancer: a randomized phase II study.

J Immunother Cancer 2020 12;8(2)

Hematology and Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA

Background: Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 and cytotoxic T lymphocyte-associated protein 4 has achieved modest clinical activity as salvage therapy in relapsed small cell lung cancer (SCLC). We conducted this signal-finding study to assess the efficacy of ICB with or without radiation in relapsed SCLC.

Methods: Patients with relapsed SCLC and ≤2 previous lines of therapy were randomized to (1) arm A: durvalumab (D) 1500 mg/tremelimumab (T) 75 mg (intravenously every 4 weeks without stereotactic body radiation therapy (SBRT)) or (2) arm B: immune-sensitizing SBRT to one selected tumor site (9 Gy × 3 fractions) followed by D/T. Treatment continued until progression or a maximum of 12 months. The co-primary endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). We evaluated circulating lymphocyte repertoire in serial peripheral blood samples and tumor infiltrating lymphocytes (TILs) from on-treatment biopsies as pharmacodynamic markers.

Results: Eighteen patients were randomized to arms A and B (n=9 each): median age 70 years; 41.2% women. The median PFS and ORR were 2.1 months and 0% in arm A and 3.3 months and 28.6% in arm B. The median overall survival (OS) was 2.8 months in arm A and 5.7 months in arm B (p=0.3772). Pooled efficacy of D/T±SBRT in 15 Response evaluation criteria in solid tumors (RECIST) evaluable patients across both arms showed the best ORR in terms of partial response in 13.3%, stable disease in 26.6% and progressive disease in 60.0%; the overall median PFS and OS were 2.76 and 3.9 months. The most common adverse events were grade 1 fatigue (66%) and grade 1 elevated amylase (56%) in arm A, and grade 1 fatigue (56%) and pain (44%) in arm B. There was a significant increase in activated CD8(+)ICOS+ T cells (p=0.048) and a reduction in naïve T cells (p=0.0454) in peripheral blood following treatment, along with a significant amount of activated CD8+ICOS+ T cells in TILs from responders.

Conclusions: The D/T combination with and without SBRT was safe but did not show sufficient efficacy signal in relapsed SCLC. Changes in peripheral blood lymphocyte and TILs were consistent with an immunologic response. NCT02701400.
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http://dx.doi.org/10.1136/jitc-2020-001302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754662PMC
December 2020

Effects of Rovalpituzumab Tesirine on Ventricular Repolarization in Patients With Small-Cell Lung Cancer.

Clin Transl Sci 2021 Mar 19;14(2):664-670. Epub 2020 Dec 19.

Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

Small cell lung cancer (SCLC) is a leading cause of cancer death worldwide, with few treatment options. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate that targets delta-like 3 on SCLC cells to deliver a cytotoxic payload directly to tumor cells. In this study, the cardiac safety profile of Rova-T was assessed by evaluating changes in QT interval, electrocardiogram (ECG) waveform, heart rate, and proarrhythmic adverse events (AEs) after treatment with Rova-T in patients with previously treated extensive-stage SCLC. Patients underwent ECG monitoring for 2 weeks after each of 2 i.v. infusions of 0.3 mg/kg Rova-T over 30 minutes, administered 6 weeks apart. Forty-six patients received at least one dose of Rova-T. At the geometric mean Rova-T maximum serum concentration of 7,940 ng/mL, ECG monitoring showed no significant changes in the Fridericia-corrected QT (QTcF) interval; the upper limit of the 2-sided 90% confidence interval did not exceed 10 msec for any time point. There were no clinically significant changes in QRS or PR intervals, ECG waveforms, or heart rate after Rova-T administration. All patients experienced a treatment-emergent AE (TEAE); 78% had a grade ≥ 3 TEAE, 59% had a serious TEAE, and 41% had a cardiac-related TEAE. The TEAEs that might signal proarrhythmia tendencies were uncommon. Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova-T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.
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http://dx.doi.org/10.1111/cts.12928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993269PMC
March 2021

A Call to Action: Dismantling Racial Injustices in Preclinical Research and Clinical Care of Black Patients Living with Small Cell Lung Cancer.

Cancer Discov 2021 Feb 14;11(2):240-244. Epub 2020 Dec 14.

Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.

Small cell lung cancer (SCLC) is an aggressive disease with dismal survival rates and limited therapeutic options. SCLC development is strongly associated with exposure to tobacco carcinogens. However, additional genetic and environmental risk factors that contribute to SCLC pathogenesis are beginning to emerge. Here, we specifically assess disparities pertaining to SCLC in Black populations. In contrast to non-small cell lung cancer, preliminary data suggest that Black individuals may actually be at a lower risk of developing SCLC relative to white individuals. This difference remains unexplained but urgently needs to be verified in larger data sets, because it could provide important new insights and approaches to understanding this recalcitrant tumor. Importantly, little biological information exists on SCLC in Black individuals, and few patient-derived preclinical SCLC models from diverse ancestries are available in the laboratory. Unfortunately, we note strikingly low numbers of Black participants in clinical trials testing new treatments for SCLC. Evidence further indicates that care for patients with SCLC may vary between communities with a large fraction of Black patients and those without. Together, these observations underscore the need to better investigate genetic, environmental, and socioeconomic factors associated with SCLC development, preclinical research, clinical care, and outcomes.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858238PMC
February 2021

YAP1 Expression in SCLC Defines a Distinct Subtype With T-cell-Inflamed Phenotype.

J Thorac Oncol 2021 03 25;16(3):464-476. Epub 2020 Nov 25.

Tissue Procurement and Pathology Shared Resource, Winship Cancer Institute of Emory University, Atlanta, Georgia; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.

Introduction: The clinical and biological significance of the newly described SCLC subtypes, SCLC-A, SCLC-N, SCLC-Y, and SCLC-P, defined by the dominant expression of transcription factors ASCL1, NeuroD1, YAP1, and POU2F3, respectively, remain to be established.

Methods: We generated new RNA sequencing expression data from a discovery set of 59 archival tumor samples of neuroendocrine tumors and new protein expression data by immunohistochemistry in 99 SCLC cases. We validated the findings from this discovery set in two independent validation sets consisting of RNA sequencing data generated from 51 SCLC cell lines and 81 primary human SCLC samples.

Results: We successfully classified 71.8% of SCLC and 18.5% of carcinoid cases in our discovery set into one of the four SCLC subtypes. Gene set enrichment analysis for differentially expressed genes between the SCLC survival outliers (top and bottom deciles) matched for clinically relevant prognostic factors revealed substantial up-regulation of interferon-γ response genes in long-term survivors. The SCLC-Y subtype was associated with high expression of interferon-γ response genes, highest weighted score on a validated 18-gene T-cell-inflamed gene expression profile score, and high expression of HLA and T-cell receptor genes. YAP1 protein expression was more prevalent and more intensely expressed in limited-stage versus extensive-stage SCLC (30.6% versus 8.5%; p = 0.0058) indicating good prognosis for the SCLC-Y subtype. We replicated the inflamed phenotype of SCLC-Y in the two independent validation data sets from the SCLC cell lines and tumor samples.

Conclusions: SCLC subtyping using transcriptional signaling holds clinical relevance with the inflamed phenotype associated with the SCLC-Y subset.
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http://dx.doi.org/10.1016/j.jtho.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920957PMC
March 2021

Benefits and limitations of real-world evidence: lessons from mutation-positive non-small-cell lung cancer.

Future Oncol 2021 Mar 26;17(8):965-977. Epub 2020 Nov 26.

Winship Cancer Institute, Emory University School of Medicine, 201 Dowman Drive, Atlanta, GA 30322, USA.

While randomized controlled trials (RCTs) are the gold standard for evidence-based medicine, they do not always reflect real-world patient populations, limiting their generalizability and external validity. Real-world evidence (RWE), generated during routine clinical practice, is increasingly important in determining effectiveness outside of the tightly controlled conditions of RCTs, and is now recognized by regulatory bodies as a valuable complement to RCTs. Consequently, it is increasingly important for physicians to understand how RWE data can be used alongside clinical trial data. Here, we discuss the different types of real-world observational studies, outline the benefits and limitations of RWE, and, using examples from mutation-positive non-small-cell lung cancer, outline how RWE can be used to help inform treatment decisions.
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http://dx.doi.org/10.2217/fon-2020-0951DOI Listing
March 2021

The novel MET inhibitor, HQP8361, possesses single agent activity and enhances therapeutic efficacy of AZD9291 (osimertinib) against AZD9291-resistant NSCLC cells with activated MET.

Am J Cancer Res 2020 1;10(10):3316-3327. Epub 2020 Oct 1.

Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute Atlanta, GA, USA.

HQP8361 (MK8033) is a novel and selective MET kinase inhibitor that has completed a phase I clinical trial. AZD9291 (osimertinib) represents the first-approved third generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) for the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations and resistant T790M mutation, but faces the giant challenge of acquired resistance developed in patients in the clinic. The current study focuses on determining the activity and mechanism of action of HQP8361 as a single agent and in combination with AZD9291 against human NSCLC cells, particularly those with acquired resistance to AZD9291. The majority of human NSCLC cell lines tested had very low levels of MET and p-MET and were insensitive to HQP8361. However, AZD9291-resistant (AR) cell lines with high levels of MET and p-MET responded to HQP8361 single agent and particularly to the combination of HQP8361 and AZD9291. The HQP8361 and AZD9291 combination synergistically decreased the survival of these HCC827/AR cell lines with enhanced induction of apoptosis that involved alteration of Bim and Mcl-1 levels via modulating their degradation. Moreover, the combination also very effectively inhibited the growth of HCC827/AR xenografts in nude mice. These preclinical findings support the potential of HQP8361 in the treatment of NSCLCs with amplification or highly activated MET and, when combined with AZD9291, in overcoming acquired resistance to EGFR-TKIs due to amplification.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642664PMC
October 2020

Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study.

Adv Ther 2021 01 29;38(1):350-365. Epub 2020 Oct 29.

Department of Oncology, Florida Cancer Specialists, Leesburg, FL, USA.

Introduction: Multilineage myelosuppression is an acute toxicity of cytotoxic chemotherapy, resulting in serious complications and dose modifications. Current therapies are lineage specific and administered after chemotherapy damage has occurred. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor that is administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation).

Methods: In this randomized, double-blind, placebo-controlled phase II trial, patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive intravenous trilaciclib 240 mg/m or placebo before topotecan 1.5 mg/m on days 1-5 of each 21-day cycle. Primary endpoints were duration of severe neutropenia (DSN) in cycle 1 and occurrence of severe neutropenia (SN). Additional endpoints were prespecified to further assess the effect of trilaciclib on myelopreservation, safety, patient-reported outcomes (PROs), and antitumor efficacy.

Results: Thirty-two patients received trilaciclib, and 29 patients received placebo. Compared with placebo, administration of trilaciclib prior to topotecan resulted in statistically significant and clinically meaningful decreases in DSN in cycle 1 (mean [standard deviation] 2 [3.9] versus 7 [6.2] days; adjusted one-sided P < 0.0001) and occurrence of SN (40.6% versus 75.9%; adjusted one-sided P = 0.016), with numerical improvements in additional neutrophil, red blood cell, and platelet measures. Patients receiving trilaciclib had fewer grade ≥ 3 hematologic adverse events than patients receiving placebo, particularly neutropenia (75.0% versus 85.7%) and anemia (28.1% versus 60.7%). Myelopreservation benefits extended to improvements in PROs, specifically in those related to fatigue. Antitumor efficacy was comparable between treatment arms.

Conclusions: Compared with placebo, the addition of trilaciclib prior to topotecan for the treatment of patients with previously treated ES-SCLC improves the patient experience of receiving chemotherapy, as demonstrated by a reduction in chemotherapy-induced myelosuppression, improved safety profile, improved quality of life and no detrimental effects on antitumor efficacy.

Trial Registration: ClinicalTrials.gov: NCT02514447.
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http://dx.doi.org/10.1007/s12325-020-01538-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854399PMC
January 2021

Optimum health and inhibition of cancer progression by microbiome and resveratrol.

Front Biosci (Landmark Ed) 2021 01 1;26:496-517. Epub 2021 Jan 1.

Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36101.

Resveratrol (RES) is a naturally occurring polyphenol found in fruits, green leafy vegetables, and peanuts. This versatile compound, which has potent regenerative, anti-oxidative, and cancer-fighting properties, is produced in plants, particularly in response to stress stimuli. By various mechanisms, including regulation of genes and proteins, RES inhibits the growth of pathogenic bacteria and the development of cancers. The gut has a prominent role in nutrient assimilation, metabolism, immunity, and cancer regression, and the endogenous microbiome protects the host from invasive bacteria that facilitate the progression of various diseases. Short-chain fatty acids (SFCAs) are the byproducts of microbial fermentation in the gastrointestinal tract. Native microflora regulates internal homeostasis, influence the activity of host immune cells, and regress some cancers via the action of SCFAs produced from a plant-based diet. This review shows the relevance of dietary constituents and gut microbial activity in ensuring optimal health of the host.
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January 2021

Inhibition of ACK1 delays and overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib.

Lung Cancer 2020 12 29;150:26-35. Epub 2020 Sep 29.

Departments of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. Electronic address:

Objectives: The emergence of acquired resistance to the third generation EGFR inhibitor, osimertinib (AZD9291 or TAGRISSO™), is an unavoidable huge clinical challenge. The involvement of ACK1, a non-receptor tyrosine kinase with an oncogenic function, in regulating cell response to osimertinib has not been investigated and thus is the focus of this study.

Material And Methods: Drug effects on cell growth were evaluated by measuring cell numbers and colony formation. Apoptosis was monitored with flow cytometry for annexin V-positive cells and Western blotting for protein cleavage. Intracellular protein and mRNA alterations were detected with Western blotting and qRT-PCR, respectively. Drug effects on delaying osimertinib acquired resistance were determined using colony formation in vitro and xenografts in nude mice in vivo, respectively. Cell senescence was assayed by β-galactosidase staining.

Results: Inhibition of ACK1 with the novel ACK1 inhibitor, (R)-9b synergized with osimertinib in inhibiting the growth of EGFR mutant NSCLC cell lines. Similar results were also generated with ACK1 gene knockdown. The combination of osimertinib and (R)-9b enhanced induction of apoptosis. In both in vitro and in vivo long-term resistance delay assays, the combination of (R)-9b and osimertinib clearly delayed the emergence of osimertinib-resistance. Further, the (R)-9b and osimertinib combination was also effective in inhibiting the growth of EGFR mutant NSCLC cell lines with acquired resistance to osimertinib, which possess elevated levels of ACK1, and the growth of osimertinib-resistant tumors in vivo. In some resistant cell lines, the combinations induced senescence in addition to induction of apoptosis.

Conclusions: These novel findings suggest that ACK1 inhibition might be a potential and innovative strategy for delaying and overcoming osimertinb acquired resistance.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722235PMC
December 2020

CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy.

J Immunother Cancer 2020 10;8(2)

Research and Development, G1 Therapeutics, Inc, Research Triangle Park, North Carolina, USA.

Background: Combination treatment with chemotherapy and immune checkpoint inhibitors (ICIs) has demonstrated meaningful clinical benefit to patients. However, chemotherapy-induced damage to the immune system can potentially diminish the efficacy of chemotherapy/ICI combinations. Trilaciclib, a highly potent, selective and reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in development to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy, has demonstrated proof of concept in recent clinical trials. Furthermore, CDK4/6 inhibition has been shown to augment T-cell activation and antitumor immunity in preclinical settings. Therefore, addition of trilaciclib has the potential to further enhance the efficacy of chemotherapy and ICI combinations.

Methods: In murine syngeneic tumor models, a schedule of 3 weekly doses of trilaciclib was combined with chemotherapy/ICI regimens to assess the effect of transient CDK4/6 inhibition on antitumor response and intratumor T-cell proliferation and function. Peripheral T-cell status was also analyzed in patients with small cell lung cancer (SCLC) treated with chemotherapy with or without trilaciclib to gain insights into the effect of transient exposure of trilaciclib on T-cell activation.

Results: Preclinically, the addition of trilaciclib to chemotherapy/ICI regimens enhanced antitumor response and overall survival compared with chemotherapy and ICI combinations alone. This effect is associated with the modulation of the proliferation and composition of T-cell subsets in the tumor microenvironment and increased effector function. Transient exposure of trilaciclib in patients with SCLC during chemotherapy treatment both preserved and increased peripheral lymphocyte counts and enhanced T-cell activation, suggesting that trilaciclib not only preserved but also enhanced immune system function.

Conclusions: Transient CDK4/6 inhibition by trilaciclib was sufficient to enhance and prolong the duration of the antitumor response by chemotherapy/ICI combinations, suggesting a role for the transient cell cycle arrest of tumor immune infiltrates in remodeling the tumor microenvironment. These results provide a rationale for combining trilaciclib with chemotherapy/ICI regimens to improve antitumor efficacy in patients with cancer.
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http://dx.doi.org/10.1136/jitc-2020-000847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534680PMC
October 2020

Phase Ib Study of Chemoprevention with Green Tea Polyphenon E and Erlotinib in Patients with Advanced Premalignant Lesions (APL) of the Head and Neck.

Clin Cancer Res 2020 Nov 17;26(22):5860-5868. Epub 2020 Sep 17.

Department of Hematology and Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia.

Purpose: On the basis of synergistic effects between green tea polyphenon E (PPE) and EGFR-tyrosine kinase inhibitor in preclinical studies, we conducted a phase Ib study of the PPE and erlotinib combination in patients with advanced premalignant lesions (APL) of the oral cavity and larynx.

Patients And Methods: Patients were treated with a fixed dose of PPE (200 mg three times a day) and dose escalation of erlotinib (50, 75, 100 mg daily) for 6 months with tissue biopsy at baseline and 6 months. Primary endpoints were safety and toxicity; secondary endpoints were evaluation of pathologic response, cancer-free survival (CFS), overall survival (OS), and biomarker modulation.

Results: Among 21 enrolled patients, 19 began treatment and 17 completed 6 months of treatment with PPE and erlotinib. Main characteristics of treated patients: 15 severe dysplasia or carcinoma and 17 oral cavity. Only skin rash was associated with dose-limiting toxicity and MTD. Recommended doses for phase II studies are PPE 600 mg daily plus erlotinib 100 mg daily for 6 months. Pathologic responses in 17 evaluable patients: pathologic complete response (47%) and pathologic partial response (18%). The 5-year CFS and OS were 66.3% and 93%, respectively. Among tested biomarkers, only phosphorylated ERK was correlated with response to treatment.

Conclusions: Treatment with PPE and erlotinib combination was well tolerated in patients with APLs of the head and neck, and showed a high rate of pathologic response with excellent CFS. This combination deserves further investigation for the chemoprevention and/or prevention of second primary tumors in early-stage head and neck cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016407PMC
November 2020

Patient-reported tolerability of veliparib combined with cisplatin and etoposide for treatment of extensive stage small cell lung cancer: Neurotoxicity and adherence data from the ECOG ACRIN cancer research group E2511 phase II randomized trial.

Cancer Med 2020 10 28;9(20):7511-7523. Epub 2020 Aug 28.

Department of Social Sciences & Health Policy, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Objectives: The ECOG-ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin-etoposide (CE) in patients with extensive stage small cell lung cancer (ES-SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the veliparib arm, and tolerability of the addition of veliparib to CE. Physician-rated and patient-reported neurotoxicity was also compared.

Materials And Methods: Patients randomized to veliparib plus CE (n = 64) or placebo plus CE (n = 64) completed the 11-item Functional Assessment of Cancer Therapy Gynecologic Oncology Group Neurotoxicity (questionnaire pre-treatment, end of cycle 4 [ie 3 months after randomization] and 3 months post-treatment [ie 6-months]). Adherence analysis was based on treatment forms.

Results And Conclusion: No significant differences in mean or magnitude of change in neurotoxicity scores were observed between treatment arms at any time point. However, patients in the placebo arm reported worsening neurotoxicity from baseline to 3-months (M difference = -1.5, P = .045), compared to stable neurotoxicity in the veliparib arm (M difference = -0.2, P = .778). Weakness was the most common treatment-emergent (>50%) and moderate to severe (>16%) symptom reported, but did not differ between treatment arms. The proportion of adherence to oral therapy in the overall sample was 75%. Three percent of patients reported clinically significant neurotoxicity that was not captured by physician assessment. Neurotoxicity scores were not different between treatment arms. The addition of veliparib to CE appeared tolerable, though weakness should be monitored. CLINICALTRIALS.

Gov Identifier: NCT01642251.
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http://dx.doi.org/10.1002/cam4.3416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571824PMC
October 2020

Efficacy of Selpercatinib in -Altered Thyroid Cancers.

N Engl J Med 2020 08;383(9):825-835

From Massachusetts General Hospital (L.J.W.) and Dana-Farber Cancer Institute (J. Lorch), Boston; Memorial Sloan Kettering Cancer Center, New York (E.S., A.D.); Royal North Shore Hospital, St. Leonards, NSW (B.R.), and Peter MacCallum Cancer Institute, Melbourne, VIC (B.S.) - both in Australia; University of California, San Francisco-Helen Diller Family Comprehensive Cancer Center, San Francisco (H.K.), David Geffen School of Medicine at UCLA, Los Angeles (J.W.G.), and Chao Family Comprehensive Cancer Center, University of California Irvine, Orange (V.W.Z.) - all in California; University of Michigan, Ann Arbor (F.W.), and START Midwest, Grand Rapids (N.L.) - both in Michigan; University of Pennsylvania, Philadelphia (M.B.); University of Chicago, Chicago (J.P.); Gustave Roussy, Villejuif (S.L.), Institut Bergonié, Bordeaux (Y.G.), Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Early Phase Cancer Trial Center CLIP2, Hospital La Timone, Marseille (F.B.), Centre Léon Bérard, Lyon (C.D.L.F.), and Hôpital Européen Georges-Pompidou, Faculté de Médecine Paris-Descartes, Paris (J.M.) - all in France; Mayo Clinic-Rochester, Rochester, MN (J.C.M.); Winship Cancer Institute of Emory University, Atlanta (T.K.O.); National Cancer Center Singapore, Singapore (D.S.W.T.); University of Bern, Bern, and Cantonal Hospital of Lucerne, Lucerne - both in Switzerland (O.G.); University of North Carolina-Chapel Hill, Chapel Hill (J.W.); University of Wisconsin-Carbone Cancer Center, Madison (M.E.B.); British Columbia Cancer Agency, Vancouver, Canada (J. Laskin); Oregon Health and Science University, Portland (M.H.T.); Universitätsklinikum Würzburg, Department of Internal Medicine I, Division of Endocrinology and Diabetology, Würzburg, Germany (M.K.); Sarah Cannon Research Institute-Tennessee Oncology, Nashville (T.M.B.); Johns Hopkins Kimmel Cancer Center, Washington, DC (B.L.); Fundación Jimenez Diaz, START-Madrid, Madrid (V.M.); Loxo Oncology, Stamford, CT (K.E., M.N., D.H., E.Y.Z., X.H., L.Y., J.K., S.M.R.); University of Texas M.D. Anderson Cancer Center, Houston (V.S., M.E.C.); and Ohio State University Comprehensive Cancer Center, Columbus (M.H.S.).

Background: mutations occur in 70% of medullary thyroid cancers, and fusions occur rarely in other thyroid cancers. In patients with -altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.

Methods: We enrolled patients with -mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.

Results: In the first 55 consecutively enrolled patients with -mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with -mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.

Conclusions: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
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http://dx.doi.org/10.1056/NEJMoa2005651DOI Listing
August 2020

An update on the immune landscape in lung and head and neck cancers.

CA Cancer J Clin 2020 Nov 25;70(6):505-517. Epub 2020 Aug 25.

Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.

Immunotherapy has dramatically changed the treatment landscape for patients with cancer. Programmed death-ligand 1/programmed death-1 checkpoint inhibitors have been in the forefront of this clinical revolution. Currently, there are 6 US Food and Drug Administration-approved checkpoint inhibitors for approximately 18 different histologic types of cancer. Lung cancer and head and neck squamous cell carcinoma (HNSCC) are 2 diseases that have led the way in the development of immunotherapy. Atezolizumab, durvalumab, nivolumab, and pembrolizumab are all currently used as part of standard-of-care treatment for different stages of lung cancer. Similarly, nivolumab and pembrolizumab have US regulatory approval as treatment for advanced metastatic HNSCC. This is significant because lung cancer represents the most common and most fatal cancer globally, and HNSCC is the sixth most common. Currently, most of the approvals for the use of immunotherapy agents are for patients diagnosed in the metastatic setting. However, research is ongoing to evaluate these drugs in earlier stage disease. There is plausible biological rationale to expect that pharmacologic activation of the immune system will be effective for early-stage and smaller tumors. In addition, selecting patients who are more likely to respond to immunotherapy and understanding why resistance develops are crucial areas of ongoing research. The objective of this review was to provide an overview of the current immune landscape and future directions in lung cancer and HNSCC.
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http://dx.doi.org/10.3322/caac.21630DOI Listing
November 2020

Allocating Scarce Health Care Resources During Pandemics: Making the Case for Patients with Advanced and Metastatic Cancer.

Oncologist 2020 10 27;25(10):e1586-e1588. Epub 2020 Aug 27.

Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.

The oncology community is concerned that patients with cancer will be unfairly classified in pandemic allocation guidance. Past guidance either excluded patients with metastatic cancer from consideration or categorized them as having a survival of less than 1 year. Given recent improvements in treatments, we recommend that the prognosis of an individual patient with cancer be determined with input from a cancer specialist or, if this is impractical, that the presence of active metastatic solid cancer or relapsed hematologic malignancy is graded as a major comorbidity, with a likelihood that survival will be less than 5 years; severe limitation in physical functioning (3 or 4 on the Eastern Cooperative Oncology Group performance status) would define a patient with advanced cancer as having a severe comorbidity, with a likelihood of less than 1 year of survival. Cancer may be the "Emperor of all Maladies," but it is no longer a certain death sentence.
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http://dx.doi.org/10.1634/theoncologist.2020-0442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436378PMC
October 2020

Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy.

Front Oncol 2020 7;10:1000. Epub 2020 Jul 7.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, United States.

Gangliosides are carbohydrate-containing sphingolipids that are widely expressed in normal tissues, making most subtypes unsuitable as targets for cancer therapy. However, the disialoganglioside GD2 subtype has limited expression in normal tissues but is overexpressed across a wide range of tumors. Disialoganglioside GD2 can be considered a tumor-associated antigen and well-suited as a target for cancer therapy. Disialoganglioside GD2 is implicated in tumor development and malignant phenotypes through enhanced cell proliferation, motility, migration, adhesion, and invasion, depending on the tumor type. This provides a rationale for targeting disialoganglioside GD2 in cancer therapy with the development of anti-GD2 monoclonal antibodies and other therapeutic approaches. Anti-GD2 monoclonal antibodies target GD2-expressing tumor cells, leading to phagocytosis and destruction by means of antibody-dependent cell-mediated cytotoxicity, lysis by complement-dependent cytotoxicity, and apoptosis and necrosis through direct induction of cell death. Anti-GD2 monoclonal antibodies may also prevent homing and adhesion of circulating malignant cells to the extracellular matrix. Disialoganglioside GD2 is highly expressed by almost all neuroblastomas, by most melanomas and retinoblastomas, and by many Ewing sarcomas and, to a more variable degree, by small cell lung cancer, gliomas, osteosarcomas, and soft tissue sarcomas. Successful treatment of disialoganglioside GD2-expressing tumors with anti-GD2 monoclonal antibodies is hindered by pharmacologic factors such as insufficient antibody affinity to mediate antibody-dependent cell-mediated cytotoxicity, inadequate penetration of antibody into the tumor microenvironment, and toxicity related to disialoganglioside GD2 expression by normal tissues such as peripheral sensory nerve fibers. Nonetheless, anti-GD2 monoclonal antibody dinutuximab (ch14.18) has been approved by the U.S. Food and Drug Administration and dinutuximab beta (ch14.18/CHO) has been approved by the European Medicines Agency for the treatment of high-risk neuroblastoma in pediatric patients. Clinical trials of anti-GD2 therapy are currently ongoing in patients with other types of disialoganglioside GD2-expressing tumors as well as neuroblastoma. In addition to anti-GD2 monoclonal antibodies, anti-GD2 therapeutic approaches include chimeric antigen receptor T-cell therapy, disialoganglioside GD2 vaccines, immunocytokines, immunotoxins, antibody-drug conjugates, radiolabeled antibodies, targeted nanoparticles, and T-cell engaging bispecific antibodies. Clinical trials should clarify further the potential of anti-GD2 therapy for disialoganglioside GD2-expressing malignant tumors.
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http://dx.doi.org/10.3389/fonc.2020.01000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358363PMC
July 2020

Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma.

Br J Cancer 2020 10 24;123(8):1228-1234. Epub 2020 Jul 24.

Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.

Background: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes.

Methods: We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment.

Results: The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit.

Conclusions: The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers.

Clinical Trial Registration: NCT01218555.
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http://dx.doi.org/10.1038/s41416-020-0988-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553949PMC
October 2020

MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor-mutant lung cancers.

Cancer 2020 Aug 4;126(16):3788-3799. Epub 2020 Jun 4.

Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia.

Background: The majority of patients with non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations respond well to osimertinib (AZD9291), a third-generation, mutation-selective EGFR inhibitor. The current study focuses on determining whether targeting MEK/ERK signaling prevents or delays the development of acquired resistance to osimertinib.

Methods: Drug effects on cell survival were determined by measuring cell number alterations. Apoptosis was assessed with flow cytometry for the detection of annexin V-positive cells and with Western blotting for protein cleavage. Alterations of proteins in cells were detected with Western blotting. Drug effects on delaying the emergence of osimertinib resistance were evaluated with colony formation in vitro and xenografts in nude mice in vivo.

Results: Osimertinib combined with an MEK or ERK inhibitor synergistically decreased cell survival with enhanced induction of apoptosis in EGFR-mutant NSCLC cells but not in EGFR wild-type NSCLC cells. These combinations were also very effective in killing cell clones with primary intrinsic resistance to osimertinib. Continuous and intermittent pharmacologic inhibition of MEK/ERK signaling delayed the emergence of osimertinib resistance both in vitro and in vivo.

Conclusions: These results provide strong preclinical evidence in support of targeting MEK/ERK signaling as a strategy for delaying or preventing acquired resistance to osimertinib in the clinic to improve the long-term therapeutic efficacy of osimertinib. From a clinical standpoint, the data support the evaluation of an intermittent treatment schedule of osimertinib in combination with an MEK or ERK inhibitor in patients with EGFR-mutated NSCLC.
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http://dx.doi.org/10.1002/cncr.32996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381372PMC
August 2020

EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair.

Oncogene 2020 06 26;39(25):4798-4813. Epub 2020 May 26.

Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor outcomes associated with resistance to cisplatin-based chemotherapy. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2), which silences transcription through trimethylation of histone H3 lysine 27 (H3K27me3) and has emerged as an important therapeutic target with inhibitors targeting its methyltransferase activity under clinical investigation. Here, we show that EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair (NER) and govern cisplatin resistance in SCLC. Using a synthetic lethality screen, we identified important regulators of cisplatin resistance in SCLC cells, including EZH2. EZH2 depletion causes cellular cisplatin and UV hypersensitivity in an epistatic manner with DDB1-DDB2. EZH2 complexes with DDB1-DDB2 and promotes DDB2 stability by impairing its ubiquitination independent of methyltransferase activity or PRC2, thereby facilitating DDB2 localization to cyclobutane pyrimidine dimer crosslinks to govern their repair. Furthermore, targeting EZH2 for depletion with DZNep strongly sensitizes SCLC cells and tumors to cisplatin. Our findings reveal a non-catalytic and PRC2-independent function for EZH2 in promoting NER through DDB2 stabilization, suggesting a rationale for targeting EZH2 beyond its catalytic activity for overcoming cisplatin resistance in SCLC.
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http://dx.doi.org/10.1038/s41388-020-1332-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305988PMC
June 2020

Integrating Genetic and Genomic Testing Into Oncology Practice.

Am Soc Clin Oncol Educ Book 2020 May;40:e259-e263

Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.

Genetic information, both germline and somatic, is an increasingly important consideration in therapeutic decision-making in cancer. Germline mutations in genes associated with increased cancer risk can identify those individuals without cancer who may benefit from enhanced screening and prevention strategies. In individuals with cancer, germline and somatic mutations may help to guide local and systemic management decisions. Here, we review considerations of these issues in selected cancer types.
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http://dx.doi.org/10.1200/EDBK_280607DOI Listing
May 2020

Prognostic significance of an invasive leader cell-derived mutation cluster on chromosome 16q.

Cancer 2020 Jul 21;126(13):3140-3150. Epub 2020 Apr 21.

Winship Cancer Institute, Emory University, Atlanta, Georgia.

Background: Intratumoral heterogeneity is defined by subpopulations with varying genotypes and phenotypes. Specialized, highly invasive leader cells and less invasive follower cells are phenotypically distinct subpopulations that cooperate during collective cancer invasion. Because leader cells are a rare subpopulation that would be missed by bulk sequencing, a novel image-guided genomics platform was used to precisely select this subpopulation. This study identified a novel leader cell mutation signature and tested its ability to predict prognosis in non-small cell lung cancer (NSCLC) patient cohorts.

Methods: Spatiotemporal genomic and cellular analysis was used to isolate and perform RNA sequencing on leader and follower populations from the H1299 NSCLC cell line, and it revealed a leader-specific mutation cluster on chromosome 16q. Genomic data from patients with lung squamous cell carcinoma (LUSC; n = 475) and lung adenocarcinoma (LUAD; n = 501) from The Cancer Genome Atlas were stratified by 16q mutation cluster (16qMC) status (16qMC+ vs 16qMC-) and compared for overall survival (OS), progression-free survival (PFS), and gene set enrichment analysis (GSEA).

Results: Poorer OS, poorer PFS, or both were found across all stages and among early-stage patients with 16qMC+ tumors within the LUSC and LUAD cohorts. GSEA revealed 16qMC+ tumors to be enriched for the expression of metastasis- and survival-associated gene sets.

Conclusions: This represents the first leader cell mutation signature identified in patients and has the potential to better stratify high-risk NSCLC and ultimately improve patient outcomes.
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http://dx.doi.org/10.1002/cncr.32903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275903PMC
July 2020

Combined Effect of Sarcopenia and Systemic Inflammation on Survival in Patients with Advanced Stage Cancer Treated with Immunotherapy.

Oncologist 2020 03 5;25(3):e528-e535. Epub 2019 Dec 5.

Department of Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

Background: Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy.

Methods: We performed a retrospective review of 90 patients enrolled on immunotherapy-based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias-adjusted log-rank test. A four-level risk stratification was used to create low-risk (PLR <242 and nonsarcopenic), intermediate-risk (PLR <242 and sarcopenic), high-risk (PLR ≥242 and nonsarcopenic), and very-high-risk (PLR ≥242 and sarcopenic) groups with subsequent association with survival.

Results: Most patients (59%) were male, and the most common cancers were melanoma (33%) and gastrointestinal (22%). Very high-risk, high-risk, and intermediate-risk patients had significantly shorter overall survival (hazard ratio [HR], 8.46; 95% confidence interval [CI], 2.65-27.01; p < .001; HR, 5.32; CI, 1.96-14.43; p = .001; and HR, 4.01; CI, 1.66-9.68; p = .002, respectively) and progression-free survival (HR, 12.29; CI, 5.15-29.32; p < .001; HR, 3.51; CI, 1.37-9.02; p = .009; and HR, 2.14; CI, 1.12-4.10; p = .022, respectively) compared with low-risk patients.

Conclusion: Baseline sarcopenia and elevated inflammatory biomarkers may have a combined effect on decreasing survival in immunotherapy-treated patients in phase I trials. These data may be immediately applicable for medical oncologists for the risk stratification of patients beginning immunotherapeutic agents.

Implications For Practice: Sarcopenia and inflammation have been associated with poor survival in patients with cancer, but it is unclear how to apply this information to patient care. The authors created a risk-stratification system that combined sarcopenia and platelet-to-lymphocyte ratio as a marker of systemic inflammation. The presence of sarcopenia and systemic inflammation decreased progression-free survival and overall survival in our cohort of 90 patients who received immunotherapy in phase I clinical trials. The data presented in this study may be immediately applicable for medical oncologists as a way to risk-stratify patients who are beginning treatment with immunotherapy.
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http://dx.doi.org/10.1634/theoncologist.2019-0751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066707PMC
March 2020

BRD4 Levels Determine the Response of Human Lung Cancer Cells to BET Degraders That Potently Induce Apoptosis through Suppression of Mcl-1.

Cancer Res 2020 06 10;80(11):2380-2393. Epub 2020 Mar 10.

Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia.

Lung cancer consists of approximately 80% non-small cell lung cancer (NSCLC) and 20% small cell lung cancer (SCLC) and remains the leading cause of cancer-related deaths worldwide despite advances in early diagnosis, targeted therapy, and immunotherapy. Thus, novel therapies are still urgently needed. Bromodomain and extraterminal (BET) proteins, primarily comprised of BRD2, BRD3, and BRD4 proteins, function as epigenetic readers and master transcription coactivators and are now recognized cancer therapeutic targets. BET degraders such as ZBC260 and dBET represent a novel class of BET inhibitors that act by inducing BET degradation. The current study demonstrates the therapeutic efficacies of BET degraders, particularly ZBC260, against lung cancer, as well as understanding the underlying mechanisms and identifying molecular markers that determine cell sensitivity to BET degraders. A panel of NSCLC cell lines possessed similar response patterns to ZBC260 and dBET but different responses to BET inhibitor JQ-1. BRD levels, particularly BRD4, correlated positively with high sensitivity to BET degraders but not to JQ-1. BET degraders potently induced apoptosis in sensitive NSCLC cells and were accompanied by reduction of Mcl-1 and c-FLIP levels, which are critical for mediating induction of apoptosis and enhancement of TRAIL-induced apoptosis. Accordingly, ZBC260 exerted more potent activity than JQ-1 against the growth of NSCLC xenografts and patient-derived xenografts. These findings warrant future clinical validation of the efficacy of BET degraders in NSCLC, particularly those with high levels of BRD proteins, especially BRD4. SIGNIFICANCE: The current study demonstrates the potential of novel BET degraders in the treatment of lung cancer and warrants clinical validation of BET degraders in lung cancer with high levels of BRD4.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3674DOI Listing
June 2020