Publications by authors named "Mary W Redman"

58 Publications

Patient Knowledge and Expectations About Return of Genomic Results in a Biomarker-Driven Master Protocol Trial (SWOG S1400GEN).

JCO Oncol Pract 2021 Apr 2:OP2000770. Epub 2021 Apr 2.

Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: Biomarker-driven master protocols represent a new paradigm in oncology clinical trials, but their complex designs and wide-ranging genomic results returned can be difficult to communicate to participants. The objective of this pilot study was to evaluate patient knowledge and expectations related to return of genomic results in the Lung Cancer Master Protocol (Lung-MAP).

Methods: Eligible participants with previously treated advanced non-small-cell lung cancer were recruited from patients enrolled in Lung-MAP. Participants completed a 38-item telephone survey ≤ 30 days from Lung-MAP consent. The survey assessed understanding about the benefits and risks of Lung-MAP participation and knowledge of the potential uses of somatic testing results returned. Descriptive statistics and odds ratios for associations between demographic factors and correct responses to survey items were assessed.

Results: From August 1, 2017, to June 30, 2019, we recruited 207 participants with a median age of 67, 57.3% male, and 94.2% White. Most participants "strongly/somewhat agreed" with statements that they "received enough information to understand" Lung-MAP benefits (82.6%) and risks (69.5%). In items asking about potential uses of Lung-MAP genomic results, 87.0% correctly indicated that the results help to select cancer treatment, but < 20% correctly indicated that the results are not used to confirm cancer diagnosis, would not reveal risk of developing diseases besides cancer, and would not indicate if family members had increased cancer risk. There were no associations between sociodemographic factors and proportions providing correct responses.

Conclusion: In a large National Clinical Trials Network biomarker-driven master protocol, most participants demonstrated incorrect knowledge and expectations about the uses of genomic results provided in the study despite most indicating that they had enough information to understand benefits and risks.
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http://dx.doi.org/10.1200/OP.20.00770DOI Listing
April 2021

A Dose-finding Study Followed by a Phase II Randomized, Placebo-controlled Trial of Chemoradiotherapy With or Without Veliparib in Stage III Non-small-cell Lung Cancer: SWOG 1206 (8811).

Clin Lung Cancer 2021 Feb 19. Epub 2021 Feb 19.

University of California Davis, Sacramento, CA.

Background: We conducted a 2-part study to evaluate the incorporation of veliparib, a PARP inhibitor, into chemoradiotherapy (CRT) for stage III non-small-cell lung cancer.

Patients And Methods: In the phase I part, patients were treated successively at 3 dose levels of veliparib (40, 80, and 120 mg) twice daily during CRT. In the phase II part, patients were randomized to receive veliparib or placebo during thoracic radiotherapy with concurrent weekly carboplatin and paclitaxel, followed by 2 cycles of consolidation carboplatin and paclitaxel with veliparib or placebo. The study was prematurely discontinued owing to the emergence of adjuvant immunotherapy as standard of care.

Results: Of 21 patients enrolled in phase I, 2 patients developed dose-limiting toxicities (DLTs): 1 grade 3 esophagitis with dysphagia (at 40 mg) and 1 grade 3 esophagitis with dehydration (at 80 mg). No DLTs were seen at veliparib dose of 120 mg twice daily, which was selected for the phase II part that enrolled 31 eligible patients. Progression-free survival (PFS) was not different between the 2 arms (P = .20). For the veliparib and placebo arms, response rates were 56% and 69%, PFS at 1 year 47% and 46%, and overall survival at 1 year 89% and 54%, respectively.

Conclusion: Veliparib with CRT was feasible and well tolerated. Efficacy could not accurately be determined because of early study closure. Nonetheless, there is enthusiasm for the evaluation of PARP inhibitors in lung cancer as predictive biomarkers are being developed and combinations with immunotherapy are attractive.
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http://dx.doi.org/10.1016/j.cllc.2021.02.009DOI Listing
February 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

SWOG S1400A (NCT02154490): A Phase II Study of Durvalumab for Patients With Previously Treated Stage IV or Recurrent Squamous Cell Lung Cancer (Lung-MAP Sub-study).

Clin Lung Cancer 2020 Nov 10. Epub 2020 Nov 10.

Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.

Introduction: The objective of the Lung-MAP sub-study S1400A was to evaluate the response rate to durvalumab, an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with squamous non-small-cell lung cancer (SqNSCLC).

Patients And Methods: Patients who progressed on at least 1 prior platinum-based chemotherapy were eligible. The study was designed as a phase II/III trial comparing durvalumab with docetaxel but was modified to a single-arm, phase II trial with the primary endpoint of objective response when immunotherapy became an approved treatment.

Results: A total of 116 patients were registered to this sub-study; 78 to durvalumab and 38 to docetaxel. Of the 78 patients, 9 were ineligible, and 1 was not evaluable for endpoints. Responses were achieved in 11 patients among the 68 eligible and evaluable patients on durvalumab (overall response rate, 16%; 95% confidence interval [CI], 7%-25%). The disease control rate was 54% (95% CI, 43%-66%), the median overall survival was 11.6 months (95% CI, 10.2-14.3 months), and the median progression-free survival was 2.9 months (95% CI, 2.0-4.0 months). PD-L1 data was available for 43 patients on durvalumab, with 14 (33%) patients who were PD-L1-positive (≥ 25%) and 2 responses (overall response rate, 14%; 95% CI, 0%-33%), the disease control rate was 57% (95% CI, 31%-83%), the median overall survival and progression-free survival were 10.7 months (95% CI, 9.2-14.3 months) and 2.3 months (95% CI, 1.4-4.2 months), respectively. Grade ≥ 3 treatment-related adverse events occurred in 22 (32%) patients on durvalumab, with 6 discontinuing owing to drug-related adverse events (9%; 95% CI, 2%-16%).

Conclusions: Durvalumab shows single-agent activity and toxicities in this sub-group of patients that is comparable with other anti-programmed cell death protein 1/PD-L1 antibodies.
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http://dx.doi.org/10.1016/j.cllc.2020.10.015DOI Listing
November 2020

A Phase II Study of Telisotuzumab Vedotin in Patients With c-MET-positive Stage IV or Recurrent Squamous Cell Lung Cancer (LUNG-MAP Sub-study S1400K, NCT03574753).

Clin Lung Cancer 2020 Oct 14. Epub 2020 Oct 14.

The University of Texas MD Anderson Cancer Center, Houston, TX (at time of study).

Introduction: Lung-MAP S1400K was designed to evaluate the response to telisotuzumab vedotin, an antibody-drug conjugate targeting c-MET, in patients with c-MET-positive squamous cell carcinoma (SCC).

Patients And Methods: Patients with previously treated SCC with c-MET-positive tumors (H score ≥ 150, Ventana SP44 assay) were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor-naive) and Cohort 2 (immune checkpoint inhibitor refractory). Telisotuzumab vedotin 2.7 mg/kg was administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included progression-free survival, overall survival, response within cohort, duration of response, and toxicities. Interim analysis was planned after 20 evaluable patients, with ≥ 3 responses needed to continue enrollment.

Results: Forty-nine patients (14% of screened patients) were assigned to S1400K, 28 patients enrolled (15 in Cohort 1 and 13 in Cohort 2), and 23 were eligible. S1400K closed on December 21, 2018 owing to lack of efficacy. Two responses (response rate of 9%; 95% confidence interval, 0%-20%) were reported in cohort 1 (1 complete and 1 unconfirmed partial response), whereas 10 patients had stable disease, with a disease control rate of 52%. The median overall and progression-free survival was 5.6 and 2.4 months, respectively. There were 3 grade 5 events (2 pneumonitis, in Cohort 2, and 1 bronchopulmonary hemorrhage, in Cohort 1).

Conclusion: Telisotuzumab vedotin failed to meet the pre-specified response needed to justify continuing enrollment to S1400K. Pneumonitis was an unanticipated toxicity observed in patients with SCC.
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http://dx.doi.org/10.1016/j.cllc.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044254PMC
October 2020

Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol.

Lancet Oncol 2020 12 27;21(12):1589-1601. Epub 2020 Oct 27.

Department of Medicine, Yale Cancer Center, New Haven, CT, USA.

Background: The Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed biomarker-driven master protocol designed to address an unmet need for better therapies for squamous non-small-cell lung cancer. Lung-MAP (S1400) was created to establish an infrastructure for biomarker screening and rapid regulatory intent evaluation of targeted therapies and was the first biomarker-driven master protocol initiated with the US National Cancer Institute (NCI).

Methods: Lung-MAP (S1400) was done within the National Clinical Trials Network of the NCI using a public-private partnership. Eligible patients were aged 18 years or older, had stage IV or recurrent squamous non-small-cell lung cancer, had previously been treated with platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The study included a screening component using the FoundationOne assay (Foundation Medicine, Cambridge, MA, USA) for next-generation sequencing, and a clinical trial component with biomarker-driven substudies and non-match substudies for patients who were ineligible for biomarker-driven substudies. Patients were pre-screened and received their substudy assignment upon progression, or they were screened at progression and received their substudy assignment upon completion of testing. Patients could enrol onto additional substudies after progression on a substudy. The study is registered with ClinicalTrials.gov, NCT02154490, and all research related to Lung-MAP (S1400) is completed.

Findings: Between June 16, 2014, and Jan 28, 2019, 1864 patients enrolled and 1841 (98·9%) submitted tissue. 1674 (90·9%) of 1841 patients had biomarker results, and 1404 (83·9%) of 1674 patients received a substudy assignment. Of the assigned patients, 655 (46·7%) registered to a substudy. The biomarker-driven substudies evaluated taselisib (targeting PIK3CA alterations), palbociclib (cell cycle gene alterations), AZD4547 (FGFR alteration), rilotumumab plus erlotinib (MET), talazoparib (homologous recombination repair deficiency), and telisotuzumab vedotin (MET). The non-match substudies evaluated durvalumab, and nivolumab plus ipilimumab for anti-PD-1 or anti-PD-L1-naive disease, and durvalumab plus tremelimumab for anti-PD-1 or anti-PD-L1 relapsed disease. Combining data from the substudies, ten (7·0%) of 143 patients responded to targeted therapy, 53 (16·8%) of 315 patients responded to anti-PD-1 or anti-PD-L1 therapy for immunotherapy-naive disease, and three (5·4%) of 56 responded to docetaxel in the second line of therapy. Median overall survival was 5·9 months (95% CI 4·8-7·8) for the targeted therapy groups, 7·7 months (6·7-9·2) for the docetaxel groups, and 10·8 months (9·4-12·3) for the anti-PD-1 or anti-PD-L1-containing groups. Median progression-free survival was 2·5 months (95% CI 1·7-2·8) for the targeted therapy groups, 2·7 months (1·9-2·9) for the docetaxel groups, and 3·0 months (2·7-3·9) for the anti-PD-1 or anti-PD-L1-containing groups.

Interpretation: Lung-MAP (S1400) met its goal to quickly address biomarker-driven therapy questions in squamous non-small-cell lung cancer. In early 2019, a new screening protocol was implemented expanding to all histological types of non-small-cell lung cancer and to add focus on immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed disease. With these changes, Lung-MAP continues to meet its goal to focus on unmet needs in the treatment of advanced lung cancers.

Funding: US National Institutes of Health, and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health.
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http://dx.doi.org/10.1016/S1470-2045(20)30475-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109255PMC
December 2020

Randomized Trial of Afatinib Plus Cetuximab Versus Afatinib Alone for First-Line Treatment of -Mutant Non-Small-Cell Lung Cancer: Final Results From SWOG S1403.

J Clin Oncol 2020 12 6;38(34):4076-4085. Epub 2020 Oct 6.

UC Davis Comprehensive Cancer Center, Sacramento, CA.

Purpose: The irreversible ErbB family tyrosine kinase inhibitor (TKI) afatinib plus the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to EGFR TKIs. We studied whether the combination of afatinib plus cetuximab compared with afatinib alone would improve progression-free survival (PFS) in patients with treatment-naive -mutant non-small-cell lung cancer (NSCLC) by preventing or delaying resistance.

Methods: Patients with -mutant NSCLC without prior treatment of advanced disease were enrolled in this phase II, multicenter trial and randomly assigned to receive afatinib 40 mg orally daily plus cetuximab 500 mg/m intravenously every 2 weeks or afatinib alone. The primary end point was PFS.

Results: Between March 25, 2015 and April 23, 2018, 174 patients were randomly assigned, and 168 (83 on afatinib + cetuximab and 85 on afatinib) were eligible. There was no improvement in PFS in patients receiving afatinib plus cetuximab compared with afatinib alone (hazard ratio [HR], 1.01; 95% CI, 0.72 to 1.43; = .94; median, 11.9 months 13.4 months). Similarly, there was no difference in response rate (67% 74%; = .38) or overall survival (HR, 0.82; 95% CI, 0.50 to 1.36; = .44). Toxicity was greater with the combination: grade ≥ 3 adverse events related to treatment occurred in 72% of patients receiving afatinib plus cetuximab compared with 40% of those receiving afatinib alone, most commonly rash and diarrhea. Dose reductions were more common in patients receiving the combination, and 30% of patients in this arm discontinued cetuximab due to toxicity. At interim analysis, there was insufficient evidence to support continued accrual, and the trial was closed.

Conclusions: The addition of cetuximab to afatinib did not improve outcomes in previously untreated -mutant NSCLC, despite recognized activity in the acquired resistance setting.
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http://dx.doi.org/10.1200/JCO.20.01149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768342PMC
December 2020

Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma: A Phase 1/2 Nonrandomized Clinical Trial.

JAMA Oncol 2020 Nov;6(11):1778-1782

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Importance: Anthracycline-based therapy is standard first-line treatment for most patients with advanced and metastatic sarcomas. Although multiple trials have attempted to show improved outcomes in patients with soft-tissue sarcoma over doxorubicin monotherapy, each has fallen short of demonstrating improved outcomes.

Objective: To evaluate the safety and efficacy of doxorubicin in combination with pembrolizumab in patients with advanced, anthracycline-naive sarcomas.

Design, Setting, And Participants: This nonrandomized clinical trial used a 2-stage phase 2 design and was performed at a single, academic sarcoma specialty center. Patients were adults with good performance status and end-organ function. Patients with all sarcoma subtypes were allowed to enroll with the exception of osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma.

Interventions: Two dose levels of doxorubicin (45 and 75 mg/m2) were tested for safety in combination with pembrolizumab.

Main Outcomes And Measures: Objective response rate (ORR) was the primary end point. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Correlative studies included immunohistochemistry, gene expression, and serum cytokines.

Results: A total of 37 patients (22 men; 15 women) were treated in the combined phase 1/2 trial. The median (range) patient age was 58.4 (25-80) years. The most common histologic subtype was leiomyosarcoma (11 patients). Doxorubicin plus pembrolizumab was well tolerated without significant unexpected toxic effects. The ORR was 13% for phase 2 patients and 19% overall. Median PFS was 8.1 (95% CI, 7.6-10.8) months. Median OS was 27.6 (95% CI, 18.7-not reached) months at the time of this analysis. Two of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses. Tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and associated with inferior PFS (log-rank P = .03). No dose-limiting toxic effects were observed.

Conclusions And Relevance: In this nonrandomized clinical trial, doxorubicin plus pembrolizumab was well tolerated. Although the primary end point for ORR was not reached, the PFS and OS observed compared favorably with prior published studies. Further studies are warranted, especially those focusing on undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.

Trial Registration: ClinicalTrials.gov Identifier: NCT02888665.
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http://dx.doi.org/10.1001/jamaoncol.2020.3689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489365PMC
November 2020

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis.

Blood 2021 Feb;137(8):1082-1089

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Heparin-induced thrombocytopenia (HIT) is a life-threatening, prothrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays, such as the platelet factor 4 (PF4) heparin enzyme-linked immunosorbent assay (ELISA) lack specificity, and the gold-standard carbon 14-labeled serotonin release assay (SRA) is of limited value for early patient management because it is available only through reference laboratories. Recent studies have demonstrated that pathogenic HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin expression assay (PEA), may provide an option for rapid and conclusive results. Based upon predefined criteria that combined 4Ts scores and HIT ELISA results, 409 consecutive adults suspected of having HIT were classified as disease positive, negative, or indeterminate. Patients deemed HIT indeterminate were considered disease negative in the primary analysis and disease positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.87-1.0) and similar to that of SRA (AUC, 0.91; 95% CI, 0.82-1.0). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (95% CI, 0.78-0.98) and 0.86 (95% CI, 0.77-0.96), respectively. The PEA, a technically simple nonradioactive assay that uses ∼20-fold fewer platelets compared with the SRA, had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.
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http://dx.doi.org/10.1182/blood.2020008195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907721PMC
February 2021

Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC.

JCI Insight 2019 12 19;4(24). Epub 2019 Dec 19.

Fred Hutchinson Clinical Research Division, Seattle, Washington, USA.

Immune checkpoint inhibitor (ICI) treatment has recently become a first-line therapy for many non-small cell lung cancer (NSCLC) patients. Unfortunately, most NSCLC patients are refractory to ICI monotherapy, and initial attempts to address this issue with secondary therapeutics have proven unsuccessful. To identify entities precluding CD8+ T cell accumulation in this process, we performed unbiased analyses on flow cytometry, gene expression, and multiplexed immunohistochemical data from a NSCLC patient cohort. The results revealed the presence of a myeloid-rich subgroup, which was devoid of CD4+ and CD8+ T cells. Of all myeloid cell types assessed, neutrophils were the most highly associated with the myeloid phenotype. Additionally, the ratio of CD8+ T cells to neutrophils (CD8/PMN) within the tumor mass optimally distinguished between active and myeloid cases. This ratio was also capable of showing the separation of patients responsive to ICI therapy from those with stable or progressive disease in 2 independent cohorts. Tumor-bearing mice treated with a combination of anti-PD1 and SX-682 (CXCR1/2 inhibitor) displayed relocation of lymphocytes from the tumor periphery into a malignant tumor, which was associated with induction of IFN-γ-responsive genes. These results suggest that neutrophil antagonism may represent a viable secondary therapeutic strategy to enhance ICI treatment outcomes.
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http://dx.doi.org/10.1172/jci.insight.130850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975266PMC
December 2019

Quantifying treatment effects using the personalized chance of longer survival.

Stat Med 2019 12 9;38(28):5317-5331. Epub 2019 Sep 9.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

The hazard ratio is widely used to measure or to summarize the magnitude of treatment effects, but it is justifiably difficult to interpret in a meaningful way to patients and perhaps for clinicians as well. In addition, it is most meaningful when the hazard functions are approximately proportional over time. We propose a new measure, termed personalized chance of longer survival. The measure, which quantifies the probability of living longer with one treatment over the another, accounts for individualized characteristics to directly address personalized treatment effects. Hence, the measure is patient focused, which can be used to evaluate subgroups easily. We believe it is intuitive to understand and clinically interpretable in the presence of nonproportionality. Furthermore, because it estimates the probability of living longer by some fixed amount of time, it encodes the probabilistic part of treatment effect estimation. We provide nonparametric estimation and inference procedures that can accommodate censored survival outcomes. We conduct extensive simulation studies, which characterize performance of the proposed method, and data from a large randomized Phase III clinical trial (SWOG S0819) are analyzed using the proposed method.
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http://dx.doi.org/10.1002/sim.8363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842038PMC
December 2019

Phase II Trial of Cediranib in Combination With Cisplatin and Pemetrexed in Chemotherapy-Naïve Patients With Unresectable Malignant Pleural Mesothelioma (SWOG S0905).

J Clin Oncol 2019 10 6;37(28):2537-2547. Epub 2019 Aug 6.

University of California Davis Cancer Center, Sacramento, CA.

Purpose: Antiangiogenic agents combined with chemotherapy have efficacy in the treatment of unresectable malignant pleural mesothelioma (MPM). Cediranib (AstraZeneca, Cheshire, United Kingdom), a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, demonstrated therapeutic potential in a prior phase I trial. We evaluated a phase II trial for efficacy.

Patients And Methods: SWOG S0905 (ClinicalTrials.gov identifier: NCT01064648) randomly assigned cediranib or placebo with platinum-pemetrexed for six cycles followed by maintenance cediranib or placebo in unresectable chemotherapy-naïve patients with MPM of any histologic subtype. Primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 progression-free survival (PFS). Secondary end points included overall survival, PFS by modified RECIST v1.1, response (modified RECIST and RECIST v1.1), disease control, and safety/toxicity. The trial was designed to detect a difference in RECIST v1.1 PFS at the one-sided 0.1 level using a stratified log-rank test.

Results: Ninety-two eligible patients were enrolled (75% epithelioid and 25% biphasic or sarcomatoid). The cediranib arm had more grade 3 and 4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved PFS by RECIST v1.1 (hazard ratio, 0.71; 80% CI, 0.54 to 0.95; = .062; 7.2 months 5.6 months) and increased modified RECIST v1.1 response (50% 20%; = .006). By modified RECIST v1.1, cediranib numerically increased PFS (hazard ratio, 0.77; 80% CI, 0.59 to 1.02; = .12; median, 6.9 months 5.6 months). No significant difference in overall survival was observed.

Conclusion: The addition of cediranib to platinum-pemetrexed improved PFS by RECIST v1.1 and response rate by modified RECIST in patients with unresectable MPM. Whereas adding antiangiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes additional development in MPM.
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http://dx.doi.org/10.1200/JCO.19.00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001793PMC
October 2019

Challenges and approaches to implementing master/basket trials in oncology.

Blood Adv 2019 07;3(14):2237-2243

UC Davis Comprehensive Cancer Center, Sacramento, CA.

The appetite for cutting-edge cancer research, across medical institutions, scientific researchers, and health care providers, is increasing based on the promise of true breakthroughs and cures with new therapeutics available for investigation. At the same time, the barriers for advancing clinical research are impacting how quickly drug development efforts are conducted. For example, we know now that under a microscope, patients with the same type of cancer and histology might look the same; however, the reality is that most cancers are driven by genomic, transcriptional, and epigenetic changes that make each patient unique. Additionally, the immunologic reaction to different tumor types is distinct among patients. The challenge for researchers developing new therapies today is vastly different than it was in the era of cytotoxics. Today, we must identify a sufficient number of patients harboring a rare mutation or other characteristic and match this to the right therapeutic option. This summary provides a guide to help inform the scientific cancer community about the benefits and challenges of conducting umbrella or basket trials (master trials), and to create a roadmap to help make this new and evolving form of clinical trial design as effective as possible.
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http://dx.doi.org/10.1182/bloodadvances.2019031229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650731PMC
July 2019

SWOG S1400C (NCT02154490)-A Phase II Study of Palbociclib for Previously Treated Cell Cycle Gene Alteration-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy).

J Thorac Oncol 2019 10 11;14(10):1853-1859. Epub 2019 Jul 11.

Medical Oncology, Yale Cancer Center, New Haven, Connecticut.

Objective: Lung-MAP (SWOG S1400) is a master platform trial assessing targeted therapies in squamous NSCLC. The objective of study C (S1400C) was to evaluate the response rate to palbociclib, a cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitor, in patients with cell cycle gene abnormalities.

Methods: Patients with squamous NSCLC, a performance status of 0 to 2, and normal organ function who had progressed after at least one prior platinum-based chemotherapy with cyclin-dependent kinase 4 gene (CDK4) or cyclin D1 gene (CCND1), cyclin D2 gene (CCND2), or cyclin D3 gene (CCND3) amplifications on tumor specimens were eligible. The study was originally designed as a phase II/III trial comparing palbociclib with docetaxel, but it was modified to a single-arm phase II trial with the primary end point of response when immunotherapy was approved. If two or fewer responses were seen in the first 20 patients, then the study would cease enrollment.

Results: A total of 88 patients (9% of patients screened) were assigned to S1400C, and 53 patients enrolled (including 17 to receive docetaxel). One patient who had been registered to receive docetaxel was re-registered to receive palbociclib after progression while taking docetaxel. The frequencies of cell cycle gene alterations in the eligible patients taking palbociclib (n = 32) were as follows: CCND1, 81% (n = 26); CCND2, 9% (n = 3); CCND3, 6% (n = 2); and CDK4, 3% (n = 1). In all, 32 eligible patients received palbociclib. There were two partial responses (response rate 6% [95% confidence interval (CI): 0%-15%]), both with CCND1 amplification. Twelve patients had stable disease (38% [95% CI: 21%-54%]). The median progression-free survival was 1.7 months (95% CI: 1.6-2.9 months) and the median overall survival was 7.1 months (95% CI: 4.2-12.5).

Conclusion: Palbociclib as monotherapy failed to demonstrate the prespecified criteria for advancement to phase III testing.
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http://dx.doi.org/10.1016/j.jtho.2019.06.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764876PMC
October 2019

SWOG S1400D (NCT02965378), a Phase II Study of the Fibroblast Growth Factor Receptor Inhibitor AZD4547 in Previously Treated Patients With Fibroblast Growth Factor Pathway-Activated Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy).

J Thorac Oncol 2019 10 11;14(10):1847-1852. Epub 2019 Jun 11.

Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Background: S1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting.

Methods: Eligible patients had tumoral FGFR alteration or mutation and had progressive disease after at least one line of platinum-based systemic therapy. Patients received AZD4547 80 mg twice daily orally. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival, and duration of response (DoR).

Results: Ninety-two patients were assigned to S1400D, 43 were enrolled, and 27 AZD4547-treated patients were evaluable. Evaluable patients were predominantly white (n = 24, 89%), median age 66 years (range, 49-88 years old), and female (n = 7, 26%). FGFR alterations included FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%). Treatment with ADZ4547 was well tolerated; grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of 27 response-evaluable patients, 1 patient with FGFR3 S249C had unconfirmed partial response with a DoR of 1.5 months and 1 patient with FGFR1 amplification had a confirmed partial response with a DoR of 2.9 months (7%, 95% confidence interval [CI]: 0%-17%). Median progression-free survival and overall survival for the AZD4547-treated cohort were 2.7 months (95% CI: 1.4- 4.5 months) and 7.5 months (95% CI: 3.7-9.3 months).

Conclusions: AZD4547 had an acceptable safety profile but minimal activity in this predominantly FGFR1/FGFR3-amplified cohort. Evaluation of other targeted agents in Lung-MAP is ongoing.
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http://dx.doi.org/10.1016/j.jtho.2019.05.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901020PMC
October 2019

SWOG S1400B (NCT02785913), a Phase II Study of GDC-0032 (Taselisib) for Previously Treated PI3K-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study).

J Thorac Oncol 2019 10 31;14(10):1839-1846. Epub 2019 May 31.

Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: S1400B is a biomarker-driven Lung-MAP substudy evaluating the phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (GDC-0032) in patients with PI3K pathway-activated squamous NSCLC (sqNSCLC).

Methods: Eligible patients had tumoral phosphatidylinositol-4,5-biphosphate 3 kinase catalytic subunit alpha (PIK3CA) alterations by next-generation sequencing and disease progression after at least one line of platinum-based therapy. Patients received 4-mg taselisib orally daily. The primary analysis population (PAP) was a subset of patients having substitution mutations believed to be associated with clinical benefit of PI3K inhibitors. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival and duration of response.

Results: Twenty-six patients treated with taselisib comprised the full evaluable population (FEP); 21 patients comprised the PAP. Median age for patients in the FEP was 68 years (range: 53-83 years), 19 were male (73%). The study was closed for futility at interim analysis with one responder in the PAP (5% response rate, 95% confidence interval [CI]: 0%-24%). Two possibly treatment-related deaths (one respiratory failure, one cardiac arrest) were observed; one patient had grades 4 and 11 had grade 3 adverse events. Median progression-free survival and overall survival in the PAP group were 2.9 months (95% CI: 1.8-4.0 mo) and 5.9 months (95% CI: 4.2-7.8 mo), respectively. These numbers were nearly the same in the FEP.

Conclusions: Study S1400B evaluating taselisib in PIK3CA-altered sqNSCLC failed to meet its primary endpoint and was closed after an interim futility analysis. The trial is unique in cataloguing the diversity of PIK3CA mutations in sqNSCLC.
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http://dx.doi.org/10.1016/j.jtho.2019.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017958PMC
October 2019

Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer.

J Thorac Oncol 2018 Dec 27;13(12):1818-1831. Epub 2018 Sep 27.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence.
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http://dx.doi.org/10.1016/j.jtho.2018.09.017DOI Listing
December 2018

Response to H. Nabi et al.

J Natl Cancer Inst 2018 12;110(12):1424-1425

Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY.

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http://dx.doi.org/10.1093/jnci/djy069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658869PMC
December 2018

Racial disparity in oncologic and quality-of-life outcomes in patients with locally advanced head and neck squamous cell carcinomas enrolled in a randomized phase 2 trial.

Cancer 2018 07 18;124(13):2841-2849. Epub 2018 Apr 18.

University of Washington, Seattle, Washington.

Background: To better understand patient-reported quality of life (PRQOL) for patients with head and neck cancer, PRQOL scores were collected in a clinical trial.

Methods: Patients were randomized to arm A (70 Gy of radiation with cisplatin) or arm B (70 Gy of radiation with cisplatin plus erlotinib at 150 mg daily). PRQOL scores were measured on days -7 (arm B only), 0, 30, and 180 with the University of Washington Quality of Life Questionnaire. Associations with clinical factors and outcomes were explored with linear mixed, logistic, and Cox regression models.

Results: One hundred eighty-nine patients (97 in arm A and 92 in arm B) consented to PRQOL collection. Patients were balanced apart from more females in arm A (20 [21%] vs 8 [9%]; P = .02). There were 17 black patients (18%) in arm A and 12 (13%) in arm B (P = .39). There was no change in the mean scores in arm B from day -7 to day 0 (P = .36). Scores were lower in both arms at day 30 (P for both < .0001), with no difference by arm (P = .10). Scores on day 180 remained lower for arm A (-6.79; 95% confidence interval [CI], -12.6 to -1.0; P = .02). In arm B, this difference was not significant, and this suggested that the scores had returned to the baseline by day 180 (P = .73). After adjustments for potential confounders, black race was an independent predictor for inferior scores (-11.4; 95% CI, -16.84 to -5.94; P < .0001), complete response rates (odds ratio, 0.34; 95% CI, 0.12-0.91; P = .03), and overall survival (hazard ratio, 3.71; 95% CI, 1.63-8.47; P < .01).

Conclusions: PRQOL scores predictably worsened during and improved after chemoradiation. Black patients had inferior PRQOL and overall survival. Cancer 2018;124:2841-2849. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31407DOI Listing
July 2018

Smoking, Sex, and Non-Small Cell Lung Cancer: Steroid Hormone Receptors in Tumor Tissue (S0424).

J Natl Cancer Inst 2018 07;110(7):734-742

Department of Cancer Prevention and Control and Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.

Background: To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking.

Methods: Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-α, ER-β, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Linear regression was used to examine differences in expression by sex and smoking status. Cox proportional hazard models were used to estimate survival associated with the receptors. All statistical tests were two-sided.

Results: In ever smokers, postmenopause and oral contraceptive use were associated with lower nuclear ER-β (P = .02) and total (nuclear + cytoplasmic) PR expression (P = .02), respectively. Women had lower cytoplasmic ER-α (regression coefficient [β], or differences in H-scores = -15.8, P = .003) and nuclear ER-β (β = -12.8, P = .04) expression than men, adjusting for age, race, and smoking. Ever smokers had both higher cytoplasmic ER-α (β = 45.0, P < .001) and ER-β (β = 25.9, P < .001) but lower total PR (β = -42.1, P < .001) than never smokers. Higher cytoplasmic ER-α and ER-β were associated with worse survival (hazard ratio = 1.73, 95% confidence interval [CI] = 1.15 to 2.58, and HR = 1.59, 95% CI = 1.08 to 2.33, respectively; quartiles 4 vs 1).

Conclusions: Lower expression of nuclear ER-β in women supports the estrogen hypothesis in lung cancer etiology. Increasing cytoplasmic ER-α and ER-β and decreasing PR protein expression may be mechanisms whereby smoking disrupts hormone pathways.
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http://dx.doi.org/10.1093/jnci/djx260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037104PMC
July 2018

Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study.

Lancet Oncol 2018 01 20;19(1):101-114. Epub 2017 Nov 20.

University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.

Background: EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive.

Methods: We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712).

Findings: Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9-39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75-1·12; p=0·40; median 5·4 months [95% CI 4·5-5·7] vs 4·8 months [3·9-5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83-1·04; p=0·22; median 10·9 months [95% CI 9·5-12·0] vs 9·2 months [8·7-10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36-0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46-1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78-1·40; p=0·77; and 1·02, 0·77-1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68-1·14; p=0·34; and 0·99, 0·78-1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85-1·17; p=0·97; and 1·03, 0·88-1·20; p=0·69; respectively). The most common grade 3-4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [<1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group.

Interpretation: Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation.

Funding: National Cancer Institute and Eli Lilly and Company.
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http://dx.doi.org/10.1016/S1470-2045(17)30694-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847342PMC
January 2018

Dynamic plasma microRNAs are biomarkers for prognosis and early detection of recurrence in colorectal cancer.

Br J Cancer 2017 Oct 15;117(8):1202-1210. Epub 2017 Aug 15.

Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D4-100, Seattle, WA 98109, USA.

Background: Plasma microRNAs (miRNAs) are promising non-invasive biomarkers for colorectal cancer (CRC) prognosis. However, the published studies to date have yielded conflicting and inconsistent results for specific plasma miRNAs.

Methods: We have conducted a study using robust assays to assess a panel of nine miRNAs for CRC prognosis and early detection of recurrence. Plasma samples from 144 patients in a prospective CRC cohort study were collected at diagnosis, 6, 12, and 24 months after diagnosis. miRNAs were assayed by Taqman qRT-PCR to generate miRNA normalised copy numbers.

Results: Preoperative high plasma miRNA levels were associated with increased recurrence risk for miR-200b (HR [95% CI]=2.04 [1.00, 4.16], P=0.05), miR-203 (HR=4.2 [1.48, 11.93], P=0.007), miR-29a (HR=2.61 [1.34,5.07], P=0.005), and miR-31 (HR=4.03 [1.76, 9.24], P=0.001). Both plasma miR-31 (AUC: 0.717) and miR-29a (AUC: 0.703) could discriminate recurrence from these patients without recurrence. In addition, high levels of miR-31 during surveillance was associated with a three-fold increased risk of recurrence across all time points. Dynamic postoperative plasma miR-141 and 16 levels correlated with recurrence in the surveillance samples.

Conclusions: Pre-operative plasma miR-29a, 200b, 203, and 31 are potential CRC prognosis biomarkers. In addition, dynamic postoperative miR-31, 141 and 16 levels are potential biomarkers for the early detection of recurrence during CRC surveillance.
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http://dx.doi.org/10.1038/bjc.2017.266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674097PMC
October 2017

Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905).

J Thorac Oncol 2017 08 6;12(8):1299-1308. Epub 2017 Jun 6.

University of California Davis Cancer Center, Sacramento, California.

Introduction: In malignant pleural mesothelioma, targeting angiogenesis with cediranib, a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, may have therapeutic potential.

Methods: S0905 phase I combined cediranib (two dose cohorts [30 mg and 20 mg daily]) with cisplatin-pemetrexed for six cycles followed by maintenance cediranib in unresectable chemonaive patients with malignant pleural mesothelioma of any histologic subtype. The primary end point established the maximum tolerated dose in combination with cisplatin-pemetrexed in a dose deescalation scheme.

Results: A total of 20 patients were enrolled (seven to the 30-mg cohort and 13 to the 20-mag cohort). In the cediranib 30-mg cohort, two of the initial six patients reported dose-limiting toxicities and the dose was deemed too toxic to continue. In the next cohort, two patients experienced dose-limiting toxicities, and thus, the maximum tolerated dose of cediranib was established as 20 mg. During the six cycles of cisplatin-pemetrexed-cediranib, 20 mg, there were grade 3 toxicities (neutropenia and gastrointestinal) and grade 4 thrombocytopenia. No patients had any significant episodes of bleeding. According to the Response Evaluation Criteria in Solid Tumors (n = 17 evaluable patients), the median progression-free survival was 12.8 months (95% confidence interval [CI]: 6.9-17.2); according to the Modified Response Evaluation Criteria in Solid Tumors (n = 19 evaluable patients), the median progression-free survival was 8.6 months (95% CI: 6.1-10.9). For all patients, the disease control rate at 6 weeks was 90% and median overall survival time was 16.2 months (95% CI: 10.5-28.7).

Conclusions: Cediranib combined with cisplatin-pemetrexed has a reasonable toxicity profile and preliminary promising efficacy. The phase II S0905 trial will evaluate the efficacy of the triplet regimen compared with the current standard of care, cisplatin-pemetrexed.
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http://dx.doi.org/10.1016/j.jtho.2017.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690479PMC
August 2017

T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas.

Cancer 2017 Sep 2;123(17):3291-3304. Epub 2017 May 2.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Patients with metastatic sarcomas have poor outcomes and although the disease may be amenable to immunotherapies, information regarding the immunologic profiles of soft tissue sarcoma (STS) subtypes is limited.

Methods: The authors identified patients with the common STS subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), well-differentiated/dedifferentiated liposarcoma, and myxoid/round cell liposarcoma. Gene expression, immunohistochemistry for programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1), and T-cell receptor Vβ gene sequencing were performed on formalin-fixed, paraffin-embedded tumors from 81 patients. Differences in liposarcoma subsets also were evaluated.

Results: UPS and leiomyosarcoma had high expression levels of genes related to antigen presentation and T-cell infiltration. UPS were found to have higher levels of PD-L1 (P≤.001) and PD-1 (P≤.05) on immunohistochemistry and had the highest T-cell infiltration based on T-cell receptor sequencing, significantly more than SS, which had the lowest (P≤.05). T-cell infiltrates in UPS also were more oligoclonal compared with SS and liposarcoma (P≤.05). A model adjusted for STS histologic subtype found that for all sarcomas, T-cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression levels (P≤.01).

Conclusions: In the current study, the authors provide the most detailed overview of the immune microenvironment in sarcoma subtypes to date. UPS, which is a more highly mutated STS subtype, provokes a substantial immune response, suggesting that it may be well suited to treatment with immune checkpoint inhibitors. The SS and liposarcoma subsets are less mutated but do express immunogenic self-antigens, and therefore strategies to improve antigen presentation and T-cell infiltration may allow for successful immunotherapy in patients with these diagnoses. Cancer 2017;123:3291-304. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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http://dx.doi.org/10.1002/cncr.30726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568958PMC
September 2017

Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study.

Cancer 2017 04 7;123(8):1464-1474. Epub 2016 Dec 7.

Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.

Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases per year in the United States, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV oncoprotein (T-antigens) have been correlated with MCC tumor burden. The present study assesses the clinical utility of MCPyV-oncoprotein antibody titers for MCC prognostication and surveillance.

Methods: MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly diagnosed MCC were followed prospectively (median follow-up, 1.9 years). Among the seropositive patients, antibody titer and disease status were serially tracked.

Results: Antibodies to MCPyV oncoproteins were rare among healthy individuals (1%) but were present in most patients with MCC (114 of 219 patients [52%]; P < .01). Seropositivity at diagnosis independently predicted decreased recurrence risk (hazard ratio, 0.58; P = .04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. After initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 time points), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence, whereas a decreasing titer had a negative predictive value of 97%.

Conclusions: Determination of oncoprotein antibody titer assists in the clinical management of patients with newly diagnosed MCC by stratifying them into a higher risk seronegative cohort, in which radiologic imaging may play a more prominent role, and into a lower risk seropositive cohort, in which disease status can be tracked in part by oncoprotein antibody titer. Cancer 2017;123:1464-1474. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384867PMC
April 2017

Enrollment Trends and Disparity Among Patients With Lung Cancer in National Clinical Trials, 1990 to 2012.

J Clin Oncol 2016 11 30;34(33):3992-3999. Epub 2016 Sep 30.

Herbert H. Pang and Perry Cheng, School of Public Health, Li Ka Shing Faculty of Medicine, Hong Kong, Special Administrative Region, People's Republic of China; Herbert H. Pang, Xiaofei Wang, Ying Zhang, Thomas E. Stinchcombe, and Harvey J. Cohen, Duke University School of Medicine, Durham, NC; Melisa L. Wong, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco; David Gandara, University of California, Davis Comprehensive Cancer Center, Sacramento, CA; Apar Kishor Ganti, Veterans Affairs Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE; Daniel J. Sargent and Sumithra J. Mandrekar, Mayo Clinic, Rochester, MN; Chen Hu, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Chen Hu, Johns Hopkins University School of Medicine, Baltimore, MD; Mary W. Redman, Fred Hutchinson Cancer Research Center, Seattle, WA; Judith B. Manola, Dana-Farber Cancer Institute, Boston, MA; Richard L. Schilsky, ASCO, Alexandria, VA; Jeffrey D. Bradley, Washington University School of Medicine, St Louis, MO; Alex A. Adjei, Roswell Park Cancer Institute, Buffalo, NY; Suresh S. Ramalingam, The Winship Cancer Institute of Emory University, Atlanta, GA; and Everett E. Vokes, University of Chicago, Chicago, IL.

Purpose Under-representation of elderly, women, and racial/ethnic minority patients with cancer in clinical trials is of national concern. The goal of this study was to characterize enrollment trends and disparities by age, sex, and race/ethnicity in lung cancer trials. Methods We analyzed data for 23,006 National Cancer Institute cooperative group lung cancer trial participants and 578,476 patients with lung cancer from the SEER registry from 1990 to 2012. The enrollment disparity difference (EDD) and enrollment disparity ratio (EDR) were calculated on the basis of the proportion of each subgroup in the trial population and the US lung cancer population. Annual percentage changes (APCs) in the subgroup proportions in each population were compared over time. Results Enrollment disparity for patients ≥ 70 years of age with non-small-cell lung cancer improved from 1990 to 2012 (test of parallelism, P = .020), with a remaining EDD of 0.22 (95% CI, 0.19 to 0.25) and EDR of 1.65 (95% CI, 1.51 to 1.82) in 2010 to 2012. No improvement was seen for elderly patients with small-cell lung cancer (SCLC), with an APC of 0.20 ( P = .714) among trial participants, despite a rising proportion of elderly patients with SCLC in the US population (APC, 0.32; P = .020). Enrollment disparity for women with lung cancer improved overall, with the gap closing by 2012 (EDD, 0.03 [95% CI, 0.00 to 0.06]; EDR, 1.07 [95% CI, 1.00 to 1.16]). Enrollment disparities persisted without significant improvement for elderly women, blacks, Asians/Pacific Islanders, and Hispanics. Conclusion Under-representation in lung cancer trials improved significantly from 1990 to 2012 for elderly patients with non-small-cell lung cancer and for women, but ongoing efforts to improve the enrollment of elderly patients with SCLC and minorities are needed. Our study highlights the importance of addressing enrollment disparities by demographic and disease subgroups to better target under-represented groups of patients with lung cancer.
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http://dx.doi.org/10.1200/JCO.2016.67.7088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477832PMC
November 2016

Concurrent cetuximab and postoperative radiation in resected high-risk squamous cell carcinomas of the head and neck: A single-institution experience.

Head Neck 2016 09 7;38(9):1318-23. Epub 2016 Apr 7.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Postoperative cisplatin and radiation is the standard of care for high-risk squamous cell carcinoma of the head and neck (SCCHN). We have used cetuximab and radiation in the postoperative setting for patients deemed poor candidates for cisplatin.

Methods: We retrospectively identified 40 patients who received cetuximab and radiation for resected locoregionally advanced SCCHN between 2006 and 2013 at our institution.

Results: The 2-year Kaplan-Meier estimates were: overall survival (OS) 41%, recurrence-free survival (RFS) 34%, locoregional control 63%, and distant metastatic control 59%. Eastern Cooperative Oncology Group (ECOG) performance status ≥1 predicted for inferior OS (hazard ratio [HR] = 5.43; p = .003), RFS (HR = 4.07; p = .007), and locoregional control (HR = 4.92; p = .04) in multivariate analysis.

Conclusion: Patients with resected high-risk SCCHN treated with postoperative cetuximab and radiation have suboptimal therapeutic outcomes. Further study of the efficacy and cost-effectiveness compared to radiation alone is warranted. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1318-1323, 2016.
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http://dx.doi.org/10.1002/hed.24437DOI Listing
September 2016

Scientific Advances in Lung Cancer 2015.

J Thorac Oncol 2016 05 22;11(5):613-638. Epub 2016 Mar 22.

Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, New Haven, Connecticut.

Lung cancer continues to be a major global health problem; the disease is diagnosed in more than 1.6 million new patients each year. However, significant progress is underway in both the prevention and treatment of lung cancer. Lung cancer therapy has now emerged as a "role model" for precision cancer medicine, with several important therapeutic breakthroughs occurring during 2015. These advances have occurred primarily in the immunotherapy field and in treatments directed against tumors harboring specific oncogenic drivers. Our knowledge about molecular mechanisms for oncogene-driven tumors and about resistance to targeted therapies has increased quickly over the past year. As a result, several regulatory approvals of new agents that significantly improve survival and quality of life for patients with lung cancer who have advanced disease have occurred. The International Association for the Study of Lung Cancer has gathered experts in different areas of lung cancer research and management to summarize the most significant scientific advancements related to prevention and therapy of lung cancer during the past year.
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http://dx.doi.org/10.1016/j.jtho.2016.03.012DOI Listing
May 2016

SWOG S0709: Randomized Phase II Trial of Erlotinib versus Erlotinib Plus Carboplatin/Paclitaxel in Patients with Advanced Non-Small Cell Lung Cancer and Impaired Performance Status as Selected by a Serum Proteomics Assay.

J Thorac Oncol 2016 Mar 25;11(3):420-5. Epub 2015 Dec 25.

University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.

Introduction: Patients with advanced-stage non-small cell lung cancer (NSCLC) and borderline performance status (performance status 2 [PS2]) are often excluded from clinical trials and platinum-based therapy. In light of the potential role for serum proteomics in predicting the benefit of erlotinib beyond that of epidermal growth factor receptor gene (EGFR) mutational status, we conducted a trial in which the Veristrat proteomics assay was used for data enrichment when selecting a cohort of patients with NSCLC and PS2 to receive erlotinib with and without chemotherapy.

Methods: Patients with metastatic NSCLC, PS2, acceptable end-organ function, and Veristrat-good status were randomly assigned to receive either 150 mg of erlotinib orally daily (arm 1) or 150 mg of erlotinib orally daily on days 2 through16 plus four cycles of carboplatin (area under the curve = 5 on day 1) and paclitaxel (200 mg/m(2) intravenously on day 1) followed by 150 mg of erlotinib orally (arm 2). The arm 2 agents were pharmacodynamically separated to mitigate potential antagonism. The arm with superior observed median progression-free survival (PFS) would be selected for further evaluation, but only if PFS lasted for at least 3 months.

Results: The trial terminated before the planned accrual of 98 patients for regulatory reasons. A total of 156 patients were screened. Of the 83 (59%) who were classified as Veristrat good, 59 met the trial eligibility criteria and were randomly assigned to one of two arms (33 patients in arm 1 and 26 in arm 2). The patients in arm 2 patients had a higher response rate (23% versus 6%, p = 0.06), disease control rate (77% versus 41%, p = 0.0046), median PFS (4.6 versus 1.6 months, p = 0.06), and median overall survival (11 versus 6 months, p = 0.27). Treatment-related grade 4 adverse events were seen in two patients in arm 1 (thrombosis and hypomagnesemia) and in five patients in arm 2 (neutropenia in five, febrile neutropenia in one, and leukopenia in one).

Conclusions: In a proteomics-enriched cohort of patients with NSCLC and PS2, pharmacodynamically separated erlotinib plus chemotherapy had better efficacy than did erlotinib alone and surpassed the protocol-specified benchmark of PFS of at least 3 months required for further study.
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http://dx.doi.org/10.1016/j.jtho.2015.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775366PMC
March 2016