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Introduction: No definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment., Methods: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS)., Results: Sixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 - 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0-22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21-34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2-23.9; p = 0.019)., Conclusion: Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bob T. Li has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Jiangsu Hengrui Pharmaceuticals, Lilly, Nuvalent, and Revolution Medicines. He has received academic travel support from Amgen. He is an inventor on three institutional patents at MSK (US62/685,057, US62/514,661, US63/424,813) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. Alexander Drilon declared as follows: Honoraria: 14ner/Elevation Oncology, Amgen, Abbvie, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Bristol Myers Squibb, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Regeneron, Repare RX, Springer Healthcare, Takeda/Ariad/Millenium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem. Advisory Boards: Bayer, MonteRosa, Abbvie, EcoR1 Capital, LLC, Amgen, Helsinn, Novartis, Lilly, AnHeart Therapeutics. Consulting: MonteRosa, Innocare, Boundless Bio, Treeline Bio, Nuvalent, 14ner/Elevation Oncology, Entos, Prelude. Associated Research Paid to Institution: Foundatin Medicine, GlaxoSmithKlein, Teva, Taiho, PharmaMar. Equity: mBrace. Copyright: Selpercatinib-Osimertinib (filed/pending). Royalties: Wolters Kluwer; Other (Food/Beverage): Merck, Puma, Merus, Boehringer Ingelheim; CME Honoraria: Answers in CME, Applied Pharmaceutical Science, Inc, AXIS, Clinical Care Options, Doc Congress, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MedTalks, MJH Life Sciences, MORE Health, Ology, OncLive, Paradigm, Peerview Institute, PeerVoice, Physicians Education, Projects in Knowledge, Resources, Remedica Ltd, Research to Practice, RV More, Targeted Oncology, TouchIME, WebMD. Sarat Chandarlapaty has received institutional grant/funding from Daiichi-Sankyo, AstraZeneca, and Lilly, Shares/Ownership interests in Odyssey Biosciences, Effector Therapeutics, and Totus Medicines, and consultation/Ad board/Honoraria from AstraZeneca, Daiichi-Sankyo, Novartis, Neogenomics, Nuvalent, Blueprint, SAGA Diagnostics, and Effector Therapeutics. Jiannan Guo is a former employee of Resolution Bioscience. Eric Gagne, Kavita Garg and Frederick Baehner are employees of Exact Sciences. All remaining authors have declared no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: Recurrent small-cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted., Patients and Methods: This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety, tolerability, and a recommended phase II dose (RP2D). The phase II primary objective was overall response rate (ORR), with secondary objectives of determining duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Correlative analyses included immunohistochemistry of pretreatment and on-treatment tumor biopsies and pharmacokinetics analysis., Results: Twenty-two patients were enrolled (phase I, n = 12; phase II, n = 10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLT) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; three patients discontinued treatment for toxicity. Three of the first 10 patients in phase II experienced DLTs triggering a stopping rule. The ORR was 4/19 or 21% [95% confidence interval (CI), 6%-46%]. The median DoR, PFS, and OS were 4.6 months, 2.2 months (95% CI, 1.3-7.6 months), and 6.6 months (95% CI, 4.3 to not reached), respectively. SLFN11/EZH2 expression and SCLC subtyping markers did not correlate with response, but MHC-I expression did increase with treatment. Two responders demonstrated subtype switching on treatment., Conclusions: Combination valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat, combined with agents without overlapping toxicity, warrants further investigation in SCLC., (©2024 American Association for Cancer Research.)

Background: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study., Methods: In a randomized phase 3 trial, we evaluated the efficacy and safety of first-line selpercatinib as compared with control treatment that consisted of platinum-based chemotherapy with or without pembrolizumab at the investigator's discretion. The primary end point was progression-free survival assessed by blinded independent central review in both the intention-to-treat-pembrolizumab population (i.e., patients whose physicians had planned to treat them with pembrolizumab in the event that they were assigned to the control group) and the overall intention-to-treat population. Crossover from the control group to the selpercatinib group was allowed if disease progression as assessed by blinded independent central review occurred during receipt of control treatment., Results: In total, 212 patients underwent randomization in the intention-to-treat-pembrolizumab population. At the time of the preplanned interim efficacy analysis, median progression-free survival was 24.8 months (95% confidence interval [CI], 16.9 to not estimable) with selpercatinib and 11.2 months (95% CI, 8.8 to 16.8) with control treatment (hazard ratio for progression or death, 0.46; 95% CI, 0.31 to 0.70; P<0.001). The percentage of patients with an objective response was 84% (95% CI, 76 to 90) with selpercatinib and 65% (95% CI, 54 to 75) with control treatment. The cause-specific hazard ratio for the time to progression affecting the central nervous system was 0.28 (95% CI, 0.12 to 0.68). Efficacy results in the overall intention-to-treat population (261 patients) were similar to those in the intention-to-treat-pembrolizumab population. The adverse events that occurred with selpercatinib and control treatment were consistent with those previously reported., Conclusions: Treatment with selpercatinib led to significantly longer progression-free survival than platinum-based chemotherapy with or without pembrolizumab among patients with advanced RET fusion-positive NSCLC. (Funded by Eli Lilly and others; ClinicalTrials.gov number, NCT04194944.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: With the recent approval of the KRAS G12C inhibitor sotorasib for patients with advanced KRAS G12C -mutant non-small cell lung cancer (NSCLC), there is a new need to identify factors associated with activity and toxicity among patients treated in routine practice., Materials and Methods: We conducted a multicenter retrospective study of patients treated with sotorasib outside of clinical trials to identify factors associated with real-world progression free survival (rwPFS), overall survival (OS), and toxicity., Results: Among 105 patients with advanced KRAS G12C -mutant NSCLC treated with sotorasib, treatment led to a 5.3-month median rwPFS, 12.6-month median OS, and 28% real-world response rate. KEAP1 comutations were associated with shorter rwPFS and OS (rwPFS hazard ratio [HR], 3.19; P = .004; OS HR, 4.10; P = .003); no significant differences in rwPFS or OS were observed across TP53 (rwPFS HR, 1.10; P = .731; OS HR, 1.19; P = .631) or STK11 (rwPFS HR, 1.66; P = .098; OS HR, 1.73; P = .168) comutation status. Notably, almost all patients who developed grade 3 or higher treatment-related adverse events (G3+ TRAEs) had previously been treated with anti-PD-(L)1 therapy. Among these patients, anti-PD-(L)1 therapy exposure within 12 weeks of sotorasib was strongly associated with G3+ TRAEs ( P < .001) and TRAE-related sotorasib discontinuation ( P = .014). Twenty-eight percent of patients with recent anti-PD-(L)1 therapy exposure experienced G3+ TRAEs, most commonly hepatotoxicity., Conclusion: Among patients treated with sotorasib in routine practice, KEAP1 comutations were associated with resistance and recent anti-PD-(L)1 therapy exposure was associated with toxicity. These observations may help guide use of sotorasib in the clinic and may help inform the next generation of KRAS G12C-targeted clinical trials.

With the rise of artificial intelligence, radiomics has emerged as a field of translational research based on the extraction of mineable high-dimensional data from radiological images to create "big data" datasets for the purpose of identifying distinct sub-visual imaging patterns. The integrated analysis of radiomic data and genomic data is termed radiogenomics, a promising strategy to identify potential imaging biomarkers for predicting driver mutations and other genomic parameters. In lung cancer, recent advances in whole-genome sequencing and the identification of actionable molecular alterations have led to an increased interest in understanding the complex relationships between imaging and genomic data, with the potential of guiding therapeutic strategies and predicting clinical outcomes. Although the integration of the radiogenomics data into lung cancer management may represent a new paradigm in the field, the use of this technique as a clinical biomarker remains investigational and still necessitates standardization and robustness to be effectively translated into the clinical practice. This review summarizes the basic concepts, potential contributions, challenges, and opportunities of radiogenomics in the management of patients with lung cancer., (Copyright © 2022. Published by Elsevier Inc.)

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. On the basis of results from randomized controlled trials, direct oral anticoagulants (DOACs) are now recommended for the treatment of cancer-associated VTE. The decision to use a DOAC requires consideration of bleeding risk, particularly in patients with gastrointestinal (GI) malignancies, the cost-benefit and convenience of oral therapy, and patient preference. While efficacy with apixaban, edoxaban, and rivaroxaban versus dalteparin has been consistent in the treatment of cancer-associated VTE, heterogeneity is evident with respect to major GI bleeding, with an increased risk with edoxaban and rivaroxaban but not apixaban. Although cost and accessibility vary in different countries of Latin America, DOACs should be considered for the long-term treatment of cancer-associated VTE in all patients who are likely to benefit. Apixaban may be the preferred DOAC in patients with GI malignancies and LMWH may be preferred for patients with upper or unresected lower GI tumors. Vitamin K antagonists should only be used for anticoagulation when DOACs and low molecular weight heparin are inaccessible or unsuitable.

Fusions involving TRK protein tyrosine kinases are oncogenic drivers in a variety of tumors in children and adults, with a prevalence of ∼0.2% in non-small cell lung cancer. Diagnosis can be challenging due to structural features such as NTRK intron length, but next-generation sequencing (NGS), including RNA-based NGS, increases detection. The first-generation TRK inhibitors, larotrectinib and entrectinib, have demonstrated clinically meaningful antitumor activity in TRK fusion-positive cancers in a tumor-agnostic fashion and should be considered first-line therapeutic options for TRK fusion-positive lung cancers. Furthermore, the first-generation TRK inhibitors are well tolerated. Care should be taken, however, to monitor on-target adverse events, such as dizziness, weight gain, paresthesias, and withdrawal pain. On-target and off-target mechanisms mediating TRK inhibitor resistance may occur. Next-generation TRK inhibitors, such as selitrectinib, repotrectinib, and taletrectinib, are available on ongoing clinical trials and address on-target resistance. This review will focus on NTRK fusions and TRK-directed targeted therapy specifically in the context of lung cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer., Materials and Methods: We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil., Results: The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria., Conclusion: The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation., Competing Interests: Maurício Fernando Silva Almeida RibeiroTravel, Accommodations, Expenses: Foundation Medicine Rodrigo Medeiros BovolinStock and Other Ownership Interests : Abbott Laboratories (ABT), Johnson & Johnson (JNJ), Novo Nordisk A/S (NVO), Edwards Lifesciences (EW), Zoetis Inc (ZTS), Gilead Sciences (GILD), Varian Medical Systems Inc. (VAR), Varex Imaging Corporation (VREX) Fernando Costa SantiniHonoraria: Merck Sharp & Dohme, Roche, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, Wyeth, AmgenConsulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Roche, Bayer, Lilly, AmgenSpeakers' Bureau: Roche, Merck Sharp & Dohme, AstraZeneca, BayerTravel, Accommodations, Expenses: Bayer, Merck Sharp & Dohme, Bristol Myers Squibb Rodrigo Ramella MunhozHonoraria: Bristol Myers Squibb, MSD, Roche, Novartis, Sanofi, Merck SeronoConsulting or Advisory Role: Roche, Merck Serono, Sanofi, Bristol Myers SquibbSpeakers' Bureau: Bristol Myers Squibb, MSD, Novartis, RocheResearch Funding: Lilly, Roche, Bristol Myers Squibb, Novartis, MSDTravel, Accommodations, Expenses: Bristol Myers Squibb, MSD, Roche, Sanofi Denis Leonardo Fontes JardimHonoraria: Janssen-Cilag, Roche/Genentech, Astellas Pharma, MSD Oncology, BMS Brazil, Pfizer, Libbs, MerckConsulting or Advisory Role: Janssen-Cilag, Pfizer, MSDTravel, Accommodations, Expenses: MSD, BMS Brazil, Janssen-Cilag Gustavo dos Santos FernandesHonoraria: Roche, MSD Oncology, BayerResearch Funding: Roche, Memorial Sloan-Kettering Cancer Center, BMS BrazilTravel, Accommodations, Expenses: Roche Maria Isabel AchatzConsulting or Advisory Role: RocheSpeakers' Bureau: AstraZeneca, MSD Oncology, Merck Sharpe & DohmeNo other potential conflicts of interest were reported.

Selpercatinib, a novel, highly selective and potent, inhibitor of RET , demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pretreated and treatment-naive RET fusion-positive non-small-cell lung cancer patients in a Phase I/II clinical trial. LIBRETTO-431 (NCT04194944) is a randomized, global, multicenter, open-label, Phase III trial, evaluating selpercatinib versus carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in treatment-naive patients with locally advanced/metastatic RET fusion-positive nonsquamous non-small-cell lung cancer. The primary end point is progression-free survival by independent review. Key secondary end points include overall survival, response rate, duration of response and progression-free survival. Clinical trial registration: NCT04194944 (ClinicalTrials.gov).

Opinion Statement: Care should be taken to ensure that the diagnostic strategy for a recently diagnosed advanced non-small cell lung cancer includes NTRK fusion testing. RNA sequencing is the gold standard method of detection of NTRK fusion; however, pan-TRK immunohistochemistry could be used as a screening method with good sensitivity. Larotrectinib and entrectinib are approved therapies for TRK fusion-positive lung cancers as first or subsequent lines of therapy. TRK inhibition has demonstrated clinically meaningful, deep, and durable systemic and central nervous system responses. Larotrectinib and entrectinib have a manageable safety profile, including some TRK-related adverse events, such as dizziness and weight gain. At disease progression on first-generation TRK inhibitors, enrollment on a clinical trial should be encouraged, as new-generation TRK inhibitors are being tested.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80-85% of cases. Epidermal growth factor receptor (EGFR) mutations are observed in approximately 40% and 20% of patients with NSCLC in Asian and non-Asian populations, respectively. First-generation (gefitinib, erlotinib) and second-generation (afatinib, dacomitinib) EGFR-tyrosine kinase inhibitors (TKIs) have been standard-of-care (SoC) first-line treatment for patients with sensitizing EGFR mutation positive advanced NSCLC following Phase III trials versus platinum-based doublet chemotherapy. However, most patients treated with first-line first- or second-generation EGFR-TKIs develop resistance. Osimertinib, a third-generation, central nervous system active EGFR-TKI which potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and the most common EGFR T790 M resistance mutations, has shown superior efficacy versus first-generation EGFR-TKIs (gefitinib / erlotinib). Osimertinib is now a treatment option for patients with advanced NSCLC harboring EGFRm in the first-line setting, and treatment of choice for patients with T790 M positive NSCLC following disease progression on first-line EGFR-TKIs. The second-generation EGFR-TKI dacomitinib has also recently been approved for the first-line treatment of EGFRm positive metastatic NSCLC. There remains a need to determine appropriate sequencing of EGFR-TKIs in this setting, including EGFR-TKIs as monotherapy or in combination with other TKIs / signaling pathway inhibitors. This review considers the evolving role of sequencing treatments to maximize benefits for patients with EGFRm positive advanced NSCLC., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Osimertinib is a first-line treatment option for patients with metastatic non-small cell lung cancer (NSCLC) harbouring EGFR mutations. Pneumonitis is a severe adverse event (AE) related to osimertinib treatment which appears to be more frequent when associated with concurrent or previous anti-PD(L)1 exposure. Data regarding the efficacy and safety of osimertinib rechallenge, especially in the setting of central nervous system (CNS) metastases, are scarce. We herein describe a case of a 53-year-old patient with metastatic EGFR-mutated NSCLC, who developed pneumonitis after osimertinib treatment and was successfully rechallenged with 40 mg daily osimertinib, with CNS response. This dose reduction strategy may be an option for selected patients with brain metastases after tyrosine kinase inhibitors-induced AEs., Competing Interests: Dr de Castro Junior reports personal fees and other from AstraZeneca, personal fees and other from Roche, personal fees and other from Boehringer-Ingelheim, outside the submitted work. The other authors declare that they have no conflicts of interest., (© the authors; licensee ecancermedicalscience.)

Considering retreatment following recovery from an immune-related adverse event (irAE) is a common clinical scenario, but the safety and benefit of retreatment is unknown. We identified patients with advanced non-small cell lung cancer (NSCLC) treated with anti-PD-(L)1 who had treatment held due to irAEs and divided them into two groups: those retreated with anti-PD-(L)1 (retreatment cohort) or those who had treatment stopped (discontinuation cohort). Out of 482 NSCLC patients treated with anti-PD-(L)1, 68 (14%) developed a serious irAE requiring treatment interruption. Of these, 38 (56%) were retreated and 30 (44%) had treatment discontinued. In the retreatment cohort, 18 (48%) patients had no subsequent irAEs, 10 (26%) had recurrence of the initial irAE, and 10 (26%) had a new irAE. Most recurrent/new irAEs were mild (58% grade 1-2) and manageable (84% resolved or improved to grade 1). Two treatment-related deaths occurred. Recurrent/new irAEs were more likely if the initial irAE required hospitalization, but the initial grade and time to retreatment did not influence risk. Among those with no observed partial responses prior to the irAE, progression-free survival (PFS) and overall survival (OS) were longer in the retreatment cohort. Conversely, for those with objective responses prior to the irAE, PFS and OS were similar in the retreatment and discontinuation cohorts. Among patients with early objective responses prior to a serious irAE, outcomes were similar, whether or not they were retreated. Together, data suggest that benefit may occur with retreatment in patients with irAEs who had no treatment response prior to irAE onset. Cancer Immunol Res; 6(9); 1093-9. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Objectives: Reports of the prognostic significance of ALK-rearrangement in resected non-small cell lung cancer (NSCLC) have been contradictory. We aimed to determine the prognosis of early-stage ALK-positive lung cancers relative to KRAS- and EGFR-mutant lung cancers., Material and Methods: We reviewed medical records of patients with resected NSCLC harboring an ALK rearrangement (n = 29) or a driver mutation in EGFR (n = 255) or KRAS (n = 480). Recurrence-free survival (RFS) was estimated for each genotype with the differences reported as a hazard ratio (HR)., Results: Among the 764 patients, 555 (73%), 101 (13%), and 108 (14%) had stage I, II, and III NSCLC, respectively. ALK-positive patients were distributed across all stages: 10 (34%) stage I, 6 (21%) stage II, and 13 (45%) stage III. Median RFS was not reached for EGFR-mutant patients, 24.3 months (95%CI 11.4-65.3) for ALK-positive patients, and 72.9 months (95%CI 59.7 to undefined) for KRAS-mutant patients. When adjusted for stage, ALK-positive NSCLC remained associated with worse RFS compared to EGFR-mutant (HR 1.8, 95%CI: 1.1-3.1), but not when compared to KRAS-mutant (HR 1.3, 95%CI: 0.8-2.1) NSCLC., Conclusions: In this large series of resected NSCLC, ALK rearrangements were associated with a trend toward inferior disease outcomes compared to other clinically relevant genomic subsets. These data support the need for clinical trials evaluating use of ALK inhibitors among ALK-positive patients with localized or locally-advanced disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cancer immunotherapies have revolutionized the treatment of non-small cell lung cancer. Yet, only a small subset of patients will benefit from PD-1 or PD-L1 blockade. PD-L1 tumor cell expression is the only approved biomarker at present. Tumor mutational burden and other emerging biomarkers should improve patient selection. Combination therapy approaches with chemotherapy or cytotoxic T-lymphocyte-associated protein 4 blockade may increase the proportion of patients who benefit from immunotherapy. Although use of immunotherapy in lung cancers with targetable oncogenes has not been particularly successful, the benefit of PD-(L)1 inhibitors in early-stage disease is emerging. This review briefly describes the evolution of the clinical development and future directions of PD-(L)1 blockade in patients with lung cancers.

Immune checkpoint inhibitors have recently become a cornerstone for the treatment of different advanced cancers. These drugs, represented mainly by monoclonal antibodies anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1) and anti-PD-1 ligand molecules (PD-L1 and L2), have the ability to reactivate the immune system against tumor cells, but can also trigger a myriad of autoimmune side effects, termed immune-related adverse events (irAEs). In particular, there are a number of endocrine-related irAEs. Current data from clinical trials show increased incidence of hypophysitis with CTLA4 inhibition and thyroid dysfunction with PD-(L)1 blockade. In addition, a few cases of type 1 diabetes mellitus and primary adrenal insufficiency have been reported. We discuss the incidence, clinical manifestations, diagnosis and management of immune-related endocrinopathies in this highly complex context of oncological patients in need of immunotherapies., (© 2017 Society for Endocrinology.)

Introduction: The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD-L1). Areas covered: This drug profile article covers the basics of the cancer-immunity cycle and reviews some aspects of innate and adaptive immunology. We discuss the discovery of PD-L1 and PD-L2 while highlight the potential differences in targeting PD-L1 versus PD-1. In addition, we briefly summarized the available pre-clinical and clinical data of atezolizumab use in NSCLC. A special section covers the challenges of PD-L1 immunohistochemistry assay. Expert commentary: PD-1:PD-L1 blockade has taken the lead in the immunotherapeutics field and represents the backbone of developing combination immunotherapies. Atezolizumab represents a step forward in the treatment of advanced NSCLC, nonetheless PD1:PD-L1 blockade in early-stage lung cancer is still a matter of debate.

Brigatinib (AP26113) is a dimethylphosphine oxide group-containing tyrosine kinase inhibitor (TKI) constructed around a bisanilinopyrimidine scaffold with potent activity against the anaplastic lymphoma kinase (ALK) and several other targets. Despite the activity of first- and second-generation ALK inhibitors in advanced ALK -rearranged lung cancers, the development of acquired resistance represents an ongoing challenge. Later generation ALK inhibitors such as brigatinib are important potential tools in the management of patients with acquired resistance characterized by continued dependency on ALK. Brigatinib is active in vitro against many ALK kinase domain mutations that may mediate acquired resistance to other ALK TKIs, with reported activity (IC 50 <50 nM) against ALK C1156Y, I1171S/T, V1180L, L1196M, L1152R/P, E1210K, and G1269A. In patients with ALK -rearranged lung cancers who receive brigatinib after crizotinib, substantial and durable responses and intracranial disease control can be achieved based on early-phase clinical trial data. The drug is also being explored in TKI-naïve patients. From a safety perspective, early pulmonary toxicity has been observed, prompting the decision to pursue lead-in dosing for the drug. Early data point to ALK G1202R and ALK E1210K as potential mechanisms of clinical resistance to brigatinib., Competing Interests: Disclosure Alexander Drilon has received honoraria from Exelixis, Ignyta, and Loxo Oncology and financial support through a grant from Foundation Medicine. The other authors report no conflicts of interest in this work.