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Background: Radiofrequency ablation (RFA) is a potential application as a salvage tool after failure of surgery, chemotherapy, or radiotherapy of non-small cell lung cancer (NSCLC). Although several studies have evaluated the use of RFA in primary NSCLC, there is little literature on its potential application as a salvage tool. Purpose: To evaluate CT-guided RFA employed as a salvage therapy for pulmonary recurrences of NSCLC after prior treatment with chemotherapy, radiation therapy, and/or surgery. Material and Methods: A retrospective computer database search yielded 33 patients with biopsy proven primary NSCLC who underwent CT-guided RFA of 39 recurrent tumors following surgery, chemotherapy, and/or radiotherapy. Follow-up imaging was performed with CT and PET-CT. The endpoints of interest were progression-free survival (PFS) and time to local progression (TTLP). PFS and TTLP were compared by lesion size (<3 cm, ≥3 cm). Results: The median PFS was 8 months. For patients with a tumor size <3 cm median PFS was 11 months, whereas the median PFS of patients with a tumor size ≥3 cm was 5 months. The difference did not reach statistical significance (P = 0.09). The median TTLP of all tumors was 14 months. TTLP of ablated tumors <3 cm in size was 24 months, compared to 8 months for ablated tumors ≥3 cm in size. The difference did not reach statistical significance (P = 0.07). Conclusion: RFA of recurrent NSCLC may be a valuable salvage tool to achieve local tumor control, especially in tumors measuring <3 cm in size. [ABSTRACT FROM AUTHOR]

Context: Lung cancer is the leading cause of cancer death. Most patients are diagnosed with advanced disease, resulting in a very low 5-year survival. Screening may reduce the risk of death from lung cancer.Objective: To conduct a systematic review of the evidence regarding the benefits and harms of lung cancer screening using low-dose computed tomography (LDCT). A multisociety collaborative initiative (involving the American Cancer Society, American College of Chest Physicians, American Society of Clinical Oncology, and National Comprehensive Cancer Network) was undertaken to create the foundation for development of an evidence-based clinical guideline.Data Sources: MEDLINE (Ovid: January 1996 to April 2012), EMBASE (Ovid: January 1996 to April 2012), and the Cochrane Library (April 2012).Study Selection: Of 591 citations identified and reviewed, 8 randomized trials and 13 cohort studies of LDCT screening met criteria for inclusion. Primary outcomes were lung cancer mortality and all-cause mortality, and secondary outcomes included nodule detection, invasive procedures, follow-up tests, and smoking cessation.Data Extraction: Critical appraisal using predefined criteria was conducted on individual studies and the overall body of evidence. Differences in data extracted by reviewers were adjudicated by consensus.Results: Three randomized studies provided evidence on the effect of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53,454 participants enrolled, screening resulted in significantly fewer lung cancer deaths (356 vs 443 deaths; lung cancer−specific mortality, 274 vs 309 events per 100,000 person-years for LDCT and control groups, respectively; relative risk, 0.80; 95% CI, 0.73-0.93; absolute risk reduction, 0.33%; P = .004). The other 2 smaller studies showed no such benefit. In terms of potential harms of LDCT screening, across all trials and cohorts, approximately 20% of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1% had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and percentage of surgical procedures performed in patients with benign lesions. Major complications in those with benign conditions were rare.Conclusion: Low-dose computed tomography screening may benefit individuals at an increased risk for lung cancer, but uncertainty exists about the potential harms of screening and the generalizability of results. [ABSTRACT FROM AUTHOR]

Purpose: Paclitaxel is an effective therapy for patients with solid tumors. While the albumin-bound formulation eliminates the hypersensitivity reaction caused by the Cremaphor solvent, significant peripheral neuropathy persists when given over the standard 30-min infusion time. We sought to determine if the incidence and severity of peripheral neuropathy could be reduced when the infusion time is lengthened to 2-h.Methods: This was an open-label, single-arm, phase 2 study of albumin-bound paclitaxel given over 2 h. Twenty-five patients with advanced non-small-cell lung cancer were enrolled to determine whether the longer infusion reduced the severity of neuropathy compared to data from an earlier cohort of 40 similar patients treated over 30 min Patients received 125 mg/m(2) of albumin-bound paclitaxel IV over 2 h without premedication on days 1, 8, and 15 of a 28-day cycle. Radiologic assessment was performed every 8 weeks.Results: There was a significant 0.45 grade decrease in average peripheral neuropathy experienced by patients in the 2-h group versus the 30-min group (90% CI, 0.03-0.87). There was, in addition, a significant decrease in grade ≥2 peripheral neuropathy in patients treated over 2 h versus 30 min (28% vs. 55%, 2-sided P = 0.04). A decrease in grade ≥2 neutropenia (20% vs. 48%, 2-sided P = 0.07) was also observed. The median survival, 11 months, was the same for both groups.Conclusion: Increasing the infusion time of albumin-bound paclitaxel from 30 min to 2 h resulted in a significant reduction in both average and grade ≥2 peripheral neuropathy without affecting survival. [ABSTRACT FROM AUTHOR]

Background: The incidence of multiple lung adenocarcinomas is rising, making it difficult to determine the stage and assign treatment in an increasing number of patients following surgery. Clinical guidelines have been developed to distinguish independent non-small cell lung cancers from metastases, that is, criteria developed by Martini and Melamed and the American College of Chest Physicians (ACCP). However, these guidelines can be difficult to apply and may give conflicting results. Here, we report on seven patients in whom epidermal growth factor receptor (EGFR) and Kirsten-rat sarcoma 2 viral oncogene homolog (KRAS) tumor mutation status was used to determine clonal relationships among multiple lung lesions.Methods: We identified seven patients whose paired lung adenocarcinomas were found to harbor distinct EGFR or KRAS mutations. We assessed these patients' disease status using established clinical guidelines. We also explored the use of comprehensive histologic subtyping (CHS) of tumor sections to distinguish multiple primaries.Results: According to the Martini-Melamed criteria, six of the seven patients had multiple primary lung tumors. By ACCP criteria, three patients had multiple primaries, and three patients had metastases. Classification of the seventh patient by ACCP criteria was indeterminate. Mutational testing suggested that all paired tumors were multiple primary adenocarcinomas, which was consistent with results from CHS.Conclusions: Assuming that independent tumor clones harbor distinct mutations, these seven cases highlight discrepancies between the existing clinical criteria used to distinguish independent tumor foci from metastases. EGFR/KRAS mutation testing of multiple lung adenocarcinomas can assist in differentiating multiple primary lung adenocarcinomas from metastatic lesions. Use of CHS in this setting should also be further explored. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a devastating disease with a poor prognosis. Novel chemotherapeutics in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin stalls and degrades RNA Polymerase II and introduces breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin's highly efficient killing of human-derived pancreatic tumor cell lines PANC-1, BxPC-3, and HPAF-II as a single agent. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in the synergistic killing of pancreatic tumor cells. Western blot analysis of combination therapy indicates an upregulation of γH2AX, a DNA damage marker, and the Chk1/ATR pathway, which is involved in replicative stress and DNA damage response. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-fluorouracil (5-FU) results in a highly efficient killing of tumor cells. Our results are developing insights regarding molecular mechanisms underlying the therapeutic efficacy of a novel combination drug treatment for pancreatic cancer.

Purpose: In patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), the standard of care is concurrent chemoradiation (CRT) followed by consolidative immunotherapy with durvalumab. Pneumonitis is a known adverse event of both radiation therapy and immune checkpoint inhibitors such as durvalumab. We sought to characterize pneumonitis rates and dosimetric predictors of pneumonitis in a real-world population of patients with NSCLC treated with definitive CRT followed by consolidative durvalumab., Methods and Materials: Patients with NSCLC from a single institution who were treated with definitive CRT followed by consolidative durvalumab were identified. Outcomes of interest included pneumonitis incidence, type of pneumonitis, progression-free survival, and overall survival., Results: Sixty-two patients were included in our data set treated from 2018 to 2021 with a median follow-up of 17 months. The rate of grade 2+ pneumonitis in our cohort was 32.3%, and the rate of grade 3+ pneumonitis was 9.7%. Lung dosimetry parameters including V20 ≥30% and mean lung dose (MLD) >18 Gy were found to be correlated with increased rates of grade 2+ and grade 3+ pneumonitis. Patients with a lung V20 ≥30% had a grade 2+ pneumonitis rate at 1 year of 49.8% compared with 17.8% in patients with a lung V20 <30% ( P  = .015). Similarly, patients with an MLD >18 Gy had a grade 2+ pneumonitis rate at 1 year of 52.4% compared with 25.8% in patients with an MLD ≤18 Gy ( P  = .01). Moreover, heart dosimetry parameters including mean heart dose ≥10 Gy were found to be correlated with increased rates of grade 2+ pneumonitis. The estimated 1-year overall survival and progression-free survival of our cohort were 86.8% and 64.1%, respectively., Conclusions: The modern management of locally advanced, unresectable NSCLC involves definitive chemoradiation followed by consolidative durvalumab. Pneumonitis rates were higher than expected in this cohort, particularly for patients with a lung V20 ≥30%, MLD >18 Gy, and mean heart dose ≥10 Gy, suggesting that more stringent radiation planning dose constraints may be needed., (© 2022 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.)

The American Cancer Society estimates that ~15% of all lung cancers are categorized as small cell lung cancer (SCLC) with an overall five-year survival rate of less than 7%. Due to disease aggressiveness, more other malignancies, the standard of care is based on clinical efficacy rather than helpful biomarkers. Lurbinectedin is a small molecule RNA polymerase II inhibitor that binds the minor groove of DNA to induce double-strand breaks. Lurbinectedin has efficacy towards SCLC cells at sub-nM concentration and received accelerated FDA approval in 2020 for metastatic SCLC that progressed on platinum-based therapy. ONC201/TIC10 is a TRAIL pathway-inducing compound that with demonstrated clinical efficacy in H3K27M-mutated diffuse midline glioma and neuroendocrine tumors, in early phase clinical trials. We hypothesized that combining ONC201 and lurbinectedin may yield synergistic and targeted killing of SCLC cells. SCLC cell lines H1048, H1105, H1882, and H1417 were treated with ONC201 and lurbinectedin and cell viability was determined using a CellTiter-Glo assay using varying drug concentrations. Synergistic growth inhibition of SCLC cells was noted with combination of ONC201 and lurbinectedin. Induction of the integrated stress response mediator ATF4 and CHOP was observed with ONC201 and lurbinectedin along with induction of PARP cleavage indicative of apoptosis in response to cellular stress. Additionally, SCLC lines treated with the combination therapy displayed increased DNA breakage-related proteins such as phosphorylated Chk-1, Wee1 and γ-H2AX. Combination index revealed the most potent synergy occurred at the concentrations of 0.16 μM ONC201 and 0.05 nM lurbinectedin in the H1048 cell line, demonstrating highly efficient and selective killing of these tumor cells in vitro . While these therapies showed potency against the cell lines derived from SCLC patients, it is noteworthy that the combination showed significantly less toxicity to healthy human lung epithelial cells. Future studies could explore the combination of ONC201 and lurbinectedin in SCLC cell lines, SCLC patient-derived organoids, other tumor types, including in vivo studies and clinical translation., Competing Interests: W.S.E-D. is a co-founder of Oncoceutics, Inc., a subsidiary of Chimerix. Dr. El-Deiry has disclosed his relationship with Oncoceutics and potential conflict of interest to his academic institution/employer and is fully compliant with NIH and institutional policy that is managing this potential conflict of interest., (AJCR Copyright © 2022.)

Background: Alectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor., Patients and Methods: Patients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy., Results: Eleven patients were enrolled between September 2015 and February 2020. Most patients (82%) had baseline brain metastases. Six patients (55%) were treatment-naive; five (46%) had received prior ALK TKIs (crizotinib, n = 3; ceritinib, n = 1; crizotinib then brigatinib, n = 1). No dose-limiting toxicities occurred. RP2D was determined as alectinib 600 mg orally twice daily plus bevacizumab 15 mg/kg intravenously every 3 weeks. Three patients experienced grade 3 treatment-related adverse events: pneumonitis related to alectinib, proteinuria related to bevacizumab, and hypertension related to bevacizumab. Treatment-related intracranial hemorrhage was not observed. Six (100%) of six treatment-naive patients and three (60%) of five ALK TKI-pretreated patients had objective responses; median progression-free survival was not reached (95% confidence interval, 9.0 months-not reached) and 9.5 months (95% confidence interval, 4.3 months-not reached), respectively. Intracranial responses occurred in four (100%) of four treatment-naive and three (60%) of five TKI-pretreated patients with baseline brain metastases. The study was stopped prematurely because of slow accrual., Conclusions: Alectinib plus bevacizumab was well tolerated without unanticipated toxicities or dose-limiting toxicities., Competing Interests: Disclosure JJL has served as a compensated consultant for Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Novartis, and Turning Point Therapeutics; received honorarium and travel support from Pfizer; received institutional research funds from Roche/Genentech, Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Linnaeus Therapeutics, and Novartis; received CME funding from OncLive, MedStar Health, and Northwell Health. CGA has participated in advisory boards with Pfizer, Regeneron/Sanofi-Genzyme, AstraZeneca, Takeda, Daiichi-Sankyo, Jazz, and Bristol-Myers Squibb. LVS has received consulting fees from AstraZeneca, Genentech, Pfizer, and Janssen, and has received institutional research support from Boehringer-Ingelheim, Novartis, AstraZeneca, and Genentech. IDJ has received honoraria from Foundation Medicine, American Lung Association, ASCO Post, OncLive, DAVA Oncology, Creative Education Concepts, Medscape, and Total Health Conferencing; consulting fees from Bayer, Boehringer Ingelheim, BostonGene, AstraZeneca, Pfizer, Xcovery, Catalyst, Novocure, Genentech, and Syros; research support from Array, Genentech, Novartis, Pfizer, and Guardant Health; and travel support from Array and Pfizer. ATS has served as a compensated consultant or received honoraria from Achilles, Archer, Ariad/Takeda, Bayer, Blueprint Medicines, Chugai, Daiichi-Sankyo, EMD Serono, Foundation Medicine, Guardant, Ignyta, KSQ Therapeutics, Loxo Oncology, Natera, Novartis, Pfizer, Roche-Genentech, Servier, Syros, Taiho Pharmaceutical, and TP Therapeutics; received institutional research funding from Ariad, Ignyta, Novartis, Pfizer, Roche-Genentech, and TP Therapeutics; received travel support from Genentech and Pfizer; and is currently employed by and owns stock in Novartis. JFG has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech/Roche, Ariad/Takeda, Loxo/Lilly, Blueprint, Oncorus, Regeneron, Gilead, AstraZeneca, Pfizer, Incyte, Karyopharm, Novartis, Merck, Agios, Amgen, iTeos, GlydeBio, Moderna, and Array; research support from Novartis, Genentech/Roche, and Ariad/Takeda; institutional research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; and has an immediate family member who is an employee of Ironwood Pharmaceuticals. All remaining authors have declared no potential conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer., (© 2021. Springer Nature Limited.)

Aims: Nuclear protein in testis (NUT) carcinoma, an aggressive tumour driven by NUTM1 rearrangements, often involves the lung/mediastinum and shows squamous differentiation. We encountered an index patient with a thoracic NUT carcinoma diagnosed by molecular testing, showing extensive pleural involvement and diffuse thyroid transcription factor-1 (TTF-1) expression, initially suggestive of lung adenocarcinoma with pseudomesotheliomatous growth. We thus gathered an institutional series of thoracic NUT carcinomas to examine their pathological spectrum., Methods and Results: We searched for thoracic NUT carcinomas in our surgical pathology files and in 2289 consecutive patients with primary thoracic tumours investigated with RNA-based assays. We performed NUT immunohistochemistry on 425 additional lung adenocarcinomas. Collectively, we identified six patients (five men and one woman; age 31-80 years; four never-smokers) with thoracic NUT carcinomas confirmed by molecular testing (including five with positive NUT immunohistochemistry). They died at 2.3-12.9 months (median, 2.8 months) after presentation. Two patients were diagnosed by histopathological assessment, and the remaining four (including the index patient) were diagnosed by molecular testing. Analysis of the index case revealed expression of multiple neuroendocrine markers and TTF-1; no ultrastructural evidence of neuroendocrine differentiation was noted. No additional NUT-positive cases were found by immunohistochemical screening., Conclusions: Although NUT carcinoma classically shows squamous differentiation, it can rarely express TTF-1 (even diffusely) and/or multiple neuroendocrine markers. This immunophenotypic spectrum may lead to diagnostic confusion with pulmonary adenocarcinoma, neuroendocrine tumour, and others. To circumvent this pitfall, NUT immunohistochemistry and/or NUTM1 molecular testing should be considered in primitive-appearing tumours, regardless of their immunophenotypic features., (© 2020 John Wiley & Sons Ltd.)

Background: How corticosteroid use affects treatment response to chemotherapy and immune-checkpoint inhibitors (CICPIs) remains unknown. We assessed how systemic corticosteroid exposure before CICPI modifies the effect of CICPI on outcomes among patients with metastatic non-small cell lung cancer (mNSCLC) or extensive-stage small-cell lung cancer (ES-SCLC)., Methods: We conducted a retrospective cohort study using electronic health records to examine patients with mNSCLC or ES-SCLC who received chemotherapy (CT) between 1st April 2015 and 31st January 2018 or CICPI between 1st February 2018 and 31st August 2019. We excluded those with an actionable driver mutation. Baseline corticosteroid use was defined as systemic corticosteroids within 28 days before the initiation of CT or CICPI, not including premedications. Coprimary outcomes included overall survival (OS), real-world progression (rwP), and real-world progression-free survival (rwPFS) in CICPI-treated corticosteroid users versus non-users. We used inverse probability of treatment weighting (IPW) to adjust for potential confounding., Results: The cohort of 316 patients (median [interquartile range] age, 67 [61-73] years; 156 [49%] male) included 228 CT-treated and 88 CICPI-treated patients. After applying IPW, characteristics were well-balanced between the CT and CICPI groups, and steroid users and non-users. Using CT-treated steroid non-users as a common comparator, CICPI-treated steroid users were as likely as CICPI-treated steroid non-users to die (users IPW hazard ratio [HR] = 0.67, 95% CI = 0.35-1.28 versus non-users IPW-HR = 0.88, 95% C = I0.55-1.42; p = 0.49), have rwP (IPW-HR = 0.35, 95% C = I0.12-0.99 versus IPW-HR = 0.41, 95% C = I0.24-0.70; p = 0.77), or experience rwPFS (IPW-HR = 0.56, 95% C = I0.29-1.09 versus IPW-HR = 0.69, 95% CI0.46-1.03; p = 0.59)., Conclusion: Corticosteroid use before CICPIs was not associated with worse outcomes, suggesting that corticosteroids should be used with CICPIs when indicated., Competing Interests: Conflict of interest statement All authors have no conflicts of interest to report., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

For patients with surgically resected disease, multiple studies suggest a benefit of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in delaying cancer recurrence. The necessary duration of therapy for benefit is unknown., Materials and Methods: This randomized phase II study enrolled patients with completely resected stage IA-IIIB EGFR -mutant non-small-cell lung cancer (American Joint Committee on Cancer 7th edition) after stage-appropriate standard-of-care adjuvant therapy. Patients were randomly assigned 1:1 to 3 months or 2 years of adjuvant afatinib starting at 30 mg by mouth daily. Computed tomography imaging was performed every 6 months for 3 years and then annually. The primary study end point for this planned 92-patient trial was recurrence rate at 2 years from randomization. A 20% improvement (from 70% with 3 months to 90% with 2 years) was targeted., Results: Forty-six patients enrolled and 45 were treated. The assigned course of afatinib treatment was completed by 96% (22/23) of patients in the 3-month group and only 41% (9/22) in the 2-year group. The 2-year recurrence-free survival (RFS) rates were 70% in the 3-month group and 81% in the 2-year group ( P = .55). The median RFS was 42.8 months in the 3-month group and 58.6 months in the 2-year group. Side effects were consistent with those previously described for afatinib., Conclusion: Recurrences at 2 years were 11% less common with 2 years versus 3 months of adjuvant afatinib. This difference did not meet the 20% primary study target, likely because of underaccrual and early drug discontinuation on the 2-year group. With the availability of osimertinib with better efficacy and tolerability than earlier-generation agents, the optimal duration of adjuvant EGFR TKI therapy remains an important question., (© 2021 by American Society of Clinical Oncology.)

Background: Metastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches., Patients and Methods: Patients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non-MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group., Results: We identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and <25 MET copy number) compared with highly amplified tumors (≥25 MET copy number)., Conclusion: MET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes., Implications for Practice: This article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice., (© AlphaMed Press 2020.)

Purpose: Most ALK -positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed., Experimental Design: We performed FISH and/or next-generation sequencing on 207 posttreatment tissue ( n = 101) or plasma ( n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance., Results: MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib ( P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy., Conclusions: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET., (©2020 American Association for Cancer Research.)

The diagnosis and treatment of lung cancer is entering a new era. With increasingly advanced diagnostic tools, we are more able than ever to pinpoint genetic changes in tumor cells that allow us to treat with highly effective, targeted therapy. In a growing number of patients, we are able to avoid cytotoxic therapies altogether. The recent advent of immunotherapy has led to a similar paradigm shift. This article will review the latest advances in tumor tissue and blood biomarkers directly as they relate to available treatments. Specifically, we will review activating and sensitizing gene mutations, gene fusions, PD-L1 tumor score, and close with an appraisal of the rapidly advancing field of peripheral blood biomarkers.

Background: Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) in metastatic esophagogastric adenocarcinoma., Methods: Patients with treatment-naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo-controlled, double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS)., Results: Sixty-four patients were randomized to receive mFOLFOX6 and ziv-aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv-aflibercept tended to be more likely to discontinue study treatment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment-related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv-aflibercept cohort., Conclusions: Ziv-aflibercept did not increase the anti-tumor activity of first-line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv-aflibercept in unselected, chemotherapy-naive patients with metastatic esophagogastric adenocarcinoma is not warranted., (© 2019 American Cancer Society.)

Purpose: Given the pivotal role of epidermal growth factor receptor (EGFR) inhibitors in advanced EGFR-mutant non-small-cell lung cancer (NSCLC), we tested adjuvant erlotinib in patients with EGFR-mutant early-stage NSCLC., Materials and Methods: In this open-label phase II trial, patients with resected stage IA to IIIA (7 th edition of the American Joint Committee on Cancer staging system) EGFR-mutant NSCLC were treated with erlotinib 150 mg per day for 2 years after standard adjuvant chemotherapy with or without radiotherapy. The study was designed for 100 patients and powered to demonstrate a primary end point of 2-year disease-free survival (DFS) greater than 85%, improving on historic data of 76%., Results: Patients (N = 100) were enrolled at seven sites from January 2008 to May 2012; 13% had stage IA disease, 32% had stage IB disease, 11% had stage IIA disease, 16% had stage IIB disease, and 28% had stage IIIA disease. Toxicities were typical of erlotinib; there were no grade 4 or 5 adverse events. Forty percent of patients required erlotinib dose reduction to 100 mg per day and 16% to 50 mg per day. The intended 2-year course was achieved in 69% of patients. The median follow-up was 5.2 years, and 2-year DFS was 88% (96% stage I, 78% stage II, 91% stage III). Median DFS and overall survival have not been reached; 5-year DFS was 56% (95% CI, 45% to 66%), 5-year overall survival was 86% (95% CI, 77% to 92%). Disease recurred in 40 patients, with only four recurrences during erlotinib treatment. The median time to recurrence was 25 months after stopping erlotinib. Of patients with recurrence who underwent rebiopsy (n = 24; 60%), only one had T790M mutation detected. The majority of patients with recurrence were retreated with erlotinib (n = 26; 65%) for a median duration of 13 months., Conclusion: Patients with EGFR-mutant NSCLC treated with adjuvant erlotinib had an improved 2-year DFS compared with historic genotype-matched controls. Recurrences were rare for patients receiving adjuvant erlotinib, and patients rechallenged with erlotinib after recurrence experienced durable benefit.

BH3 mimetic drugs, which inhibit prosurvival BCL2 family proteins, have limited single-agent activity in solid tumor models. The potential of BH3 mimetics for these cancers may depend on their ability to potentiate the apoptotic response to chemotherapy and targeted therapies. Using a novel class of potent and selective MCL1 inhibitors, we demonstrate that concurrent MEK + MCL1 inhibition induces apoptosis and tumor regression in KRAS -mutant non-small cell lung cancer (NSCLC) models, which respond poorly to MEK inhibition alone. Susceptibility to BH3 mimetics that target either MCL1 or BCL-xL was determined by the differential binding of proapoptotic BCL2 proteins to MCL1 or BCL-xL, respectively. The efficacy of dual MEK + MCL1 blockade was augmented by prior transient exposure to BCL-xL inhibitors, which promotes the binding of proapoptotic BCL2 proteins to MCL1. This suggests a novel strategy for integrating BH3 mimetics that target different BCL2 family proteins for KRAS -mutant NSCLC. SIGNIFICANCE: Defining the molecular basis for MCL1 versus BCL-xL dependency will be essential for effective prioritization of BH3 mimetic combination therapies in the clinic. We discover a novel strategy for integrating BCL-xL and MCL1 inhibitors to drive and subsequently exploit apoptotic dependencies of KRAS -mutant NSCLCs treated with MEK inhibitors. See related commentary by Leber et al., p. 1511 . This article is highlighted in the In This Issue feature, p. 1494 ., (©2018 American Association for Cancer Research.)

Background: There are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20., Patients and Methods: Twenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype., Results: Among the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4-5.6) and median OS (mOS) was 13 months (95% CI 4.9-19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD ≥3 months. The most common luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination., Conclusion: The study met its primary end point, suggesting that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other hsp90 inhibitors in this population is warranted., Study Registration (clinicaltrials.gov): NCT01854034.

Purpose: ALK rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived. Serial molecular analysis is an informative strategy for identifying genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer., Methods: Using a 566-gene hybrid-capture next-generation sequencing (NGS) assay, we performed longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue-plasma concordance, we compared plasma findings to results of repeat biopsies., Results: At progression, we detected an ALK fusion in plasma from 19 (86%) of 22 patients, and identified ALK resistance mutations in plasma specimens from 11 (50%) patients. There was 100% agreement between tissue- and plasma-detected ALK fusions. Among 16 cases where contemporaneous plasma and tissue specimens were available, we observed 100% concordance between ALK mutation calls. ALK mutations emerged and disappeared during treatment with sequential ALK TKIs, suggesting that plasma mutation profiles were dependent on the specific TKI administered. ALK G1202R, the most frequent plasma mutation detected after progression on a second-generation TKI, was consistently suppressed during treatment with lorlatinib., Conclusions: Plasma genotyping by NGS is an effective method for detecting ALK fusions and ALK mutations in patients progressing on ALK TKIs. The correlation between plasma ALK mutations and response to distinct ALK TKIs highlights the potential for plasma analysis to guide selection of ALK-directed therapies., Competing Interests: The remaining authors have no financial interests to declare.

The discovery of gene rearrangements involving the receptor tyrosine kinase genes ALK and ROS1 has revolutionized management of the subset of non-small cell lung cancers characterized by these alterations. The oncogenic fusion proteins expressed in these tumors drive cancer cell growth and survival, and targeted inhibition of this signaling can lead to dramatic and durable responses in patients. While the best characterized gene fusions in non-small cell lung cancer (NSCLC) involve ALK and ROS1 , fusions involving other kinases including RET , NTRK , EGFR and BRAF are now established as additional targetable drivers. Here we review data supporting the roles of these fusions as oncogenic drivers, and the potential for targeting these fusions for improved clinical outcomes. These discoveries should encourage multiplexed molecular profiling of lung cancers using next-generation platforms which identify these gene fusions in order to expand treatment options for patients., Competing Interests: Conflicts of Interest: AF Farago serves as consulting or advisory role for Abbive, Pharmamar, Merrimack Pharmaceuticals, Takeda, Intervention Insights, and received honorarium from Foundation Medicine. CG Azzoli has no conflicts of interest to declare.

Purpose The panel updated the American Society of Clinical Oncology (ASCO) adjuvant therapy guideline for resected non-small-cell lung cancers. Methods ASCO convened an update panel and conducted a systematic review of the literature, investigating adjuvant therapy in resected non-small-cell lung cancers. Results The updated evidence base covered questions related to adjuvant systemic therapy and included a systematic review conducted by Cancer Care Ontario current to January 2016. A recent American Society for Radiation Oncology guideline and systematic review, previously endorsed by ASCO, was used as the basis for recommendations for adjuvant radiation therapy. An update of these systematic reviews and a search for studies related to radiation therapy found no additional randomized controlled trials. Recommendations Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections. For individuals with stage IB, adjuvant cisplatin-based chemotherapy is not recommended for routine use. However, a postoperative multimodality evaluation, including a consultation with a medical oncologist, is recommended to assess benefits and risks of adjuvant chemotherapy for each patient. The guideline provides information on factors other than stage to consider when making a recommendation for adjuvant chemotherapy, including tumor size, histopathologic features, and genetic alterations. Adjuvant chemotherapy is not recommended for patients with stage IA disease. Adjuvant radiation therapy is not recommended for patients with resected stage I or II disease. In patients with stage IIIA N2 disease, adjuvant radiation therapy is not recommended for routine use. However, a postoperative multimodality evaluation, including a consultation with a radiation oncologist, is recommended to assess benefits and risks of adjuvant radiation therapy for each patient with N2 disease. Additional information is available at www.asco.org/lung-cancer-guidelines and www.asco.org/guidelineswiki .

Purpose: PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients., Experimental Design: We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORR) were assessed using RECIST v1.1. PD-L1 expression and CD8(+) tumor-infiltrating lymphocytes (TIL) were evaluated by IHC., Results: Objective responses were observed in 1 of 28 (3.6%) EGFR-mutant or ALK-positive patients versus 7 of 30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- (≤10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced EGFR-mutant (N = 68) and ALK-positive (N = 27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre-tyrosine kinase inhibitor (TKI) biopsies using cutoffs of ≥1%, ≥5%, and ≥50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI-resistant biopsies (N = 57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (≥5%) and high levels of CD8(+) TILs (grade ≥2) were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens and was not observed in any ALK-positive, pre- or post-TKI specimens., Conclusions: NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8(+) TILs within the tumor microenvironment may underlie these clinical observations. Clin Cancer Res; 22(18); 4585-93. ©2016 AACRSee related commentary by Gettinger and Politi, p. 4539., (©2016 American Association for Cancer Research.)

Introduction: Cancer will be diagnosed in one in 1000 women during pregnancy. The outcomes of NSCLC diagnosed during pregnancy are dismal, with most patients dying within 1 year. Actionable mutations are more likely to be found among younger patients with NSCLC. However, most previous reports of NSCLC diagnosed during pregnancy did not include molecular genotyping., Methods: We performed a retrospective analysis of patients seen at our institution between 2009 and 2015 to identify women in whom NSCLC was diagnosed during pregnancy or the peripartum period and determined clinicopathologic features, including molecular genotype., Results: We identified 2422 women with NSCLC, including 160 women of reproductive age. Among the women of reproductive age, eight cases of NSCLC diagnosed during pregnancy or the peripartum period were identified; all were diagnosed in minimal or never-smokers with metastatic adenocarcinoma. Six of these patients were found to have anaplastic lymphoma kinase gene (ALK) rearrangements, whereas the remaining two were EGFR mutation positive. We observed a borderline significant association between a diagnosis of NSCLC during pregnancy or the peripartum period and ALK positivity (p = 0.053). All eight women in whom NSCLC was diagnosed during pregnancy or the peripartum period received treatment with genotype-directed therapies after delivery. The median overall survival has not been reached at a median follow-up of 30 months., Conclusions: Although a diagnosis of NSCLC during pregnancy or the peripartum period is rare, diagnostic evaluation should not be delayed in pregnant women presenting with symptoms worrisome for lung cancer. Evaluation should include testing for targetable molecular alterations., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Although perioperative chemotherapy improves survival in patients with resectable lung cancers, systemic recurrence remains common. Neoadjuvant chemotherapy permits response assessment and an opportunity to switch treatment regimens. Response measured by fludeoxyglucose ((18)F-FDG) positron emission tomography (PET) correlates with clinical outcomes better than computed tomography (CT) does. This trial assessed PET-measured response rate to alternative chemotherapy in patients with a suboptimal PET response after two cycles of neoadjuvant chemotherapy., Methods: This phase II study enrolled patients with resectable stage IB-IIIA lung cancers (primary tumor ≥ 2 cm and peak standard uptake value [SUVpeak] ≥ 4.5). Patients had a pretreatment (18)F-FDG PET/CT scan before two cycles of cisplatin (or carboplatin) plus gemcitabine (squamous cell carcinoma) or pemetrexed (adenocarcinoma) and then a repeat PET/CT scan. If SUVpeak in the primary tumor decreased by at least 35%, patients continued the initial chemotherapy. Individuals with less than a 35% PET response were switched to vinorelbine plus docetaxel. Postoperative radiotherapy was recommended to all patients with positive N2 nodes. A Simon's optimal two-stage design was used to evaluate the primary end point of a PET Response in Solid Tumors-defined response rate to vinorelbine plus docetaxel in previously nonresponding patients., Results: Forty patients were enrolled. Fifteen patients (38% [95% confidence interval: 38-53]) had less than a 35% decrease in SUVpeak, and 13 received vinorelbine plus docetaxel. The study met its primary end point with 10 of 15 PET metabolic responses to alternate therapy (67%). Chemotherapy toxicities never precluded surgical exploration., Conclusions: Utilizing (18)F-FDG PET/CT to assess response and change preoperative chemotherapy in nonresponding patients can improve radiographic measures of response. This adaptive approach can also be used to test new drugs, attempting to optimize perioperative chemotherapy to achieve better long-term outcomes., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Lung cancers account for the majority of brain metastases which pose major therapeutic challenges. Biomarkers prognosticating for the development of brain metastases in patients with non-small cell lung cancers (NSCLC) may improve personalized care. Six serum proteomic biomarkers were previously investigated at Memorial Sloan Kettering but their associations with brain metastases were unknown., Methods: Serum NSE, CYFRA 21-1, ProGRP, SCC-Ag, TIMP1, and HE4 by ELISA-based proteomic assays were prospectively collected from consecutive patients with stage IV NSCLC. Pre-treatment serum biomarker levels as well as age, histology, and epidermal growth factor receptor (EGFR) mutation status were evaluated for association with the baseline presence of brain metastases using logistic regression and multivariable analysis. For patients without brain metastases at baseline, the cumulative incidence of subsequent brain metastases were compared according to baseline biomarkers and clinical factors using Gray's test., Results: A total of 118 patients were enrolled, 31 (26%; 95% CI 0.19-0.35) had brain metastases at baseline and a further 26 (22%; 95% CI 0.15-0.30) developed brain metastases subsequently. Pre-treatment serum biomarker levels were available in 104 patients. There was no significant association between the six serum biomarkers and the baseline presence or subsequent development of brain metastases. Age younger than 65 years was the only clinical factor significantly associated with brain metastasis at baseline (OR 3.00; 95% CI 1.22-7.34, P = 0.02) by multivariable analysis. A trend toward increased cumulative incidence of subsequent brain metastases was observed in patients with EGFR mutation (p = 0.2), but this was not statistically significant possibly due to small sample size., Conclusions: Serum NSE, CYFRA 21-1, Pro-GRP, SCC-Ag, TIMP1, and HE4 are not significantly associated with brain metastases. Our methods taking into account follow-up time may be applied to independent datasets to identify a patient cohort with a higher biologic propensity for developing brain metastases. Such information may be useful for the study of agents targeting the development of brain metastases.

Background: While previous studies have reported on the prognostic value of total plasma cell-free deoxyribonucleic acid (cfDNA) in lung cancers, few have prospectively evaluated its predictive value for systemic therapy response., Patients and Methods: We conducted a prospective study to evaluate the association between changes in total cfDNA and radiologic response to systemic therapy in patients with stage IIIB/IV non-small-cell lung cancers (NSCLCs). Paired blood collections for cfDNA and computed tomography (CT) assessments by RECIST v1.0 were performed at baseline and 6-12 weeks after therapy initiation. Total cfDNA levels were measured in plasma using quantitative real-time polymerase chain reaction. Associations between changes in cfDNA and radiologic response, progression-free survival (PFS), and overall survival (OS) were measured using Kruskal-Wallis and Kaplan-Meier estimates., Results: A total of 103 patients completed paired cfDNA and CT response assessments. Systemic therapy administered included cytotoxic chemotherapy in 57% (59/103), molecularly targeted therapy in 17% (17/103), and combination therapy in 26% (27/103). Median change in cfDNA from baseline to response assessment did not significantly differ by radiologic response categories of progression of disease, stable disease and partial response (P = 0.10). However, using radiologic response as continuous variable, there was a weak positive correlation between change in radiologic response and change in cfDNA (Spearman's correlation coefficient 0.21, P = 0.03). Baseline cfDNA levels were not associated with PFS [hazard ratio (HR) = 1.06, 95% confidence interval (CI) 0.93-1.20, P = 0.41] or OS (HR = 1.04, 95% CI 0.93-1.17, P = 0.51), neither were changes in cfDNA., Conclusions: In this large prospective study, changes in total cfDNA over time did not significantly predict radiologic response from systemic therapy in patients with advanced NSCLC. Pretreatment levels of total cfDNA were not prognostic of survival. Total cfDNA level is not a highly specific predictive biomarker and future investigations in cfDNA should focus on tumor-specific genomic alterations using expanded capabilities of next-generation sequencing., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To provide evidence-based recommendations to update the American Society of Clinical Oncology guideline on systemic therapy for stage IV non-small-cell lung cancer (NSCLC)., Methods: An Update Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of randomized controlled trials from January 2007 to February 2014., Results: This guideline update reflects changes in evidence since the previous guideline., Recommendations: There is no cure for patients with stage IV NSCLC. For patients with performance status (PS) 0 to 1 (and appropriate patient cases with PS 2) and without an EGFR-sensitizing mutation or ALK gene rearrangement, combination cytotoxic chemotherapy is recommended, guided by histology, with early concurrent palliative care. Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 (bevacizumab may be added to carboplatin plus paclitaxel if no contraindications); combination or single-agent chemotherapy or palliative care alone for those with PS 2; afatinib, erlotinib, or gefitinib for those with sensitizing EGFR mutations; crizotinib for those with ALK or ROS1 gene rearrangement; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma. Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens, alternative chemotherapy, or a chemotherapy break. In the second-line setting, recommendations include docetaxel, erlotinib, gefitinib, or pemetrexed for patients with nonsquamous cell carcinoma; docetaxel, erlotinib, or gefitinib for those with squamous cell carcinoma; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib. In the third-line setting, for patients who have not received erlotinib or gefitinib, treatment with erlotinib is recommended. There are insufficient data to recommend routine third-line cytotoxic therapy. Decisions regarding systemic therapy should not be made based on age alone. Additional information can be found at http://www.asco.org/guidelines/nsclc and http://www.asco.org/guidelineswiki., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

Over a decade since the discovery of EGFR mutation, and 6 years since prospective clinical trial data proved that routine molecular pathology tests improve survival in stage IV lung cancer, there is still debate whether to test patients with earlier stages of disease (stage I-III). As discoveries of targeted drugs for stage IV patients accelerate-prompting routine testing for ALK, ROS1, RET, BRAF V600E, and HER2, among others-there is an argument that all lung cancers should be genotyped for the purpose of classification, regardless of stage of disease. The counterargument is that because targeted drugs have only been validated for use in stage IV disease, these molecular tests need only be conducted at the time of disease recurrence. This review will describe current, practical applications of molecular pathology testing in early stage lung cancer, focusing on the immediate diagnostic, prognostic, and therapeutic implications for individual patient management. Meanwhile, large-scale clinical trials are underway to test targeted drugs as adjuvant therapies in patients with early stage disease.

Purpose: The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on external-beam radiotherapy for patients with locally advanced non-small-cell lung cancer (NSCLC). Because of its relevance to the American Society of Clinical Oncology (ASCO) membership, ASCO endorsed the guideline after applying a set of procedures and a policy that are used to critically examine and endorse guidelines developed by other guideline development organizations., Methods: The ASTRO guideline was reviewed by ASCO content experts for clinical accuracy and by ASCO methodologists for developmental rigor. On favorable review, an ASCO expert panel was convened and endorsed the guideline. The ASCO guideline approval body, the Clinical Practice Guideline Committee, approved the final endorsement., Results: The recommendations from the ASTRO guideline, published in Practical Radiation Oncology, are clear, thorough, and based on the most relevant scientific evidence. The ASCO Endorsement Panel endorsed the guideline and added qualifying statements., Recommendations: For curative-intent treatment of locally advanced NSCLC, concurrent chemoradiotherapy improves local control and overall survival compared with sequential chemotherapy followed by radiation. The standard dose-fractionation of radiation is 60 Gy given in 2-Gy once-daily fractions over 6 weeks. There is no role for the routine use of induction therapy before chemoradiotherapy. Current data fail to support a clear role for consolidation therapy after chemoradiotherapy; however, consolidation therapy remains an option for patients who did not receive full systemic chemotherapy doses during radiotherapy. Important questions remain about the ideal concurrent chemotherapy regimen and optimal management of patients with resectable stage III disease., (© 2015 by American Society of Clinical Oncology.)