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Brain metastases are frequent in neuropathology practices; however, the literature on their distribution is frequently derived from imaging studies. This work examined metastases of lung cancer to the brain through the lens of pathology specimens. All brain surgical pathology cases accessioned from 2011-2020 were retrieved from a regional laboratory. Specimens were classified by neuroanatomical location, diagnostic category, and diagnosis with a hierarchical free text string-matching algorithm. All reports classified as probable metastasis per algorithm were reviewed by a pathologist. Lung biomarkers and selected immunostains were retrieved with text parsing and reviewed. Among 4,625 cases of brain surgical resection specimens, 854 were classified as probable metastasis by the algorithm. On report review, 538/854 cases were confirmed as metastasis with a known primary site. The 538 cases were from 511 patients and 234/511 patients had lung primaries. Small cell lung cancer lesions were most frequently found in the cerebellum (17/30). Lesions from lung adenocarcinoma (59/164) and non-small cell carcinoma-not otherwise specified (NSCLC-NOS) (15/34) were most commonly found in the frontal lobe. Squamous cell carcinoma lesions were most commonly found in the frontal and occipital lobes (8/27). 72/234 cases were reported as NSCLC-NOS and could be further subclassified using immunostaining (41/72). Lung biomarker data were retrieved in ~38% of cases. PD-L1 positivity was dependent on neuroanatomical distribution (p = 0.04); other examined biomarkers were not. The distribution of lung tumours metastatic to the brain is dependent on the lung cancer subtype (p<0.001). The reporting of histologic subtype could be further optimized in the local environment., Competing Interests: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.The corresponding author (MB) retains the copyright on the computer code that was written outside of his employment relationship with McMaster University/St. Joseph’s Healthcare Hamilton/Hamilton Regional Laboratory Medicine Program. The above does not in any way limit adherence to the PLOS ONE data availability policy, as found here: https://journals.plos.org/plosone/s/data-availability. There is no financial conflict of interest. There are no conflicts for the other authors., (Copyright: © 2024 Bonert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lung cancer is the leading cause of cancer-related deaths in Canada, with non-small-cell lung cancer (NSCLC) accounting for the majority of cases. Timely access to comprehensive molecular profiling is critical for selecting biomarker-matched targeted therapies, which lead to improved outcomes in advanced NSCLC. Tissue biopsy samples are the gold standard for molecular profiling; however, several challenges can prevent timely and complete molecular profiling from being performed, causing delays in treatment or suboptimal therapy selection. Liquid biopsy offers a minimally invasive method for molecular profiling by analyzing circulating tumour DNA (ctDNA) and RNA (cfRNA) in plasma, potentially overcoming these barriers. This paper discusses the outcomes of a multidisciplinary working group in Ontario, which proposed three eligibility criteria for liquid biopsy reimbursement: (1) insufficient tissue for complete testing or failed tissue biomarker testing; (2) suspected advanced NSCLC where tissue biopsy is not feasible; and (3) high-risk patients who may deteriorate before tissue results are available. The group also addressed considerations for assay selection, implementation, and economic impact. These discussions aim to inform reimbursement and implementation strategies for liquid biopsy in Ontario's public healthcare system, recognizing the need for ongoing evaluation as technology and evidence evolve.

Cure of cancer is a sensitive and multidimensional concept that is challenging to define, difficult to assert at the individual patient level, and often surrounded by controversy. The notion of cure in non-small cell lung cancer (NSCLC) has changed and continues to evolve with improvements in diagnosis and treatment. Targeted and immune therapies have recently entered the treatment landscape of stage I-III NSCLC. While some initial pivotal trials of such agents failed to improve survival, recently approved epidermal growth factor receptor (EGFR) inhibitors (in EGFR-mutated NSCLC) and immune checkpoint inhibitors have shown delays in disease recurrence or progression and unprecedented survival gains compared to previous standards of care. Additional data is now emerging supporting the benefit of treatment strategies based on alternation-matched targeting (anaplastic lymphoma kinase [ALK] inhibition in ALK-altered disease) and immune checkpoint inhibition in stage I-III NSCLC. Similar to previous developments in the treatment of early and locally advanced NSCLC, it is expected that statistically significant and clinically meaningful trial-level benefits will translate into real-world benefits, including improvements in cure measures. Parallel advances in molecular testing (e.g., circulating tumor DNA analyses) are also allowing for a deeper and more comprehensive characterization of disease status and treatment response. Given the impact that curative-intent treatments have on survival, it is critical that various stakeholders, including clinicians and patients, are aware of new opportunities to pursue cure in stage I-III NSCLC., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients' access to best care. A modified Delphi methodology was used to identify consensus on 30 questions involving five themes: accountability, disparities, endpoints, timeliness, and cost-effectiveness. It was agreed that greater transparency is required across regulatory and HTA processes. Health professionals in oncology are frustrated for their patients because they are unable to deliver the modern guideline-supported therapies they want to provide due to delays in approval or funding. Canadian health care providers request improvements in timely access to life-saving therapeutics in line with other comparator countries. Clinicians expect urgent improvements in Canadian health systems to give our patients their best chance of survival.

As far back as 3000 years ago, the immune system was observed to play a role in mediating tumor regression. Since then, many strategies have been developed to leverage the anti-tumor immune response. However, while many patients respond to ICIs up front some do not, and many of those that do eventually experience tumor progression. Currently, there are several predictive biomarkers of the immune checkpoint inhibitor response; however, no one test appears to be universally predictive and their application varies by disease site. There are many ways in which cancer cells develop primary or acquired resistance to immune checkpoint inhibitors. Efforts to reverse resistance include ways to combat T cell exhaustion, reprogram the tumor microenvironment, increase the availability of tumor neo-antigens, target alternative immune checkpoints, restore a normal/healthy patient gut microbiome, oncolytic viruses and tumor vaccines. The most studied and most promising methods include combining ICIs with therapies targeting alternative immune checkpoints and restoring a normal/healthy patient gut microbiome. This review will discuss T cell-mediated immunity, how this is leveraged by modern immunotherapy to treat cancer and mechanisms of immune checkpoint inhibitor resistance, while highlighting strategies to overcome primary and secondary resistance mechanisms.

Brain metastases are a frequent occurrence in neuropathology practices. The literature on their neuroanatomical location is frequently derived from radiological analyses. This work examines brain metastases through the lens of pathology specimens. All brain surgical pathology reports for cases accessioned 2011-2020 were retrieved from a laboratory. Specimens were classified by neuroanatomical location, diagnosis and diagnostic category with a hierarchical free text string-matching algorithm (HFTSMA) and also subsequently audited. All reports classified as probable metastasis were reviewed by a pathologist. The provided history was compared to the final categorization by a pathologist. The cohort had 4,625 cases. The HFTSMA identified 854 cases (including metastases from a definite primary, metastases from primary not known and improperly classified cases). 514/854 cases had one definite primary site per algorithm and on report review 538/854 cases were confirmed as such. The 538 cases originated from 511 patients. Primaries from breast, gynecologic tract, and gastrointestinal tract not otherwise specified were most frequently found in the cerebellum. Kidney metastases were most frequently found in the occipital lobe. Lung, metastatic melanoma and colorectal primaries were most commonly found in the frontal lobe. The provided clinical history predicted the primary in 206 cases (40.3%), was discordant in 17 cases (3.3%) and non-contributory in 280 cases (54.8%). The observed distribution of the metastatic tumours in the brain is dependent on the primary site. In the majority (54.8%) of cases, the provided clinical history was non-contributory; this suggests surgeon-pathologist communication may have the potential for optimization., Competing Interests: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.The corresponding author (MB) retains the copyright on the computer code that was written outside of his employment relationship with McMaster University/St. Joseph’s Healthcare Hamilton/Hamilton Regional Laboratory Medicine Program. The above does not in any way limit adherence to the PLOS ONE data availability policy, as found here: https://journals.plos.org/plosone/s/data-availability. There is no financial conflict of interest. There are no conflicts for the other authors., (Copyright: © 2023 Bonert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

For much of the past two decades, the treatment options for patients with stage III NSCLC were mostly stagnant. In the past 5 years, ongoing innovations have dovetailed alongside advances in biomarker testing, novel therapeutics, precision surgery, and radiotherapy, all of which are leading to an increase in more personalized option for the treatment. This review article will focus on several completed and ongoing initiatives involving treatment of patients with stage III NSCLC. First, it will tackle the progress made in curative treatment of unresectable stage III NSCLC, starting with PACIFIC, and branching out into topics such as concurrent immunotherapy and chemoradiation, intensification of consolidative immunotherapy, dual immunotherapy consolidation, and a reflection on those subpopulations that may not benefit from consolidative immunotherapy. Second, there will be discussion of novel strategies in the setting of resectable stage III disease, most notably neoadjuvant therapy using combined chemoimmunotherapy and immunotherapy alone before surgical resection. Third, it will delve into recent data evaluating adjuvant immunotherapy for resectable stage III NSCLC, including adjuvant targeted therapy (for those harboring driver mutations) and postoperative radiotherapy. Finally, a look to future trials/initiatives will be interspersed throughout the review, to reveal the ongoing efforts being made to continue to improve outcomes in this group of patients., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer. In the first of two independent stages, 50 patients with advanced non-small cell lung cancer received pembrolizumab as standard of care. The primary objectives of stage 1 were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of time to ctDNA response and correlation with progression-free and overall survival. Maximal mutant allele fraction clearance at the third cycle of pembrolizumab signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% confidence interval (CI): 52-97%) and a specificity of 75% (90% CI: 56.5-88.5%). Median time to ctDNA response was 2.1 months (90% CI: 1.5-2.6), and patients with mR attained longer progression-free survival (5.03 months versus 2.6 months) and overall survival (not reached versus 7.23 months). These findings are incorporated into the ctDNA-driven interventional molecular response-adaptive second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy. ClinicalTrials.gov ID: NCT04093167 ., (© 2023. The Author(s).)

Lorlatinib is the only targeted therapy approved in Canada to treat patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) whose tumor has progressed despite treatment with second-generation ALK tyrosine kinase inhibitor (TKI), a patient population with high unmet need and lack of publicly reimbursed targeted treatments in Canada. We prospectively examined the real-world effectiveness and impact of lorlatinib on quality-of-life in 59 lorlatinib-treated patients, characterized as: median age of 62.0 years; 47.5% were female; 32.2% had central nervous system metastases; 50.8% had 2+ prior ALK TKI lines; and alectinib was the most common ALK TKI (72.9%) administered before lorlatinib, including 44.1% who received first-line alectinib. With a median follow-up of 15.3 months (IQR: 6.2-19.2), median time-to-treatment discontinuation of lorlatinib was 15.3 months (95% CI: 7.9-not reached), with 54.2% (95% CI: 40.8-65.9%) of patients without treatment discontinuation at 12 months. At baseline, the mean health utility score (HUS) was 0.744 (SD: 0.200). At 3 months, patients receiving lorlatinib demonstrated a 0.069 (95% CI: 0.020-0.118; p = 0.007) average HUS increase over baseline; HUS was maintained at 6 and 12 months. Thus, patients with ALK-positive NSCLC post second-generation ALK TKI remained on lorlatinib for a meaningful duration of time while their quality-of-life was preserved.

Purpose: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents., Methods: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284)., Results: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response., Conclusions: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.

Background The prevalence of thyroid transcription factor-1 (TTF-1) and napsin A expression are poorly characterized in lung core biopsies of small cell carcinoma. Locally, the TTF-1 clone is 8G7G3/1 (Agilent/Dako), and the napsin A clone is IP64 (Leica Biosystems). Methods All in-house lung core biopsy reports for cases accessioned at a regional laboratory from January 2011 to December 2020 were retrieved and analyzed using a validated hierarchical free-text string matching algorithm (HFTSMA) to establish the diagnosis. TTF-1 and napsin A were manually coded with the assistance of a logical text parsing tool. All TTF-1-negative small cell lung carcinoma (SCLC) cases had a full report review by pathologists. Results The cohort had 5,867 lung core biopsies, and 232 cases were confirmed as small cell carcinoma on pathologist review. TTF-1 immunostain results were available in 173 SCLC cases, and 16 cases of TTF-1-negative SCLC were confirmed on full report review. These 16 cases had at least one positive neuroendocrine (NE) marker and positive keratin staining; cases with mixed histology or positive CK5/6 staining were excluded. Ki-67 was done in 10/16 cases; the average Ki-67 was 75%. Napsin A was negative in 50/51 small cell carcinomas, and 0/3 TTF-1-negative SCLC had napsin A positivity. Conclusions Standardized immunostain reporting would simplify such analyses. Based on the cohort, approximately 9% (16/173) of SCLC is TTF-1 negative. Napsin A positivity in suspected small cell carcinoma should prompt consideration of an alternate diagnosis or explanation., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Sayeda et al.)

Introduction: Fucosyl-GM1 is a monosialoganglioside with limited expression in healthy tissues and high expression on SCLC cells. BMS-986012 is a nonfucosylated, first-in-class, fully human immunoglobulin G1 monoclonal antibody that binds to fucosyl-GM1., Methods: CA001-030 is a phase 1/2, first-in-human study of BMS-986012 as monotherapy or in combination with nivolumab for adults with relapsed or refractory SCLC. Safety is the primary end point. Additional end points include objective response rate, duration of response, progression-free survival, pharmacokinetics, and overall survival., Results: Patients (BMS-986012 monotherapy, n = 77; BMS-986012 + nivolumab, n = 29) were predominantly of male sex (58%), 63 years old (mean), current or past tobacco users (97%), and treated previously with first-line systemic therapy (99%). The most common treatment-related adverse event was pruritus (n = 95 [90%]). Grade 4 treatment-related adverse events were reported in 2% (n = 2) of patients. The objective response rate (95% confidence interval [CI]) was higher with BMS-986012 plus nivolumab (38% [20.7%-57.7%]) than with monotherapy (4% [0.8%-11.0%]). Median (95% CI) duration of response with BMS-986012 plus nivolumab was 26.4 (4.4-not reached) months. Progression-free survival (95% CI) at 24 weeks with monotherapy and BMS-986012 plus nivolumab was 12.2% (6.0%-20.7%) and 39.3% (21.7%-56.5%), respectively. The pharmacokinetics profile of monotherapy and BMS-986012 plus nivolumab suggested dose proportionality across the tested dose range. Median overall survival (95% CI) with monotherapy and BMS-986012 plus nivolumab was 5.4 (4.0-7.3) and 18.7 (8.2-37.3) months, respectively., Conclusions: BMS-986012 in combination with nivolumab represents a well-tolerated, potential new therapy for relapsed or refractory SCLC. BMS-986012 is currently being explored in combination with carboplatin, etoposide, and nivolumab as a first-line therapy in extensive-stage SCLC (NCT04702880)., (© 2022 by the International Association for the Study of Lung Cancer.)

Background Ineffective communication between healthcare providers is a known risk factor for adverse events. Objective The aim of this study was to retrospectively assess the communication with pathology via an analysis of the information provided on the pathology requisitions over ten years. Methods All in-house surgical specimens and all non-gynecologic cytopathology specimens accessioned from 2011 to 2020 were retrieved at a regional laboratory. Cases with any clinical information were deemed to have a clinical history present (CHP). CHP was tabulated by submitting physicians/surgeons (SPS), hospital site, year, and tissue group. Results The study period contained 554,817 relevant pathology reports, of which 553,966 could be extracted. The overall CHP rate was 74% and varied from 76% to 67% over the study period. SPSes submitting ≥200 cases (n=314) had a mean/median/standard deviation/max/min CHP rate of 81%/92%/23%/100%/5%. The CHP varied between four hospital sites, from 53% to 97%. CHP varied from 61% to 99% by tissue group. Conclusions CHP is associated with several factors and appears to depend on the hospital culture, specialty, and individual physician/surgeon. The pathology requisition is a way to measure and track the communication that is clinically relevant. Improving communication with pathologists/the pathology department will likely require process changes and mandates. Hospital and laboratory accreditation bodies should consider effective communication with pathology a marker of quality and an accreditation issue., Competing Interests: The corresponding author (MB) retains the copyright on the computer code that was written outside of his employment relationship with McMaster University/Hamilton Regional Laboratory Medicine Program/St. Joseph’s Healthcare Hamilton. At the time of final submission, there are no patents, products in development or marketed products to declare. There are no conflicts for the other authors., (Copyright © 2022, Bonert et al.)

Background: Liquid biopsy (LB) can detect actionable genomic alterations in plasma circulating tumor circulating tumor DNA beyond tissue testing (TT) alone in advanced non-small cell lung cancer (NSCLC) patients. We estimated the cost-effectiveness of adding LB to TT in the Canadian healthcare system., Methods: A cost-effectiveness analysis was conducted using a decision analytic Markov model from the Canadian public payer (Ontario) perspective and a 2-year time horizon in patients with treatment-naïve stage IV non-squamous NSCLC and ⩽10 pack-year smoking history. LB was performed using the comprehensive genomic profiling Guardant360™ assay. Standard of care TT for each participating institution was performed. Costs and outcomes of molecular testing by LB + TT were compared to TT alone. Transition probabilities were calculated from the VALUE trial (NCT03576937). Sensitivity analyses were undertaken to assess uncertainty in the model., Results: Use of LB + TT identified actionable alterations in more patients, 68.5 versus 52.7% with TT alone. Use of the LB + TT strategy resulted in an incremental cost savings of $3065 CAD per patient (95% CI, 2195-3945) and a gain in quality-adjusted life-years of 0.02 (95% CI, 0.01-0.02) versus TT alone. More patients received chemo-immunotherapy based on TT with higher overall costs, whereas more patients received targeted therapy based on LB + TT with net cost savings. Major drivers of cost-effectiveness were drug acquisition costs and prevalence of actionable alterations., Conclusion: The addition of LB to TT as initial molecular testing of clinically selected patients with advanced NSCLC did not increase system costs and led to more patients receiving appropriate targeted therapy., Competing Interests: Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2022.)

Purpose: There is increasing interest in using stereotactic body radiation therapy (SBRT) in areas of oligoprogressive metastatic disease (OPD). Our main objective was to investigate the impact of SBRT on overall survival (OS) and the incidence of systemic therapy treatment switches in this population., Methods: A retrospective institutional review of patients treated with SBRT for OPD was performed. Patients were included if they received SBRT for 1-3 discrete progressing metastases, using a dose of at least 5 Gy per fraction. The study aimed to calculate progression-free survival (PFS), overall survival (OS), local control (LC), and incidence of treatment switch (TS). PFS and OS were calculated using the Kaplan-Meier methodology, while LC and TS were determined using cumulative incidence., Results: Eighty-one patients with a total of 118 lesions were treated with SBRT from July 2014 to November 2020. The Median SBRT dose was 40 (18-60) Gy in 5 (2-8) fractions. Patients had primarily kidney, lung, or breast cancer. Most patients were treated with a tyrosine kinase inhibitor (TKI) (30.9%) or chemotherapy (29.6%) before OPD. The median follow-up post-SBRT was 14 months. Median OS and PFS were 25.1 (95% CI 11.2-39.1) months and 7.8 (95% CI 4.6-10.9) months, respectively. The cumulative incidence of local progression of treated lesions was 5% at 1 year and 7.3% at 2 years. Sixty patients progressed after SBRT and 17 underwent additional SBRT. Thirty-eight patients (47%) changed systemic therapy following SBRT; the cumulative incidence of TS was 28.5% at 6 months, 37.4% at 1 year, and 43.9% at 2 years., Conclusions: SBRT effectively controls locally progressing lesions but distant progression still occurs frequently. A sizeable number of patients can be salvaged by further SBRT or have minimally progressing diseases that may not warrant an immediate initiation/switch in systemic therapy. Further prospective studies are needed to validate this benefit.

Background: Adjuvant platinum-based chemotherapy is standard of care for patients with resected stage IIA/B or IIIA NSCLC. Overall survival is suboptimal due to the high metastatic potential of early-stage NSCLC and there is substantial clinical need for additional efficacious adjuvant treatment options., Methods: PubMed (all time to 4 February 2021) and related conference databases were searched using the key search terms 'NSCLC' AND 'Adjuvant' AND 'EGFR inhibitor' OR respective aliases., Results: The literature search identified five adjuvant phase III trials of EGFR inhibitors in early NSCLC. The earlier BR19 and RADIANT trials failed to demonstrate statistically significant improvements in either OS or DFS for gefitinib and erlotinib, respectively, compared with placebo in patients with EGFR mutation-unselected NSCLC. Three subsequent phase III trials, ADAURA, CTONG1104, and IMPACT, were conducted in EGFR-mutant NSCLC. IMPACT showed no statistically significant DFS benefit for adjuvant gefitinib, and although CTONG1104 did report improved DFS for gefitinib (HR = 0.56, p  = 0.001), this benefit was not enduring, resulting in comparable 5-year DFS rates. Statistically significant and clinically meaningful DFS benefits were observed in ADAURA for osimertinib compared with placebo in patients with stage IB-IIIA and II-IIIA disease (7th Edition Staging), and these benefits, coupled with a meaningful improvement in 2-year CNS DFS and favorable HRQoL, make osimertinib an important new treatment option for the adjuvant treatment of EGFR exon 19 deletion or exon 21 L858R-mutated stage II-IIIA NSCLC (UICC/AJCC 8th Edition Staging), with final mature OS data eagerly awaited., Conclusion: Adjuvant osimertinib used alone or following platinum-based chemotherapy is now recommended in patients with stage II-IIIA EGFR-mutated NSCLC., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BM has received honoraria from and served in a compensated consultancy or advisory role for Merck, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Novartis, and AstraZeneca, and has received research funding from Roche. PC has served in a compensated consultancy or advisory role for Roche, AstraZeneca, Amgen, Merck, Bayer, Novartis, Pfizer, EMD Serono, Takeda, and Bristol-Myers SquibbBMS; has received honoraria from AstraZeneca, Pfizer, Merck, and Novartis; and has received research funding from AstraZeneca, Roche, and Turning Point. RAJ has served in a compensated consultancy or advisory role for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, BMSBristol-Myers Squibb, EMD Serono, Fusion Pharmaceuticals, Merck, Novartis, Pfizer, Roche, and Takeda; has received honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, BMSBristol-Myers Squibb, EMD Serono, Merck, Novartis, Pfizer, Roche, and Takeda; and has received research funding from AstraZeneca, BMSBristol-Myers Squibb, and Merck. NBL has received research funding from Pfizer, Roche, Bristol-Myers Squibb Canada, Array, Guardant Health, Amgen, Eli Lilly, Takeda, MSD, and Bayer. GL has served in a compensated consultancy or advisory role for Takeda, Merck, BMSBristol-Myers Squibb, Novartis, Pfizer, Roche, and AstraZeneca; has received honoraria from Takeda, AstraZeneca, and Pfizer; and has received research funding from Takeda, Boehringer Ingelheim, AstraZeneca, and Roche. PW-P has served in a compensated consultancy or advisory role for Sanofi, EMD Serono, Merck, Astra Zeneca, Pfizer, Bayer, BMSBristol-Myers Squibb, Roche, and Novartis; has received honoraria from AstraZeneca, Pfizer, Bayer, Merck, and Takeda; and has received research funding from Roche, AbbVie, GSK, Turning Point, Pfizer, and Merck. ASAdrian Sacher has served in a compensated consultancy or advisory role for Amgen, AstraZeneca, Bayer, Genentech-Roche, Bristol-Myers SquibbBMS, and KisoJi; has received honoraria from Amgen, AstraZeneca, Merck, Genentech-Roche, Bayer, Bristol-Myers SquibbBMS, Pfizer, Tesaro, KisoJi, Iovance, and Galvanize Therapeutics; and has received research funding from AstraZeneca, Amgen, Genentech, Merck, Lilly, Pfizer, Bayer, Bristol-Myers SquibbBMS, Spectrum, GlaxoSmithKline?GSK, Iovance, CRISPR Therapeutics, and RAIN Therapeutics. SS has served in a compensated consultancy or advisory role for AstraZeneca, Amgen, Bayer, Bristol-Myers SquibbBMS, EMD Serono, Eisai, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, and Taiho; has received honoraria from AstraZeneca, Amgen, Bayer, BMSBristol-Myers Squibb, and Merck; and has received research funding from AstraZeneca, BMSBristol-Myers Squibb, Merck, Novartis, and Takeda. M-ST has served in a compensated consultancy or advisory role for AstraZeneca, Pfizer, Bayer, Takeda, Amgen, Roche, and Eli Lilly; has received honoraria from Bayer and Roche; and has received research funding from Bayer. DM has nothing to disclose. QC has received honoraria from and served in a compensated consultancy or advisory role for AbbVie, AstraZeneca, BIBoehringer Ingelheim, BMSBristol-Myers Squibb, Eli Lilly, Eisai, Merck, Novartis, Pfizer, Roche, and Takeda, and has received research funding from Astra Zeneca and BMSBristol-Myers Squibb., (© The Author(s), 2021.)

In Canada, the therapeutic management of patients with advanced non-small cell lung cancer (NSCLC) with rare actionable mutations differs between provinces, territories, and individual centres based on access to molecular testing and funded treatments. These variations, together with the emergence of several novel mesenchymal-epithelial transition ( MET ) factor-targeted therapies for the treatment of NSCLC, warrant the development of evidence-based consensus recommendations for the use of these agents. A Canadian expert panel was convened to define key clinical questions, review evidence, discuss practice recommendations and reach consensus on the treatment of advanced MET -altered NSCLC. Questions addressed by the panel include: 1. How should the patients most likely to benefit from MET- targeted therapies be identified? 2. What are the preferred first-line and subsequent therapies for patients with MET exon 14 skipping mutations? 3. What are the preferred first-line and subsequent therapies for advanced NSCLC patients with de novo MET amplification? 4. What is the preferred therapy for patients with advanced epidermal growth factor receptor ( EGFR )-mutated NSCLC with acquired MET amplification progressing on EGFR inhibitors? 5. What are the potential strategies for overcoming resistance to MET inhibitors? Answers to these questions, along with the consensus recommendations herein, will help streamline the management of MET -altered NSCLC in routine practice, assist clinicians in therapeutic decision-making, and help ensure optimal outcomes for NSCLC patients with MET alterations.

Cancer immunotherapy has the goal of enhancing a patient's intrinsic immune processes in order to mount a successful immune response against tumor cells. Cancer cells actively employ tactics to evade, delay, alter, or attenuate the anti-tumor immune response. Immune checkpoint inhibitors (ICIs) modulate endogenous regulatory immune mechanisms to enhance immune system activation, and have become the mainstay of therapy in many cancer types. This activation occurs broadly and as a result, activation is supraphysiologic and relatively non-specific, which can lead to immune-related adverse events (irAEs), the frequency of which depends on the patient, the cancer type, and the specific ICI antibody. Careful assessment of patients for irAEs through history taking, physical exam, and routine laboratory assessments are key to identifying irAEs at early stages, when they can potentially be managed more easily and before progressing to higher grades or more serious effects. Generally, most patients with low grade irAEs are eligible for re-challenge with ICIs, and the use of corticosteroids to address an irAE is not associated with poorer patient outcomes. This paper reviews immune checkpoint inhibitors (ICIs) including their mechanisms of action, usage, associated irAEs, and their management.

Lung cancer is a highly heterogeneous disease often driven by well-characterized driver mutations. Although the best studied are common alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) oncogenes, rapid advances in molecular characterization has led to the development of novel therapeutics that inhibit additional oncogenic alterations in advanced NSCLC. The literature search identified 62 eligible phase I/II clinical trials or integrated analyses of assessing novel targeted agents against the following molecular alterations: ROS1-rearranged, BRAF V600E-mutant, NTRK-rearranged, MET-altered, uncommon EGFR-mutant, RET-rearranged, HER2-positive, KRAS G12C-mutant and NRG1-rearranged. This rapidly evolving field has produced many new targeted treatment options and promising outcomes have led to the FDA approval of seven novel agents for use in ROS1-rearranged, BRAF V600E-mutant, NTRK-rearranged, MET exon 14 skipping-mutant or RET-rearranged advanced NSCLC. Research continues at a rapid pace, with a number of phase III trials underway to fully evaluate new promising agents under development for improving outcomes in patients with NSCLC harboring distinct molecular subtypes. This review will provide a comprehensive summary of existing data as well as a user-friendly guide on the current status of novel targeted therapy in oncogene-driven advanced NSCLC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Predictive cancer tools focus on survival; none predict severe symptoms., Aim: To develop and validate a model that predicts the risk for having low performance status and severe symptoms in cancer patients., Design: Retrospective, population-based, predictive study., Setting/participants: We linked administrative data from cancer patients from 2008 to 2015 in Ontario, Canada. Patients were randomly selected for model derivation (60%) and validation (40%). Using the derivation cohort, we developed a multivariable logistic regression model to predict the risk of an outcome at 6 months following diagnosis and recalculated after each of four annual survivor marks. Model performance was assessed using discrimination and calibration plots. Outcomes included low performance status (i.e. 10-30 on Palliative Performance Scale), severe pain, dyspnea, well-being, and depression (i.e. 7-10 on Edmonton Symptom Assessment System)., Results: We identified 255,494 cancer patients (57% female; median age of 64; common cancers were breast (24%); and lung (13%)). At diagnosis, the predicted risk of having low performance status, severe pain, well-being, dyspnea, and depression in 6-months is 1%, 3%, 6%, 13%, and 4%, respectively for the reference case (i.e. male, lung cancer, stage I, no symptoms); the corresponding discrimination for each outcome model had high AUCs of 0.807, 0.713, 0.709, 0.790, and 0.723, respectively. Generally these covariates increased the outcome risk by >10% across all models: lung disease, dementia, diabetes; radiation treatment; hospital admission; pain; depression; transitional performance status; issues with appetite; or homecare., Conclusions: The model accurately predicted changing cancer risk for low performance status and severe symptoms over time.

Objectives: Immune checkpoint inhibitors have become the standard of care for metastatic non-small-cell lung cancer (NSCLC) progressing during or after platinum-based chemotherapy. Real-world clinical practice tends to represent more diverse patient characteristics than randomized clinical trials. We sought to evaluate overall survival (OS) outcomes in the total study population and in key subsets of patients who received nivolumab for previously treated advanced NSCLC in real-world settings in France, Germany, or Canada., Materials and Methods: Data were pooled from two prospective observational cohort studies, EVIDENS and ENLARGE, and a retrospective registry in Canada. Patients included in this analysis were aged ≥18 years, had stage IIIB/IV NSCLC, and received nivolumab after at least one prior line of systemic therapy. OS was estimated in the pooled population and in various subgroups using the Kaplan-Meier method. Timing of data collection varied across cohorts (2015-2019)., Results: Of the 2585 patients included in this analyses, 1235 (47.8 %) were treated in France, 881 (34.1 %) in Germany, and 469 (18.1 %) in Canada. Median OS for the total study population was 11.3 months (95 % CI: 10.5-12.2); this was similar across France, Germany, and Canada. The OS rate was 49 % at 1 year and 28 % at 2 years for the total study population. In univariable Cox analyses, the presence of epidermal growth factor receptor mutations in nonsquamous disease, liver, or bone metastases were associated with significantly shorter OS, whereas tumor programmed death ligand 1 expression and Eastern Cooperative Oncology Group performance status 0-1 were associated with significantly prolonged OS. Similar OS was noted across subgroups of age and prior lines of therapy., Conclusion: OS rates in patients receiving nivolumab for previously treated advanced NSCLC in real-world clinical practice closely mirrored those in phase 3 studies, suggesting similar effectiveness of nivolumab in clinical trials and clinical practice., (Copyright © 2021 Bristol Myers Squibb. Published by Elsevier B.V. All rights reserved.)

Objective: Quantify changes in workload in relation to the anatomic pathologist workforce., Methods: In house pathology reports for cytology and surgical specimens from a regional hospital laboratory over a nine- year period (2011-2019) were analyzed, using custom computer code. Report length for the diagnosis+microscopic+synoptic report, number of blocks, billing classification (L86x codes), billings, national workload model (L4E 2018), regional workload model (W2Q), case count, and pathologist workforce in full-time equivalents (FTEs) were quantified. Randomly selected cases (n = 1,100) were audited to assess accuracy., Results: The study period had 574,093 pathology reports that could be analyzed. The coding accuracy was estimated at 95%. From 2011 to 2019: cases/year decreased 6% (66,056 to 61,962), blocks/year increased 20% (236,197 to 283,751), L4E workload units increased 23% (165,276 to 203,894), W2Q workload units increased 21% (149,841 to 181,321), report lines increased 19% (606,862 to 723,175), workforce increased 1% (30.42 to 30.77 FTEs), billings increased 13% ($6,766,927 to $7,677,109). W2Q in relation to L4E underweights work in practices with large specimens by up to a factor of 2x., Conclusions: Work by L4E for large specimens is underrated by W2Q. Reporting requirements and pathology work-up have increased workload per pathology case. Work overall has increased significantly without a commensurate workforce increase. The significant practice changes in the pathology work environment should prompt local investment in the anatomic pathology workforce., Competing Interests: MB and RM are part of the Canadian Association of Pathologists’ Workload Committee. The Workload Committee defines the Level 4 Equivalent (L4E) system. MB retains the copyright on the computer code that was written outside of his employment relationship with McMaster University/Hamilton Regional Laboratory Medicine Program/St. Joseph’s Healthcare Hamilton. This does not alter our adherence to PLOS ONE policies on sharing data and materials. At the time of final submission, there are no patents, products in development or marketed products to declare.

Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration.

Background: Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma., Methods: CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing., Findings: Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients., Interpretation: These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab)., Funding: MacroGenics., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This multicenter phase Ib study aimed to establish a recommended phase II dose for durvalumab (Du) ± tremelimumab (Tr) in combination with standard platinum-doublet chemotherapy. Eligible patients were enrolled into one of six dose levels (DL) of Du ± Tr which included concomitant treatment with standard platinum-doublet regimens; (pemetrexed, gemcitabine, etoposide, (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)). Dose escalation was according to a Rolling Six type design. Both weight-based and fixed dosing of Du and Tr were explored. Du was continued until progression. Tr dosing was finite (up to 6 doses) with increasing dose and/or frequency by DL. 136 patients were enrolled. The majority of drug-related adverse events (AEs) were ≤ grade 2 and attributable to chemotherapy. AEs considered related to immunotherapy were mainly ≤ grade 2; the most frequent (occurring ≥10 %) were colitis/diarrhea, skin, and thyroid dysfunction. Seven patients had DLTs including pneumonitis, myocarditis, diarrhea, encephalitis, motor neuropathy, and enterocolitis. There were 2 treatment-related deaths. Tr and Du exposures did not appear affected by chemotherapy. Among the 73 non-small cell lung cancer (NSCLC) patients treated, the objective response rate was 51 % (95 %CI = 38.7-62.6 %) with a median progression-free and overall survival of 6.5 months (95 % CI = 5.5-9.4 months) and 19.8 months (95 % CI = 14.8 months - not yet reached) respectively. Anti-tumour activity was observed across PD-L1 subtypes. Du 1500 mg q3w and Tr 75 mg q3wx5 can be safely combined with platinum-doublet chemotherapy. Efficacy among NSCLC patients appears comparable to results from other immunotherapy and chemotherapy combination trials. NCT02537418., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Systemic therapy is an essential part of treatment for all patients with small-cell lung cancer (sclc) and for most patients with non-small-cell lung cancer (nsclc). Standards of care have evolved dramatically since 2009, especially in the setting of incurable or advanced nsclc. Part of that evolution has been the incorporation of immuno-oncology drugs, especially immune checkpoint inhibitors (icis) into multiple therapeutic scenarios. In the present review, we discuss the role of the immune system in lung cancer and the previous failures of immunotherapy for patients with lung cancer. We then provide an overview of the existing evidence for the use of icis in patients with advanced nsclc that is either treatment-naïve or pretreated, for consolidative treatment after chemoradiotherapy in stage iii nsclc, and for palliative therapy in patients with sclc. Finally, we discuss duration of treatment, special populations, and the future of immuno-oncology for patients with lung cancer. Overall, we provide an evidence-based snapshot of immuno-oncology agents in the treatment of lung cancer up to early 2019., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: DED has participated on advisory boards for AstraZeneca and Merck and has received an honorarium from Boehringer Ingelheim for providing educational content. RAJ has received honoraria from Bristol–Myers Squib, AstraZeneca, Roche Canada, Merck Sharp and Dohme, Novartis Canada Pharmaceuticals Inc., Amgen, and Boehringer Ingelheim, and has consulted or advised for AstraZeneca, Bristol–Myers Squib, Novartis, Pfizer, Roche Canada, Takeda, AbbVie, and Fusion Pharmaceuticals. CHH has no conflicts to disclose., (2020 Multimed Inc.)

Cancer recurrence after surgery remains an unresolved clinical problem 1-3 . Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites 4-6 . There are currently no effective interventions that prevent the formation of the premetastatic microenvironment 6,7 . Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.

Background: End-of-life cancer care involves multidisciplinary teams working in various settings. Evaluating the quality of care and the feedback from such processes is an important aspect of health care quality improvement. Our retrospective cohort study reviewed health care use by lung cancer patients at end of life, their reasons for visiting the emergency department (ed), and feedback from regional health care professionals., Methods: We assessed 162 Ontario patients with small-cell and relapsed or advanced non-small-cell lung cancer. Demographics, disease characteristics, and resource use were collected, and the consenting caregivers for patients with ed visits were interviewed. Study results were disseminated, and feedback about barriers to care was sought., Results: Median patient age was 69 years; 73% of the group had non-small-cell lung cancer; and 39% and 69% had received chemotherapy and radiation therapy respectively. Median overall survival was 5.6 months. In the last 3 months of life, 93% of the study patients had visited an oncologist, 67% had telephoned their oncology team, 86% had received homecare, and 73% had visited the ed. Death occurred for 55% of the patients in hospital; 23%, at home; and 22%, in hospice. Goals of care had been documented for 68% of the patients. Homecare for longer than 3 months was associated with fewer ed visits (80.3% vs. 62.1%, p = 0.022). Key themes from stakeholders included the need for more resources and for effective communication between care teams., Conclusions: Use of acute-care services and rates of death in an acute-care facility are both high for lung cancer patients approaching end of life. In our study, interprofessional and patient-provider communication, earlier connection to homecare services, and improved access to community care were highlighted as having the potential to lower the need for acute-care resources., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

Background: Nivolumab was the first immuno-oncology agent available for the treatment of lung cancer in Canada. In the present study, we evaluated the real-world benefit of nivolumab in Canadian patients with lung cancer., Methods: Patients included in the cohort were identified from a registry of patients treated through expanded access to nivolumab before and after Health Canada approval. Demographics were collected from the application forms. Outcome data for the duration of treatment and survival were collected retrospectively., Results: In contrast to the randomized clinical trial populations, our study cohort included patients who were older (median age: 66 years; range: 36-92 years) and who had an Eastern Cooperative Oncology Group performance status of 2 (8.9%). Despite the poorer-prognosis cohort, median overall survival was 12.0 months, which is comparable to the survival demonstrated in the randomized phase iii trials of nivolumab in lung cancer. Median time to treatment discontinuation was 3.45 months and was similar for all patient subgroups, including poorer-prognosis groups such as those with a performance status of 2, those 75 years of age and older, and those with brain metastases., Conclusions: Nivolumab given in a real-world clinical setting was associated with results similar to those reported in the phase iii clinical trial setting., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: CL reports personal fees from Bristol–Myers Squibb, Merck, Pfizer, and AstraZeneca, outside the submitted work; CB reports personal fees from Bristol–Myers Squibb, Merck, and AstraZeneca, outside the submitted work; MNR reports personal fees from Bristol–Myers Squibb outside the submitted work; FAS reports personal fees and a grant from Bristol–Myers Squibb; personal fees, stock ownership, and an advisory role with Eli Lilly; personal fees, stock ownership, and an advisory role with Astra-Zeneca; personal fees from Roche/Genentech; personal fees from Merck Sharp and Dohme; personal fees from Merck Serono; and grants from Pfizer, AstraZeneca/MedImmune, Roche Canada, and Merrimack, outside the submitted work; JR reports personal fees from Bristol–Myers Squibb, Roche, Merck, AstraZeneca, Boehringer Ingelheim, and Pfizer, outside the submitted work; SO reports personal fees from Bristol–Myers Squibb outside the submitted work; RAJ reports grants, personal fees, and an advisory role with Bristol-Myers Squibb; grants, personal fees, and an advisory role with Merck Sharp and Dohme; personal fees and an advisory role with Roche Canada; personal fees and an advisory role with Boehringer Ingelheim; grants and personal fees from AstraZeneca/MedImmune; personal fees from Eli Lilly; personal fees and an advisory role with Pfizer; personal fees from Amgen; personal fees and an advisory role with Novartis, outside the submitted work; FP, FR, and JV report being employees of Bristol–Myers Squibb. The remaining authors have no conflicts to disclose.

Introduction: This phase I study evaluated nivolumab combined with erlotinib in patients with advanced EGFR-mutant NSCLC., Methods: Patients with advanced EGFR-mutant NSCLC who were EGFR tyrosine kinase inhibitor (TKI)-naive or TKI-treated but had not received chemotherapy were treated with nivolumab 3 mg/kg every 2 weeks and erlotinib 150 mg/d until disease progression or unacceptable toxicity. The primary objective was safety and tolerability., Results: Twenty patients with TKI-treated and one with TKI-naive EGFR-mutant NSCLC were treated with nivolumab plus erlotinib. Treatment-related grade 3 toxicities occurred in five patients (liver enzyme elevations, n = 2; diarrhea, n = 2; weight loss, n = 1), with no grade ≥4 toxicities. In the TKI-treated population, the objective response rate was 15% (3 of 20, including one complete response), and the 24-week progression-free survival rate was 48%. Responses lasted 13.8, 17.6, and 38.2 months per investigator records. A fourth patient had a nonconventional immune-related response lasting 12.5 months. Among these four patients, two were never-smokers and one each had 35- and <1-pack-year histories. Post-EGFR TKI pre-trial tumor biopsy specimens from these patients detected EGFR T790M mutations in two patients and MNNG HOS Transforming gene (MET) amplification in a third; two patients each had primary EGFR exon 19 deletions or L858R mutations. The TKI-naive patient, who had compound EGFR mutations (L858R and S768I) and ultimately achieved a complete response, had an ongoing response lasting more than 5 years based on investigator records., Conclusions: Nivolumab plus erlotinib was tolerable, with durable responses in patients with EGFR-mutant, TKI-treated NSCLC., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Lung cancer is the most common cause of cancer-related death among males and the second leading cause among females globally. Checkpoint inhibitors re-engage the immune system to fight cancer. This review evaluates phase III data on the use of checkpoint inhibitors in the treatment of advanced NSCLC and addresses PD-L1 expression in predicting efficacy., Methods: Six phase III clinical trials investigating checkpoint inhibitors for NSCLC were identified through a search of PubMed (to November 15, 2016) and conference databases, with findings updated from a directed search of eligible studies conducted in January 2018., Results: Significant reductions in the risk of death ranging from 27% to 41% and were observed second-line and beyond. A relationship between PD-L1 expression and survival was apparent in most trials with optimal benefit for the highest expression levels (≥50%). Benefit was also observed at low or no PD-L1 expression levels and in third-line in some studies. Significantly improved PFS was observed for pembrolizumab at high PD-L1 expression levels (≥50%) first-line. Immune-related adverse events associated with checkpoint inhibitors are tolerable and rates of pneumonitis may be lower among PD-L1 inhibitors. Use of checkpoint inhibitors for tumors with driver mutations should only be considered after all appropriate targeted therapy and chemotherapy have been exhausted. PD-L1 testing presents a valuable tool to guide treatment sequencing and we recommend use of agent-specific PD-L1 tests and respective scoring systems until a standardized, convenient and broadly applicable test is identified., Conclusions: Checkpoint inhibitors represent a major advance in the treatment of advanced NSCLC and PD-L1 status can inform treatment decisions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to compare the percentage change in 18 F-fluorothymidine (FLT) standard uptake value (SUV) between baseline and after one cycle of chemotherapy in patients categorized by RECIST 1.1 computed tomography (CT) as responders or non-responders after two cycles of therapy. Change in 18 F-fluorodeoxyglucose (FDG) uptake was also compared between these time points. Nine patients with newly diagnosed, operable, non-small cell lung cancer (NSCLC) were imaged with FDG positron emission tomography/CT (PET), FLT PET/CT, and CT at baseline, following one cycle of neoadjuvant therapy (75 mg/m 2 docetaxel + 75 mg/m 2 cisplatin), and again after the second cycle of therapy. All patients had a biopsy prior to enrollment and underwent surgical resection within 4 weeks of post-cycle 2 imaging., Results: Between baseline and post-cycle 1, non-responders had mean SULmax (maximum standard uptake value adjusted for lean body mass) increases of 7.0 and 3.4% for FDG and FLT, respectively. Responders had mean decreases of 44.8 and 32.0% in FDG and FLT SULmax, respectively, between baseline and post-cycle 1 imaging. On post-cycle 1 imaging, primary tumor FDG SUL values were significantly lower in responders than in non-responders (P = 0.016). Primary tumor FLT SUL values did not differ significantly between these groups. Using the change from baseline to post-cycle 1, receiver-operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.94 for FDG and 0.78 for FLT in predicting anatomic tumor response after the second cycle of therapy., Conclusions: Fractional decrease in FDG SULmax from baseline to post-cycle 1 imaging was significantly different between anatomic responders and non-responders, while percentage changes in FLT SULmax were not significantly different between these groups over the same period of time.

Background: Despite the reported benefits of physical activity in alleviating the impact of cancer and its treatments, oncology care providers (OCPs) are not routinely discussing exercise with their patients, suggesting a knowledge to action gap. We sought to determine OCP's knowledge, beliefs, barriers, and facilitators to exercise discussion., Methods: A survey was administered to OCPs at the cancer center in Hamilton, Ontario. Questions comprised of demographics, knowledge and beliefs regarding exercise guidelines, and barriers and facilitators to exercise discussion. Analysis of survey responses was descriptive. Pearson's chi-squared test was used to examine select associations., Results: There were 120 respondents (61% response rate) representing a diversity of professions. Approximately, 80% of OCPs were not aware of any exercise guidelines in cancer and self-reported poor knowledge on when, how, and which patients to refer to exercise programs. OCPs who reported meeting Canada's Physical Activity guidelines were significantly more likely to identify correct guidelines (p = 0.023) and to report good knowledge on how to provide exercise counseling (p = 0.014). Across OCP groups, barriers to exercise discussion included poor knowledge, lack of time, and safety concerns. Most felt that educational sessions and having an exercise specialist on the clinical team would be beneficial., Conclusions: OCPs have low knowledge regarding exercise counseling, but believe that discussing exercise is a multidisciplinary task and expressed a desire for further training. Interventions will require a multi-pronged approach including education for OCPs and guidance on assessment for exercise safety.

Purpose: Non-small-cell lung cancer (NSCLC) has a large worldwide prevalence with a high mortality rate. Chemotherapy has offered modest improvements in survival over the past two decades. Immune checkpoint modulation with programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibition has shown the promise of changing the future landscape of cancer therapy. This update reviews recent advances in the treatment of NSCLC with immune checkpoint modulation., Methods: Publications and proceedings were identified from searching PubMed and proceedings from the annual meetings of the American Society of Clinical Oncology, European Society for Medical Oncology, and European Lung Cancer Conference., Results: Atezolizumab, nivolumab, and pembrolizumab increase overall survival in second-line treatment of Stage III/IV squamous and non-squamous NSCLC when compared to docetaxel. Pembrolizumab increases progression-free survival in the first-line treatment of Stage IV NSCLC with 50% PD-L1 expression when compared to platinum-based chemotherapy. Combination therapy with chemotherapy and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors has shown promise in early trials., Conclusion: Immune checkpoint modulation produces durable responses and overall survival benefits with less toxicity compared to conventional chemotherapy. Future investigations are combining PD-1/L1 inhibition with chemotherapy, targeted therapy, or other immuno-oncology agents in an effort to further improve efficacy.

Starting in the early 2000s, non-small-cell lung cancer (nsclc) subtypes have evolved from being histologically described to molecularly defined. Management of lung adenocarcinomas now generally requires multiple molecular tests at baseline to define the optimal treatment strategy. More recently, second biopsies performed at progression in patients treated with tyrosine kinase inhibitors (tkis) have further defined the continued use of molecularly targeted therapy. In the present article, we focus on one molecular subtype: EGFR- mutated nsclc. For that patient population, multiple lines of tki therapy are now available either clinically or in clinical trials. Each line of treatment is guided by the specific mutations (for example, L858R, T790M, C797S) identified in EGFR. We first describe the various mechanisms of acquired resistance to EGFR tki treatment. We then focus on strategies that clinicians and pathologists can both use during tissue acquisition and handling to optimize patient results. We also discuss future directions for the molecular characterization of lung cancers with driver mutations, including liquid biopsies. Finally, we provide an algorithm to guide treating physicians managing patients with EGFR- mutated nsclc. The same framework can also be applied to other molecularly defined nsclc subgroups as resistance patterns are elucidated and additional lines of treatment are developed., Competing Interests: We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: MST declares research grants from AstraZeneca, Pfizer, and Merck, and honoraria from AstraZeneca, Pfizer, Merck, Hoffman–La Roche, Bristol–Myers Squibb, and Boehringer Ingelheim; RS declares honoraria from AstraZeneca, Boehringer Ingelheim, Pfizer, Merck, Bristol–Myers Squibb, Roche, Eli Lilly, and Novartis; SKR declares a research grant from Pfizer and honoraria from AstraZeneca, Pfizer, Bristol–Myers Squibb, Roche, and Novartis; AK declares honoraria from AstraZeneca, Pfizer, Merck, Hoffman–La Roche, and Bristol–Myers Squibb; MP declare honoraria from AstraZeneca; DI declares honoraria from AstraZeneca, Pfizer, Merck, Hoffman–La Roche, and Bristol–Myers Squibb; RAJ declares a research grant from AstraZeneca and honoraria from AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, and Roche; CB declares honoraria from AstraZeneca, Pfizer, Merck, Bristol–Myers Squibb, and Boehringer Ingelheim; MC, BSS, and MS have no declarations to make.

The identification of common molecular aberrations that drive cancer progression has led to targeted therapies that improve treatment efficacy in many tumor types. Epidermal growth factor receptor (EGFR) inhibitors have been used to treat both lung and head and neck cancers with squamous cell histology. These tumors often show high EGFR expression and/or increased gene copy number, but low incidence of the activating kinase domain mutations common to adenocarcinomas of the lung. In this manuscript, we review clinical trial data on EGFR-inhibitors in the treatment of squamous cell carcinoma (SqCC) of the lung and head and neck (SCCHN), including both efficacy and biomarker analyses. Although some efficacy with use of EGFR inhibitors is observed, the level of benefit varies within and across tumor types, and the predictive capacity of high EGFR protein expression and/or gene amplification, if any, is limited. Due to the lack of candidate biomarkers that consistently predict response to EGFR-inhibitor therapy across treatment setting and class of agent in SqCC of the lung and SCCHN, we explore the biology, genomics and patterns of response to EGFR-inhibitors to inform identification of potential biomarkers, highlighting several key molecules that have shown promise in preclinical studies and clinical trials across multiple cancer sites., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non-small-cell lung cancer with EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes., Patients and Methods: We performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR-mutation positive, advanced non-small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival., Results: After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results., Conclusion: Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Nivolumab has shown improved survival in the treatment of advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. We assessed the safety and activity of combination nivolumab plus ipilimumab as first-line therapy for NSCLC., Methods: The open-label, phase 1, multicohort study (CheckMate 012) cohorts reported here were enrolled at eight US academic centres. Eligible patients were aged 18 years or older with histologically or cytologically confirmed recurrent stage IIIb or stage IV, chemotherapy-naive NSCLC. Patients were randomly assigned (1:1:1) by an interactive voice response system to receive nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicities, or withdrawal of consent. Data from the latter two cohorts, which were considered potentially suitable for further clinical development, are presented in this report; data from the other cohort (as well as several earlier cohorts) are described in the appendix. The primary outcome was safety and tolerability, assessed in all treated patients. This ongoing study is registered with ClinicalTrials.gov, number NCT01454102., Findings: Between May 15, 2014, and March 25, 2015, 78 patients were randomly assigned to receive nivolumab every 2 weeks plus ipilimumab every 12 weeks (n=38) or nivolumab every 2 weeks plus ipilimumab every 6 weeks (n=40). One patient in the ipilimumab every-6-weeks cohort was excluded before treatment; therefore 77 patients actually received treatment (38 in the ipilimumab every-12-weeks cohort; 39 in the ipilimumab every-6-weeks cohort). At data cut-off on Jan 7, 2016, 29 (76%) patients in the ipilimumab every-12-weeks cohort and 32 (82%) in the ipilimumab every-6-weeks cohort had discontinued treatment. Grade 3-4 treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three [8%] and no patients), pneumonitis (two [5%] and one [3%] patients), adrenal insufficiency (one [3%] and two [5%] patients), and colitis (one [3%] and two [5%] patients). Treatment-related serious adverse events were reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11 (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any grade) prompted treatment discontinuation in four (11%) patients in the every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No treatment-related deaths occurred. Confirmed objective responses were achieved in 18 (47% [95% CI 31-64]) patients in the ipilimumab every-12-weeks cohort and 15 (38% [95% CI 23-55]) patients in the ipilimumab every-6-weeks cohort; median duration of response was not reached in either cohort, with median follow-up times of 12·8 months (IQR 9·3-15·5) in the ipilimumab every-12-weeks cohort and 11·8 months (6·7-15·9) in the ipilimumab every-6-weeks cohort. In patients with PD-L1 of 1% or greater, confirmed objective responses were achieved in 12 (57%) of 21 patients in the ipilimumab every-12-weeks cohort and 13 (57%) of 23 patients in the ipilimumab every-6-weeks cohort., Interpretation: In NSCLC, first-line nivolumab plus ipilimumab had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate and durable response. To our knowledge, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further assessment of this combination in a phase 3 study., Funding: Bristol-Myers Squibb., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non-small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC)., Patients and Methods: Patients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression., Results: No dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed death ligand-1 expression., Conclusion: The safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%., (© 2016 by American Society of Clinical Oncology.)

Purpose: Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved survival over docetaxel in previously treated advanced non-small-cell lung cancer (NSCLC). First-line monotherapy with nivolumab for advanced NSCLC was evaluated in the phase I, multicohort, Checkmate 012 trial., Methods: Fifty-two patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity; postprogression treatment was permitted per protocol. The primary objective was to assess safety; secondary objectives included objective response rate (ORR) and 24-week progression-free survival (PFS) rate; overall survival (OS) was an exploratory end point., Results: Any-grade treatment-related adverse events (AEs) occurred in 71% of patients, most commonly: fatigue (29%), rash (19%), nausea (14%), diarrhea (12%), pruritus (12%), and arthralgia (10%). Ten patients (19%) reported grade 3 to 4 treatment-related AEs; grade 3 rash was the only grade 3 to 4 event occurring in more than one patient (n = 2; 4%). Six patients (12%) discontinued because of a treatment-related AE. The confirmed ORR was 23% (12 of 52), including four ongoing complete responses. Nine of 12 responses (75%) occurred by first tumor assessment (week 11); eight (67%) were ongoing (range, 5.3+ to 25.8+ months) at the time of data lock. ORR was 28% (nine of 32) in patients with any degree of tumor PD-ligand 1 expression and 14% (two of 14) in patients with no PD-ligand 1 expression. Median PFS was 3.6 months, and the 24-week PFS rate was 41% (95% CI, 27 to 54). Median OS was 19.4 months, and the 1-year and 18-month OS rates were 73% (95% CI, 59 to 83) and 57% (95% CI, 42 to 70), respectively., Conclusion: First-line nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC., (© 2016 by American Society of Clinical Oncology.)

Purpose: Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of linsitinib, a potent oral IGF1R/INSR inhibitor, with EGFR inhibitor erlotinib., Experimental Design: This open-label, dose-escalation study investigated linsitinib schedules S1: once daily intermittent (days 1-3 weekly); S2, once daily continuous; S3, twice-daily continuous; each with erlotinib 100-150 mg once daily; and a non-small cell lung cancer (NSCLC) expansion cohort., Results: Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150 mg (S1), 400/100 mg (S2). On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. There was no evidence of drug-drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38 of 75 (51%), and 28 of 91 (31%) patients were on study >12 weeks., Conclusions: The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy. Clin Cancer Res; 22(12); 2897-907. ©2016 AACR., (©2016 American Association for Cancer Research.)

Immune-based therapies have been in use for decades but recent work with immune checkpoint inhibitors has now changed the landscape of cancer treatment as a whole. While these advances are encouraging, clinicians still do not have a consistent biomarker they can rely on that can accurately select patients or monitor response. Molecular imaging technology provides a noninvasive mechanism to evaluate tumors and may be an ideal candidate for these purposes. This review provides an overview of the mechanism of action of varied immunotherapies and the current strategies for monitoring patients with imaging. We then describe some of the key researches in the preclinical and clinical literature on the current uses of molecular imaging of the immune system and cancer.

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade.

Introduction: Preclinical studies have suggested that the oral antifungal agent itraconazole specifically inhibits proliferation, migration, and tube formation of endothelial cells. Itraconazole has potent antiangiogenic activity and enhances the efficacy of cytotoxic chemotherapy in multiple primary xenograft lung cancer models. On the basis of these data, we performed an exploratory clinical study, assessing the efficacy of itraconazole with cytotoxic chemotherapy in the treatment of patients with advanced lung cancer., Methods: The study enrolled patients with progressive nonsquamous non-small-cell lung cancer after one prior cytotoxic therapy for metastatic disease, randomized 2:1 to intravenous administration of pemetrexed 500 mg/m2 on day 1, with or without itraconazole 200 mg orally daily, on a 21-day cycle. Outcome measures included percent progression-free at 3 months, progression-free survival, overall survival, and observed toxicity., Results: A total of 23 patients were enrolled; the study was stopped early because of increasing use of pemetrexed in the first-line setting. At 3 months, 67% of the patients on itraconazole plus pemetrexed were progression-free versus 29% on the control arm of pemetrexed alone (p = 0.11). Median progression-free survivals were 5.5 months (itraconazole) versus 2.8 months (control) (hazard ratio = 0.399, p = 0.089). Overall survival was longer in patients receiving itraconazole (median 32 months) versus control (8 months) (hazard ratio = 0.194, p = 0.012). There were no evident differences in toxicity between the study arms., Conclusion: Itraconazole is well tolerated in combination with pemetrexed. Consistent with our preclinical data, daily itraconazole administration is associated with trends suggestive of improved disease control in patients receiving chemotherapy for advanced lung cancer.

Carcinogenesis is driven by a combination of genetic and epigenetic abnormalities. Aberrancies in gene promoter methylation patterns and histone acetylation are associated with silencing of tumor suppressor genes in lung cancer and other solid tumors. Identification of key epigenetic modifications has been shown to be prognostic in early-stage non-small cell lung cancer. Previous clinical trials aimed at modifying the epigenome with single-agent demethylating agents or histone deacetylase inhibitors given at maximally tolerated doses have provided disappointing results. A recent clinical trial using a combination of a demethylating agent and a histone deacetylase inhibitor at "epigenetically targeted" doses concomitantly has shown promising results, including a patient with a complete objective response. Biomarkers associated with this clinical trial suggest that patients who undergo robust demethylation, as detected in the peripheral blood after a month on treatment, identifies those who gain the most benefit from this novel treatment strategy. Based on observations of unusually durable responses to subsequent therapy after administration of combined epigenetic therapy, epigenetic therapy may also play a role in "priming" patients to better respond to standard cytotoxic therapy or immunotherapy. This manuscript will review the data on the role of epigenetics in lung cancer and the history of epigenetic treatments in lung cancer spanning over the last 40 years.

Unlabelled: Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non-small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8-9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy., Significance: This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.