Real-World Impact of Comprehensive Genomic Profiling on Biomarker Detection, Receipt of Therapy, and Clinical Outcomes in Advanced Non-Small Cell Lung Cancer.

PURPOSE: Therapeutic decision making for patients with advanced non-small cell lung cancer (aNSCLC) includes a growing number of options for genomic, biomarker-guided, targeted therapies. We compared actionable biomarker detection, targeted therapy receipt, and real-world overall survival (rwOS) in patients with aNSCLC tested with comprehensive genomic profiling (CGP) versus small panel testing (SP) in real-world community health systems. METHODS: Patients older than 18 years diagnosed with aNSCLC between January 1, 2015, and December 31, 2020, who received biomarker testing were followed until death or study end (September 30, 2021), and categorized by most comprehensive testing during follow-up: SP (≤52 genes) or CGP (>52 genes). RESULTS: Among 3,884 patients (median age, 68 years; 50% female; 73% non-Hispanic White), 20% received CGP and 80% SP. The proportion of patients with ≥one actionable biomarker (actionability) was significantly higher in CGP than in SP (32% v 14%; P < .001). Of patients with actionability, 43% (CGP) and 38% (SP) received matched therapies (P = .20). Among treated patients, CGP before first-line treatment was associated with higher likelihood of matched therapy in any line (odds ratio, 3.2 [95% CI, 1.84 to 5.53]). CGP testing (hazard ratio [HR], 0.80 [95% CI, 0.72 to 0.89]) and actionability (HR, 0.84 [95% CI, 0.77 to 0.91]) were associated with reduced risk of mortality. Among treated patients with actionability, matched therapy receipt showed improved median rwOS in months in CGP (34 [95% CI, 21 to 49] matched v 14 [95% CI, 10 to 18] unmatched) and SP (27 [95% CI, 21 to 43] matched v 10 [95% CI, 8 to 14] unmatched). CONCLUSION: Patients who received CGP had improved detection of actionable biomarkers and greater use of matched therapies, both of which were associated with significant increases in survival.

Perspective: rethinking therapeutic strategies in oncology.

Immuno-oncology has revolutionized cancer care, drug development, the design of clinical trials, standard treatment paradigms, and the evaluation of response to therapy. These are all areas, however, that have not fully incorporated principles of tumor immunology. Insufficient emphasis is put on the effect drugs have on the immune system, and specifically, the impact that multiple lines of therapy can have on the functioning of the immune system, hindering a robust anti-tumor immune response. A paradigm shift in how we approach the development of novel immunotherapeutic agents is necessary to facilitate the effective improvements in patient outcomes.

SPACEWALK: A Remote Participation Study of ALK Resistance Leveraging Plasma Cell-Free DNA Genotyping.

INTRODUCTION: Remote consent and enrollment offer a unique opportunity to provide rare cancer populations with access to clinical research. The genomic analysis of plasma cell-free DNA (cfDNA) permits remote characterization of the cancer genome. We hypothesized we could leverage these approaches to remotely study drug resistance in patients with metastatic ALK-positive NSCLC. METHODS: The SPACEWALK study (Study of Plasma Next-Generation Sequencing for Remote Assessment, Characterization, Evaluation of Patients With ALK Drug Resistance) enrolled patients with ALK-positive NSCLC and progression on a next-generation ALK inhibitor who could participate remotely. Plasma was collected for next-generation sequencing (NGS) of cfDNA before initiating subsequent therapy, with results returned and subsequent therapy studied. RESULTS: Of the 62 patients enrolled, an ALK fusion was detected in 27 (44%) with a median allelic fraction of 2.6%. Among these 27 patients, a potential resistance mechanism was identified in 17 patients (63%): eight cases (30%) had secondary ALK kinase domain resistance mutations, three cases (11%) had bypass track resistance, and six cases (22%) had both ALK resistance mutations and bypass resistance. The most frequently detected mechanism of bypass resistance was MET amplification. Repeat plasma NGS was performed in 14 patients after subsequent treatment was initiated, with seven (50%) patients exhibiting greater than 50% reductions in ALK fusion allelic fraction. CONCLUSIONS: Through the leveraging of remote participation, plasma NGS offers an optimal mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations, though sensitivity depends on adequate tumor DNA samples. Repeat cfDNA analysis on therapy may offer an objective monitoring approach to remotely study treatment response.

Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials.

BACKGROUND: Radiotherapy might augment systemic antitumoral responses to immunotherapy. In the PEMBRO-RT (phase 2) and MDACC (phase 1/2) trials, patients with metastatic non-small-cell lung cancer were randomly allocated immunotherapy (pembrolizumab) with or without radiotherapy. When the trials were analysed individually, a potential benefit was noted in the combination treatment arm. However, owing to the small sample size of each trial, differences in response rates and outcomes were not statistically significant but remained clinically notable. We therefore did a pooled analysis to infer whether radiotherapy improves responses to immunotherapy in patients with metastatic non-small-cell lung cancer. METHODS: Inclusion criteria for the PEMBRO-RT and MDACC trials were patients (aged ≥18 years) with metastatic non-small-cell lung cancer and at least one unirradiated lesion to monitor for out-of-field response. In the PEMBRO-RT trial, patients had previously received chemotherapy, whereas in the MDACC trial, patients could be either previously treated or newly diagnosed. Patients in both trials were immunotherapy-naive. In the PEMBRO-RT trial, patients were randomly assigned (1:1) and stratified by smoking status (<10 vs ≥10 pack-years). In the MDACC trial, patients were entered into one of two cohorts based on radiotherapy schedule feasibility and randomly assigned (1:1). Because of the nature of the intervention in the combination treatment arm, blinding to radiotherapy was not feasible in either trial. Pembrolizumab was administered intravenously (200 mg every 3 weeks) with or without radiotherapy in both trials. In the PEMBRO-RT trial, the first dose of pembrolizumab was given sequentially less than 1 week after the last dose of radiotherapy (24 Gy in three fractions), whereas in the MDACC trial, pembrolizumab was given concurrently with the first dose of radiotherapy (50 Gy in four fractions or 45 Gy in 15 fractions). Only unirradiated lesions were measured for response. The endpoints for this pooled analysis were best out-of-field (abscopal) response rate (ARR), best abscopal disease control rate (ACR), ARR at 12 weeks, ACR at 12 weeks, progression-free survival, and overall survival. The intention-to-treat populations from both trials were included in analyses. The PEMBRO-RT trial (NCT02492568) and the MDACC trial (NCT02444741) are registered with ClinicalTrials.gov. FINDINGS: Overall, 148 patients were included in the pooled analysis, 76 of whom had been assigned pembrolizumab and 72 who had been assigned pembrolizumab plus radiotherapy. Median follow-up for all patients was 33 months (IQR 32·4-33·6). 124 (84%) of 148 patients had non-squamous histological features and 111 (75%) had previously received chemotherapy. Baseline variables did not differ between treatment groups, including PD-L1 status and metastatic disease volume. The most frequently irradiated sites were lung metastases (28 of 72 [39%]), intrathoracic lymph nodes (15 of 72 [21%]), and lung primary disease (12 of 72 [17%]). Best ARR was 19·7% (15 of 76) with pembrolizumab versus 41·7% (30 of 72) with pembrolizumab plus radiotherapy (odds ratio [OR] 2·96, 95% CI 1·42-6·20; p=0·0039), and best ACR was 43·4% (33 of 76) with pembrolizumab versus 65·3% (47 of 72) with pembrolizumab plus radiotherapy (2·51, 1·28-4·91; p=0·0071). Median progression-free survival was 4·4 months (IQR 2·9-5·9) with pembrolizumab alone versus 9·0 months (6·8-11·2) with pembrolizumab plus radiotherapy (hazard ratio [HR] 0·67, 95% CI 0·45-0·99; p=0·045), and median overall survival was 8·7 months (6·4-11·0) with pembrolizumab versus 19·2 months (14·6-23·8) with pembrolizumab plus radiotherapy (0·67, 0·54-0·84; p=0·0004). No new safety concerns were noted in the pooled analysis. INTERPRETATION: Adding radiotherapy to pembrolizumab immunotherapy significantly increased responses and outcomes in patients with metastatic non-small-cell lung cancer. These results warrant validation in a randomised phase 3 trial. FUNDING: Merck Sharp & Dohme.

Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies.

PURPOSE: The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+). METHODS: A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation. RESULTS: Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16-0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04-0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25-1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation. CONCLUSION: Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.

Phase 1/2 Trial of Pembrolizumab and Concurrent Chemoradiation Therapy for Limited-Stage SCLC.

INTRODUCTION: Few advancements in treating limited-stage SCLC (LS-SCLC) have been made in decades. We report here a phase 1/2 trial of concurrent chemoradiotherapy (CRT) and pembrolizumab. METHODS: This single-center, open-label phase 1/2 study recruited adults with LS-SCLC or other neuroendocrine tumors and good performance status (Eastern Cooperative Oncology Group ≤ 2). The primary end point was safety, as assessed by dose-limiting toxicities. Concurrent CRT consisted of etoposide and a platin with 45 Gy radiotherapy (30 twice daily). Prophylactic cranial irradiation (25 Gy, 10 fractions) was given at the physician's discretion. Pembrolizumab was started concurrently with CRT and continued for up to 16 cycles. The phase 1 portion consisted of a 3 + 3 design. Toxicity was assessed with Common Terminology Criteria for Adverse Events version 4.0. Secondary outcomes were progression-free survival, overall survival, and tumor response as measured by the immune-related response criteria. RESULTS: A total of 45 patients were screened, and 40 were enrolled. All completed radiation therapy and received greater than or equal to one cycle of pembrolizumab. A total of 27 (61%) received percutaneous coronary intervention. One dose-limiting toxicity was observed in the phase 1 portion. There were no grade 5 toxicities, but there were three grade 4 events (two neutropenia, one respiratory failure). Pneumonitis rate was 15% (three grade 2 and three grade 3). All 17 esophagitis events (42.5%) were grades 1 to 2. At median follow-up time of 23.1 months, the median progression-free survival time was 19.7 months (95% confidence interval: 8.8‒30.5) and the median overall survival time was 39.5 months (95% confidence interval: 8.0‒71.0). CONCLUSION: Concurrent CRT and pembrolizumab for LS-SCLC was well tolerated and yielded favorable outcomes, providing a basis for randomized studies.

A Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma.

LESSONS LEARNED: Treatment with the Aurora kinase A inhibitor yields often durable disease control, but limited tumor regression, in heavily pretreated patients with unresectable malignant pleural or peritoneal mesothelioma. In a limited sample size, MYC copy-number gain or gene amplification, a candidate predictive biomarker for alisertib, did not correlate with improved response numbers or patient outcomes. BACKGROUND: Malignant mesothelioma is an aggressive disease for which few effective therapies are available. The Aurora family kinases are critical for mitotic fidelity and highly expressed in mesothelioma, wherein their inhibition leads to growth arrest in vitro. We evaluated the efficacy of alisertib, an Aurora A kinase inhibitor, in relapsed malignant mesothelioma. METHODS: Twenty-six patients with previously treated, unresectable pleural or peritoneal mesothelioma were enrolled on a single-arm, single-institution phase II trial of alisertib at a dosage of 50 mg twice daily for 7 of every 21 days. The primary endpoint was 4-month disease control rate. Secondary endpoints included overall response rate, progression free survival, overall survival, safety/toxicity, and correlation of endpoints with MYC copy number. RESULTS: Of the 25 evaluable patients treated on study, 8 (32%) experienced 4-month disease control, surpassing the futility endpoint. There were no confirmed partial or complete responses. Median progression-free and overall survival were 2.8 months and 6.3 months, respectively. No associations between MYC copy number and outcomes were observed. CONCLUSION: Alisertib has modest activity in this unselected malignant mesothelioma population. Several patients achieved durable disease control. Although the study did meet its prespecified futility endpoint, the sponsor elected to close the trial at the interim analysis.

Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC.

INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC. METHODS: PD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed. RESULTS: PD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (<1%, 1%-49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival. CONCLUSIONS: PD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.

A Phase I/II Study of Neoadjuvant Cisplatin, Docetaxel, and Nintedanib for Resectable Non-Small Cell Lung Cancer.

PURPOSE: Nintedanib enhances the activity of chemotherapy in metastatic non-small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint. PATIENTS AND METHODS: Eligible patients had stage IB (≥4 cm)-IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m2), docetaxel (75 mg/m2) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%. RESULTS: Twenty-one patients (stages I/II/III, N = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%-32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%-54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%-93%) and 91% (95% CI, 79%-100%), respectively. Most frequent treatment-related grade 3-4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3+ and cytotoxic CD3+CD8+ T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm2, P = 0.048; 142.3 vs. 35.6 cells/mm2, P = 0.018). CONCLUSIONS: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies.See related commentary by Blakely and McCoach, p. 3499.

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer.

INTRUDUCTION: Radiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ESCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiotherapy (TRT) after induction chemotherapy for SCLC. METHODS: Patients with ESCLC who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity in the 35 days following initiation of treatment. RESULTS: Thirty-eight patients with ESCLC (median age 65 years, range: 37-79 years) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100 to 200 mg with no dose-limiting toxicity in the 35-day window. There were no grade 4-5 toxicities; 2 (6%) patients experienced grade 3 events (n = 1 rash, n = 1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range: 1-13 months); median progression-free and overall survival times were 6.1 months (95% confidence interval: 4.1-8.1) and 8.4 months (95% confidence interval: 6.7-10.1). CONCLUSIONS: Concurrent pembrolizumab-TRT was tolerated well with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g., enrolling progressors on induction chemotherapy). Although randomized studies have shown benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.

Phase II Trial of Ipilimumab with Stereotactic Radiation Therapy for Metastatic Disease: Outcomes, Toxicities, and Low-Dose Radiation-Related Abscopal Responses.

Ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors. We report a phase II trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung (NCT02239900). Ipilimumab (every 3 weeks for 4 doses) was given with radiotherapy begun during the first dose (concurrent) or 1 week after the second dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions. In total, 106 patients received ≥1 cycle of ipilimumab with radiation. Median follow-up was 10.5 months. Median progression-free survival time was 2.9 months (95% confidence interval, 2.45-3.40), and median overall survival time was not reached. Rates of clinical benefit of nonirradiated tumor volume were 26% overall, 28% for sequential versus 20% for concurrent therapy (P = 0.250), and 31% for lung versus 14% for liver metastases (P = 0.061). The sequential lung group had the highest rate of clinical benefit at 42%. There were no differences in treatment-related adverse events between groups. Exploratory analysis of nontargeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31% vs. 5%, P = 0.0091). This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers.

Pembrolizumab plus chemotherapy for first-line treatment of metastatic nonsquamous non-small-cell lung cancer: a network meta-analysis.

AIM: A systematic review and network meta-analysis were conducted to evaluate the efficacy of pembrolizumab + pemetrexed + platinum relative to other regimens in metastatic nonsquamous non-small-cell lung cancer (NSq-NSCLC). PATIENTS & METHODS: Eligible studies evaluated first-line regimens in NSq-NSCLC patients without known targetable mutations. Relative treatment effects were synthesized with random effects proportional hazards Bayesian network meta-analyses. RESULTS: The hazard ratio (HR) for overall survival (OS) for pembrolizumab + pemetrexed + platinum was statistically significant over all platinum-doublet (HR range: 0.42-0.61), platinum-doublet + bevacizumab (HR range: 0.44-0.53) and platinum-doublet + atezolizumab regimens (HR range: 0.56-0.62). Additionally, pembrolizumab + pemetrexed + platinum numerically improved OS over atezolizumab + paclitaxel + carboplatin + bevacizumab (HR: 0.65; 95% credible interval: 0.43, 1.01). Pembrolizumab + pemetrexed + platinum had 95.6% probability of being the best treatment regimen for OS. CONCLUSION: Pembrolizumab + pemetrexed + platinum is likely the most efficacious first-line regimen for metastatic NSq-NSCLC.

Randomized-controlled phase II trial of salvage chemotherapy after immunization with a TP53-transfected dendritic cell-based vaccine (Ad.p53-DC) in patients with recurrent small cell lung cancer.

Small cell lung cancer TP53 mutations lead to expression of tumor antigens that elicits specific cytotoxic T-cell immune responses. In this phase II study, dendritic cells transfected with wild-type TP53 (vaccine) were administered to patients with extensive-stage small cell lung cancer after chemotherapy. Patients were randomized 1:1:1 to arm A (observation), arm B (vaccine alone), or arm C (vaccine plus all-trans-retinoic acid). Vaccine was administered every 2 weeks (3 times), and all patients were to receive paclitaxel at progression. Our primary endpoint was overall response rate (ORR) to paclitaxel. The study was not designed to detect overall response rate differences between arms. Of 69 patients enrolled (performance status 0/1, median age 62 years), 55 were treated in stage 1 (18 in arm A, 20 in arm B, and 17 in arm C) and 14 in stage 2 (arm C only), per 2-stage Simon Minimax design. The vaccine was safe, with mostly grade 1/2 toxicities, although 1 arm-B patient experienced grade 3 fatigue and 8 arm-C patients experienced grade 3 toxicities. Positive immune responses were obtained in 20% of arm B (95% confidence interval [CI], 5.3-48.6) and 43.3% of arm C (95% CI 23.9-65.1). The ORRs to the second-line chemotherapy (including paclitaxel) were 15.4% (95% CI 2.7-46.3), 16.7% (95% CI 2.9-49.1), and 23.8% (95% CI 9.1-47.5) for arms A, B, and C, with no survival differences between arms. Although our vaccine failed to improve ORRs to the second-line chemotherapy, its safety profile and therapeutic immune potential remain. Combinations with the other immunotherapeutic agents are reasonable options.

Models to Predict Hepatitis B Virus Infection Among Patients With Cancer Undergoing Systemic Anticancer Therapy: A Prospective Cohort Study.

PURPOSE: Most patients with cancer are not screened for hepatitis B virus (HBV) infection before undergoing anticancer therapy, and optimal screening strategies are unknown. We sought to develop selective HBV screening strategies for patients who require systemic anticancer therapy. METHODS: This prospective cohort study included adults age ≥ 18 years with solid or hematologic malignancies who received systemic anticancer therapy at a comprehensive cancer center during 2013 and 2014. Patients underwent hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody testing, and completed a 19-question modified Centers for Disease Control and Prevention (CDC) HBV survey. Multivariable models that predict chronic or past HBV infection were developed and validated using bootstrapping. RESULTS: A total of 2,124 patients (mean age, 58 ± 13 years) completed the risk survey and HBV testing. Of these, 54% were women; 77% were non-Hispanic white, 11% Hispanic, 8% black, and 4% Asian; and 20% had a hematologic malignancy and 80% a solid tumor. Almost 12% were born outside the United States. The prevalence was 0.3% for chronic HBV infection and 6% for past HBV infection. Significant predictors of positive hepatitis B surface antigen or hepatitis B core antibody tests were as follows: men who had sex with men, black or Asian race, birthplace outside the United States, parent's birthplace outside the United States, household exposure to HBV, age ≥ 50 years, and history of injection drug use. The area under the receiver operating characteristic curve of the model on the basis of these seven predictors was 0.79 (95% CI, 0.73 to 0.82). The modified CDC survey and brief tools with fewer than seven questions yielded similar false-negative rates (0% and 0% to 0.7%, respectively). CONCLUSION: An internally validated risk tool performed as well as the modified CDC survey; however, more than 90% of patients who completed the tool would still require HBV testing. Universal HBV testing is more efficient than risk-based screening.

Impact of the timing of hepatitis B virus identification and anti-hepatitis B virus therapy initiation on the risk of adverse liver outcomes for patients receiving cancer therapy.

BACKGROUND: Data on the incidence of adverse liver outcomes are limited for cancer patients with chronic (hepatitis B surface antigen [HBsAg]-positive/hepatitis B core antibody [anti-HBc]-positive) or past (HBsAg-negative/anti-HBc-positive) hepatitis B virus (HBV) after chemotherapy. This study was aimed at determining the impact of test timing and anti-HBV therapy on adverse liver outcomes in these patients. METHODS: Patients with solid or hematologic malignancies who received chemotherapy between 2004 and 2011 were retrospectively studied. HBV testing and anti-HBV therapy were defined as early at the initiation of cancer therapy and as late after initiation. Outcomes included hepatitis flares, hepatic impairment, liver failure, and death. Time-to-event analysis was used to determine incidence, and multivariate hazard models were used to determine predictors of outcomes. RESULTS: There were 18,688 study patients (80.4% with solid tumors). The prevalence of chronic HBV was 1.1% (52 of 4905), and the prevalence of past HBV was 7.1% (350 of 4905). Among patients with solid tumors, late identification of chronic HBV was associated with a higher risk of hepatitis flare (hazard ratio [HR], 4.02; 95% confidence interval [CI], 1.26-12.86), hepatic impairment (HR, 8.48; 95% CI, 1.86-38.66), liver failure (HR, 9.38; 95% CI, 1.50-58.86), and death (HR, 3.90; 95% CI, 1.19-12.83) in comparison with early identification. Among patients with hematologic malignancies and chronic HBV, the risk of death was 7.8 (95% CI, 1.73-35.27) times higher for persons with late initiation of anti-HBV therapy versus early initiation. Patients with late identification of chronic HBV had late or no anti-HBV therapy. Chronic HBV predicted liver failure in patients with solid or hematologic malignancies, whereas male sex and late identification were predictors for patients with solid tumors. CONCLUSIONS: Early identification correlates with early anti-HBV therapy and reduces the risk of liver failure and death in chronic HBV patients receiving chemotherapy. Cancer 2017;123:3367-76. © 2017 American Cancer Society.

ALK: a tyrosine kinase target for cancer therapy.

The anaplastic lymphoma kinase (ALK) gene plays an important physiologic role in the development of the brain and can be oncogenically altered in several malignancies, including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL). Most prevalent ALK alterations are chromosomal rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other tumors, ALK copy-number gains and activating ALK mutations have been described. Dramatic and often prolonged responses are seen in patients with ALK alterations when treated with ALK inhibitors. Three of these-crizotinib, ceritinib, and alectinib-are now FDA approved for the treatment of metastatic NSCLC positive for ALK fusions. However, the emergence of resistance is universal. Newer ALK inhibitors and other targeting strategies are being developed to counteract the newly emergent mechanism(s) of ALK inhibitor resistance. This review outlines the recent developments in our understanding and treatment of tumors with ALK alterations.

Utilization Patterns and Trends in Epidermal Growth Factor Receptor (EGFR) Mutation Testing Among Patients With Newly Diagnosed Metastatic Lung Cancer.

INTRODUCTION: Epidermal growth factor receptor (EGFR)-targeted therapy significantly improves outcomes among patients with non-small-cell lung cancer (NSCLC) whose tumors harbor sensitizing mutations. Patterns of EGFR testing have not been well-documented. The objective of this population-based study is to assess the testing pattern on a national scale. PATIENTS AND METHODS: Using MarketScan 2012 to 2014 data, we identified 5842 patients newly diagnosed with metastatic lung cancer from January 2013 to June 2014 and assessed their EGFR mutation testing pattern in the 6 months after diagnosis. We further examined the testing rate among patients who received the EGFR inhibitor erlotinib. Because histology information is not available in this database, we also conducted a subgroup analysis of EGFR testing among patients who were treated with bevacizumab or pemetrexed, who are likely to have non-squamous NSCLC. Multivariable logistic regression was performed to ascertain factors associated with EGFR testing. RESULTS: Of 5842 patients with metastatic lung cancer, 1039 (18%) had claims for EGFR testing within 6 months of diagnosis, and 283 (5%) received erlotinib. The testing rate among patients who received erlotinib was 42%. Within a subgroup of 1685 patients treated with bevacizumab or pemetrexed, 616 (37%) underwent EGFR testing. Multivariable logistic regression showed that younger patients, female patients, patients with fewer comorbidities, and patients living in the West region were more likely to receive EGFR testing. CONCLUSION: This population-based study demonstrates low EGFR testing rates among advanced lung cancer patients in 2013 and 2014.

Recent Advances in Immunotherapy in Metastatic NSCLC.

Non-small cell lung cancer (NSCLC) is one of most common malignancies and the leading cause of cancer deaths worldwide. Despite advances in targeted therapies, majority of NSCLC patients do not have targetable genomic alterations. Nevertheless, recent discovery that NSCLC is an immunogenic tumor type, and several breakthroughs in immunotherapies have led to rapid expansion of this new treatment modality in NSCLC with recent FDA approvals of programed death receptor-1 inhibitors, such as nivolumab and pembrolizumab. Here, we review promising immunotherapeutic approaches in metastatic NSCLC, including checkpoint inhibitors, agents with other mechanisms of action, and immunotherapy combinations with other drugs. With advent of immunotherapy, therapeutic options in metastatic NSCLC are rapidly expanding with the hope to further expand life expectancy in metastatic lung cancer.

Recent Advances in Targetable Therapeutics in Metastatic Non-Squamous NSCLC.

Lung adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC). With the discovery of epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and effective targeted therapies, therapeutic options are expanding for patients with lung adenocarcinoma. Here, we review novel therapies in non-squamous NSCLC, which are directed against oncogenic targets, including EGFR, ALK, ROS1, BRAF, MET, human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR2), RET, and NTRK. With the rapidly evolving molecular testing and development of new targeted agents, our ability to further personalize therapy in non-squamous NSCLC is rapidly expanding.

A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin.

PURPOSE: LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclinical efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation study evaluated the combination of LY with pemetrexed/carboplatin. PATIENTS AND METHODS: Forty-one patients with advanced solid tumors received single-dose LY monotherapy lead-in and 37 patients received LY (10-120 mg) plus pemetrexed/carboplatin (500 mg/m(2) and 5-6 AUC, respectively) across 8 dose levels every 21 days. Primary objective was maximum tolerated dose (MTD) determination; secondary endpoints included safety, antitumor activity, pharmacokinetics, and beta-catenin pharmacodynamics. RESULTS: MTD of LY with pemetrexed/carboplatin was 40 mg. Eleven dose-limiting toxicities (DLTs) occurred in ten patients. DLTs during LY monotherapy occurred at ≥ 40 mg: grade 2 visual disturbance (n = 1) and grade 3/4 peri-infusional thoracic pain during or shortly post infusion (n = 4; chest, upper abdominal, and back pain). Ranitidine was added after de-escalation to 80 mg LY to minimize peri-infusional thoracic pain. Following LY with pemetrexed/carboplatin therapy, DLTs included grade 3/4 thrombocytopenia (n = 4) and grade 4 neutropenia (n = 1). Best overall response by RECIST included 5 confirmed partial responses (non-small cell lung cancer [n = 3], mesothelioma, and breast cancer) and 19 patients having stable disease. Systemic LY exposure was approximately linear over dose range studied. Transient upregulation of beta-catenin measured in peripheral blood mononuclear cells (PBMCs) occurred at 40 mg LY. CONCLUSIONS: The initial safety profile of LY2090314 was established. MTD LY dose with pemetrexed/carboplatin is 40 mg IV every 3 weeks plus ranitidine. Efficacy of LY plus pemetrexed/carboplatin requires confirmation in randomized trials.