Jared Weiss

Resection of the Primary Colorectal Cancer Is Not Necessary in Nonobstructed Patients with Metastatic Disease

Asymptomatic patients with metastatic colorectal cancer do not routinely need to undergo resection of the primary tumor. Although several retrospective analyses suggest that patients who undergo resection of the primary tumor live longer, most of these reviewed data prior to the advent of modern polychemotherapy and are subject to considerable bias, as patients who were considered able to undergo surgery likely had better overall prognoses than those who were not. In addition to significant prolongation of overall survival, current combinations of systemic chemotherapeutic agents and targeted agents have allowed improved local and distant tumor control, decreasing the likelihood of local tumor-related complications requiring colon resection.

Carboplatin/Pemetrexed/Bevacizumab in the Treatment of Patients With Advanced Non-Small- Cell Lung Cancer: A Single-Institution Experience

PURPOSE The purpose of this study was to determine the efficacy and tolerability of carboplatin, pemetrexed, and bevacizumab in patients with advanced, nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS The charts of consecutive patients with stage IIIB/IV nonsquamous NSCLC were reviewed. All patients receiving at least 1 cycle of the 3-drug regimen (pemetrexed 500 mg/m2, carboplatin area under the curve of 5-6, bevacizumab 15 mg/kg intravenously), were included for assessment of response, safety, and toxicity. RESULTS A total of 27 patients received this regimen between February 2008 and July 2009; 63% were women. Median follow-up was 6.3 months (range, 1.6-21.1 months). Median number of cycles was 6 (range, 1-6 cycles); 67% completed 6 cycles; 83% went on to receive maintenance bevacizumab/pemetrexed. Among those who received maintenance, the median number of cycles administered was 4.5 (range, 1-18 cycles). Response rate was 52%; stable disease was observed in another 40%. On the basis of Kaplan-Meier analysis, actuarial overall survival was 83% at 12 months; actuarial progression-free survival was 83% and 63% at 6 and 12 months, respectively. Clinical improvement was noted in 41% of the patients, with clinical stability in another 48%. Grade 2 and 3 toxicities from the regimen included anemia (11% and 15%), fatigue (37% and 7.4%), febrile neutropenia (7.4%; grade 3 only), thrombocytopenia (7.4% and 0), and thromboembolic disorders (3.7% and 3.7%). Bevacizumab-induced side effects (any grade) included headaches (22.2%), epistaxis (30%), hemoptysis (3.7%), and hypertension (11%). No grade 4 or 5 toxicities were seen. CONCLUSION Combination carboplatin/pemetrexed and bevacizumab followed by maintenance therapy with pemetrexed/bevacizumab is effective, with response rates > 50%, acceptable toxicity, and promising early survival in patients with advanced nonsquamous NSCLC.

NSCLC in the elderly--the legacy of therapeutic neglect.

Opinion statementAlthough the majority of patients diagnosed with non-small cell lung cancer (NSCLC) are elderly, most clinical trials available to guide care either exclude the elderly or underrepresent them. This disregard for the elderly lung cancer patient extends to the clinical realm, where the elderly with lung cancer are less likely to be treated with either curative, or life-extending, palliative therapy. Few elderly-specific phase III trials are available to provide level I evidence. However, subgroup analyses and meta-analyses of large clinical trials enrolling substantial numbers of elderly patients are available to guide care, although these are potentially subject to selection bias. These trials suggest that the fit elderly derive as much benefit from surgery, chemoradiation, and platinum-based doublet chemotherapy as younger patients across all stages of disease. For the less fit elderly, in particular those with limited performance status or significant co-morbidities, less aggressive regimens are likely preferred, with the goal of extending life and delaying or suppressing cancer symptoms. Ultimately, care decisions must incorporate knowledge of the literature, evaluation of the patient’s clinical characteristics, and patient priorities. The elderly should be aggressively recruited to clinical trials, including elderly-specific trials and trials of patients with limited performance status and co-morbidities.

Quantitative Electron Holography

Electron holography is necessarily a two-step process. First, the object and reference waves must be coherently superimposed in recording the electron hologram. Second, reconstruction of the hologram is required in order to extract the desired phase and/or amplitude of the electron wave which has passed through the object. Historically, hologram recording has been carried out photographically, and the subsequent reconstruction has been done optically.261,451 In addition to inevitable time delays, the use of these techniques in electron holography can result in unsuspected artefactual information, thus motivating the utilization of alternative recording and processing methods that offer greater reliability and the possibility of more accurate quantification.

Adjuvant cisplatin and docetaxel for non-small cell lung cancer: the Hospital of the University of Pennsylvania experience.

Introduction: Cisplatin and docetaxel (Doc) are commonly used for adjuvant therapy for non-small cell lung cancer based on extrapolation from the metastatic setting. Nevertheless, essentially no data have been published on this regimen in the adjuvant context, leading to controversy, particularly surrounding feasibility. Methods: Using a tumor database augmented with chart reviews, we retrospectively evaluated treatment outcomes of all patients receiving postoperative cisplatin (75 mg/m2) and Doc (75 mg/m2) between August 2003 and November 2008. During this period, this regimen was considered to be the first choice regimen for sufficiently fit patients at the University of Pennsylvania Results: The database captured 54 patients. Overall, 85.2% received all four planned cycles (83.3% at full dose). Chart review allowed definitive assessment of toxicity in 47 patients. A single patient (2%) died of grade 5 febrile neutropenia. There was no grade 4 toxicity, and 8.5% experienced grade 3 febrile neutropenia. No febrile neutropenia was observed in 26 patients given prophylactic peg-filgrastim. The incidence was 23.8% in the 21 patients not given peg-filgrastim during the first cycle; 6.4% each experienced grade 3 gastritis, anorexia, nausea, and fatigue, and 2.1% experienced grade 3 diarrhea. Median progression-free survival was 17.9 months, and median overall survival has not been reached. Conclusion: Cisplatin and Doc are feasible in the adjuvant setting with superior dose delivery and convenience compared with historic data with cisplatin and vinorelbine.

A Phase I, Dose Escalation Study of Oral ASP8273 in Patients with Non–small Cell Lung Cancers with Epidermal Growth Factor Receptor Mutations

Purpose: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including EGFR T790M. Experimental Design: In this multicohort, phase I study (NCT02113813), escalating doses of ASP8273 (25–500 mg) were administered once daily to non–small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. EGFR T790M was required for all cohorts, except the dose escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint. Results: A total of 110 patients were treated with ASP8273 across dose escalation (n = 36), response–expansion (n = 36), RP2D (300 mg; n = 19) and food–effect (n = 19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% (n = 27/88; 95% CI, 19.5%–44.5%), and median progression-free survival was 6.8 months (95% CI, 5.5–10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression. Conclusions: ASP8273 was well tolerated and promoted antitumor activity in patients with EGFR-mutant lung cancer with disease progression on prior EGFR TKI therapy. Clin Cancer Res; 23(24); 7467–73. ©2017 AACR.

Induction chemotherapy with carboplatin, nab-paclitaxel and cetuximab for at least N2b nodal status or surgically unresectable squamous cell carcinoma of the head and neck

BACKGROUND Although induction studies of TPF in SCCHN have not improved outcomes compared to chemoradiotherapy alone, phase II studies of weekly carboplatin (CbP), paclitaxel and cetuximab (C225) have shown promising results. Nano-albumin-paclitaxel (nab-paclitaxel) based chemotherapy has demonstrated a higher response rate (RR) than solvent-based paclitaxel in squamous cell carcinoma of the lung with favorable toxicity. MATERIALS AND METHODS Patients with treatment naïve SCCHN of any site with ≥N2b disease or that was unresectable by strict criteria were eligible. Patients were treated with nab-paclitaxel 100 mg/m2, CbP area under the curve (AUC) 2 and C225 400 mg/m2 week 1 then 250 mg/m2 for six weeks, followed by standard of care chemoradiotherapy (CRT). The primary endpoint was clinical response rate to induction therapy as defined by RECIST version 1.1. Secondary measures included toxicity, progression-free survival, overall survival and quality of life as measured by FACT-HN. RESULTS 38 eligible subjects were treated. Primary sites were: oropharynx (OPX) (25), larynx (3) oral cavity (OC) (9), hypopharynx (1). The most common grade 3 or 4 toxicity during induction was acneiform rash (26%) followed by neutropenia (16%). RR was 76.3%. Median PFS and OS have not been reached (median follow-up of 3.3 years); they were superior in patients with response. CONCLUSIONS The combination of nab-paclitaxel, CbP and C225 is feasible, tolerable and active against locally advanced SCCHN.

nab-Paclitaxel-Based Therapy in Underserved Patient Populations: The ABOUND.70+ Study in Elderly Patients With Advanced NSCLC

The phase 4 ABOUND.70+ trial assessed the safety and efficacy of nab-paclitaxel/carboplatin continuously or with a 1-week break between cycles in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients ≥70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-paclitaxel days 1, 8, 15 plus carboplatin day 1 of a 21-day cycle (21d) or the same nab-paclitaxel/carboplatin regimen with a 1-week break between cycles (21d + break; 28d). The primary endpoint was the percentage of patients with grade ≥ 2 peripheral neuropathy (PN) or grade ≥ 3 myelosuppression. Other key endpoints included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). A total of 143 patients were randomized (71 to 21d, 72 to 21d + break). The percentage of patients with grade ≥ 2 PN or grade ≥ 3 myelosuppression was similar between the 21d and 21d + break arms (76.5 and 77.1%; P = 0.9258). Treatment exposure was lower in the 21d arm compared with the 21d + break arm. Median OS was 15.2 and 16.2 months [hazard ratio (HR) 0.72, 95% CI 0.44–1.19; P = 0.1966], median PFS was 3.6 and 7.0 months (HR 0.48, 95% CI 0.30–0.76; P < 0.0019), and ORR was 23.9 and 40.3% (risk ratio 1.68, 95% CI 1.02–2.78; P = 0.0376) in the 21d and 21d + break arms, respectively. In summary, the 1-week break between treatment cycles significantly improved PFS and ORR but did not significantly reduce the percentage of grade ≥ 2 PN or grade ≥ 3 myelosuppression. Overall, the findings support the results of prior subset analyses on the safety and efficacy of first-line nab-paclitaxel/carboplatin in elderly patients with advanced NSCLC.

Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next-generation sequencing assays

Purpose: In this era of precision-based medicine, for optimal patient care, results reported from commercial next-generation sequencing (NGS) assays should adequately reflect the burden of somatic mutations in the tumor being sequenced. Here, we sought to determine the prevalence of clonal hematopoiesis leading to possible misattribution of tumor mutation calls on unpaired Foundation Medicine NGS assays. Experimental Design: This was a retrospective cohort study of individuals undergoing NGS of solid tumors from two large cancer centers. We identified and quantified mutations in genes known to be frequently altered in clonal hematopoiesis (DNMT3A, TET2, ASXL1, TP53, ATM, CHEK2, SF3B1, CBL, JAK2) that were returned to physicians on clinical Foundation Medicine reports. For a subset of patients, we explored the frequency of true clonal hematopoiesis by comparing mutations on Foundation Medicine reports with matched blood sequencing. Results: Mutations in genes that are frequently altered in clonal hematopoiesis were identified in 65% (1,139/1,757) of patients undergoing NGS. When excluding TP53, which is often mutated in solid tumors, these events were still seen in 35% (619/1,757) of patients. Utilizing paired blood specimens, we were able to confirm that 8% (18/226) of mutations reported in these genes were true clonal hematopoiesis events. The majority of DNMT3A mutations (64%, 7/11) and minority of TP53 mutations (4%, 2/50) were clonal hematopoiesis. Conclusions: Clonal hematopoiesis mutations are commonly reported on unpaired NGS testing. It is important to recognize clonal hematopoiesis as a possible cause of misattribution of mutation origin when applying NGS findings to a patients care. See related commentary by Pollyea, p. 5790

Abstract B295: A Phase Ib study of bavituximab plus carboplatin and pemetrexed in chemotherapy-naïve incurable stage IIIb/IV non-squamous non-small cell lung cancer.

Background: Bavituximab (B) is a phosphatidylserine (PS) targeting monoclonal antibody that modulates the tumor microenvironment from a primarily immunosuppressive state to an immune activating state. PS exposure in the tumor microenvironment is immunosuppressive, and increases in response to chemotherapy, radiotherapy and oxidative stress. B has been shown to overcome immune suppression and stimulate antitumor immunity in preclinical models. A randomized phase II study of B in combination with docetaxel showed a 60% improvement in median OS in second line NSCLC, and a phase III trial is planned. We report on B in combination with pemetrexed (P) and carboplatin (C), in treatment naive locally advanced or metastatic non-squamous NSCLC. Methods: We conducted an open-label, single arm phase Ib study (standard 3+3 design) of B (0.3mg/kg, 1mg/kg, and 3mg/kg) with fixed dose with C (AUC 6) plus P (500mg/m2) q3wks x maximum 6 cycles, with optional maintenance B until disease progression. Primary objectives are to characterize the safety, determine dose limiting toxicities (DLT), and establish the recommended phase 2 dose (RP2D). Secondary objectives include determining ORR and PFS. At the MTD, up to 16 patients (pts) are enrolled to further characterize safety and preliminary evidence of efficacy, incorporating an early stopping rule based on an excessive proportion of DLTs observed. DCE-MRI at baseline and end of cycle 1 was explored as a potential pharmacodynamic biomarker. Results: Currently 21 of 25 pts have received at least one dose of CPB (48% female, 90% white), median age of 53 (range 43-73y). Most commonly reported drug-related AEs (>10%), include (all %; G3/4%): anemia (62; 10), fatigue (48; 10), nausea (48; 5), thrombocytopenia (43; 29), neutropenia (38; 19), vomiting (38; 19), ALT and AST increase each (29; 0), anorexia (24; 5), thromboembolic event (19; 19), diarrhea (19; 0), rash (19; 0), leukopenia (14; 10), hyponatremia (14; 5), edema (14; 0), insomnia (14; 0), skin disorder (14; 0). No DLTs have been reported. 16 SAEs have been reported in 7 pts, of which 3 were considered related to study. As of 8/8/13, 14 completed planned 4 cycles CPB therapy; 5 came off study prior to completion due to SAEs (2 venous and 2 arterial thromboembolism, 1 hematologic toxicity), 1 due to PD, and 1 withdrew consent. 2 completed >10 cycles with maintenance B. Best unconfirmed response includes 35% PR, 50% SD, 10%PD, 1 pt not available. 3 pts have completed the optional DCE-MRI biomarker imaging. Conclusions: CPB is relatively well tolerated, with most toxicities attributable to CP. No unexpected adverse events were identified. A DLT was not identified and the RP2D is yet to be determined. Response rates reported to date are encouraging, although conclusions are limited due to the small number. Data are not sufficiently mature to report PFS and OS. Results including DCE-MRI imaging will be updated. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B295. Citation Format: Juneko E. Grilley-Olson, Liza C. Villaruz, Thomas E. Stinchcombe, Jared Weiss, Joseph Shan, Anshu Vashishtha, Anastasia Ivanova, Mark A. Socinski. A Phase Ib study of bavituximab plus carboplatin and pemetrexed in chemotherapy-naive incurable stage IIIb/IV non-squamous non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B295.