Publications by authors named "Stephen V Liu"

75 Publications

Safety and Efficacy of First-Line Pembrolizumab in Black Patients with Metastatic Non-Small-Cell Lung Cancer.

Oncologist 2021 Apr 12. Epub 2021 Apr 12.

MedStar Georgetown University Hospital, Washington, DC.

Introduction: Pembrolizumab, an immune checkpoint inhibitor (ICI), has become an integral part of front-line treatment of metastatic non-small-cell lung cancer (NSCLC). However, pivotal trials had significant underrepresentation of Black patients (pts). Lack of sufficient evidence regarding safety and efficacy of ICIs among minority racial groups poses a challenge in delivery of optimal cancer directed care.

Methods: We retrospectively reviewed pts with stage IV NSCLC treated with first-line pembrolizumab across three MedStar facilities between January 1st, 2014 and May 31st, 2019. Progression-free survival (PFS) and overall survival (OS) were primary endpoints and were calculated using the Kaplan-Meier method. Immune-related adverse events (irAEs) were assessed according to CTCAE v5.0.

Results: 136 pts were identified with 74 (54.4%) White, 53 (39%) Black, 2 (1.5%) Asian and 7 (5.1%) other racial groups. Median age in White pts was 70 years and 65 years in Black pts (p<0.01). There was no difference in median PFS (5.7 vs 5.9 months, p= 0.651) or OS (11.8 vs 12.4 months, p= 0.949) between White and Black pts. In the subset of patients whose tumors had high programmed death-ligand 1 (PD-L1) expression (≥ 50%), there was still no difference in efficacy by race. Median PFS (8.7 vs 3.9 months, p= 0.843) and OS (14.7 vs 11.3 months, p= 0.581) in White versus Black pts were not different. Incidence of irAEs in White versus Black pts was 24.3% and 22.6%, respectively (p=0.83).

Conclusions: We found no major differences in either safety or efficacy of first-line pembrolizumab between White and Black pts. Use of first-line pembrolizumab-based treatment in Black pts with stage IV NSCLC is safe and efficacious, based on these real-world data.

Implications For Practice: Immunotherapy has revolutionized treatment of solid and hematological malignancies. There are certain populations of patients underrepresented in the original trials including minority racial groups, patients with autoimmune diseases and those with chronic viral illnesses. Our study focuses on Black patients with metastatic lung cancer who received pembrolizumab and concludes similar safety and response to treatment when compared to White patients. Black patients are an important demographic group in clinical practice often facing systemic healthcare disparities. Our study paves a path for future studies in underrepresented populations receiving immunotherapy across various malignancies.
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http://dx.doi.org/10.1002/onco.13787DOI Listing
April 2021

Novel Cytotoxic Chemotherapies in Small Cell Lung Carcinoma.

Cancers (Basel) 2021 Mar 8;13(5). Epub 2021 Mar 8.

SC Oncologia Medica Toraco-Polmonare, IRCCS Istituto Nazionale dei Tumori, Fondazione Pascale, 80100 Napoli, Italy.

Small cell lung cancer (SCLC) is one of the deadliest thoracic neoplasms, in part due to its fast doubling time and early metastatic spread. Historically, cytotoxic chemotherapy consisting of platinum-etoposide or anthracycline-based regimens has demonstrated a high response rate, but early chemoresistance leads to a poor prognosis in advanced SCLC. Only a fraction of patients with limited-disease can be cured by chemo-radiotherapy. Given the disappointing survival rates in advanced SCLC, new cytotoxic agents are eagerly awaited. Unfortunately, few novel chemotherapy drugs have been developed in the latest decades. This review describes the results and potential application in the clinical practice of novel chemotherapy agents for SCLC.
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http://dx.doi.org/10.3390/cancers13051152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962524PMC
March 2021

COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials.

Nat Rev Clin Oncol 2021 Mar 15. Epub 2021 Mar 15.

Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Emerging efficacy data have led to the emergency use authorization or approval of COVID-19 vaccines in several countries worldwide. Most trials of COVID-19 vaccines excluded patients with active malignancies, and thus data on the safety, tolerability and efficacy of the vaccines in patients with cancer are currently limited. Given the risk posed by the COVID-19 pandemic, decisions regarding the use of vaccines against COVID-19 in patients participating in trials of investigational anticancer therapies need to be addressed promptly. Patients should not have to choose between enrolling on oncology clinical trials and receiving a COVID-19 vaccine. Clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently enrolled or might seek to enrol in clinical trials. Considering the high morbidity and mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related adverse events. Herein, we provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials. In our perspective, continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility.
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http://dx.doi.org/10.1038/s41571-021-00487-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957448PMC
March 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
April 2021

Combining Osimertinib With Chemotherapy in EGFR-Mutant NSCLC at Progression.

Clin Lung Cancer 2021 Jan 27. Epub 2021 Jan 27.

Department of Medicine, Division of Oncology, Stanford University, Stanford, CA. Electronic address:

Background: Osimertinib is a third-generation EGFR tyrosine kinase inhibitor that has improved survival and central nervous system (CNS) outcomes in patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. However, little is known about the efficacy and safety of combining osimertinib with chemotherapy.

Methods: This was a retrospective study performed at 3 institutions. Patients with advanced EGFR-mutated NSCLC who received concurrent osimertinib with chemotherapy in the third-line or beyond were identified by chart review. Efficacy outcomes including duration on treatment (DOT), overall survival (OS), and CNS outcomes were assessed. Safety outcomes were also evaluated.

Results: A total of 44 patients met inclusion criteria. Median DOT with osimertinib plus platinum doublet (n = 28) was 6.1 months (95% CI 4.1 months-not reached), and with osimertinib plus single-agent chemotherapy (n = 29) was 2.6 months (95% CI 1.8-4.8 months). Median OS from the start of osimertinib plus chemotherapy was 10.4 months (95% CI 7.0-13.2 months). At initiation of osimertinib plus chemotherapy, 37 patients (84%) had CNS metastases; 9 of these (24%) had CNS disease progression on osimertinib plus chemotherapy. Chemotherapy was delayed or dose reduced due to toxicity in 8 patients (18%); osimertinib was discontinued in 1 patient (2%) for reduced cardiac ejection fraction, and dose reduced in 2 patients (5%).

Conclusions: The combination of osimertinib plus chemotherapy appeared safe and showed favorable control of CNS disease in this cohort of patients who had progressed systemically with multiple prior lines of therapy, with DOT and survival outcomes similar to historical chemotherapy controls.
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http://dx.doi.org/10.1016/j.cllc.2021.01.010DOI Listing
January 2021

Real-world survival outcomes with immune checkpoint inhibitors in large-cell neuroendocrine tumors of lung.

J Immunother Cancer 2021 Feb;9(2)

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Little is known regarding the efficacy of immune checkpoint inhibitors (ICI) in patients with advanced large-cell neuroendocrine lung carcinoma (aLCNEC).

Methods: 125 consecutive patients with aLCNEC were identified in the electronic databases of 4 participating cancer centers. The patients were divided into group A (patients who received ICI, n=41) and group B (patients who did not receive ICI, n=84). Overall survival since advanced disease diagnosis (OS DX) and OS since ICI initiation (OS ICI) were captured.

Results: With a median follow-up of 11.8 months (mo) (IQR 7.5-17.9) and 6.0mo (IQR 3.1-10.9), 66% and 76% of patients died in groups A and B, respectively. Median OS DX was 12.4mo (95% CI 10.7 to 23.4) and 6.0mo (95% CI 4.7 to 9.4) in groups A and B, respectively (log-rank test, p=0.02). For ICI administration, HR for OS DX was 0.59 (95% CI 0.38 to 0.93, p=0.02-unadjusted), and 0.58 (95% CI 0.34 to 0.98, p=0.04-adjusted for age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), presence of liver metastases and chemotherapy administration). In a propensity score matching analysis (n=74; 37 patients in each group matched for age and ECOG PS), median OS DX was 12.5 mo (95% CI 10.6 to 25.2) and 8.4 mo (95% CI 5.4 to 16.9) in matched groups A and B, respectively (log-rank test, p=0.046). OS ICI for patients receiving ICI as monotherapy (n=36) was 11.0 mo (95% CI 6.1 to 19.4).

Conclusions: With the limitations of retrospective design and small sample size, the results of this real-world cohort analysis suggest a positive impact of ICI on OS in aLCNEC.
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http://dx.doi.org/10.1136/jitc-2020-001999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893659PMC
February 2021

Immunotherapy in lung cancer.

J Surg Oncol 2021 Mar;123(3):718-729

Division of Medical Oncology, Georgetown University, Washington, District of Columbia, USA.

Immunotherapy has emerged as an important treatment modality throughout oncology with a particularly important role in the treatment of lung cancer. Early signals showed responses could be achieved in nonsmall cell lung cancer and small cell lung cancer and these monoclonal antibodies have become standards of care for advanced stage disease. They have also shown promise in earlier-stage disease as complements to radiation or surgery, offering the potential for durable, meaningful survival gains.
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http://dx.doi.org/10.1002/jso.26347DOI Listing
March 2021

Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133).

J Clin Oncol 2021 Feb 13;39(6):619-630. Epub 2021 Jan 13.

Vanderbilt University Medical Center, Nashville, TN.

Purpose: IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported.

Patients And Methods: Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted.

Results: Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status.

Conclusion: Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.
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http://dx.doi.org/10.1200/JCO.20.01055DOI Listing
February 2021

Chemo-immunotherapy as first-line treatment for small-cell lung cancer.

Ther Adv Med Oncol 2020 18;12:1758835920980365. Epub 2020 Dec 18.

Lombardi Comprehensive Cancer Center, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA.

Small-cell lung cancer (SCLC) is a highly lethal subtype of lung cancer. Despite concerted efforts over the past several decades, there have been limited therapeutic advances. Traditional chemotherapy offers a high response rate and rapid symptomatic improvement, but its benefit is fleeting, and relapse is quick and unforgiving. Immunotherapy has delivered improved outcomes for patients with many cancers and there was compelling rationale for development in SCLC. While initial efforts with cytotoxic T-lymphocyte protein-4 inhibitors failed to improve upon chemotherapy alone, the addition of programmed death ligand-1 (PD-L1) inhibitors to first-line chemotherapy finally provided long-awaited gains in survival. Atezolizumab, when added to carboplatin and etoposide, improved both progression-free survival and overall survival. Durvalumab, when added to platinum plus etoposide, similarly improved OS. Biomarker development has stalled as PD-L1 expression and tumor mutational burden have not been useful predictive biomarkers. However, based on the significant survival improvements, both atezolizumab and durvalumab were approved by the US Food and Drug Administration to be given with first-line chemotherapy, and these regimens represent the new standards of care for SCLC.
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http://dx.doi.org/10.1177/1758835920980365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750570PMC
December 2020

Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes.

Clin Cancer Res 2021 Mar 22;27(5):1463-1475. Epub 2020 Dec 22.

Department of Medicine, Division of Medical Oncology, University of Colorado, Aurora, Colorado.

Purpose: Approved therapies for exon 20, mutations, and fusions are currently lacking for non-small cell lung cancer and other cancers. Tarloxotinib is a prodrug that harnesses tumor hypoxia to generate high levels of a potent, covalent pan-HER tyrosine kinase inhibitor, tarloxotinib-effector (tarloxotinib-E), within the tumor microenvironment. This tumor-selective delivery mechanism was designed to minimize the dose-limiting toxicities that are characteristic of systemic inhibition of wild-type EGFR.

Experimental Design: Novel and existing patient-derived cell lines and xenografts harboring exon 20 insertion mutations, mutations and amplification, and fusions were tested and with tarloxotinib to determine its impact on cancer cell proliferation, apoptosis, and cell signaling.

Results: Tarloxotinib-E inhibited cell signaling and proliferation in patient-derived cancer models by directly inhibiting phosphorylation and activation of EGFR, HER2, and HER2/HER3 heterodimers. , tarloxotinib induced tumor regression or growth inhibition in multiple murine xenograft models. Pharmacokinetic analysis confirmed markedly higher levels of tarloxotinib-E in tumor tissue than plasma or skin. Finally, a patient with lung adenocarcinoma harboring an exon 20 p.A775_G776insYVMA mutation demonstrated a dramatic clinical response to tarloxotinib.

Conclusions: Experimental data with tarloxotinib validate the novel mechanism of action of a hypoxia-activated prodrug in cancer models by concentrating active drug in the tumor versus normal tissue, and this activity can translate into clinical activity in patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926264PMC
March 2021

Novel mutation with durable response to brigatinib-a case report.

Transl Lung Cancer Res 2020 Oct;9(5):2145-2148

Department of Medicine, Georgetown University, Washington, DC, USA.

Anaplastic lymphoma kinase () tyrosine kinase inhibitors are the preferred initial treatment for rearranged non-small cell lung cancer (NSCLC). While initial responses to next-generation inhibitors are robust, acquired resistance is expected for nearly all patients. Resistance is often mediated by point mutations along the solvent front. Use of the acquired mutational profile to guide therapy is still investigational and largely based on preclinical data demonstrating sensitivity of resistant cell lines to available kinase inhibitors. Here, we describe outcomes after development of an L1196Q mutation. We present a patient with stage IV rearranged lung cancer received who received first line crizotinib at 250 mg twice daily, then at progression, second line alectinib at 600 mg twice daily. When radiographic evidence of progression was noted, a biopsy was performed. Next generation sequencing (NGS) identified an acquired L1196Q mutation. The patient was treated with third line brigatinib, at 90 mg daily and escalating to 180 mg daily, and achieved a partial response that is still ongoing, one year later. We highlight false-negative mutation results when only plasma is used, particularly in early metastatic disease. We also discuss how the use of specific resistance mutations to guide therapy is clinically relevant is being investigated.
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http://dx.doi.org/10.21037/tlcr-20-145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653135PMC
October 2020

Drugs in development for small cell lung cancer.

J Thorac Dis 2020 Oct;12(10):6298-6307

Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

Small cell lung cancer (SCLC) is a particularly lethal subtype of lung cancer whose treatment landscape has been relatively devoid of advance. The recent integration of immunotherapy in the first-line treatment of SCLC has improved overall survival (OS), prompting the first major paradigm shift for this disease in decades. Despite this improvement in outcomes, most patients with SCLC will relapse after initial response. Standard salvage systemic therapy for SCLC remains disappointing, with few approved agents and consistently poor outcomes. The need for novel agents to combat this disease remains pressing. Fortunately, there are several agents in various stages of development that hold potential as novel treatments for advanced SCLC. Lurbinectedin, which targets active transcription, has shown activity in platinum-sensitive and platinum-resistant SCLC as monotherapy and in combination with doxorubicin. Aurora A kinase (AAK) inhibitors showed initial activity when given with paclitaxel but in randomized studies, failed to improve outcomes over paclitaxel plus placebo. However, in the subset of patients with MYC expression, targeting AAK was effective. Similarly, agents targeting poly-ADP ribose (PARP) pair well with other DNA damaging drugs but in the subset of patients whose tumors express Schlafen-11 (SLFN-11), efficacy appeared greater. CDK 4/6 inhibition is being explored, primarily as a means to protect myeloid cells during cytotoxic chemotherapy in a strategy expected to be uniquely effective in SCLC. Ongoing trials are also studying are novel formulations of established cytotoxic agents. Delta-like protein 3 (DLL3) is an appealing therapeutic target given its selective expression on SCLC cells, but after initial exciting results, the antibody-drug conjugate (ADC) Rovalpituzumab tesirine (Rova-T) did not have a favorable efficacy to toxicity profile in randomized trials. Other agents targeting DLL3 are under study. Targeting angiogenesis has yielded modest improvements in the past but newer agents such as anlotinib are renewing interest. While the current therapeutic landscape beyond chemo-immunotherapy remains the same as it was decades ago, drug development for SCLC is rapidly moving forward and promises to deliver the needed novel agents in the very near future.
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http://dx.doi.org/10.21037/jtd-2019-sclc-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656445PMC
October 2020

Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2020 Dec 23;86(6):815-827. Epub 2020 Oct 23.

Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: We conducted a phase 1 trial of the HSP90 inhibitor onalespib in combination with the CDK inhibitor AT7519, in patients with advanced solid tumors to determine the safety profile and maximally tolerated dose, pharmacokinetics, preliminary antitumor activity, and to assess the pharmacodynamic (PD) effects on HSP70 expression in patient-derived PBMCs and plasma.

Methods: This study followed a 3 + 3 trial design with 1 week of intravenous (IV) onalespib alone, followed by onalespib/AT7519 (IV) on days 1, 4, 8, and 11 of a 21-days cycle. PK and PD samples were collected at baseline, after onalespib alone, and following combination therapy.

Results: Twenty-eight patients were treated with the demonstration of downstream target engagement of HSP70 expression in plasma and PBMCs. The maximally tolerated dose was onalespib 80 mg/m IV + AT7519 21 mg/m IV. Most common drug-related adverse events included Grade 1/2 diarrhea (79%), fatigue (54%), mucositis (57%), nausea (46%), and vomiting (50%). Partial responses were seen in a palate adenocarcinoma and Sertoli-Leydig tumor; a colorectal and an endometrial cancer patient both remained on study for ten cycles with stable disease as the best response. There were no clinically relevant PK interactions for either drug.

Conclusions: Combined onalespib and AT7519 is tolerable, though below monotherapy RP2D. Promising preliminary clinical activity was seen. Further benefit may be seen with the incorporation of molecular signature pre-selection. Further biomarker development will require the assessment of the on-target impact on relevant client proteins in tumor tissue.
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http://dx.doi.org/10.1007/s00280-020-04176-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954579PMC
December 2020

Tracking the tail.

J Immunother Cancer 2020 09;8(2)

Oncology, Geneva University Hospitals, Geneva, Switzerland

Immune-checkpoint inhibitors have deeply changed the therapeutic landscape of advanced non-small cell lung cancer without actionable genomic alterations. Immune-checkpoint inhibitors have become standard front-line therapy, especially among patients with tumours expressing high levels of programmed death ligand-1; yet, many patients do not respond to therapy. This has led to the adoption of front-line combination therapies, administering programmed death-1 inhibitors concomitantly either with other checkpoint inhibitors, chemotherapy or both. Today's approved standard of care includes options with chemoimmunotherapy or dual checkpoint blockade, but each combination has only been compared to chemotherapy alone and no head-to-head trials exist. In cross-trial comparisons, combinations trials appear to show numerically superior responses to single-agent checkpoint inhibitors but the question is whether they ultimately offer a survival advantage. In this manuscript, we summarize and analyse all currently available front-line immune-checkpoint inhibitor trials in non-small cell lung cancer, whether as monotherapy or in combination with chemotherapy, second immunotherapy agents or both. Should standards of care change given the current data? While we ponder this question, we illustrate current data and conclude that the answer lies in tracking the tail of the survival curves.
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http://dx.doi.org/10.1136/jitc-2020-000971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473618PMC
September 2020

Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series.

Oncologist 2021 Jan 23;26(1):7-16. Epub 2020 Sep 23.

University of British Columbia, BC Cancer, Vancouver, British Columbia, Canada.

Background: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors.

Patients And Methods: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib.

Results: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.

Conclusion: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors.

Key Points: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.
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http://dx.doi.org/10.1634/theoncologist.2020-0379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794194PMC
January 2021

Phase I study of the Lu-DOTA-Tyr-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung.

J Immunother Cancer 2020 07;8(2)

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA

Background: Lutathera is a Lutetium-labeled somatostatin analog approved for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). Somatostatin receptors are expressed in small cell lung cancer (SCLC). Nivolumab, an anti-PD-1 antibody, may act synergistically with lutathera to generate antitumor immunity. We conducted a phase I study of lutathera plus nivolumab in patients with advanced NETs of the lung.

Methods: Patients with relapsed/refractory extensive-stage SCLC (ES-SCLC), non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary NETs were eligible. The primary objective was to determine the recommended phase 2 dose (RP2D). The phase I portion followed a standard 3+3 design, assessing two dose levels (dose level 1: lutathera 3.7 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks; dose level 2: lutathera 7.4 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks).

Results: Nine patients were enrolled (six ES-SCLC, two pulmonary atypical carcinoid, one high-grade pulmonary neuroendocrine carcinoma). No dose-limiting toxicities (DLTs) were observed at dose level 1. At dose level 2, one patient with refractory ES-SCLC developed a DLT (grade 3 rash). The most common treatment-related adverse events (TRAEs) were lymphopenia (n=7), thrombocytopenia (n=4), anemia (n=3), and nausea (n=3). The most common grade 3 TRAE was lymphopenia (n=4). Among the seven patients with measurable disease, one patient with ES-SCLC had a partial response. Two patients with pulmonary atypical carcinoid had stable disease lasting 6 months. The RP2D was dose level 2.

Conclusions: Lutathera plus nivolumab was well tolerated and showed signs of antitumor activity. This combination warrants further exploration.

Trial Registration Number: NCT03325816.
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http://dx.doi.org/10.1136/jitc-2020-000980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333915PMC
July 2020

COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study.

Lancet Oncol 2020 07 12;21(7):914-922. Epub 2020 Jun 12.

Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.

Background: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies.

Methods: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data.

Findings: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death.

Interpretation: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(20)30314-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292610PMC
July 2020

The Role of Performance Status in Small-Cell Lung Cancer in the Era of Immune Checkpoint Inhibitors.

Clin Lung Cancer 2020 11 30;21(6):e539-e543. Epub 2020 Apr 30.

Oncology Department, University Hospital of Geneva, Geneva, Switzerland. Electronic address:

After decades of platinum-based chemotherapy for advanced small-cell lung cancer, there has finally been a therapeutic advance. The combination of a platinum chemotherapy, etoposide, and an immune checkpoint inhibitor has yielded overall survival benefits in two successive phase 3 trials. Unfortunately, these trials only included fit patients, namely those with an Eastern Cooperative Oncology Group performance status of 0-1. In the real-world setting, roughly a third of patients with advanced small-cell lung cancer has a performance status of 2, and an additional 15% have a performance status of 3 or 4, meaning that approximately half of all patients are excluded from chemoimmunotherapy trials. Poor performance status is a known negative prognostic factor, with a dismal prognosis among patients with disease that does not respond to the first cycle of chemotherapy.We review current data on immunotherapy in advanced small-cell lung cancer and discuss how we integrate the new therapeutic options into daily practice.
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http://dx.doi.org/10.1016/j.cllc.2020.04.006DOI Listing
November 2020

Small Cell Lung Cancer: Advances in Diagnosis and Management.

Semin Respir Crit Care Med 2020 06 25;41(3):435-446. Epub 2020 May 25.

Division of Medical Oncology, Georgetown University, Washington, District of Columbia, Washington, DC.

Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer characterized by rapid growth and early spread. It is a highly lethal disease that typically is diagnosed at a late stage. Surgery plays a very small role in this cancer, and management typically involves chemotherapy, delivered with thoracic radiation in early-stage disease. Platinum-based chemotherapy is initially very effective, inducing rapid and often deep responses. These responses, though, are transient, and upon relapse, SCLC is highly refractory to therapy. Immunotherapy has shown promise in delivering meaningful, durable responses and the addition of immunotherapy to first-line chemotherapy has led to the first improvements in survival in decades. Still, the disease remains difficult to manage. Incorporating radiation therapy at specific points in patient management may improve disease control. The development of predictive biomarkers and novel targeted therapies will hopefully improve options for patients in the near future. This review focuses on the current standards of care and future directions.
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http://dx.doi.org/10.1055/s-0039-1700566DOI Listing
June 2020

Oral Chemotherapy for Treatment of Lung Cancer.

Front Oncol 2020 28;10:793. Epub 2020 Apr 28.

Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, United States.

The global COVID-19 pandemic has disrupted healthcare delivery, particularly for patients with advanced lung cancer. While certain aspects of care can be safely omitted or delayed, systemic therapy plays an important role in survival and quality of life for patients with advanced lung cancer; limiting access to systemic therapy will compromise cancer-related outcomes. This can be at odds with strategies to mitigate risk of COVID-19 exposure, which include reducing hospital and clinic visits. One important strategy is implementation of oral cancer therapies. Many standard regimens require intravenous infusions but there are specific circumstances where an oral agent could be an acceptable alternative. Integrating oral therapeutics can permit patients to receive effective systemic treatment without the exposure risks associated with frequent infusions. Here, we review currently available oral cytotoxic agents with a potential role in the treatment of lung cancer.
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http://dx.doi.org/10.3389/fonc.2020.00793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212352PMC
April 2020

Dashing Decades of Defeat: Long Anticipated Advances in the First-line Treatment of Extensive-Stage Small Cell Lung Cancer.

Curr Oncol Rep 2020 02 7;22(2):20. Epub 2020 Feb 7.

Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC, 20007, USA.

Purpose Of Review: Small cell lung cancer (SCLC) is an exceptionally lethal subtype of lung cancer. For patients with extensive-stage (ES) disease, which is the majority of patients, platinum-doublet chemotherapy has been the standard of care for decades. Dozens of phase III trials have failed to improve survival over standard platinum plus etoposide. Recent results, however, have met with long-overdue success. This manuscript reviews the new standards of care for ES-SCLC.

Recent Findings: Two recent phase III trials have shown an improvement in overall survival with concurrent immunotherapy and chemotherapy. In IMpower 133, the addition of the anti-PD-L1 antibody atezolizumab to carboplatin plus etoposide significantly improved both progression-free survival (PFS) and overall survival (OS). This was the first trial in over 30 years to improve survival. In CASPIAN, concurrent durvalumab, another anti-PD-L1 antibody, also led to an improvement in survival. While there is clearly a need to further improve outcomes, the improvement in survival with the addition of atezolizumab or durvalumab to platinum-doublet chemotherapy is a major advance. We now have new standards of care and the potential of a more meaningful benefit for patients with advanced SCLC.
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http://dx.doi.org/10.1007/s11912-020-0887-yDOI Listing
February 2020

Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.

J Immunother Cancer 2019 12 17;7(1):353. Epub 2019 Dec 17.

Lombardi Comprehensive Cancer Center MedStar Georgetown University Hospital, 3800 Reservoir Rd. N.W., LCCC Bldg, 2nd FL, Pod B P413, Washington, DC, 20007, USA.

Background: Patients with chronic viral infections including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) are at increased risk of developing malignancies. The safety and efficacy of ICI therapy in patients with both cancer and chronic viral infections is not well established as most clinical trials of ICIs excluded these patient populations.

Methods: We performed a retrospective analysis of patients with advanced-stage cancers and HIV, HBV, or HCV infection treated with ICI therapy at 5 MedStar Health hospitals from January 2011 to April 2018.

Results: We identified 50 patients including 16 HIV, 29 HBV/HCV, and 5 with concurrent HIV and either HBV or HCV. In the HIV cohort (n = 21), any grade immune-related adverse events (irAEs) were 24% with grade ≥ 3 irAEs 14%. Among 5 patients with matched pre/post-treatment results, no significant changes in HIV viral load and CD4+ T-cell counts were observed. RECIST confirmed (n = 18) overall response rate (ORR) was 28% with 2 complete responses (CR) and 3 partial responses (PR). Responders included 2 patients with low baseline CD4+ T-cell counts (40 and 77 cells/ul, respectively). In the HBV/HCV cohort (n = 34), any grade irAEs were 44% with grade ≥ 3 irAEs 29%. RECIST confirmed ORR was 21% (6 PR). Among the 6 patients with known pre/post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation.

Conclusions: Our retrospective series is one of the largest case series to report clinical outcomes among HIV, HBV and HCV patients treated with ICI therapy. Toxicity and efficacy rates were similar to those observed in patients without chronic viral infections. Viral reactivation was not observed. Tumor responses occurred in HIV patients with low CD4 T-cell counts. While prospective studies are needed to validate above findings, these data support not excluding such patients from ICI-based clinical trials or treatment.
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http://dx.doi.org/10.1186/s40425-019-0771-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918622PMC
December 2019

Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.

Lancet Oncol 2020 02 11;21(2):271-282. Epub 2019 Dec 11.

Dana-Farber Cancer Institute and Ludwig Center, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.

Methods: An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or 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) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.

Interpretation: Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.

Funding: Ignyta/F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(19)30691-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461630PMC
February 2020

Combining immunotherapy and epidermal growth factor receptor kinase inhibitors: worth the risk?

Ann Transl Med 2019 Jul;7(Suppl 3):S76

Department of Medicine, Georgetown University, Washington, DC, USA.

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http://dx.doi.org/10.21037/atm.2019.03.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685870PMC
July 2019

Linear IgA Disease of the Gingiva Following Nivolumab Therapy.

J Immunother 2019 Nov/Dec;42(9):345-347

Department of Medicine, Lombardi Comprehensive Cancer Center.

Immunotherapy has advanced the treatment of solid organ malignancies. Although generally well tolerated, treatment with immune checkpoint inhibitors can be complicated by immune-related adverse events, some of which are relatively uncommon. We report the first case of gingival linear immunoglobulin A disease related to treatment with an antiprogrammed cell death protein 1 antibody. A 73-year-old male with advanced non-small cell lung cancer achieved a durable response to nivolumab monotherapy. After 1 year of treatment, he developed gingival swelling and pain. Biopsy revealed linear immunoglobulin A disease of the gingiva which was effectively treated with systemic steroids. Ongoing vigilance for immune-mediated toxicity is paramount during and after treatment with immune checkpoint inhibitors.
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http://dx.doi.org/10.1097/CJI.0000000000000288DOI Listing
July 2020

Clinical Activity, Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC.

J Thorac Oncol 2019 10 20;14(10):1794-1806. Epub 2019 Jun 20.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Introduction: Durvalumab is a selective, high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 (PD-L1) binding to programmed death 1. Here we report safety and clinical activity in the NSCLC cohort of a phase I/II trial that included multiple tumor types (Study 1108; NCT01693562).

Methods: Patients with stage IIIB-IV NSCLC (squamous or nonsquamous) received durvalumab 10 mg/kg every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. Primary objectives were safety and antitumor activity. Tumoral PD-L1 expression was assessed using the VENTANA SP263 Assay. Responses were assessed by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1). Adverse events were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events (v4.03).

Results: Of 304 patients, 79.0% were previously treated. Confirmed objective response rate was 21.8% in patients with greater than or equal to 25% PD-L1 expression and 6.4% in those with less than 25%; 25.9% in first-line patients and 12.7% in previously treated patients; and 14.0% in squamous and 16.7% in nonsquamous disease. Median overall survival was 12.4 months and median progression-free survival was 1.7 months; both were numerically longer in the PD-L1 greater than or equal to 25% group than in the PD-L1 less than 25% group (overall survival 16.4 versus 7.6 months, respectively; progression-free survival 2.6 versus 1.4 months, respectively). Treatment-related adverse events occurred in 57.2%, were grade 3/4 in 10.2%, and led to discontinuation in 5.6%. One patient (0.3%) died of treatment-related pneumonia with underlying pneumonitis.

Conclusions: Durvalumab was clinically active irrespective of histology in this mostly pretreated population, with a manageable safety profile. Response rates and survival appeared to be enhanced in patients with greater tumoral PD-L1 expression.
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http://dx.doi.org/10.1016/j.jtho.2019.06.010DOI Listing
October 2019

Immune Checkpoint Inhibitors in Small Cell Lung Cancer: A Partially Realized Potential.

Adv Ther 2019 08 17;36(8):1826-1832. Epub 2019 Jun 17.

Department of Medicine, Georgetown University, Washington, DC, USA.

Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer that has seen few therapeutic advances, despite ongoing concerted efforts. Immunotherapy has been an effective option in other carcinogen-related cancers and has shown modest activity in SCLC. Monotherapy with the anti-PD-1 antibody nivolumab in patients with at least two prior lines of therapy was associated with a response rate of 11.9% and a median duration of response of 17.9 months, leading to accelerated approval by the Food and Drug Administration (FDA) as third-line therapy for SCLC. Second-line checkpoint inhibitors have not performed well enough to change the standard of care, and maintenance immunotherapy has not shown significant benefit. However, the incorporation of concurrent immunotherapy in the first-line treatment of SCLC has improved outcomes. The addition of the anti-PD-L1 antibody atezolizumab to standard carboplatin plus etoposide led to an improvement in progression free survival (PFS) and overall survival, the first such improvement in over 30 years leading to the approval of atezolizumab as part of first-line therapy for advanced SCLC. While these landmark approvals offer promising novel treatment options for this recalcitrant disease, more work is needed to optimize their delivery and to build upon these important advances.
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http://dx.doi.org/10.1007/s12325-019-01008-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822836PMC
August 2019

A Phase I/II Trial of Cetuximab in Combination with Interleukin-12 Administered to Patients with Unresectable Primary or Recurrent Head and Neck Squamous Cell Carcinoma.

Clin Cancer Res 2019 08 29;25(16):4955-4965. Epub 2019 May 29.

Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio.

Purpose: mAbs including cetuximab can induce antibody-dependent cellular cytotoxicity (ADCC) and cytokine production mediated via innate immune cells with the ability to recognize mAb-coated tumors. Preclinical modeling has shown that costimulation of natural killer (NK) cells via the Fc receptor and the IL12 receptor promotes NK-cell-mediated ADCC and production of cytokines.

Patients And Methods: This phase I/II trial evaluated the combination of cetuximab with IL12 for the treatment of EGFR-expressing head and neck cancer. Treatment consisted of cetuximab 500 mg/m i.v. every 2 weeks with either 0.2 mcg/kg or 0.3 mcg/kg IL12 s.c. on days 2 and 5 of the 2-week cycle, beginning with cycle 2. Correlative studies from blood draws obtained prior to treatment and during therapy included measurement of ADCC, serum cytokine, and chemokine analysis, determination of NK cell FcγRIIIa polymorphisms, and an analysis of myeloid-derived suppressor cell (MDSC) frequency in peripheral blood.

Results: The combination of cetuximab and IL12 was well tolerated. No clinical responses were observed, however, 48% of patients exhibited prolonged progression-free survival (PFS; average of 6.5 months). Compared with patients that did not exhibit clinical benefit, patients with PFS >100 days exhibited increased ADCC as therapy continued compared with baseline, greater production of IFNγ, IP-10, and TNFα at the beginning of cycle 8 compared with baseline values and had a predominance of monocytic MDSCs versus granulocytic MDSCs prior to therapy.

Conclusions: Further investigation of IL12 as an immunomodulatory agent in combination with cetuximab in head and neck squamous cell carcinoma is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697573PMC
August 2019

Detection of NRG1 Gene Fusions in Solid Tumors.

Clin Cancer Res 2019 Aug 15;25(16):4966-4972. Epub 2019 Apr 15.

Georgetown University, Washington, DC.

Purpose: gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of fusions across multiple tumor types and described fusion partners.

Experimental Design: Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner.

Results: Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer.

Conclusions: fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470623PMC
August 2019