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News from the IASLC Tobacco Control Committee
IN THIS ISSUE/RESEARCH WATCH/NEWS-IN-BRIEF/NEWS FROM THE IASLC TOBACCO CONTROL COMMITTEE In This Issue Emergence of Preexisting MET Y1230C Mutation as a Resistance Mechanism to Crizotinib in NSCLC with MET Exon 14 Skipping This brief report describes the assessment of the mechanism underlying resistance to crizotinib in NSCLC harboring MNNG HOS Transforming gene (MET) exon 14 skipping (METex14) alterations using hybrid captureebased comprehensive genomic profiling from tumor specimen at diagnosis and a hybrid captureebased assay of circulating tumor DNA (ctDNA) at progression during crizotinib treatment. Retrospective analysis detected MET D1010H and MET Y1230C in 0.3% of pretreated tumor biopsy specimen. Both mutations were also detected in the ctDNA prospectively after a confirmed response during a 13-month crizotinib treatment followed by progression. In summary, the results suggest that preexisting MET Y1230C may modulate the response to type I MET tyrosine kinase inhibitors and confers resistance to crizotinib in this METex14-positive NSCLC. Plasma-based ctDNA assays are convenient and noninvasive tools for the detection of resistance mutations in patients harboring previously known driver mutations. (p. 137)
Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry This study retrospectively analyzed the International Thymic Malignancy Interest Group database for determinants of complete resection (R0) among patients treated with minimally invasive thymectomy (MIT) and open thymectomy (OT). Of the 2514 patients underwent thymectomy for thymoma (1997-2012), OT accounted for 82% and MIT for 18%, with significant increase in MIT use in recent years. The rate of R0 resection was 86% in the OT group and 94% in the MIT group (p < 0.0001), but it did not differ between propensity matched groups (p ¼ 0.7). Geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy were independently associated with R0 resection, while minimally invasive or open surgical approach did not show the association. In summary, though substantial increase in the use of MIT for thymoma has been observed, rates of R0 were comparable between MIT and OT. (p. 129)
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Quantitative Analysis of Circulating Cell-Free DNA for Correlation with Lung Cancer Survival: A Systematic Review and Meta-Analysis The authors conducted a systematic review and meta-analysis of primary studies up to March 2016 on PubMed, Web of Knowledge, and Cochrane databases to determine the impact of higher baseline cfDNA levels on survival outcomes of patients with lung cancer. Of the 17 studies identified, 16 (n ¼ 1723) were included in the meta-analysis of overall survival (OS), and 5 (n ¼ 640) for progression-free survival (PFS). Pooled analysis for OS demonstrated increase risk of death in patients with higher baseline cfDNA levels (hazard ratio, HR 1.76; p < 0.001) while the association with PFS was not significant (HR 1.12). No statistical evidence of publication bias in the results was detected by the Egger’s test. All in all, the findings support the clinical validity of quantitative analysis of cfDNA for predicting lung cancer survival, and warrant the development of a robust standardized method to determine optimal cutoff thresholds. (p. 43)
A Two-Gene Prognostic Classifier for Early-Stage Lung Squamous Cell Carcinoma in Multiple Large-Scale and Geographically Diverse Cohorts The study evaluated the expression of 253 genes selected by literature based on their known functions in lung squamous cell carcinoma (SCC) development and prognosis in order to establish a robust prognostic classifier for stage I/II lung SCC. The analysis included 2 independent cohorts of 121 and 91 patients with SCC for associations with survival, and 6 additional publicly available data sets of stage I/II lung SCC expression profiles (n ¼ 358) for examining the classifier score. Meta-analysis of patients with stage I/II (n ¼ 479) and stage I (n ¼ 326) lung SCC was conducted to assess the prognostic value of the classifier. Prognostic outcome in two independent patient cohorts was associated with dual specificity phosphatase 6 gene (DUSP6) and actinin alpha 4 gene (ACTN4), of which expression values were used to derive a classifier to identify patients with stage I/II lung SCC at high risk for recurrence (hazard ratio [HR] ¼ 4.7; p ¼ 0.018) or cancer-specific mortality (HR ¼ 3.5; p ¼ 0.016). The same was observed in publicly available data sets of stage I/II and in meta-analysisof stage I patients: identified high risk for recurrence (HR ¼ 2.7; p ¼ 0.008) or death (HR ¼ 2.2; p ¼ 0.001). To conclude, the authors have established and validated a prognostic 2-gene classifier to guide clinical management of surgically resected lung SCC patients. (p. 65)
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Research Watch Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients with ALK-Positive NSCLC Pooled analysis of 2 single-arm phase II studies (NCT01871805 and NCT01801111, respectively) was aimed to assess CNS response to alectinib in patients with ALK-positive NSCLC previously treated with crizotinib. At a median follow-up of 12.4 months, patients with measureable CNS disease at baseline had an independent review committee (IRC) CNS objective response rate (CORR) of 64.0%, CNS disease control rate (CDCR) of 90.0%, and median CNS duration of response (CDOR) of 10.8 months. Patients with measurable and/or nonmeasurable baseline CNS disease demonstrated an IRC CORR of 42.6%, CDCR of 85.3%, and median CDOR of 11.1 months. CORR was 35.8% for patients with prior radiotherapy, and 58.5% for those without prior radiotherapy. Toxicity results were aligned with previous study regardless of baseline CNS disease. In summary, alectinib demonstrated good efficacy against CNS metastases, in addition to systemic activity, in crizotinib-refractory ALK-positive NSCLC. Gadgeel SM, Shaw AT, Govindan R, et al. Pooled analysis of CNS response to alectinib in two studies of pretreated patients with ALK-positive nonesmall-cell lung cancer [e-pub ahead of print]. J Clin Oncol. http://dx.doi.org/10. 1200/JCO.2016.68.4639, accessed November 9, 2016.
Pembrolizumab versus Chemotherapy for PD-L1ePositive NSCLC The phase III trial, KEYNOTE-024, randomized 305 patients with previously untreated advanced NSCLC, harboring 50% tumor PD-L1 expression, without sensitizing EGFR mutations or ALK translocation, to penbrolizumab or platinum-based chemotherapy. Compared with the chemotherapy group, the pembrolizumab group achieved a median progression-free survival (PFS) of 10.3 months versus 6.0 months (hazard ratio, HR: 0.50; p < 0.001), an estimated 6-month overall survival (OS) rate of 80.2% versus 72.4% (HR: 0.60; p ¼ 0.005), an objective response rate of 44.8% versus 27.8%, and a longer median duration of response (not reached) versus 6.3 months. Less treatment-related adverse events and those of grade 3, 4, or 5 were observed in the pembrolizumab group versus the chemotherapy group (73.4% versus 90.0% and 26.6% versus 53.3%, respectively). Taken together, pembrolizumab resulted in significantly improved PFS and OS, with a better safety profile in patients with advanced NSCLC harboring 50% tumor PD-L1 expression when compared with platinum-based chemotherapy. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1epositive none small-cell lung cancer [e-pub ahead of print]. N Engl J Med. http://dx.doi.org/10.1056/NEJMoa1606774, accessed November 9, 2016.
Osimertinib for Pretreated EGFR Thr790Met-Positive Advanced NSCLC (AURA2): A Multicenter, Open-Label, Single-Arm, Phase 2 Study The phase 2, open-label, single-arm study (AURA2) assessed the efficacy and safety of osimertinib in 199 evaluable patients with EGFR Thr790Met-positive, stage IIIB/IV NSCLC that progressed on prior EGFR TKI therapy. At data cutoff (Nov 1, 2015), 58% patients remained on treatment, with the median duration of follow-up of 13.0 months. Objective response was achieved in 70% of patients, of which 3% were complete responses and 67% were partial responses. Pulmonary embolism, prolonged electrocardiogram QT, decreased neutrophil count, anaemia, dyspnoea, hyponatraemia, increased alanine aminotransferase, and thrombocytopenia were the most common all-causality grade 3 and 4 adverse events (AEs). Potentially treatment-related serious AEs were found in 5% of patients, with one death due to interstitial lung disease. In summary, the findings demonstrated clinical activity with tolerable safety profile of osimertinib for patients with EGFR Thr790Met-positive NSCLC, indicating a potential treatment for the study patient population. Goss G, Tsai C-M, Shepherd FA, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study [e-pub ahead of print]. Lancet Oncology. http://dx.doi.org/10.1016/S1470-2045(16)30508-3, accessed November 9, 2016.
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Have Combustible Cigarettes Met Their Match? The Nicotine Delivery Profiles and Harmful Constituent Exposures of Second-Generation and Third-Generation Electronic Cigarette Users This study evaluated the nicotine delivery profile of third- (G3) versus second-generation (G2) e-cigarette devices and their users’ exposure to nicotine and select harmful/potentially harmful constituents (HPHCs) compared with cigarette smokers in 30 participants. Comparable cotinine levels at baseline were observed in smokers, G2 and G3 users, while 4 and 7 times higher levels of eCO (p < 0.0001) and total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (i.e., NNAL, p < 0.01), respectively, were found in smokers versus G2 or G3 users. Compared with G2s, G3 users received significantly lower nicotine concentrations from e-cigarette liquids, thought devices delivered higher power to the atomiser, achieved higher plasma nicotine concentrations after the first 10 puffs (17.5 versus 7.3 ng/mL) and at 25 and 40 min of ad libitum use, and consumed more e-liquid. To conclude, G3 devices delivered the amount and speed of nicotine comparable to that of conventional cigarette. G2 and G3 e-cigarettes led to significantly lower levels of exposure to potent lung carcinogen and cardiovascular toxicant. The results help further understand addiction to these devices and their values in smoking cessation. Wagener TL, Floyd EL, Stepanov I, et al. Have combustible cigarettes met their match? The nicotine delivery profiles and harmful constituent exposures of second-generation and third-generation electronic cigarette users. Tob Control. http://dx.doi.org/10.1136/tobaccocontrol-2016-053041, accessed November 9, 2016. State-Level Cancer Mortality Attributable to Cigarette Smoking in the United States The study aimed to determine the proportion of cancer deaths in adults aged 35 years or younger attributable to cigarette smoking in 2014 in each state and the District of Columbia. The main outcome was population-attributable fraction (PAF) of cancer deaths due to cigarette smoking, based on relative risks for 12 smoking-related cancers from large U.S. prospective studies and state-specific smoking prevalence data from the Behavioral Risk Factor Surveillance System. The data estimated that at least 28.6% of all cancer deaths in the United States in 2014 were attributable to cigarette smoking. The proportion in men ranged from 21.8% in Utah to 39.5% in Arkansas, with at least 30% in every state except Arkansas while that in women ranged from 11.1% in Utah to 29.0% in Kentucky, with at least 20% in every state except Utah, California, and Hawaii. States in the South constituted more than half of the top 10 ranked states for both men and women. In the top 5 ranked states, smoking attributed to almost 40% of cancer deaths in men, and less than 26% in women. In summary, substantial differences across states were observed in the proportion of cancer deaths attributable to cigarette smoking, in which the South scores the highest, with up to 40% of men’s cancer deaths due to smoking. Enhanced tobacco control strategies are warranted to reduce morbidity and mortality associated with smoking-related cancers in the future. Lortet-Tieulent J, Goding Sauer A, Siegel RL, et al. State-level cancer mortality attributable to cigarette smoking in the United States [e-pub ahead of print]. JAMA Intern Med. http://dx.doi.org/10.1001/jamainternmed.2016.6530, accessed November 9, 2016. News-in-Brief Pembrolizumab Approved for First-Line Treatment of PD-L1ePositive NSCLC Pembrolizumab received FDA approval for first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression ( 50%) as determined by an FDAapproved test, and without EGFR or ALK gene aberrations. This approval also expands the indication in second-line treatment of patients with metastatic NSCLC tumors to include all patients with PD-L1-expressing NSCLC. The approval was based on findings from two randomized, controlled trials demonstrating significantly improved progression-free survival (PFS) and overall survival (OS) for the pembrolizumab arm versus the chemotherapy arm. Comparing with chemotherapy, pembrolizumab resulted in improved PFS (10.3 versus 6.0 months; hazard ratio [HR] ¼ 0.50; p <0.001) and OS (HR ¼ 0.60; p < 0.005) in
Image credit: The website of the National Cancer Institute (http://www.cancer.gov).
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KEYNOTE-024. KEYNOTE-010 showed improved OS in the pembrolizumab arm versus the chemothepray arm. (Pembrolizumab at 2 mg/kg every 3 weeks: HR ¼ 0.71, p < 0.001; 10 mg/kg every 3 weeks: HR ¼ 0.61, p < 0.001). The most common side effects of treatment with pembrolizumab included decreased appetite, fatigue, nausea, dyspnea, cough, and constipation. Rare but serious adverse events included immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. The recommended dose and schedule of pembrolizumab for NSCLC is 200 mg intravenously every 3 weeks.
Indication of Erlotinib in NSCLC Modified to Patients with Specific EGFR Mutations The indication for erlotinib was modified by the FDA for patients with NSCLC treated with maintenance, second-line, or later treatment to limit its use in patients with tumors harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations. The labeling change was based on the findings of the randomized, double-blind, placebocontrolled, IUNO trial, which demonstrated that overall survival of the patients treated with erlotinib was not better than the placebo group as maintenance for metastatic NSCLC tumors without EGFR-activating mutations. Progression-free survival was comparable between the erlotinib arm and the placebo arm.
Image source: The website of the National Cancer Institute (http://www.cancer.gov).
Atezolizumab Approved for Metastatic NSCLC Progressed During or After Platinum-Based Therapy The anti-PD-L1 antibody, atezolizumab, was granted approval by the FDA for the treatment of patients with metastatic NSCLC that progressed on platinum-based chemotherapy, and of patients with tumor harboring EGFR or ALK aberrations that progressed on FDA-approved targeted therapies. The approval was based on two international, randomized, open-label trials, OAK and POPLAR, which demonstrated consistently that atezolizumab improved overall survival of a total of 1,137 patients with NSCLC by 4.2 months (hazard ratio [HR] ¼ 0.74; p ¼ 0.0004) and 2.9 months (HR ¼ 0.69), respectively, compared with docetaxel. The most common grade 3/4 adverse events in the atezolizumab arm were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate aminotransferase increase, alanine aminotransferase increase, dysphagia, and arthralgia. The atezolizumab arm experienced clinically significant immune-related adverse events that included pneumonitis, hepatitis, colitis, and thyroid disease.
ESMO 2016: Neoadjuvant Anti-PD1, Nivolumab, In Early Stage Resectable NSCLC (Abstract LBA41_PR) Forde and colleagues reported for the first time that neoadjuvant administration of nivolumab is safe and feasible for patients with stage I-IIIA NSCLC, suggesting that the treatment could have activity in early stage lung cancer. Of 15 resected patients, 80% demonstrated pathologic evidence of tumor regression, and 40% had major pathologic
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responses (MPR; <10% residual viable tumor), of which 3 had no radiographic evidence of response. Three out of 4 MPR cases tested were PD-L1 positive. Both unique and shared T cell clones were expanded in both tumor and peripheral blood, including new infiltration of T cell clones found only in the post-treatment tumor specimen.
ESMO 2016: Ceritinib versus Chemotherapy (CT) In Patients (pts) with Advanced Anaplastic Lymphoma Kinase (ALK)-Rearranged (ALKþ) NSCLC Previously Treated with CT and Crizotinib (CRZ): Results from the Confirmatory Phase 3 ASCEND-5 Study (Abstract LBA42_PR) According to the phase III ASCEND-5 trial findings reported by Scagliotti and colleagues, ceritinib provides improved progression-free survival (PFS) versus chemotherapy (pemetrexed or docetaxel) in patients with ALK-positive NSCLC, who received crizotinib and chemotherapy previously. When compared with the chemotherapy group (n ¼ 116), the ceritinib group (n ¼ 115) achieved significantly improved PFS (median 5.4 versus 1.6 months; HR ¼ 0.49, p < 0.001) and overall response rate (39.1% versus 6.9%). Most frequent adverse events (AEs) with ceritinib were diarrhea, nausea, and vomiting, with 5.2% of patients discontinued due to AEs versus 6.9% of the chemotherapy group. Lung cancer-specific symptoms and overall health status were also significantly improved for the ceritinib group.
ESMO 2016: Selumetinib In Combination with Docetaxel as Second-Line Treatment for Patients with KRAS-Mutant Advanced NSCLC: Results from the Phase III SELECT-1 Trial (Abstract LBA47_PR) According to the findings of the phase III, double-blind, randomized SELECT-1 trial, Jänne and colleagues demonstrated that MEK inhibitor selumetinib in combination with docetaxel did not improve progression-free survival (PFS) or overall survival (OS) when compared with docetaxel plus placebo in 510 patients with KRAS-mutant nonsmall cell lung cancer (NSCLC). At data cut-off, no significant difference between the selumetinib arm and the placebo arm was observed in terms of median PFS (3.9 versus 2.8 months, HR 0.93, p ¼ 0.44) and median OS (8.7 versus 7.9 months, HR 1.05, p ¼ 0.64). A trend towards a higher objective response rate was observed in the selumetinib group versus the placebo group (20.1% versus 13.7%, OR 1.61, p ¼ 0.051). Serious adverse events and those leading to hospitalization were more frequent in the selumetinib group versus the placebo group (49% versus 32% and 46% versus 30%, respectively). The authors concluded that this treatment strategy does not yield clinical benefit for this subset of NSCLC patients, therefore more studies are required to develop new treatments.
ESMO 2016: Randomized, Phase 2 Study of Carboplatin and Pemetrexed with or without Pembrolizumab as First-Line therapy for Advanced NSCLC: KEYNOTE-021 Cohort G (Abstract LBA46_PR) Langer and colleagues reported that the addition of PD-L1 antibody pembrolizumab to standard chemotherapy (carboplatin þ pemetrexed; CP) in the first-line setting significantly improved objective response rates (ORR) and progression-free survival (PFS) for 123 treatment-naïve, stage IIIB/IV, nonsquamous NSCLC patients. At a median follow-up of 10.6 months, the pembrolizumab group demonstrated significantly higher ORR (55% versus 29%, p ¼ 0.0016; particularly those with high PD-L1 expression [ORR w 80%], improved median PFS (13.0 months versus 8.9 months). OS rates at 6 months were comparable between groups (92%). Higher incidence of grade 3 or less adverse events was found in the pembrolizumab group (39% versus 26%), with most common treatment-related events being fatigue and nausea. An ongoing phase III trial would confirm the findings.
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ESMO 2016: CheckMate 026: A Phase 3 Trial of Nivolumab versus Investigator’s Choice (IC) of Platinum-Based Doublet Chemotherapy (PT-DC) as First-Line Therapy for Stage IV/Recurrent Programmed Death Ligand 1 (PDL1) Positive NSCLC (Abstract LBA7_PR) In the open-label, randomized phase III CheckMate 026 trial comparing nivolumab to platinum-based doublet chemotherapy as first-line treatment for patients with advanced NSCLC and PD-L1 positive tumors, Socinski and colleagues demonstrated that greater patient selection may be needed for first-line nivolumab to improve progression-free survival (PFS) of the study population. In patients with less than or equal to 5% PD-L1 expression (n ¼ 423), nivolumab did not improve PFS (hazard ratio, HR 1.15; p ¼ 0.25), the same was observed with overall survival (HR 1.02). No new adverse events were observed with nivolumab, which was also less toxic than chemotherapy (any grade: 71% nivolumab, 92% chemotherapy; grade 3/4: 18% nivolumab, 51% chemotherapy). A phase III CheckMate 227 study is currently evaluating nivolumab plus ipilimumab and nivolumab plus chemotherapy in patients with treatment-naive NSCLC. News from the IASLC Tobacco Control Committee Superannuation Again This is just a short note on a topic that keeps appearing in this column. Regular readers will now be very familiar with the history of Tobacco Free Portfolios (http://www.tobaccofreeportfolios.org/), a not-for-profit organization that works to promote tobacco-free investment in the financial world (see this column in JTO, October 2016). A short piece in a recent issue of the Sydney Morning Herald highlights this problem in relation to Australia’s Prime Minister1, an accomplished businessman who, even after planning to divest, may still have tobacco in his portfolio. This is close to home for TFP, as the Australian oncologist, Dr Bronwyn King, founded that organization. It shows that even leaders can be caught by the tentacles of the tobacco industry. Perhaps even the Leader of the Free World. Whoever that might be. Nonetheless, this column has just checked its own tobacco-free status and it seems that the relevant superannuation fund, while expressing commitment to responsible investing, will not invest in companies that derive more than 10% of annual revenue from tobacco (among other socially unacceptable activities). Does this equal tobacco-free investing? Possibly not. This column will make enquiries and report back. 1. Gartrell A. Malcolm Turnbull told to quit the cigs after stakes in big tobacco revealed. The Sydney Morning Herald, October 23, 2016. http://www.smh.com.au/federal-politics/political-news/malcolm-turnbull-told-to-quit-thecigs-after-stakes-in-big-tobacco-revealed-20161021-gs87em.html. Accessed November 9, 2016.
More Politics Just like economics, smoking and tobacco seem impossible to extricate from politics. There is a promising move in the Philippines where the current President plans to introduce a nationwide smoking ban1, an expansion of a policy that he previously instituted in the region of Davao.2 This latter policy is discussed in detail in a paper that can be downloaded from the WHO page 3; it came into effect in November 2009 and was preceded by mass media campaigns and intensive dissemination of information. It involved the appointment of a Smoke-Free Davao Cocoordinator and involved lectures given by health professional in schools, at work and in the community. A quick stop on tobaccoatlas.org tells that the Philippines still lacks bans in offices, restaurants, pubs and bars.4 This is a development worth watching as the Philippines still has very high smoking rates in men at 42% (much lower in women, as is common in Asia, at 8.2%).4 Will such complex implementation work at the national level as well as at the regional level? We shall see. 1. Aljazeera. Duterte wants to ban public smoking in Philippines. October 12, 2016. http://www.aljazeera.com/ news/2016/10/duterte-ban-public-smoking-philippines-161012053010958.html. Accessed November 9, 2016. 2. World Health Organization. From “sleeping ordinance” to smoke-free enforcement. http://www.who.int/kobe_ centre/interventions/smoke_free/davao/en/. Accessed November 9, 2016.
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3. World Health Organization. WHO smoke-free city case study: advancing the enforcement of the smoking ban in public places—Davao City, Philippines. http://www.who.int/kobe_centre/interventions/smoke_free/davao_city_ web_final.pdf?ua¼1. Accessed November 9, 2016. 4. The Tobacco Atlas. Country fact sheet: Philippines. http://www.tobaccoatlas.org/country-data/philippines/. Accessed November 9, 2016.
Politics Again! At the time of writing it is election season so maybe it would be unreasonable to escape politics at all. Or it may be that the tobacco and the issue of tobacco control are just so complex that simple human social interactions can’t handle them and the machinations of politics are required. Whatever the case may be, an article in Medpage Today1 presents us with the combination of California, an election, multiple propositions and a dazzling set of numbers that tells quite how much the tobacco companies are willing to spend to protect their turf. First of all, California is putting a large number of propositions to voters in the general election (which, viewed from a far point on the globe, is utterly baffling). One of these proposals (no. 56) seeks to increase taxes on cigarettes to up to $2.00 (compared with $0.87 at the moment). This would raise at least $1 billion in revenue and increase the price of cigarettes by about the same amount ($2.00) over the current average cost of a pack at $5.53.2 This is an increase in cigarette price of just over a third e a 10% increase in the price is usually associated with a 4% decrease in smoking. At the moment the excise tax in California is about 15% of the price; in New York (number 1 on the list in the States) the excise tax is about 42% of the price. The WHO benchmark for excise tax is that it equate to 75% of the retail price.3 The power of taxation in reducing smoking rates is highlighted by the response of the tobacco industry. Several companies have just spent more than $100 million in opposing this proposition alone. 1. Boyles S. Big tobacco spends $100M to defeat state tax hikes. Medpage Today, November 4, 2016. http://www. medpagetoday.com/Pulmonology/Smoking/61248. Accessed November 9, 2016. 2. Campaign for Tobacco-Free Kids. State excise and sales taxes per pack of cigarettes total amounts and state rankings. September 16, 2016. https://www.tobaccofreekids.org/research/factsheets/pdf/0202.pdf. Accessed November 9, 2016. 3. The Tobacco Atlas. Country fact sheet: United States. http://www.tobaccoatlas.org/country-data/united-states/. Accessed November 9, 2016.
Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry This study retrospectively analyzed the International Thymic Malignancy Interest Group database for determinants of complete resection (R0) among patients treated with minimally invasive thymectomy (MIT) and open thymectomy (OT). Of the 2514 patients underwent thymectomy for thymoma (1997-2012), OT accounted for 82% and MIT for 18%, with significant increase in MIT use in recent years. The rate of R0 resection was 86% in the OT group and 94% in the MIT group (p < 0.0001), but it did not differ between propensity matched groups (p ¼ 0.7). Geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy were independently associated with R0 resection, while minimally invasive or open surgical approach did not show the association. In summary, though substantial increase in the use of MIT for thymoma has been observed, rates of R0 were comparable between MIT and OT. (p. 129)
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Quantitative Analysis of Circulating Cell-Free DNA for Correlation with Lung Cancer Survival: A Systematic Review and Meta-Analysis The authors conducted a systematic review and meta-analysis of primary studies up to March 2016 on PubMed, Web of Knowledge, and Cochrane databases to determine the impact of higher baseline cfDNA levels on survival outcomes of patients with lung cancer. Of the 17 studies identified, 16 (n ¼ 1723) were included in the meta-analysis of overall survival (OS), and 5 (n ¼ 640) for progression-free survival (PFS). Pooled analysis for OS demonstrated increase risk of death in patients with higher baseline cfDNA levels (hazard ratio, HR 1.76; p < 0.001) while the association with PFS was not significant (HR 1.12). No statistical evidence of publication bias in the results was detected by the Egger’s test. All in all, the findings support the clinical validity of quantitative analysis of cfDNA for predicting lung cancer survival, and warrant the development of a robust standardized method to determine optimal cutoff thresholds. (p. 43)
A Two-Gene Prognostic Classifier for Early-Stage Lung Squamous Cell Carcinoma in Multiple Large-Scale and Geographically Diverse Cohorts The study evaluated the expression of 253 genes selected by literature based on their known functions in lung squamous cell carcinoma (SCC) development and prognosis in order to establish a robust prognostic classifier for stage I/II lung SCC. The analysis included 2 independent cohorts of 121 and 91 patients with SCC for associations with survival, and 6 additional publicly available data sets of stage I/II lung SCC expression profiles (n ¼ 358) for examining the classifier score. Meta-analysis of patients with stage I/II (n ¼ 479) and stage I (n ¼ 326) lung SCC was conducted to assess the prognostic value of the classifier. Prognostic outcome in two independent patient cohorts was associated with dual specificity phosphatase 6 gene (DUSP6) and actinin alpha 4 gene (ACTN4), of which expression values were used to derive a classifier to identify patients with stage I/II lung SCC at high risk for recurrence (hazard ratio [HR] ¼ 4.7; p ¼ 0.018) or cancer-specific mortality (HR ¼ 3.5; p ¼ 0.016). The same was observed in publicly available data sets of stage I/II and in meta-analysisof stage I patients: identified high risk for recurrence (HR ¼ 2.7; p ¼ 0.008) or death (HR ¼ 2.2; p ¼ 0.001). To conclude, the authors have established and validated a prognostic 2-gene classifier to guide clinical management of surgically resected lung SCC patients. (p. 65)
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Research Watch Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients with ALK-Positive NSCLC Pooled analysis of 2 single-arm phase II studies (NCT01871805 and NCT01801111, respectively) was aimed to assess CNS response to alectinib in patients with ALK-positive NSCLC previously treated with crizotinib. At a median follow-up of 12.4 months, patients with measureable CNS disease at baseline had an independent review committee (IRC) CNS objective response rate (CORR) of 64.0%, CNS disease control rate (CDCR) of 90.0%, and median CNS duration of response (CDOR) of 10.8 months. Patients with measurable and/or nonmeasurable baseline CNS disease demonstrated an IRC CORR of 42.6%, CDCR of 85.3%, and median CDOR of 11.1 months. CORR was 35.8% for patients with prior radiotherapy, and 58.5% for those without prior radiotherapy. Toxicity results were aligned with previous study regardless of baseline CNS disease. In summary, alectinib demonstrated good efficacy against CNS metastases, in addition to systemic activity, in crizotinib-refractory ALK-positive NSCLC. Gadgeel SM, Shaw AT, Govindan R, et al. Pooled analysis of CNS response to alectinib in two studies of pretreated patients with ALK-positive nonesmall-cell lung cancer [e-pub ahead of print]. J Clin Oncol. http://dx.doi.org/10. 1200/JCO.2016.68.4639, accessed November 9, 2016.
Pembrolizumab versus Chemotherapy for PD-L1ePositive NSCLC The phase III trial, KEYNOTE-024, randomized 305 patients with previously untreated advanced NSCLC, harboring 50% tumor PD-L1 expression, without sensitizing EGFR mutations or ALK translocation, to penbrolizumab or platinum-based chemotherapy. Compared with the chemotherapy group, the pembrolizumab group achieved a median progression-free survival (PFS) of 10.3 months versus 6.0 months (hazard ratio, HR: 0.50; p < 0.001), an estimated 6-month overall survival (OS) rate of 80.2% versus 72.4% (HR: 0.60; p ¼ 0.005), an objective response rate of 44.8% versus 27.8%, and a longer median duration of response (not reached) versus 6.3 months. Less treatment-related adverse events and those of grade 3, 4, or 5 were observed in the pembrolizumab group versus the chemotherapy group (73.4% versus 90.0% and 26.6% versus 53.3%, respectively). Taken together, pembrolizumab resulted in significantly improved PFS and OS, with a better safety profile in patients with advanced NSCLC harboring 50% tumor PD-L1 expression when compared with platinum-based chemotherapy. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1epositive none small-cell lung cancer [e-pub ahead of print]. N Engl J Med. http://dx.doi.org/10.1056/NEJMoa1606774, accessed November 9, 2016.
Osimertinib for Pretreated EGFR Thr790Met-Positive Advanced NSCLC (AURA2): A Multicenter, Open-Label, Single-Arm, Phase 2 Study The phase 2, open-label, single-arm study (AURA2) assessed the efficacy and safety of osimertinib in 199 evaluable patients with EGFR Thr790Met-positive, stage IIIB/IV NSCLC that progressed on prior EGFR TKI therapy. At data cutoff (Nov 1, 2015), 58% patients remained on treatment, with the median duration of follow-up of 13.0 months. Objective response was achieved in 70% of patients, of which 3% were complete responses and 67% were partial responses. Pulmonary embolism, prolonged electrocardiogram QT, decreased neutrophil count, anaemia, dyspnoea, hyponatraemia, increased alanine aminotransferase, and thrombocytopenia were the most common all-causality grade 3 and 4 adverse events (AEs). Potentially treatment-related serious AEs were found in 5% of patients, with one death due to interstitial lung disease. In summary, the findings demonstrated clinical activity with tolerable safety profile of osimertinib for patients with EGFR Thr790Met-positive NSCLC, indicating a potential treatment for the study patient population. Goss G, Tsai C-M, Shepherd FA, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study [e-pub ahead of print]. Lancet Oncology. http://dx.doi.org/10.1016/S1470-2045(16)30508-3, accessed November 9, 2016.
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Have Combustible Cigarettes Met Their Match? The Nicotine Delivery Profiles and Harmful Constituent Exposures of Second-Generation and Third-Generation Electronic Cigarette Users This study evaluated the nicotine delivery profile of third- (G3) versus second-generation (G2) e-cigarette devices and their users’ exposure to nicotine and select harmful/potentially harmful constituents (HPHCs) compared with cigarette smokers in 30 participants. Comparable cotinine levels at baseline were observed in smokers, G2 and G3 users, while 4 and 7 times higher levels of eCO (p < 0.0001) and total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (i.e., NNAL, p < 0.01), respectively, were found in smokers versus G2 or G3 users. Compared with G2s, G3 users received significantly lower nicotine concentrations from e-cigarette liquids, thought devices delivered higher power to the atomiser, achieved higher plasma nicotine concentrations after the first 10 puffs (17.5 versus 7.3 ng/mL) and at 25 and 40 min of ad libitum use, and consumed more e-liquid. To conclude, G3 devices delivered the amount and speed of nicotine comparable to that of conventional cigarette. G2 and G3 e-cigarettes led to significantly lower levels of exposure to potent lung carcinogen and cardiovascular toxicant. The results help further understand addiction to these devices and their values in smoking cessation. Wagener TL, Floyd EL, Stepanov I, et al. Have combustible cigarettes met their match? The nicotine delivery profiles and harmful constituent exposures of second-generation and third-generation electronic cigarette users. Tob Control. http://dx.doi.org/10.1136/tobaccocontrol-2016-053041, accessed November 9, 2016. State-Level Cancer Mortality Attributable to Cigarette Smoking in the United States The study aimed to determine the proportion of cancer deaths in adults aged 35 years or younger attributable to cigarette smoking in 2014 in each state and the District of Columbia. The main outcome was population-attributable fraction (PAF) of cancer deaths due to cigarette smoking, based on relative risks for 12 smoking-related cancers from large U.S. prospective studies and state-specific smoking prevalence data from the Behavioral Risk Factor Surveillance System. The data estimated that at least 28.6% of all cancer deaths in the United States in 2014 were attributable to cigarette smoking. The proportion in men ranged from 21.8% in Utah to 39.5% in Arkansas, with at least 30% in every state except Arkansas while that in women ranged from 11.1% in Utah to 29.0% in Kentucky, with at least 20% in every state except Utah, California, and Hawaii. States in the South constituted more than half of the top 10 ranked states for both men and women. In the top 5 ranked states, smoking attributed to almost 40% of cancer deaths in men, and less than 26% in women. In summary, substantial differences across states were observed in the proportion of cancer deaths attributable to cigarette smoking, in which the South scores the highest, with up to 40% of men’s cancer deaths due to smoking. Enhanced tobacco control strategies are warranted to reduce morbidity and mortality associated with smoking-related cancers in the future. Lortet-Tieulent J, Goding Sauer A, Siegel RL, et al. State-level cancer mortality attributable to cigarette smoking in the United States [e-pub ahead of print]. JAMA Intern Med. http://dx.doi.org/10.1001/jamainternmed.2016.6530, accessed November 9, 2016. News-in-Brief Pembrolizumab Approved for First-Line Treatment of PD-L1ePositive NSCLC Pembrolizumab received FDA approval for first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression ( 50%) as determined by an FDAapproved test, and without EGFR or ALK gene aberrations. This approval also expands the indication in second-line treatment of patients with metastatic NSCLC tumors to include all patients with PD-L1-expressing NSCLC. The approval was based on findings from two randomized, controlled trials demonstrating significantly improved progression-free survival (PFS) and overall survival (OS) for the pembrolizumab arm versus the chemotherapy arm. Comparing with chemotherapy, pembrolizumab resulted in improved PFS (10.3 versus 6.0 months; hazard ratio [HR] ¼ 0.50; p <0.001) and OS (HR ¼ 0.60; p < 0.005) in
Image credit: The website of the National Cancer Institute (http://www.cancer.gov).
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KEYNOTE-024. KEYNOTE-010 showed improved OS in the pembrolizumab arm versus the chemothepray arm. (Pembrolizumab at 2 mg/kg every 3 weeks: HR ¼ 0.71, p < 0.001; 10 mg/kg every 3 weeks: HR ¼ 0.61, p < 0.001). The most common side effects of treatment with pembrolizumab included decreased appetite, fatigue, nausea, dyspnea, cough, and constipation. Rare but serious adverse events included immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. The recommended dose and schedule of pembrolizumab for NSCLC is 200 mg intravenously every 3 weeks.
Indication of Erlotinib in NSCLC Modified to Patients with Specific EGFR Mutations The indication for erlotinib was modified by the FDA for patients with NSCLC treated with maintenance, second-line, or later treatment to limit its use in patients with tumors harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations. The labeling change was based on the findings of the randomized, double-blind, placebocontrolled, IUNO trial, which demonstrated that overall survival of the patients treated with erlotinib was not better than the placebo group as maintenance for metastatic NSCLC tumors without EGFR-activating mutations. Progression-free survival was comparable between the erlotinib arm and the placebo arm.
Image source: The website of the National Cancer Institute (http://www.cancer.gov).
Atezolizumab Approved for Metastatic NSCLC Progressed During or After Platinum-Based Therapy The anti-PD-L1 antibody, atezolizumab, was granted approval by the FDA for the treatment of patients with metastatic NSCLC that progressed on platinum-based chemotherapy, and of patients with tumor harboring EGFR or ALK aberrations that progressed on FDA-approved targeted therapies. The approval was based on two international, randomized, open-label trials, OAK and POPLAR, which demonstrated consistently that atezolizumab improved overall survival of a total of 1,137 patients with NSCLC by 4.2 months (hazard ratio [HR] ¼ 0.74; p ¼ 0.0004) and 2.9 months (HR ¼ 0.69), respectively, compared with docetaxel. The most common grade 3/4 adverse events in the atezolizumab arm were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate aminotransferase increase, alanine aminotransferase increase, dysphagia, and arthralgia. The atezolizumab arm experienced clinically significant immune-related adverse events that included pneumonitis, hepatitis, colitis, and thyroid disease.
ESMO 2016: Neoadjuvant Anti-PD1, Nivolumab, In Early Stage Resectable NSCLC (Abstract LBA41_PR) Forde and colleagues reported for the first time that neoadjuvant administration of nivolumab is safe and feasible for patients with stage I-IIIA NSCLC, suggesting that the treatment could have activity in early stage lung cancer. Of 15 resected patients, 80% demonstrated pathologic evidence of tumor regression, and 40% had major pathologic
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responses (MPR; <10% residual viable tumor), of which 3 had no radiographic evidence of response. Three out of 4 MPR cases tested were PD-L1 positive. Both unique and shared T cell clones were expanded in both tumor and peripheral blood, including new infiltration of T cell clones found only in the post-treatment tumor specimen.
ESMO 2016: Ceritinib versus Chemotherapy (CT) In Patients (pts) with Advanced Anaplastic Lymphoma Kinase (ALK)-Rearranged (ALKþ) NSCLC Previously Treated with CT and Crizotinib (CRZ): Results from the Confirmatory Phase 3 ASCEND-5 Study (Abstract LBA42_PR) According to the phase III ASCEND-5 trial findings reported by Scagliotti and colleagues, ceritinib provides improved progression-free survival (PFS) versus chemotherapy (pemetrexed or docetaxel) in patients with ALK-positive NSCLC, who received crizotinib and chemotherapy previously. When compared with the chemotherapy group (n ¼ 116), the ceritinib group (n ¼ 115) achieved significantly improved PFS (median 5.4 versus 1.6 months; HR ¼ 0.49, p < 0.001) and overall response rate (39.1% versus 6.9%). Most frequent adverse events (AEs) with ceritinib were diarrhea, nausea, and vomiting, with 5.2% of patients discontinued due to AEs versus 6.9% of the chemotherapy group. Lung cancer-specific symptoms and overall health status were also significantly improved for the ceritinib group.
ESMO 2016: Selumetinib In Combination with Docetaxel as Second-Line Treatment for Patients with KRAS-Mutant Advanced NSCLC: Results from the Phase III SELECT-1 Trial (Abstract LBA47_PR) According to the findings of the phase III, double-blind, randomized SELECT-1 trial, Jänne and colleagues demonstrated that MEK inhibitor selumetinib in combination with docetaxel did not improve progression-free survival (PFS) or overall survival (OS) when compared with docetaxel plus placebo in 510 patients with KRAS-mutant nonsmall cell lung cancer (NSCLC). At data cut-off, no significant difference between the selumetinib arm and the placebo arm was observed in terms of median PFS (3.9 versus 2.8 months, HR 0.93, p ¼ 0.44) and median OS (8.7 versus 7.9 months, HR 1.05, p ¼ 0.64). A trend towards a higher objective response rate was observed in the selumetinib group versus the placebo group (20.1% versus 13.7%, OR 1.61, p ¼ 0.051). Serious adverse events and those leading to hospitalization were more frequent in the selumetinib group versus the placebo group (49% versus 32% and 46% versus 30%, respectively). The authors concluded that this treatment strategy does not yield clinical benefit for this subset of NSCLC patients, therefore more studies are required to develop new treatments.
ESMO 2016: Randomized, Phase 2 Study of Carboplatin and Pemetrexed with or without Pembrolizumab as First-Line therapy for Advanced NSCLC: KEYNOTE-021 Cohort G (Abstract LBA46_PR) Langer and colleagues reported that the addition of PD-L1 antibody pembrolizumab to standard chemotherapy (carboplatin þ pemetrexed; CP) in the first-line setting significantly improved objective response rates (ORR) and progression-free survival (PFS) for 123 treatment-naïve, stage IIIB/IV, nonsquamous NSCLC patients. At a median follow-up of 10.6 months, the pembrolizumab group demonstrated significantly higher ORR (55% versus 29%, p ¼ 0.0016; particularly those with high PD-L1 expression [ORR w 80%], improved median PFS (13.0 months versus 8.9 months). OS rates at 6 months were comparable between groups (92%). Higher incidence of grade 3 or less adverse events was found in the pembrolizumab group (39% versus 26%), with most common treatment-related events being fatigue and nausea. An ongoing phase III trial would confirm the findings.
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ESMO 2016: CheckMate 026: A Phase 3 Trial of Nivolumab versus Investigator’s Choice (IC) of Platinum-Based Doublet Chemotherapy (PT-DC) as First-Line Therapy for Stage IV/Recurrent Programmed Death Ligand 1 (PDL1) Positive NSCLC (Abstract LBA7_PR) In the open-label, randomized phase III CheckMate 026 trial comparing nivolumab to platinum-based doublet chemotherapy as first-line treatment for patients with advanced NSCLC and PD-L1 positive tumors, Socinski and colleagues demonstrated that greater patient selection may be needed for first-line nivolumab to improve progression-free survival (PFS) of the study population. In patients with less than or equal to 5% PD-L1 expression (n ¼ 423), nivolumab did not improve PFS (hazard ratio, HR 1.15; p ¼ 0.25), the same was observed with overall survival (HR 1.02). No new adverse events were observed with nivolumab, which was also less toxic than chemotherapy (any grade: 71% nivolumab, 92% chemotherapy; grade 3/4: 18% nivolumab, 51% chemotherapy). A phase III CheckMate 227 study is currently evaluating nivolumab plus ipilimumab and nivolumab plus chemotherapy in patients with treatment-naive NSCLC. News from the IASLC Tobacco Control Committee Superannuation Again This is just a short note on a topic that keeps appearing in this column. Regular readers will now be very familiar with the history of Tobacco Free Portfolios (http://www.tobaccofreeportfolios.org/), a not-for-profit organization that works to promote tobacco-free investment in the financial world (see this column in JTO, October 2016). A short piece in a recent issue of the Sydney Morning Herald highlights this problem in relation to Australia’s Prime Minister1, an accomplished businessman who, even after planning to divest, may still have tobacco in his portfolio. This is close to home for TFP, as the Australian oncologist, Dr Bronwyn King, founded that organization. It shows that even leaders can be caught by the tentacles of the tobacco industry. Perhaps even the Leader of the Free World. Whoever that might be. Nonetheless, this column has just checked its own tobacco-free status and it seems that the relevant superannuation fund, while expressing commitment to responsible investing, will not invest in companies that derive more than 10% of annual revenue from tobacco (among other socially unacceptable activities). Does this equal tobacco-free investing? Possibly not. This column will make enquiries and report back. 1. Gartrell A. Malcolm Turnbull told to quit the cigs after stakes in big tobacco revealed. The Sydney Morning Herald, October 23, 2016. http://www.smh.com.au/federal-politics/political-news/malcolm-turnbull-told-to-quit-thecigs-after-stakes-in-big-tobacco-revealed-20161021-gs87em.html. Accessed November 9, 2016.
More Politics Just like economics, smoking and tobacco seem impossible to extricate from politics. There is a promising move in the Philippines where the current President plans to introduce a nationwide smoking ban1, an expansion of a policy that he previously instituted in the region of Davao.2 This latter policy is discussed in detail in a paper that can be downloaded from the WHO page 3; it came into effect in November 2009 and was preceded by mass media campaigns and intensive dissemination of information. It involved the appointment of a Smoke-Free Davao Cocoordinator and involved lectures given by health professional in schools, at work and in the community. A quick stop on tobaccoatlas.org tells that the Philippines still lacks bans in offices, restaurants, pubs and bars.4 This is a development worth watching as the Philippines still has very high smoking rates in men at 42% (much lower in women, as is common in Asia, at 8.2%).4 Will such complex implementation work at the national level as well as at the regional level? We shall see. 1. Aljazeera. Duterte wants to ban public smoking in Philippines. October 12, 2016. http://www.aljazeera.com/ news/2016/10/duterte-ban-public-smoking-philippines-161012053010958.html. Accessed November 9, 2016. 2. World Health Organization. From “sleeping ordinance” to smoke-free enforcement. http://www.who.int/kobe_ centre/interventions/smoke_free/davao/en/. Accessed November 9, 2016.
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3. World Health Organization. WHO smoke-free city case study: advancing the enforcement of the smoking ban in public places—Davao City, Philippines. http://www.who.int/kobe_centre/interventions/smoke_free/davao_city_ web_final.pdf?ua¼1. Accessed November 9, 2016. 4. The Tobacco Atlas. Country fact sheet: Philippines. http://www.tobaccoatlas.org/country-data/philippines/. Accessed November 9, 2016.
Politics Again! At the time of writing it is election season so maybe it would be unreasonable to escape politics at all. Or it may be that the tobacco and the issue of tobacco control are just so complex that simple human social interactions can’t handle them and the machinations of politics are required. Whatever the case may be, an article in Medpage Today1 presents us with the combination of California, an election, multiple propositions and a dazzling set of numbers that tells quite how much the tobacco companies are willing to spend to protect their turf. First of all, California is putting a large number of propositions to voters in the general election (which, viewed from a far point on the globe, is utterly baffling). One of these proposals (no. 56) seeks to increase taxes on cigarettes to up to $2.00 (compared with $0.87 at the moment). This would raise at least $1 billion in revenue and increase the price of cigarettes by about the same amount ($2.00) over the current average cost of a pack at $5.53.2 This is an increase in cigarette price of just over a third e a 10% increase in the price is usually associated with a 4% decrease in smoking. At the moment the excise tax in California is about 15% of the price; in New York (number 1 on the list in the States) the excise tax is about 42% of the price. The WHO benchmark for excise tax is that it equate to 75% of the retail price.3 The power of taxation in reducing smoking rates is highlighted by the response of the tobacco industry. Several companies have just spent more than $100 million in opposing this proposition alone. 1. Boyles S. Big tobacco spends $100M to defeat state tax hikes. Medpage Today, November 4, 2016. http://www. medpagetoday.com/Pulmonology/Smoking/61248. Accessed November 9, 2016. 2. Campaign for Tobacco-Free Kids. State excise and sales taxes per pack of cigarettes total amounts and state rankings. September 16, 2016. https://www.tobaccofreekids.org/research/factsheets/pdf/0202.pdf. Accessed November 9, 2016. 3. The Tobacco Atlas. Country fact sheet: United States. http://www.tobaccoatlas.org/country-data/united-states/. Accessed November 9, 2016.