MET alterations in advanced non-small cell lung cancer.

Precision medicine has helped identify several tumor molecular aberrations to be treated with targeted therapies. These therapies showed substantial improvement in efficacy without excessive toxicity in patients with specific oncogenic drivers with advanced cancers. In metastatic lung cancers, the implementation of broad platforms for molecular tumor sequencing has helped oncology providers identify oncogenic drivers linked with better outcomes when treated upfront with targeted therapies. Mesenchymal-epithelial transition factor (MET) alterations are present in up to 60% of non-small cell lung cancer and are associated with a poor prognosis. Capmatinib and tepotinib are currently the only two approved targeted therapies by the U.S. Food and Drug Administration (FDA) for patients with MET exon 14 skipping mutation. Several agents are being developed to tackle an unmet need in patients with MET alterations. Some of these agents are being used in combination with EGFR targeted therapy to mitigate resistance to EGFR inhibitor. These agents are poised to provide new hope for these patients.

A Phase 1/2 Study to Evaluate the Safety and Activity of Nivolumab in Combination With Vorolanib, a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor, in Patients With Refractory Thoracic Tumors.

Introduction: Targeting the tumor microenvironment may enhance response to immunotherapy (immune checkpoint inhibitors) and improve outcomes for patients. This study tested the safety and efficacy of vorolanib, a novel tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and c-KIT, in combination with programmed cell death protein 1 blockade using nivolumab for refractory thoracic malignancies. Methods: This single-arm multicenter study enrolled patients with extensive-stage SCLC, thymic carcinoma, and NSCLC, either naive or had progressed on previous chemotherapy or immune checkpoint inhibitors (either primary or acquired resistance). The primary objective of phase 1 was to determine the maximum tolerated dose, and the primary end point for each dose-expansion cohort was the objective response rate. Results: A total of 88 patients were enrolled in phase 1 (n = 11) and dose expansion (n = 77) cohorts. Transaminitis was dose-limiting and expansion proceeded with oral vorolanib 200 mg daily combined with intravenous nivolumab 240 mg every 2 weeks. The objective response rate per cohort were as follows: NSCLC naive 33% (five of 15, 95% confidence interval [CI]: 13%-60%), NSCLC primary refractory 5.9% (one of 17, 95% CI: 0%-17.6%), NSCLC acquired resistance 11.1% (two of 18, 95% CI: 0%-27.8%); SCLC 0% (zero of 18), and thymic carcinoma 11% (one of nine, 95% CI: 0%-33%). Disease control rate ranged from 11.1% in SCLC (two of 18, 0%-27.8%) to 66.7 % in thymic carcinoma (six of nine, 95% CI: 33.3%-100%). The most common adverse events were fatigue (32%), aspartate transaminase (27%) and alanine transaminase elevation (25%), and diarrhea (19%). Transaminitis was more common in patients with thymic carcinoma than other tumors. Conclusions: Vorolanib plus nivolumab had a manageable safety profile and may have clinical benefits in various thoracic malignancies. The disease control rate in thymic malignancies warrants further assessment.

Novel targeted therapies for advanced non-small lung cancer.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer accounting for almost 80%-85% of all lung cancer cases. Unfortunately, more than half of the patients will be diagnosed with advanced disease at the time of presentation, which makes their disease incurable. Historically, the 5 year overall survival for advanced NSCLC was 5%. However, there has been a significant increase in our understanding of the genetic basis of NSCLC, which has led to development of both immunotherapy and targeted therapy agents. This has improved the 5 year overall survival to become within the range of 15%-50% depending on certain mutations and biomarkers. Over the last decade the United States Food and Drug Administration (FDA) has approved almost 20 new targeted therapies and clinical trials are still undergoing to evaluate more novel agents. In this review, we will present recent updates on novel targeted therapies.

Characteristics and Outcomes of Patients With Metastatic KRAS-Mutant Lung Adenocarcinomas: The Lung Cancer Mutation Consortium Experience.

INTRODUCTION: Mutations in the KRAS gene are the most common driver oncogenes present in lung adenocarcinomas. We analyzed the largest multi-institutional database available containing patients with metastatic KRAS-mutant lung adenocarcinomas. METHODS: The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional collaboration to study the genomic characteristics of lung adenocarcinomas, treat them with genomically directed therapeutic approaches, and assess their outcomes. Since its inception in 2009, the LCMC has enrolled more than 1900 patients and has performed pretreatment, multiplexed, molecular characterization along with collecting clinical data. We evaluated the characteristics of patients with KRAS mutation in the LCMC and the association with overall survival. RESULTS: Data from 1655 patients with metastatic lung adenocarcinomas were analyzed. Four hundred fifty (27%) patients had a KRAS mutation, 58% were female, 93% were smokers, and there was a median age of 65 years. Main KRAS subtypes were: G12C 39%; and G12D and G12V at 18% each. Among patients with KRAS mutation, G12D had a higher proportion of never-smokers (22%, p < 0.001). Patients with KRAS-mutant tumors had a trend toward shorter median survival compared to all others in the series (1.96 versus 2.22; P = 0.08) and lower 2-year survival rate (49% [95% confidence interval: 44%-54%] and 55% [95% confidence interval: 52%-58%], respectively). CONCLUSIONS: In the LCMC study, 27% of lung adenocarcinomas patients harbored a KRAS mutation and up to one-third of them had another oncogenic driver. Patients with both KRAS and STK11 mutations had a significantly inferior clinical outcome.

Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation.

In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAFV600E metastatic colorectal cancer, further augmented by irinotecan. The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAFV600E-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAFV600E circulating cell-free DNA (cfDNA) trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression. SIGNIFICANCE: Vemurafenib, in combination with irinotecan and cetuximab, was well tolerated in patients with refractory, BRAF-mutated metastatic colorectal cancer, and both survival outcomes and response rates exceeded prior reports for vemurafenib and for irinotecan plus cetuximab in BRAFV600E metastatic colorectal cancer. In vivo models demonstrated regressions with the triplet, in contrast with vemurafenib and cetuximab alone. cfDNA predicted radiographic response and identified mutations reactivating the MAPK pathway upon progression. Cancer Discov; 6(12); 1352-65. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1293.

Innovative Strategies for Decreasing Blood Collection Wait Times for Patients in Early-Phase Cancer Clinical Trials.

PURPOSE: Long wait times are a primary source of dissatisfaction among patients enrolled in early-phase clinical trials. We hypothesized that an automated patient check-in system with readily available display for increasing awareness of waiting intervals would improve patient flow and use of our rooms, with decreased turnover time and increased throughput. METHODS: We recorded in-room wait times for patients seen in our clinic and observed the logistics involved in the blood collection process to delineate causes for delays. We then implemented a three-step strategy to alleviate the causes of these delays: (1) changing the collection of materials and the review of faxed orders, (2) improving our LabTracker automated database system that included wait time calculators and real-time information regarding patient status, and (3) streamlining lower complexity appointments. RESULTS: After our intervention, we observed a 19% decrease in mean wait times and a 30% decrease in wait times among patients waiting the longest (95th percentile). We also observed an increase in staff productivity during this process. Modifications in LabTracker provided the biggest reduction in mean wait times (17%). CONCLUSION: We observed a significant decrease in mean wait times after implementing our intervention. This decrease led to increased staff productivity and cost savings. Once wait times became a measurable metric, we were able to identify causes for delays and improve our operations, which can be performed in any patient care facility.

Bisphosphonate-related osteonecrosis of the jaw: awareness and level of knowledge of Lebanese physicians.

PURPOSE: Bisphosphonate-induced osteonecrosis of the jaw (ONJ) is a potentially destructive complication, particularly encountered in oncology. It is supposed that awareness and good knowledge of this disease by physicians are important factors of its early detection and management. This study aims to evaluate the level of knowledge among a sample of Lebanese physicians with regard to this complication. METHODS: An observational cross-sectional study was conducted at Hôtel-Dieu de France hospital between March and June 2013. Data were collected through a self-administered questionnaire distributed to 190 eligible physicians in the departments involved in prescribing bisphosphonates and managing the ONJ. RESULTS: A total of 136 valid responses were obtained (response rate 71.6 %). Eighty-six (63.2 %) physicians were treating patients with bisphosphonates: the most prescribed form being the weekly oral bisphosphonates for osteoporosis followed by zoledronate several times yearly for bone malignancies. Fifty-one (37.5 %) participants were unaware of bisphosphonate-related ONJ. Furthermore, the level of knowledge was relatively poor: the mean score of all participants was 12.42 ± 10.08, while 77 (56.6 %) had a global score more than 16 over 30. There were statistically significant associations between the level of knowledge and physicians' specialty (p value <0.0001), whether or not they prescribe bisphosphonates (p value = 0.039), the most frequently form prescribed (p value = 0.048), whether or not they attend patients already on bisphosphonate (p value = 0.047), whether or not they have observed (p value = 0.004) and treated (p value = 0.002) exposed necrotic bone of the jaw. CONCLUSIONS: Our study revealed a deficient knowledge regarding bisphosphonate-related ONJ among Lebanese physicians. Appropriate training strategies to increase their awareness are required.

Characteristics of patients who refuse do-not-resuscitate orders upon admission to an acute palliative care unit in a comprehensive cancer center.

BACKGROUND: Refusal of appropriately indicated do-not-resuscitate (DNR) orders may cause harm and distress for patients, families, and the medical team. We conducted a retrospective study to determine the frequency and predictors of refusals of DNR in advanced cancer patients admitted to an acute palliative care unit. METHODS: A total of 2538 consecutive admissions were reviewed. Demographic and clinical characteristics from 200 consecutive patients with DNR orders and 100 consecutive patients who refused DNR were collected, and differences between the groups were determined by multivariate regression and recursive partitioning analysis. RESULTS: Of 2538 admissions, 2530 (99%) were appropriate for DNR discussion. Of the 2530 admissions, 2374 were unique patients, and 100 (4%) of 2374 refused DNR. Refusers had median (interquartile range, IQR) pain of 7 (4-9) versus 5 (3-8, P = .0005), nausea of 2 (0-7) versus 1 (0-4, P = .05), and dyspnea of 1 (0-5) versus 4 (0-7, P = .002) as compared with DNR nonrefusers, respectively. Patients with hematological malignancies and advance directives had a lower DNR refusal risk (odds ratio [OR], 0.38; P = .02, and OR, 0.36; P < .0001, respectively). Multivariate regression analysis revealed that patients with moderate-severe pain (OR, 3.19; P = .002) and with no advance directives (OR, 2.94; P < or = .001) had higher DNR refusal risk. There were more inpatient deaths among DNR nonrefusers (87 of 200 vs 1 of 100, P < .0001). Median (IQR) time from discharge to death was 18 (8-35) days for those with DNR orders and 85 (25-206) days for DNR refusers (P < or = .0001). CONCLUSIONS: DNR refusal in patients admitted to the acute palliative care unit is low, more frequent in patients with more pain and nausea and no advance directives, and associated with longer survival. This study demonstrates possible predictors of complicated DNR discussions.

Methadone initiation and rotation in the outpatient setting for patients with cancer pain.

BACKGROUND: Methadone is an effective and inexpensive opioid for cancer pain treatment. It has been reported as difficult to use in the outpatient setting because of its variable relative potency and long half-life. The purpose of this study was to determine the outcome of methadone initiation or rotation for cancer pain treatment in outpatient settings. METHODS: Chart review was done of 189 consecutive patients who underwent methadone initiation or rotation at the authors' palliative care outpatient center. Data were collected regarding demographic and clinical characteristics, symptoms, and opioid side effects at baseline and for 2 follow-up visits (F1, F2). Failure was defined as methadone discontinuation by the palliative care physician or patient's hospitalization for uncontrolled pain or methadone-related side effects at F1. RESULTS: One hundred (53%) initiations and 89 (47%) rotations were conducted. Success rates for methadone initiation and rotation were 82 of 89 (92%) and 85 of 100 (84%), respectively. Mean (standard deviation) age was 60 (11) years. One hundred (53%) patients were women, 138 (73%) were white, and 182 (96%) had solid cancers. The main reason for rotation was pain (65 of 89 patients, 47%). Median (interquartile range, IQR) pain scores (Edmonton Symptom Assessment Scale/0-10) were 6 (5-8), 4 (3-6), and 3 (2-5) at baseline, F1, and F2, respectively (P < .0001). Median (IQR) daily methadone dose for initiation and rotation was 10 (5-15) mg and 15 (10-30) mg at F1 (P < .0001) and 10 (8-15) mg and 18 (10-30) mg at F2 (P < .0001), respectively. Constipation and nausea improved (P < .005) after initiation/rotation to methadone. Frequency of sedation, hallucinations, myoclonus, and delirium did not increase after initiation/rotation to methadone. CONCLUSIONS: Outpatient methadone initiation and rotation for cancer pain treatment were safe, with high success rates and low side effect profiles.

The effect of oral methadone on the QTc interval in advanced cancer patients: a prospective pilot study.

BACKGROUND: Recent reports suggest that high doses of methadone may prolong QTc interval and occasionally cause torsades de pointes; however, few of these studies involved the palliative care population. OBJECTIVE: The purpose of this study was to determine the effect of initiation of methadone on QTc interval in patients with cancer pain seen at the palliative care setting. METHODS: We enrolled 100 patients with cancer in this prospective study. Patients were followed clinically and electrocardiographically for QTc changes at baseline, 2, 4, and 8 weeks. Contributing factors for QTc prolongation such as medications, cardiovascular diseases, and electrolytes disturbances were documented. QTc prolongation was defined as greater than 430 ms in males and greater than 450 ms in females, and significant QTc prolongation was defined as QTc interval greater than 25% increase from baseline or 500 ms or more. RESULTS: Electrocardiographic (ECG) assessments were available for 100, 64, 41, and 27 patients at baseline, 2-, 4-, and 8-week follow-up, respectively. At baseline prior to initiation of methadone, 28 (28%) patients had QTc prolongation. Clinically significant increase in QTc occurred in only 1 of 64 (1.6%) patients at week 2, and none at weeks 4 and 8. There was no clinical evidence of torsades de pointes, ventricular fibrillation, or sudden death. QTc prolongation was more frequent among patients with increased baseline QTc interval. CONCLUSIONS: Baseline QTc prolongation was common, whereas significant QTc interval 500 ms or more after methadone initiation rarely occurred, with no evidence of clinically significant arrhythmias. This study supports the safety of methadone use for pain control in patients with advanced cancer in the palliative care setting.

The influence of tumor necrosis factor-alpha -308 G/A and IL-6 -174 G/C on pain and analgesia response in lung cancer patients receiving supportive care.

INTRODUCTION: We previously showed that select cytokine gene polymorphisms are a significant predictor for pain reported at initial presentation in 446 white patients newly diagnosed with non-small cell lung cancer. This follow-up study explores the extent to which polymorphisms in tumor necrosis factor-alpha (TNF- alpha-308 G/A), interleukin (IL)-6 -174G/C, and IL-8 -251T/A could explain variability in pain and analgesic response among those patients (n = 140) subsequently referred for pain treatment. METHODS: Pain severity (0, no pain; 10, worst pain) was assessed at initial consultation and at follow-up visit. The total dose of opioids at the time of first-follow up visit (30 days postconsult) was converted to an equivalent dose of parenteral morphine. RESULTS: Forty-one percent (57 of 140) of the patients reported severe pain (score > 7/10) at initial consultation (mean, 5.5), which significantly decreased to 25% (mean, 4) at first follow-up visit (McNemar = P < 0.001). Polymorphisms in TNF and IL-6 were significantly associated with pain severity (for TNF GG, 4.12; GA, 5.38; AA, 5.50; P = 0.04) and with morphine equivalent daily dose (IL-6 GG, 69.61; GC, 73.17; CC, 181.67; P = 0.004), respectively. Adjusting for demographic and clinical variables, variant alleles in TNFalpha -308 G/A remained significantly associated with pain severity (b = 0.226; P = 0.036) and carriers of the IL-6 -174C/C genotypes required 4.7 times higher dose of opioids for pain relief (odds ratio, 4.7; 95% confidence interval, 1.2;15.0) relative to GG and GC genotypes. CONCLUSIONS: We provide preliminary evidence of the influence of cytokine genes on pain and response to analgesia in lung cancer patients. Additional studies are needed to validate our findings. The long-term application is to tailored pain therapies.

Alcoholism screening in patients with advanced cancer: impact on symptom burden and opioid use.

PURPOSE: Alcoholism is a devastating disease that can cause patient and family suffering and is frequently underdiagnosed. Preliminary studies suggest that it is associated with increased symptom expression and opioid dose escalation. The CAGE questionnaire is a widely used tool for alcoholism screening. The purpose of this study was to determine the frequency and characteristics of patients who screen positive for alcoholism in a palliative care outpatient clinic (PCOC). METHODS: We reviewed 665 consecutive charts of patients referred to the PCOC and collected data regarding age, gender, and type of cancer. For the first 100 consecutive CAGE positive (CAGE+) and 100 consecutive CAGE negative (CAGE-) patients, time from advanced cancer diagnosis (AC) to PCOC was calculated, and symptoms (Edmonton Symptom Assessment Scale, ESAS) and Morphine Equivalent Daily Dose (MEDD) were collected. RESULTS: CAGE was available for 598 of 665 (90%) patients. Of 598 patients, 100 (17%) were CAGE+. CAGE+ patients were younger (58 versus 60 years, p < 0.05), predominantly male (68% versus 47%, p < 0.0001), and with head/neck malignancies (24% versus 9%, p < 0.05). CAGE+ patients were referred earlier (5 +/- 27 months after AC, p < 0.0001). At baseline, pain, sleep, dyspnea, well-being, and total symptom distress were significantly worse among CAGE+ patients. Both groups showed similar improvement in symptoms. CAGE+ patients were more frequently on opioids upon referral (47/100 versus 29/100, p < 0.05) and follow-up (27/65 versus 16/68, p < 0.05). At follow-up, opioid doses did not show significant changes. CONCLUSION: Seventeen percent of the patients were CAGE+. These patients were referred earlier to palliative care, had more symptom expression, and were more frequently on opioids. The palliative care team successfully improved symptom control in both groups without opioid dose escalation.

Comparison of symptom burden among patients referred to palliative care with hematologic malignancies versus those with solid tumors.

BACKGROUND: Patients with hematologic malignancies have reduced and later access to palliative care services (APCS) than do those with solid tumors. It is unclear whether these patients develop a high symptom burden at the end of life that requires special palliative care interventions. The purposes of this retrospective study were to determine whether symptoms are less severe in patients with hematologic than in those with solid malignancies on APCS and whether symptom severity is associated with early APCS. METHODS: We studied the records of consecutive patients with hematologic and solid malignancies at their first palliative care consultation (PC1). We collected information about demographics, cancer type, date of PC1, and the interval from PC1 to death (PC1-D). We reviewed the charts for the Edmonton Symptoms Assessment System (ESAS) and presence of delirium. RESULTS: We included 250 patients (125 with each type of malignancy). Median pain and drowsiness were 4 (3-5) and 7 (5-10) among hematologic compared to 5 (4-6, p=0.043) and 5 (3-6, p=0.0008) among patients with solid malignancies, respectively. Delirium was detected in 51 of 125 (41%) hematologic versus 20 of 125 (16%) solid (p=0.0001). Median PC1-D was 13 days for hematologic versus 46 days for solid (p=0.0001). There was no correlation between PC1-D and pain (r= -0.117, p=0.4 for hematologic and r=0.09, p=0.37 for solid), dyspnea (r= -0.02, p=0.85 for hematologic and r=0.09, p=0.42 for solid) or the Symptom Distress Score (r= -0.047, p=0.72 for hematologic and r= -0.093, p=0.32 for solid). CONCLUSIONS: Hematologic patients had increased delirium and drowsiness and later APCS The overall symptom severity was similar in both groups of patients and did not correlate with early APCS. Future prospective studies are needed to better define APCS patterns in this group.

Characteristics, findings, and outcomes of palliative care inpatient consultations at a comprehensive cancer center.

PURPOSE: There is limited information available about the role and effect of a palliative care consultation service (mobile team, MT) in patient care. The purpose of this retrospective chart review was to determine the characteristics, findings, and outcomes of patients referred to MT in a comprehensive cancer center and to thereby gain information about its role in this setting. PATIENTS AND METHODS: The study group was 61 consecutive patients assessed by one MT during 2-month period. We reviewed their charts for information about demographic and disease features, reasons for consultation, findings, interventions, and outcomes. RESULTS: Patients were mainly referred by thoracic (n = 21; 34%), genitourinary (n = 10; 16%), and gynecology (n = 9; 15%) services. The majority of patients had metastatic disease (n = 56; 92%). Evaluation of pain was the main reason for the consultation (n = 47; 77%) followed by delirium (n = 10; 16%). The MT found a total of 449 symptoms (median 8 per patient), whereas the referring team had mentioned only 86 (1 symptom per patient) in their requests. Twenty patients (38%) screened positive for a history of alcoholism. The MT diagnosed delirium in 34 patients (56%) and frequently found features of opioid-induced side effects, such as sedation (n = 46; 75%), constipation (n = 43; 70%), and confusion (n = 34; 56%). Frequent MT interventions were: administration of neuroleptics (n = 33; 54%), opioid rotation (n = 30; 49%), and enema (n = 33; 54%). Seventeen patients (28%) showed symptoms improvement within 24 hours and 23 patients within 72 hours (38%). Twenty-five patients (41%) required transfer to the palliative care unit. CONCLUSIONS: The MT had a positive impact on these patients' care in terms of clinical findings and outcomes. Further investigations are warranted.

Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial.

PURPOSE: To evaluate the effectiveness of donepezil compared with placebo in cancer patients with fatigue as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F). PATIENTS AND METHODS: Patients with fatigue score >or= 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) for more than 1 week were included. Patients were randomly assigned to receive donepezil 5 mg or placebo orally every morning for 7 days. A research nurse contacted the patients by telephone daily to assess toxicity and fatigue level. All patients were offered open-label donepezil during the second week. FACIT-F and/or the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 11, and 15. The FACIT-F fatigue subscale score on day 8 was considered the primary end point. RESULTS: Of 142 patients randomly assigned to treatment, 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis. Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .57) or ESAS (P = .18) between groups. In the open-label phase, fatigue intensity continued to be low as compared with baseline. No significant toxicities were observed. CONCLUSION: Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue.