Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial.

BACKGROUND: Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti-programmed death 1 (anti-PD-1) immunotherapy, pembrolizumab, in programmed death ligand 1 (PD-L1)-positive, recurrent glioblastoma. METHODS: Adult patients with PD-L1-positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator-assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD-L1 expression levels (prospectively) and T-cell-inflamed gene expression profile score (retrospectively). RESULTS: After a median follow-up of 14 months (range, 2-55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%-26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progression-free survival (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD-L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment-related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune-mediated adverse events and infusion reactions occurred in 7 patients (27%). CONCLUSIONS: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal-finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.

Clinical Activity of Nivolumab for Human Papilloma Virus-Related Juvenile-Onset Recurrent Respiratory Papillomatosis.

BACKGROUND: Juvenile-onset recurrent respiratory papillomatosis (JO-RRP) is a human papilloma virus-mediated progressive benign neoplasm that affects children and young adults. Primary management consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO-RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth. MATERIALS AND METHODS: We treated two patients with refractory JO-RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling. RESULTS: Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on-treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma. CONCLUSION: Nivolumab appears to have promising activity in JO-RRP, and further clinical investigation with more patients in clinical trials is warranted. IMPLICATIONS FOR PRACTICE: To the authors' knowledge, this article is the first report describing clinical activity with a programed cell death-1 (PD-1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD-1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.

Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study.

BACKGROUND: Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma. METHODS: We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0-2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis. FINDINGS: 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14-26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8-38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity. INTERPRETATION: Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential. FUNDING: Merck & Co.

A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumours.

BACKGROUND: Veliparib is a potent poly(ADP-ribose) polymerase inhibitor. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib combined with various FOLFIRI regimens in patients with solid tumours. METHODS: Patients received veliparib (10-270 mg BID, days 1-5, 15-19) and FOLFIRI (days 1-3, 15-17) in three regimens containing 5-fluorouracil 2,400 mg/m2: irinotecan 150 mg/m2 and folinic acid 400 mg/m2 (part 1); irinotecan 180 mg/m2, folinic acid 400 mg/m2, and 5-fluorouracil 400 mg/m2 bolus (part 2), or irinotecan 180 mg/m2 (part 3). The RP2D was further evaluated in safety expansion cohorts. Preliminary antitumour activity was also assessed. RESULTS: Ninety-two patients received ≥1 veliparib dose. MTD was not reached; RP2D was set at 200 mg BID veliparib plus FOLFIRI (without 5-fluorouracil bolus). Most common treatment-emergent adverse events were neutropenia (66.3%), diarrhoea, and nausea (60.9% each). Dose-limiting toxicities (n = 4) were grade 3 gastritis and grade 4 neutropenia and febrile neutropenia. Veliparib exposure was dose-proportional, with no effects on the pharmacokinetics of FOLFIRI components. Fifteen patients had a partial response (objective response rate, 17.6%). CONCLUSIONS: The acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination.

Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non-small cell lung cancer patients with KRAS-activated tumors.

BACKGROUND: The type 3 Dearing reovirus (Reolysin) is a naturally occurring virus that preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. It induces host immunity and cell cycle arrest and acts synergistically with cytotoxic agents. METHODS: This study evaluated Reolysin combined with paclitaxel and carboplatin in patients with metastatic/recurrent KRAS-mutated or epidermal growth factor receptor (EGFR)-mutated/amplified non-small cell lung cancer. RESULTS: Thirty-seven patients were treated. Molecular alterations included 20 KRAS mutations, 10 EGFR amplifications, 3 EGFR mutations, and 4 BRAF-V600E mutations. In total, 242 cycles (median, 4; range, 1-47) were completed. The initial doses were area under the curve (AUC) 6 mg/mL/min for carboplatin, 200 mg/m(2) for paclitaxel on day 1, and 3 × 10(10) 50% tissue culture infective dose for Reolysin on days 1 to 5 of each 21-day cycle. Because of diarrhea and febrile neutropenia (in the first 2 patients), subsequent doses were reduced to 175 mg/m(2) for paclitaxel and AUC 5 mg/mL/min for carboplatin. Toxicities included fatigue, diarrhea, nausea/vomiting, neutropenia, arthralgia/myalgia, anorexia, and electrolyte abnormalities. Response Evaluation Criteria in Solid Tumors 1.0 responses included the following: partial response for 11 patients, stable disease (SD) for 20 patients, progressive disease for 4 patients, and not evaluable for 2 patients (objective response rate, 31%; 90% 1-sided lower confidence interval, 21%). Four SD patients had >40% positron emission tomography standardized uptake value reductions. The median progression-free survival, median overall survival, and 12-month overall survival rate were 4 months, 13.1 months, and 57%, respectively. Seven patients were alive after a median follow-up of 34.2 months; they included 2 patients without disease progression at 37 and 50 months. CONCLUSIONS: Reolysin in combination with paclitaxel and carboplatin was well tolerated. The observed response rate suggests a benefit of the reovirus for chemotherapy. A follow-up randomized study is recommended. The proportion of patients surviving longer than 2 years (30%) suggests a second/third-line treatment effect or possibly the triggering of an immune response after tumor reovirus infiltration.

A phase 1 study of cetuximab and lapatinib in patients with advanced solid tumor malignancies.

BACKGROUND: Acquired resistance to antiepidermal growth factor receptor (anti-EGFR) therapy may be caused by EGFR-v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) heterodimerization and pathway reactivation. In preclinical studies, inhibiting ErbB2 blocked this resistance mechanism and resensitized cells to anti-EGFR therapy. Cetuximab targets EGFR, whereas lapatinib inhibits both EGFR and ErbB2. The objective of this phase 1 trial was to assess the safety, dose-limiting toxicities (DLTs), and maximum tolerated doses (MTDs) of cetuximab and lapatinib in patients with solid tumors. METHODS: Patients received standard weekly cetuximab with escalating lapatinib doses of 750 mg, 1000 mg, or 1250 mg daily in 3-week cycles. DLTs were monitored through the end of cycle 2. Pretreatment and post-treatment tumor biopsies and germline DNA samples were obtained for correlative studies. RESULTS: Twenty-two patients were enrolled, and 18 patients each were evaluable for toxicity and response. Fifty-nine percent of patients had received prior anti-EGFR therapy. Common toxicities included rash and diarrhea. No patient experienced a DLT at the highest dose level, and no grade 4 toxicity was observed. Response included no complete responses, 3 partial responses, 9 patients with stable disease, and 6 patients with disease progression, for an overall response rate of 17% and a clinical benefit rate of 67%. The clinical benefit rate in patients who had previously received anti-EGFR therapy was 70%. The mean treatment duration was 4.7 cycles (range, 1-14 cycles). Decreased expression of EGFR/ErbB2 pathway components after treatment was correlated with response, whereas increased expression in the PI3K, Jak/Stat, and MAPK pathways occurred in nonresponders. CONCLUSIONS: The combination of cetuximab and lapatinib was well tolerated, had the expected toxicities, and exhibited notable clinical activity, including in patients who had received previous anti-EGFR therapy. Further clinical study of this combination is warranted.

Emerging protein kinase inhibitors for non-small cell lung cancer.

INTRODUCTION: In the current paradigm of precision medicine in non-small cell lung cancer (NSCLC), the therapeutic strategy is determined by the molecular characteristics. The best examples of this approach are the kinase inhibitors that selectively target tumors bearing an epidermal growth factor receptor (EGFR) mutation or an anaplastic lymphoma kinase (ALK) rearrangement. Emerging protein kinase inhibitors may enhance our ability to effectively treat these and other genomic subtypes of NSCLC. AREAS COVERED: This article reviews the next-generation kinase inhibitors targeting EGFR and ALK-positive NSCLC. In addition, targeted kinase inhibitors in clinical development for other specific molecular subtypes of NSCLC are covered, including ROS1, BRAF, RET, HER2, KRAS (upstream of the MEK kinase), MET, PIK3CA, FGFR1, DDR2, VEGFR and AAK. EXPERT OPINION: In EGFR-mutant NSCLC, there are several kinase inhibitors with promising activity, most notably dacomitinib and CO-1686 in tumors with acquired resistance to EGFR-targeted therapy. Next-generation ALK inhibitors appear to have greater potency than crizotinib and several ongoing trials may shed light on their role in both ALK- and ROS1-positive NSCLC. While there is optimism regarding the role of kinase inhibitors in other molecular subtypes, the available evidence is too immature to make recommendations and results from prospective trials are needed.

Biphasic Calcium Phosphate in the Extraction Socket Preservation: A Systematic Review.

Introduction: Various studies have suggested use of socket grafting materials after dental extraction for socket preservation. However, there is no single material that has been accepted as standard for preserving the socket. The purpose of this systematic review was to analyze the evidence for the use of biphasic calcium phosphate for socket regeneration. Materials and Methods: The team conducted a systematic literature search in accordance with the protocol registered at PROSPERO. PubMed, OVID, and EMBASE databases were used in the search. The articles were then screened using RAYYAN open-source software for the synthesis of evidence. Results: Of the 240 articles found in the search, two studies could be included in the review. Conclusion: Biphasic calcium phosphate (60% hydroxyapatite, HA and 40% beta-tricalcium phosphate, ß-TCP) has a significant effect in the socket preservation and quality of bone regeneration.

Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors.

BACKGROUND: Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors. METHODS: Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures. RESULTS: 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%). CONCLUSION: Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes. TRIAL REGISTRATION NUMBER: NCT02335918.

A Phase I Trial of Dasatinib and Osimertinib in TKI Naïve Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer.

BACKGROUND: Osimertinib is an effective first-line therapy option for EGFR-mutant NSCLC, but virtually all patients develop resistance. CRIPTO, through Src activation, has been implicated in resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Dasatinib, a Src inhibitor, has shown preclinical synergy with EGFR-TKI therapy. METHOD: This is a single-arm phase I/II trial of osimertinib and dasatinib in TKI-naïve advanced EGFR-mutant NSCLC (NCT02954523). A 3 + 3 design was used in the phase I to establish the recommended phase II dose (RP2D). Osimertinib 80 mg QD was combined with dasatinib 70 mg BID (DL2), 50 mg BID (DL1), 70 mg QD (DL-1), and 50 mg QD (DL-2). RESULTS: Ten patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches/body pain, neutropenia, rash, one each). Common treatment-related adverse events included pleural effusion (n=10), diarrhea (n=8), rash (n=7), transaminitis (n=7), thrombocytopenia (n=7), and neutropenia (n=7). While the MTD was not determined by protocol-defined DLT criteria, DL-2 was chosen as the RP2D, considering overall tolerability. Nine (90%) patients had a PR, including 1 unconfirmed PR. Median PFS was 19.4 months and median OS 36.1 months. The trial was closed to accrual prematurely due to slow accrual after the approval of osimertinib as first-line therapy. CONCLUSIONS: The combination of dasatinib and osimertinib demonstrated anticancer activity. The treatment was limited by chronic toxicities mainly attributed to dasatinib. To improve the safety and tolerability of Src and EGFR co-inhibition, Src inhibitors with a more favorable safety profile should be utilized in future studies. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02954523.

Real-world impact of brain metastases on healthcare utilization and costs in patients with non-small cell lung cancer treated with EGFR-TKIs in the US.

BACKGROUND: Non-small cell lung cancer (NSCLC) with brain metastases (BM) is difficult to treat and associated with poor survival. This study assessed the impact of BM on healthcare-related utilization and costs (HRUC) among patients receiving epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). PATIENTS AND METHODS: Adults newly-diagnosed with metastatic NSCLC, initiating first-/second-generation EGFR-TKI treatment, with BM or no BM (NBM), were identified retrospectively from IBM MarketScan healthcare claims databases (2013-2017). HRUC were measured during the variable-length follow-up period. Generalized linear models assessed the impact of BM on total healthcare costs, standardized to 2017 US$. RESULTS: Overall, 222 BM and 280 NBM patients were included, with a mean duration of follow-up of 14 months. Adjusted NSCLC-related and all-cause costs over average follow-up were 1.2 times higher among BM patients (Δ$5,640 and Δ$6,366, respectively; p <0.05); differences were driven primarily by radiation treatment and radiology. More than two times more BM than NBM patients received NSCLC-related radiation treatment, in both inpatient (15.3% vs 6.8%; p <0.05) and outpatient settings (87.8% vs 37.5%; p <0.05). Per-patient per-month (PPPM) radiation costs were also higher among BM patients, both inpatient ($796 vs $464, p =0.172) and outpatient ($2,443 vs $747, p <0.05). All-cause PPPM radiology visits (2.0 vs 1.3) and associated costs ($3,824 vs $1,621) were higher among BM patients (both p <0.05). CONCLUSION: NSCLC-related HRUC, especially those attributable to radiation treatment, were higher among patients with BM. Future research should compare the potential for CNS-active EGFR-TKIs vs first-/second-generation EGFR-TKIs combined with radiotherapy to reduce HRUC.

A phase I trial of the mTOR inhibitor temsirolimus in combination with capecitabine in patients with advanced malignancies.

BACKGROUND: Temsirolimus is an mTOR antagonist with proven anticancer efficacy. Preclinical data suggest greater anticancer effect when mTOR inhibitors are combined with cytotoxic chemotherapy. We performed a Phase I assessment of the combination of temsirolimus and capecitabine in patients with advanced solid tumors. METHODS: Patients were enrolled in an alternating dose escalation of temsirolimus (at 15 or 25 mg IV weekly) and capecitabine (at 750, 1000, and 1250 mg/m2 twice daily) in separate Q2-week and Q3-week cohorts. At the recommended Phase II doses (RP2Ds) of temsirolimus and capecitabine (Q2), seven patients were also treated with oxaliplatin (85 mg/m2 , day 1) to determine triplet combination safety and efficacy. RESULTS: Forty-five patients were enrolled and 41 were evaluable for dose-limiting toxicities (DLTs). The most common adverse events (AEs) were mucositis, fatigue, and thrombocytopenia. The most common grade 3/4 AEs were hypophosphatemia and anemia. Five patients had DLTs, including hypophosphatemia, mucositis, and thrombocytopenia. The RP2Ds were temsirolimus 25 mg +capecitabine 1000 mg/m2 (Q2); and temsirolimus 25 mg +capecitabine 750 mg/m2  (Q3). Of the 38 patients evaluable for response, one had a partial response (PR) and 19 had stable disease (SD). The overall disease control rate was 52%. Five of the 20 patients with SD/PR maintained disease control for >6 months. CONCLUSIONS: The combination of temsirolimus and capecitabine is safe on both a Q2-week and a Q3-week schedule. The combination demonstrated promising evidence of disease control in this highly refractory population and could be considered for testing in disease-specific phase II trials.

Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells.

The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1- T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells. SIGNIFICANCE: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy.See related commentary by Burton and Tawbi, p. 1008.This article is highlighted in the In This Issue feature, p. 995.

Phase I study of the 177Lu-DOTA0-Tyr3-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung.

BACKGROUND: Lutathera is a 177Lutetium-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.

Implementation of the Smoking Treatment and Recovery (STAR) program: healthy cancer survivorship through integrated tobacco control.

PURPOSE: It is well-established that persistent tobacco use among patients with cancer results in numerous adverse outcomes. However, the assessment and treatment of tobacco use with evidence-based methods have been lacking in cancer care. Our cancer center has established its first tobacco treatment program, a multidisciplinary, evidence-based, clinical program for hematology/oncology patients. METHODS: We describe the development and implementation of the program, emphasizing lessons learned in treating nicotine addiction among patients who are at very high risk for continuing to use tobacco throughout the survivorship phase. RESULTS: We developed a system to assess tobacco use at each outpatient visit, from those recently diagnosed to long-term survivors. For patients who have smoked in the past month, the protocol offers standard behavioral and pharmacological treatments, delivered by tobacco treatment specialists and nurse practitioners over four in-person and/or telephone-based sessions. Partnerships with the Psychosocial Oncology and Cancer Survivorship Programs have provided integrated and comprehensive care for patients during and after their cancer treatment. CONCLUSIONS: The systematic efforts to reach and engage current smokers have laid the groundwork for maximizing the program's future effectiveness and impact. Our initial results demonstrate not only the complexities but also the feasibility of developing a new tobacco treatment program in the oncology setting. IMPLICATIONS FOR CANCER SURVIVORS: The implications for cancer survivors are the significant improvements in treatment outcomes that occur with tobacco abstinence.

Molecular diagnostics and targeted therapies in non-small cell lung cancer (NSCLC): an update.

The understanding of genetic alterations that drive non-small cell lung cancer (NSCLC) is evolving. As many of these molecularly-defined subtypes are potentially actionable, new strategies in molecular diagnostics and targeted therapies in NSCLC to detect and treat them are being explored. At the International Association for Study of Lung Cancer 19th World Conference, several abstracts and oral presentations related to this topic. In this report, we discuss some of these updates.

A phase I study of HER1, HER2 dual kinase inhibitor lapatinib plus the proteasome inhibitor bortezomib in patients with advanced malignancies.

PURPOSE: This phase I trial evaluated the maximum tolerated dose, safety and preliminary efficacy of lapatinib, a HER1, HER2 dual kinase inhibitor plus bortezomib, a proteasome inhibitor, in adult patients with advanced malignancies. METHODS: Patients were enrolled in a standard 3 + 3 design with lapatinib (L) 750, 1000, 1250 or 1500 mg daily, and bortezomib (B) 0.7, 1.0, 1.3 or 1.6 mg/m2 for 3 weeks with 1 week off. Dose-limiting toxicities (DLT) were assessed during the first 28 days RESULTS: Fifteen patients received the combination of lapatinib and bortezomib in three different cohorts and ten were evaluable for DLT. There were no DLTs. Anorexia was the most common adverse event. Biomarker analysis showed upregulation of p27 expression with lapatinib and the combination. No tumor response was observed and thus the study was closed early. CONCLUSION: The combination of lapatinib and bortezomib was well tolerated but no complete or partial tumor responses were observed at the dose levels tested. CLINICALTRIALS. GOV IDENTIFIER: NCT01497626.

Electromagnetic fields alter the motility of metastatic breast cancer cells.

Interactions between cells and their environment influence key physiologic processes such as their propensity to migrate. However, directed migration controlled by extrinsically applied electrical signals is poorly understood. Using a novel microfluidic platform, we found that metastatic breast cancer cells sense and respond to the net direction of weak (∼100 µV cm-1), asymmetric, non-contact induced Electric Fields (iEFs). iEFs inhibited EGFR (Epidermal Growth Factor Receptor) activation, prevented formation of actin-rich filopodia, and hindered the motility of EGF-treated breast cancer cells. The directional effects of iEFs were nullified by inhibition of Akt phosphorylation. Moreover, iEFs in combination with Akt inhibitor reduced EGF-promoted motility below the level of untreated controls. These results represent a step towards isolating the coupling mechanism between cell motility and iEFs, provide valuable insights into how iEFs target multiple diverging cancer cell signaling mechanisms, and demonstrate that electrical signals are a fundamental regulator of cancer cell migration.

Understanding molecular diagnostic technology in oncology through the lens of lung cancer.

Historically, advanced lung cancer conferred a poor prognosis, and chemotherapy only improved outcomes in patients with good performance status. The identification of certain molecular subtypes of non-small cell lung cancer changed the treatment paradigm by incorporating tumor genomic information into clinical decision-making. To meet the demands of this emerging approach, genomic technology rapidly expanded in an effort to detect specific driver mutations. While polymerase-chain reaction testing, immunohistochemistry, and fluorescent-in-situ hybridization have been standard-of-care, next-generation sequencing is increasingly replacing older technologies. Plasma-based testing is also gaining use given its convenience. Advances in molecular technology in this new era of precision medicine have led to the parallel development of companion diagnostics and novel tyrosine kinase inhibitors.