Exemptions to state laws regulating opioid prescribing for patients with cancer-related pain: A summary.

BACKGROUND: Cancer-related pain is highly prevalent and is commonly treated with prescription opioids. The Centers for Disease Control and Prevention (CDC) now encourages conservative opioid prescribing in recognition of potential opioid-related risks. However, CDC guidelines have been misapplied to patients with cancer. Recent laws at the state level reflect the CDC's guidance by limiting opioid prescribing. It is unclear whether states exempt cancer-related pain, which may affect cancer pain management. Thus, the objective of this study was to summarize current state-level opioid prescribing laws and exemptions for patients with cancer. METHODS: Two study authors reviewed publicly available state records to identify the most recent opioid prescribing laws and cancer-related exemptions. Documents were required to have the force of law and be enacted at the time of the search (November 2020). RESULTS: Results indicated that 36 states had enacted formal legislation limiting the duration and/or dosage of opioid prescriptions, and this was largely focused on acute pain and/or initial prescriptions. Of these states, 32 (89%) explicitly exempted patients with cancer-related pain from opioid prescribing laws. Exemptions were broadly applied, with few states providing specific guidance for cancer-related pain prescribing. CONCLUSIONS: The results of this study indicate that most states recognize the importance of prescription opioids in cancer-related pain management. However, drafting nuanced and clinically relevant opioid legislation is challenging for a heterogenous population. Additionally, current attempts to regulate opioid prescribing by state law may unintentionally undermine patient-centered approaches to pain management. Additional resources are needed to facilitate clarity at the intersection of opioid-related legislation and clinical management for cancer-related pain. LAY SUMMARY: In this review of state-level legislation, current limitations on opioid prescribing are summarized and detailed information is provided on exemptions for patients with cancer. The majority of states have enacted specific dosage and/or duration limitations on opioid prescribing while including broad exemptions for cancer-related pain. Cancer-related pain exemptions are important to include, as is consistent with national and professional guidelines (eg, the Centers for Disease Control and Prevention). However, these exemptions may also unintentionally undermine patient-centered approaches to pain management. Additional resources, including specific guidance for patients with cancer, are needed to facilitate clarity at the intersection of opioid-related legislation and clinical pain management. ​.

Rociletinib in EGFR-mutated non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. METHODS: In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles. RESULTS: A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51). CONCLUSIONS: Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).

Risk of brain metastases in patients with nonmetastatic lung cancer: Analysis of the Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) data.

BACKGROUND: Brain metastases (BM) remain an important cause of morbidity and mortality in patients with lung cancer. The current study evaluated population-based incidence and outcomes of BM in patients with nonmetastatic lung cancer. METHODS: Patients diagnosed with nonmetastatic first primary lung cancer between 1973 and 2011 in the Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) registry were used for the current analysis. Age-adjusted odds ratios of developing BM based on various demographic characteristics and histology were calculated with 95% confidence intervals. Adjusted Cox proportional hazard ratios and log-rank tests of Kaplan-Meier survival curves were calculated to evaluate survival differences for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). RESULTS: The incidence of BM in patients with nonmetastatic NSCLC and SCLC was 9% and 18%, respectively. There was variation in the incidence of BM according to NCSLC histology. The incidence of BM was higher in patients aged <60 years for both NSCLC and SCLC, but there were no differences noted by race for either histological group. Female patients with NSCLC were more likely to have BM than male patients. There was variation in the proportion of BM in both patients with NSCLC and SCLC over the three 13-year periods of diagnosis. The risk of death (hazard ratio) was found to be significantly higher for patients with NSCLC with BM, but was not significantly higher in patients with SCLC with BM. CONCLUSIONS: The incidence of BM in patients with nonmetastatic lung cancer varies according to histology, age, and sex. BM are associated with worse survival for patients with NSCLC but not those with SCLC. Cancer 2016;122:1921-7. © 2016 American Cancer Society.

Effectiveness of bevacizumab exposure beyond disease progression in patients with non-small-cell lung cancer: analyses of the ARIES observational cohort study.

PURPOSE: Bevacizumab used in combination with first-line chemotherapy confers an overall survival (OS) benefit for patients with non-squamous non-small-cell lung cancer (NSCLC). This analysis from the ARIES observational cohort study (OCS) was initiated to evaluate the effect of bevacizumab use beyond disease progression (BBP) on clinical outcomes in patients with NSCLC receiving first-line treatment with bevacizumab and chemotherapy. METHODS: The ARIES OCS prospectively enrolled patients from 2006 to 2009 in the United States who had advanced non-squamous NSCLC, received bevacizumab with chemotherapy in the first-line setting, and survived progressive disease (PD). A dichotomous landmark analysis examined post-PD OS (ppOS) in patients who received BBP versus no BBP within 30 days post PD. A time-dependent Cox model assessed the effect of cumulative BBP exposure on ppOS. RESULTS: The ARIES OCS enrolled 1967 patients with first-line NSCLC; 1358 patients had first PD and were alive at the 30-day landmark (351 patients with BBP and 1007 patients with no BBP). The landmark analysis showed that BBP was associated with a lower risk of death (BBP versus No-BBP); hazard ratio [HR], 0.75; 95% confidence interval 0.65-0.86. In the cumulative exposure analysis of 1461 patients who had PD, HRs for ppOS decreased by approximately 4% for each additional 21-day interval of bevacizumab received. Protocol-specified bevacizumab-select adverse events occurred in 14% of BBP patients. CONCLUSIONS: BBP was associated with a lower risk of death in patients with NSCLC treated with first-line bevacizumab and chemotherapy. Copyright © 2016 John Wiley & Sons, Ltd.

"I Refused to Get Addicted to Opioids": Exploring Attitudes About Opioid Use Disorder in Patients With Advanced Cancer Pain and Their Support People.

Patients with advanced cancer are commonly prescribed opioids, yet patient attitudes about opioid risks (eg, opioid use disorder, or OUD) are understudied. Our objective was to use in-depth qualitative interviews to understand perceptions of opioid prescribing and OUD in patients with advanced, solid-tumor cancers and their support people. We conducted a qualitative study using a rigorous inductive, qualitative descriptive approach to examine attitudes about OUD in patients with advanced cancer (n = 20) and support providers (n = 11). Patients with cancer hold 2 seemingly distinct views: prescription opioids are addictive, yet OUD cannot happen to me or my loved one. Participants described general concerns about the addictive nature of prescription opioids ("My biggest concern… would just be the risk of getting addicted to the medication or even like, overdosing it"), while separating cancer pain management from OUD when considering prescription opioid risks and benefits ("They need to make sure they get the right ones, when they're taking it away from you."). Finally, participants identified personal characteristics and behaviors that they felt were protective against developing OUD (commonly control, willpower, and responsibility). This rigorous qualitative study demonstrates that patients with advanced cancer and their support people simultaneously hold concerns about the addictive nature of prescription opioids, while distancing from perceptions of OUD risks when using opioids for cancer pain management. Given high rates of opioid exposure during advanced cancer treatment, it is important to explore opportunities to promote a balanced understanding of prescription opioid use and OUD risks in this population. PERSPECTIVE: Though prescription opioids carry risk of OUD, there is little data to help guide patients with advanced cancer. Findings suggest that there is a need to develop new, innovative strategies to promote effective pain management and minimize opioid risks in this complex population.

Brief Report: Safety and Antitumor Activity of Durvalumab Plus Tremelimumab in Programmed Cell Death-(Ligand)1-Monotherapy Pretreated, Advanced NSCLC: Results From a Phase 1b Clinical Trial.

INTRODUCTION: Although first-line immunotherapy approaches are standard, in patients with non-small cell lung cancer (NSCLC) previously treated with programmed cell death protein-1 or programmed death-(ligand)1 (PD-[L]1) inhibitors, the activity of combined CTLA-4 plus PD-(L)1 inhibition is unknown. This phase 1b study evaluated the safety and efficacy of durvalumab plus tremelimumab in adults with advanced NSCLC who received anti-PD-(L)1 monotherapy as their most recent line of therapy. METHODS: Patients with PD-(L)1-relapsed or refractory NSCLC were enrolled between October 25, 2013, and September 17, 2019. Durvalumab 20 mg/kg plus tremelimumab 1 mg/kg was administered intravenously every 4 weeks for four doses, followed by up to nine doses of durvalumab monotherapy every 4 weeks for up to 12 months of treatment or disease progression. Primary end points included safety and objective response rate (ORR) on the basis of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) per blinded independent central review; secondary end points were ORR on the basis of RECIST v1.1 per investigator; duration of response, disease control, and progression-free survival on the basis of RECIST v1.1 per blinded independent central review and investigator; and overall survival. CLINICALTRIALS: gov identifier: NCT02000947. RESULTS: PD-(L)1-refractory (n = 38) and PD-(L)1-relapsed (n = 40) patients were treated. The most common treatment-related adverse events were fatigue (26.3%, PD-(L)1-refractory patients) and diarrhea (27.5%, PD-(L)1-relapsed patients). Grade 3 to 4 treatment-related adverse events occurred in 22 patients. Median follow-up duration was 43.6 months for PD-(L)1-refractory patients and 41.2 months for PD-(L)1-relapsed patients. The ORR was 5.3% for PD-(L)1-refractory patients (one complete response, one partial response) and 0% for PD-(L)1-relapsed patients. CONCLUSIONS: Durvalumab plus tremelimumab had a manageable safety profile, but the combination did not have efficacy after PD-(L)1 treatment failure.

Impact of gender and mutational differences in hormone receptor expressing non-small cell lung cancer.

Background: The incidence of lung cancer in the US has been decreasing but a bigger decline has been observed in men despite similar declines in tobacco use between men and women. Multiple theories have been proposed, including exposure to exogenous estrogens. Our study seeks to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of non-small lung cancer (NSCLC). Methods: 3,256 NSCLC tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified and assessed for HR expression. Hormone receptor (HR+) was defined as ≥ 1% nuclear staining of estrogen receptor-alpha (ER-a) or progesterone receptor (PR) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n=2753) and Illumina NextSeq 592 gene panel (n=503). An adjusted p-value (q-value) <0.05 was determined significant. Results: HR+ was identified in 18.3% of NSCLC. HR+ occurred more commonly in women compared to men (19.6% vs 11.4%, p <0.0001, q <0.0001). EGFR mutations occurred more commonly in HR+ NSCLC than HR- NSCLC (20.2% vs. 14.6%, p = 0.002, q=0.007). Overall, men with EGFR mutations were affected by HR status with a higher prevalence in HR+ NSCLC while such differences were not seen in women. However, in women ages ≤45, there was a trend towards greater prevalence HR+ NSCLC (25.25% vs. 11.32%, q= 0.0942) and 10/25 (40.0%) of HR+ cases in young women were found to be EGFR mutated. KRAS mutations and ALK+ IHC expression occurred more in HR+ NSCLC whereas TP53 mutations occurred more in HR- NSCLC. Conclusions: Women were more likely to have HR+ NSCLC than men and EGFR and KRAS mutations occurred more commonly in HR+ NSCLC. Additional studies with more strict inclusion criteria for HR+ are warranted to see if there is benefit to targeting HR in these subgroups.

A prospective analysis of the influence of older age on physician and patient decision-making when considering enrollment in breast cancer clinical trials (SWOG S0316).

PURPOSE: Patients older than 65 years are underrepresented in clinical trials. We conducted a prospective study (SWOG S0316) to determine physician- and patient-perceived barriers to breast cancer clinical trial enrollment for older patients. METHODS: Eight geographically diverse SWOG institutions participated. The study assessed patients' and physicians' decisions to enroll in or decline clinical treatment trials, including demographics, trial availability, and eligibility. Patient and physician questionnaires elicited concerns related to treatment, medical status, age, family, and financial or transportation concerns. RESULTS: A total of 1,079 patients were registered and eligible and 909 (84%) returned for follow-up. The major reason for nonaccrual was either trial unavailability or ineligibility (60%). Older patients were less likely to be eligible for trials (65% for age ≥65 years vs. 78% for age <65 years). If eligible, trial participation rates did not differ significantly by age (34% for age ≥65 years vs. 40% for age <65 years). Patients ≥65 years more often were concerned about side effects, had friends opposed to participation, or believed that participation would not benefit other generations. When trials were available and patients were eligible, physicians discussed trial participation with 76% of patients <65 years versus 58% of patients ≥65 years of age. For patients ≥65 years, 11% of physicians indicated age as a reason they did not enroll a patient in a clinical trial. CONCLUSION: Trial unavailability or patient ineligibility were the major reasons for lack of enrollment in breast cancer clinical trials for patients of all ages in this prospective study. Older patients were less likely to be eligible for trials, but if eligible they participated at similar rates to younger patients.

Framework for opioid stigma in cancer pain.

ABSTRACT: Millions of patients with cancer pain are treated with prescription opioids each year. However, efforts to mitigate the ongoing opioid crisis result in unintended consequences with opioid pain management, including opioid stigma. Emerging research indicates that opioid stigma is problematic in patients with cancer, but few studies have examined contributors to and impacts of opioid stigma in this population. To guide future research in this area, we propose a conceptual framework-the opioid stigma framework (OSF)-with which to understand and improve opioid stigma in patients with cancer pain. Development of the OSF was guided by a literature review of stigma in health-related conditions, adaptation of the existing Health Stigma and Discrimination Framework, a topical review of challenges related to opioid cancer pain management, and author expertise in cancer, pain, and opioid prescribing. The proposed OSF highlights 5 domains: (1) contributors to opioid stigma, or factors that increase the likelihood that a patient will experience opioid stigma; (2) intersecting stigmas, or the convergence of multiple stigmatized identities within a patient; (3) stigma manifestations, or the ways opioid stigma is manifested in patients, clinicians, and the community; (4) proximal outcomes, or the immediate consequences of opioid stigma in patients; and (5) long-term impacts in patients. The OSF provides 2 main avenues to facilitate future research: (1) providing a framework to explore the mechanisms that underlie opioid stigma and its impact on cancer pain management and (2) supporting the development of targeted, tailored interventions to eliminate opioid stigma.

Brief Report: Safety and Antitumor Activity of Alectinib Plus Atezolizumab From a Phase 1b Study in Advanced ALK-Positive NSCLC.

Introduction: Alectinib is a preferred first-line treatment option for advanced ALK-positive NSCLC. Combination regimens of alectinib with immune checkpoint inhibitors are being evaluated for synergistic effects. Methods: Adults with treatment-naive, stage IIIB/IV, or recurrent ALK-positive NSCLC were enrolled into a two-stage phase 1b study. Patients received alectinib 600 mg (twice daily during cycle 1 and throughout each 21-d cycle thereafter) plus atezolizumab 1200 mg (d8 of cycle 1 and then d1 of each 21-d cycle). Primary objectives were to evaluate safety and tolerability of alectinib plus atezolizumab. Secondary objectives included assessments of antitumor activity. Results: In total, 21 patients received more than or equal to 1 dose of alectinib or atezolizumab. As no dose-limiting toxicities were observed in stage 1 (n = 7), the starting dose and schedule were continued into stage 2 (n = 14). Median duration of follow-up was 29 months (range: 1-39). Grade 3 treatment-related adverse events occurred in 57% of the patients, most often rash (19%). No grade 4 or 5 treatment-related adverse events were reported. Confirmed objective response rate was 86% (18 of 21; 95% confidence interval [CI]: 64-97). Median progression-free survival was not estimable (NE) (95% CI: 13 mo-NE), neither was median overall survival (95% CI: 33 mo-NE). Conclusions: The combination of alectinib and atezolizumab is feasible, but increased toxicity was found compared with the individual agents. With small sample sizes and relatively short follow-up, definitive conclusions regarding antitumor activity cannot be made.

Manifestations of Opioid Stigma in Patients With Advanced Cancer: Perspectives From Patients and Their Support Providers.

PURPOSE: Stigma surrounding prescription opioids, or opioid stigma, is increasingly recognized as a barrier to effective and guideline-concordant cancer pain management. Patients with advanced cancer report high rates of pain and prescription opioid exposure, yet little is known about how opioid stigma may manifest in this population. METHODS: We conducted in-depth qualitative interviews with 20 patients with advanced cancer and 11 support providers between March 2020, and May 2021. We took a rigorous inductive, qualitative descriptive approach to characterize how opioid stigma manifests in the lives of patients with advanced cancer. RESULTS: Patients and their support providers described three primary manifestations of opioid stigma: (1) direct experiences with opioid stigma and discrimination in health care settings (eg, negative, stigmatizing interactions in pharmacies or a pain clinic); (2) concerns about opioid stigma affecting patient care in the future, or anticipated stigma; and (3) opioid-restricting attitudes and behaviors that may reflect internalized stigma and fear of addiction (eg, feelings of guilt). CONCLUSION: This qualitative study advances our understanding of opioid stigma manifestations in patients with advanced cancer, as well as coping strategies that patients may use to alleviate their unease (eg, minimizing prescription opioid use, changing clinicians, and distancing from perceptions of addiction). In recognition of the costs of undermanaged cancer pain, it is important to consider innovative treatment strategies to address opioid stigma and improve pain management for patients with advanced cancer. Future research should examine opportunities to build an effective, multilevel opioid stigma intervention targeting patients, clinicians, and health care systems.

The Effects of HER2 Alterations in EGFR Mutant Non-small Cell Lung Cancer.

BACKGROUND: HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors. METHODS: We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data. RESULTS: Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004). CONCLUSION: A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.

Parameters for individualizing systemic therapy in non-small cell lung cancer.

Rational drug design based on molecular targets is starting to revolutionize cancer care. To maximize its potential for patients, a concomitant leveraging of molecular knowledge for selection of patients to future and current therapeutic options is paramount. The terms "individualized", "personalized", or "precision therapy" are currently used to describe these efforts. Here, we summarize current knowledge for selection of systemic targeted and cytotoxic therapy for patients with non-small-cell lung cancer. Based on this knowledge, we present a potential decision algorithm to best select patients for currently available therapies, which include the treatment options single-agent erlotinib or gefitinib, the ALK inhibitor crizotinib, double agent gemcitabine and platinum, double agent platinum and pemetrexed, and as a default option a taxane combined with a non-platinum drug, for instance a vinca alkaloid. The addition of bevacizumab to double-agent chemotherapy is also discussed. Currently available data on predictive biomarkers are largely based on subgroup or companion biomarker analyses of patient cohorts or clinical trials. Current and emerging markers must be incorporated prospectively into the design of clinical trials that test novel and established agents to better understand their clinical utility and to refine selection parameters and marker interactions. Future development will lead to increasing complexity in clinical decision making with substantial anticipated benefits to patients including increased therapeutic efficacy, reduced toxicity, and better quality of life.

Risk Factors Associated with a Second Primary Lung Cancer in Patients with an Initial Primary Lung Cancer.

BACKGROUND: Increased patient survivorship following initial primary lung cancer (IPLC) diagnosis and treatment has uncovered new clinical challenges as individuals post-IPLC are at growing subsequent risk of developing second primary lung cancer (SPLC). Proper SPLC surveillance guidelines aimed at monitoring IPLC survivors are crucial to enhancing health outcomes. This study aims to categorize risk factors associated with SPLC emergence in IPLC survivors for clinical use following IPLC treatment. MATERIALS AND METHODS: Using the Karmanos Cancer Institute Tumor Registry, patients diagnosed with IPLC from 2000 to 2017 were identified. Patients diagnosed with SPLC were matched to individuals who did not develop SPLC. Logistic and Cox regression analyses were performed to identify risk factors for SPLC emergence and overall survival (OS). RESULTS: One hundred twenty-one patients diagnosed with IPLC who later developed SPLC were identified and compared with 120 patients with IPLC who did not develop SPLC. Several factors such as stage at first diagnosis, histology, age, and smoking history were not associated with SPLC risk. The median time to SPLC was 1.79 years. Patients who were treated with surgical resection had a significantly higher probability of developing SPLC. After correcting for potential immortal time bias, the median OS was 3.63 years (95% confidence interval [CI], 3.05-5.00) and 7.31 years (95% CI, 4.62-10.90) for SPLC and no SPLC groups, respectively. CONCLUSION: This study uncovered notable associations and lack thereof between several competing SPLC risk factors, as well as mortality. Further characterization of SPLC risk factors is essential for enhancing surveillance recommendations.

Effects of Rovalpituzumab Tesirine on Ventricular Repolarization in Patients With Small-Cell Lung Cancer.

Small cell lung cancer (SCLC) is a leading cause of cancer death worldwide, with few treatment options. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate that targets delta-like 3 on SCLC cells to deliver a cytotoxic payload directly to tumor cells. In this study, the cardiac safety profile of Rova-T was assessed by evaluating changes in QT interval, electrocardiogram (ECG) waveform, heart rate, and proarrhythmic adverse events (AEs) after treatment with Rova-T in patients with previously treated extensive-stage SCLC. Patients underwent ECG monitoring for 2 weeks after each of 2 i.v. infusions of 0.3 mg/kg Rova-T over 30 minutes, administered 6 weeks apart. Forty-six patients received at least one dose of Rova-T. At the geometric mean Rova-T maximum serum concentration of 7,940 ng/mL, ECG monitoring showed no significant changes in the Fridericia-corrected QT (QTcF) interval; the upper limit of the 2-sided 90% confidence interval did not exceed 10 msec for any time point. There were no clinically significant changes in QRS or PR intervals, ECG waveforms, or heart rate after Rova-T administration. All patients experienced a treatment-emergent AE (TEAE); 78% had a grade ≥ 3 TEAE, 59% had a serious TEAE, and 41% had a cardiac-related TEAE. The TEAEs that might signal proarrhythmia tendencies were uncommon. Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova-T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.

Characterization of KRAS Mutation Subtypes in Non-small Cell Lung Cancer.

KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS-mutated non-small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type.Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS-mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%).KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.

Phase II trial of fenretinide (NSC 374551) in patients with recurrent small cell lung cancer.

BACKGROUND: Alterations in retinoid signaling appear to be involved in the pathogenesis of small cell lung cancer (SCLC). Fenretinide [N-(4-hydroxyphenyl)retinamide], a synthetic retinoid, inhibits the growth of SCLC cells in vitro via the induction of apoptosis. Since these data suggested that SCLC is the adult solid tumor that is most susceptible to fenretinide, a trial to evaluate the clinical activity of fenretinide in patients with SCLC was considered the definitive test of its clinical potential in adult oncology. METHODS: Patients with progressive SCLC after one or two prior chemotherapy regimens and a performance status of 0-2 were eligible for the study. Patients with stable, treated brain metastases were eligible. Fenretinide 900 mg/m(2) twice daily was administered orally on days 1-7 of each 21-day cycle. Blood and saliva were collected pre-treatment and on day 7 of cycle 1 to measure fenretinide and retinol levels by high-pressure liquid chromatography (HPLC). RESULTS: Nineteen patients were enrolled. Fifteen patients had one prior chemotherapy regimen and four patients had two prior regimens. The median time from diagnosis to enrollment was 10 months. A median of two cycles of fenretinide was administered. There were no objective responses, but four of 17 evaluable patients (24%) had stable disease after 2-17 cycles. The median time to treatment failure was 5.7 weeks overall, while the four patients with stable disease demonstrated treatment failure at 11, 13, 19, and 52 weeks. Median survival was 25 weeks, with one patient alive 22 months after the start of treatment. The 1-year survival rate was 29%. Toxicity included mild, reversible visual changes (haziness, altered night vision), grade 1-3 nausea/vomiting, and grade 1-2 diarrhea. The mean day 7 plasma fenretinide level was 2.90 +/- 1.66 µg/ml (7.40 +/- 4.25 muM; n = 14). The mean pre-treatment and day 7 plasma retinol levels were 0.47 +/- 0.16 µg/ml and 0.05 +/- 0.07 µg/ml (n = 8), respectively. The mean day 7 salivary fenretinide level was 0.08 +/- 0.18 µg/ml, with no correlation between salivary and plasma drug levels. CONCLUSIONS: Fenretinide is well tolerated in patients with SCLC and stabilization of disease was noted in 24% of patients with this aggressive disease. However, after the first stage of enrollment, the response rate did not meet criteria to proceed with full trial accrual. Plasma concentrations of fenretinide that induce cytotoxicity in vitro in SCLC cell lines are clinically achievable, but there were no objective responses. Non-invasive drug monitoring using saliva underestimates systemic exposure.

A retrospective study evaluating the pretreatment tumor volume (PTV) in non-small cell lung cancer (NSCLC) as a predictor of response to program death-1 (PD-1) inhibitors.

INTRODUCTION OF HYPOTHESIS: Little information is available regarding the imaging characteristics that assist in differentiating responders from non-responders. We hypothesized that patients with higher pretreatment tumor volume (PTV) would have lower response rates and shorter overall survival (OS). METHODS: Data from patients who received at least one dose of program death-1 (PD-1) inhibitors before August 31, 2016 were captured from our institution's pharmacy database. The primary objective was to determine the association of PTV with best response, evaluated utilizing RECIST v1.1 criteria. Secondary objectives were estimation of progression-free survival (PFS) and OS. PTV was measured using the Philips Intellispace Multi-Modality Tumor Tracking application. RESULTS: 116 non-small cell lung cancer (NSCLC) patients were evaluated. 66% patients had adenocarcinoma, 28% had squamous cell carcinoma and 5% had poorly differentiated NSCLC. Median PTV was 53.7 cm3 (95% CI: 13.3-107.9). Only one individual had no metastases and the remainder had M1 disease; 38% M1a, 10% M1b, 51% M1c. Most (79%) were previously treated. There were no complete responses; among those followed for at least 6 weeks, 26% had a partial response, 39% stable disease and 34% PD; 4% had no recorded response. There were no strong associations of PTV with any of the demographic or clinical characteristics. There was no association between PTV and OS (HR 1.2, P=0.26) or PFS (HR 1.1, P=0.47). Liver metastasis was associated with shorter survival (HR=2.8, P=0.05). CONCLUSION: PTV in NSCLC did not prove to be a predictor of response to PD-1 inhibitors but having liver metastasis was associated with significantly shorter survival.

Cancer Site and Adverse Events Induced by Immune Checkpoint Inhibitors: A Retrospective Analysis of Real-life Experience at a Single Institution.

BACKGROUND: Data on the characteristics of patients who are likely to experience adverse events, both immune-related and non-immune-related, from programmed cell death-1 (PD1) inhibitors are limited. PATIENTS AND METHODS: Data from patients who received ≥1 dose of single-agent PD1 inhibitor between August 3, 2011 and August 31, 2016 were obtained from our Institution's pharmacy database. AEs were graded using Common Terminology Criteria for Adverse Events version 4. RESULTS: One hundred and eighty-two patients received at least one dose of single-agent PD1 inhibitor prior to data cut-off. After excluding 14 patients with uncommon malignancies, the total number of patients were 168. The median age was 63 (range=24-92) years. There were 87 (52%) cases of non-small cell lung cancer (NSCLC), 35 (21%) of renal cell carcinoma (RCC), 12 (7%) of melanoma, 18 (11%) of Hodgkin's lymphomas, eight (5%) of head and neck squamous cell carcinoma (HNSCC) and eight (5%) of small cell lung cancer. Considering grade 2 or more AEs, 30 (18%) patients had kidney injury, 34 (20%) hypothyroidism, 36 (21%) transaminitis, 20 (12%) pneumonitis, and 18 (11%) colitis. Patients with RCC had higher odds of experiencing grade 2 or more kidney injury than patients with other primary tumor types (adjusted p=0.025), whereas patients with Hodgkin's lymphoma and HNSCC had higher odds of grade 2 hypothyroidism (adjusted p=0.005). Patients with NSCLC had higher risk of death with pneumonitis than those whose primary cancer was not NSCLC (adjusted p=0.005). DISCUSSION: The increased odds of patients with Hodgkin's lymphoma and HNSCC experiencing grade 2 or more hypothyroidism may be related to previous radiation exposure. Most patients with RCC had undergone nephrectomy, making them more susceptible to acute kidney injury. When pneumonitis occurred in patients with primary NSCLC, the overall survival was significantly worse. The duration of PD1 therapy was significantly associated with onset of pneumonitis (p=0.007). CONCLUSION: The site of primary tumor or metastasis may help predict the most common AEs in patients treated with PD1 inhibitors.

Detection of NRG1 Gene Fusions in Solid Tumors.

PURPOSE: NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners. EXPERIMENTAL DESIGN: Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner. RESULTS: Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer. CONCLUSIONS: NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865.