Immune Checkpoint Inhibitors in the Management of Lung Cancer.

Immune checkpoint inhibitors, specifically PD-1-directed agents, have changed the treatment paradigm of non-small cell lung cancer (NSCLC) and are being actively evaluated in patients with small cell lung cancer. After initial studies demonstrated survival advantage with these agents in patients with recurrent NSCLC, these agents now have demonstrated survival advantage in some patients with early-stage NSCLC. Further evaluation of these agents in combination with chemotherapy regimens and other checkpoint inhibitors is ongoing. Recent data suggest that addition of these agents to chemotherapy may improve survival compared with chemotherapy alone. Promising results have also been observed in patients with recurrent small cell lung cancer. Ongoing studies will define the role of these agents in the management of patients with small cell lung cancer. Tumor PD-L1 assessment has become standard of care since use of frontline pembrolizumab in patients with advanced NSCLC is based on tumor PD-L1 expression. Other biomarkers are being actively evaluated to identify the patients most likely to benefit from these agents. Unique adverse effects are observed with the use of immune checkpoint inhibitors. Knowledge of the adverse effects and their management is crucial in treating patients with lung cancer using immune checkpoint inhibitors

Circulating Cell-free DNA as a Prognostic Biomarker in Patients with Advanced ALK+ Non-small Cell Lung Cancer in the Global Phase III ALEX Trial.

We retrospectively assessed prognostic value of circulating cell-free DNA (cfDNA) using data from the phase III ALEX study in treatment-naïve, advanced ALK+ non-small cell lung cancer (NSCLC). Patients were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151). cfDNA was quantified from baseline plasma samples, with patients stratified into ≤median and >median cfDNA biomarker-evaluable populations (BEP). Effect of cfDNA concentration on outcomes was analyzed using a Cox regression model with treatment group as covariate, and in multivariate analyses. Median cfDNA concentration in the BEP was 11.53 ng/mL (n = 276). A positive correlation was found between cfDNA concentration and number of lesions, organ lesion sites, and tumor size (sum of longest diameter; all P < 0.0001). In both treatment arms, patients in the >median BEP were more likely to experience disease progression than the ≤median BEP [alectinib adjusted HR = 2.04; 95% confidence interval (CI), 1.07-3.89; P = 0.0305 and crizotinib adjusted HR = 1.83; 95% CI, 1.11-3.00, P = 0.0169]. Median progression-free survival was longer with alectinib than crizotinib in both ≤median and >median BEPs (P < 0.0001). Overall survival data remain immature; survival probability was lower in the >median versus ≤median BEP in both treatment arms (alectinib HR = 2.52; 95% CI, 1.08-5.88; P = 0.0333 and crizotinib HR = 2.63; 95% CI, 1.27-5.47; P = 0.0096). These data suggest that plasma cfDNA concentration may have prognostic value in advanced ALK+ NSCLC. Prospectively designed studies are warranted to investigate this finding

1966P - Treatment with BLU-667, a potent and selective RET inhibitor, provides rapid clearance of ctDNA in patients with RET-altered non-small cell lung cancer (NSCLC) and thyroid cancer

BLU667, an investigational agent, is a potent and selective inhibitor of oncogenic rearranged during transfection (RET) alterations and predicted resistance mutations. Up to 90% of advanced medullary thyroid cancer (MTC) is characterized by single nucleotide variants and short insertions/deletions in the RET gene. In NSCLC, 1-2% of patients (pts) harbor rearrangements resulting in RET fusions. In the first-in-human ARROW study (NCT03037385), BLU-667 has demonstrated significant clinical activity in RET-altered NSCLC and MTC and has been well tolerated. Previous data has shown that early declines in circulating tumor DNA (ctDNA) may predict for treatment outcome. We investigated the change in ctDNA levels from baseline following treatment with BLU-667 and whether early changes in ctDNA during treatment were associated with clinical responses and outcomes.Blood was collected at baseline and prespecified time points during treatment. Plasma from 111 pts with locally documented RET-altered MTC and NSCLC were profiled with the Personal Genome Diagnostics PlasmaSELECT™ R64 sequencing panel.RET fusions were detected at baseline in 45/63 (71%) pts with NSCLC and RET mutations in 35/48 (73%) pts with MTC. Baseline ctDNA mutant allele fraction (MAF; MTC) or unique fusion reads (NSCLC) correlated with the sum of target lesions (p<0.01). BLU-667 led to rapid RET ctDNA declines in almost all pts and across all doses (60-600mg QD, 100-200mg BID). Eighty-one percent of pts with NSCLC and detectable ctDNA at baseline had undetectable RET ctDNA after 8 weeks of treatment. Clearance of RET fusions in NSCLC was observed for multiple fusion partners including CCDC6 and KIF5B. Forty-one percent of pts with MTC harboring somatic RET mutations also had undetectable RET ctDNA after 8 weeks. The correlation between changes in ctDNA levels and clinical outcomes are currently not mature and will be reported at the meeting.Treatment with BLU-667 led to a robust and rapid decline in ctDNA in almost all patients regardless of treatment dose or tumor diagnosis and in NSCLC irrespective of fusion partner studied.NCT03037385.Blueprint Medicines Corporation.Blueprint Medicines Corporation.G. Curigliano: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Seattle Genetics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer. V. Subbiah: Advisory / Consultancy: MedImmune; Research grant / Funding (institution): Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech (Inst), Roche (Inst), Berg Pharma (Inst), Bayer AG (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Ins; Travel / Accommodation / Expenses: PharmaMar, Bayer AG. J.F. Gainor: Honoraria (self): Merck, Incyte, ARIAD Pharmaceuticals, Novartis, Pfizer; Advisory / Consultancy: Genentech, Bristol-Myers Squibb, Theravance, Loxo, Takeda, Array BioPharma, Amgen, Merck, Agios, Regeneron, Oncorus, Jounce Therapeutics; Research grant / Funding (institution): Merck (Inst), Novartis (Inst), Genentech (Inst), Bristol-Myers Squibb (Inst), Adaptimmune (Inst), AstraZeneca (Inst), ARIAD Pharmaceuticals (Inst), Jounce Therapeutics (Inst), Blueprint Medicines (Inst), Moderna Therapeutics (Inst), Tesaro (Inst), Alexo T. D.H. Lee: Honoraria (self): AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, CJ Healthcare, Eli Lilly, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm and ST Cube; Advisory / Consultancy: Ministry of Food and Drug Safety, Korea, Health Insurance Review and Assessment Service, Korea, National Evidence-based Collaborating Agency, Korea, and National Cancer Control Planning Board, Korea. M.H. Taylor: Honoraria (self), Advisory / Consultancy: BMS, Eisai Inc, Array Biopharma, Bayer, LOXO, Blueprint, Arqule, Novartis; Speaker Bureau / Expert testimony: BMS, Eisai Inc; Research grant / Funding (institution): BioAtla; Travel / Accommodation / Expenses: BMS, Eisai Inc, Array Biopharma, Bayer, Loxo, Blueprint. V. Zhu: Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca, Roche-Foundation Medicine, Roche/Genentech, Takeda; Advisory / Consultancy, Shareholder / Stockholder / Stock options: TP Therapeutics. R.C. Doebele: Honoraria (self): Pfizer, AstraZeneca, ARIAD Pharmaceuticals, Guardant Health, Takeda Pharmaceuticals, Spectrum Pharmaceuticals, Trovagene; Advisory / Consultancy: Pfizer, OncoMed Pharmaceuticals, Trovagene, Ignyta, GreenPeptide, AstraZeneca; Research grant / Funding (institution): Ignyta (Inst); Travel / Accommodation / Expenses: Ignyta, ARIAD Pharmaceuticals, Guardant Health; Shareholder / Stockholder / Stock options: Rain Therapeutics; Licensing / Royalties: Other Intellectual Property: Licensing fees from Abbott Molecular for patent PCT/US2013/057495, licensing fees from Ignyta for biologic materials (Inst). G. Lopes: Advisory / Consultancy: Pfizer; Research grant / Funding (self): AstraZeneca; Research grant / Funding (institution): Merck Sharp & Dohme (Inst); EMD Serono (Inst), AstraZeneca (Inst), AstraZeneca, Blueprint Medicines (Inst), Tesaro (Inst), Bavarian Nordic (Inst), Novartis (Inst), G1 Therapeutics (Inst). E. Garralda: Research grant / Funding (self), Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: BMS, Menarini, Glycotope; Licensing / Royalties: MSD. S.M. Gadgeel: Advisory / Consultancy: Pfizer, Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, AbbVie; Speaker Bureau / Expert testimony: AstraZeneca; Research grant / Funding (self), Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer (Inst), Merck, Genentech (Inst), Blueprint Medicines (Inst), ARIAD Pharmaceuticals (Inst), Takeda (Inst); Travel / Accommodation / Expenses: ARIAD Pharmaceuticals, Takeda. C.D. Turner: Full / Part-time employment: Blueprint Medicines Corporation. M. Palmer: Full / Part-time employment: Blueprint Medicines Corporation. S. Miller: Full / Part-time employment: Blueprint Medicines Corporation. All other authors have declared no conflicts of interest

Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.

The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32-0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46-0.98). The 5-year OS rate was 62.5% (95% CI 54.3-70.8) with alectinib and 45.5% (95% CI 33.6-57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34-1.00)] and those without [HR 0.76 (95% CI 0.45-1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. NCT02075840

Supplementary Material for: Phase I Dose-Escalation and Pharmacokinetic Study of Intravenous Aflibercept in Combination with Docetaxel, Cisplatin, and 5-Fluorouracil in Patients with Advanced Solid Malignancies

<b><i>Purpose:</i></b> This phase I study (EudraCT No. 2006-001177-25) investigated aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients with advanced solid tumors. <b><i>Patients and Methods:</i></b> Patients received 2, 4, or 6 mg/kg of intravenous aflibercept with docetaxel 75 mg/m², cisplatin 75 mg/m², and 5-fluorouracil 750 mg/m² in 3-week cycles until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLTs) during cycle 1 and to determine the recommended phase II dose. Pharmacokinetics, tolerability, and antitumor activity were also investigated. <b><i>Results:</i></b> Forty-four patients were enrolled and treated (29 patients in a dose-escalation phase and 15 patients in an expansion cohort). Following three cases of febrile neutropenia in patients receiving aflibercept at 4 mg/kg, the protocol was amended to allow earlier granulocyte colony-stimulating factor support (from day 6) and prophylactic use of ciprofloxacin. Subsequently, there were two DLTs: febrile neutropenia (2 mg/kg) and grade 4 pulmonary embolism (6 mg/kg). An excess of free over VEGF-bound aflibercept was observed at 6 mg/kg. The most frequent grade 3/4 adverse events (AEs) were neutropenia (54.5%), lymphopenia (47.7%), and stomatitis (38.6%). AEs associated with VEGF blockade (any grade) included epistaxis (61.4%), dysphonia (40.9%), hypertension (38.6%), and proteinuria (11.4%). There were 15 partial responses, including 9 in patients with gastroesophageal cancers. Thirteen patients had stable disease. <b><i>Conclusion:</i></b> Aflibercept 6 mg/kg administered every 3 weeks in combination with docetaxel, cisplatin, and 5- fluorouracil is the recommended dose for further clinical development based on tolerability, pharmacokinetics, and antitumor activity

Impact of lorlatinib on patient-reported outcomes in patients with advanced ALK-positive or ROS1-positive non-small cell lung cancer.

To evaluate patient-reported outcomes (PROs) from a phase 1/2 study (NCT01970865) in patients with anaplastic lymphoma kinase (ALK)- or ROS1-positive advanced non-small cell lung cancer (NSCLC) treated with lorlatinib 100 mg once daily. PRO measures, including global quality of life (QoL), functioning domains and symptoms, were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the 13-item Lung Cancer (QLQ-LC13) module. Mean changes of absolute scores from baseline were assessed. Percentages of patients showing improvement, stability or worsening on each scale were reported, with a change of ≥10 points considered clinically meaningful (CM). 255 patients completed baseline and ≥1 post-baseline PRO assessment. Most patients had CM improvement (42.4 %) or stable (38.0 %) scores for global QoL. Functioning domains with the greatest proportion of patients with improved scores were role (37.6 %) and emotional (36.9 %); only one domain had more patients showing worsening than improving function (cognitive [24.3 % vs 22.4 %]). Most patients showed improved or stable scores for disease-related symptoms. No QLQ-C30 symptom domains had more patients worsening than improving. Symptoms on the QLQ-C30 scale with the greatest proportion of patients with improved scores were fatigue (49.4 %) and insomnia (46.3 %). Four QLQ-LC13 domains had more patients worsening than improving (two most affected were peripheral neuropathy [37.3 % vs 13.7 %] and alopecia [19.2 % vs 13.3 %]). Symptoms on the QLQ-LC13 scale with the greatest proportion of patients with improved scores were cough (42.7 %) and pain in other parts (32.9 %). Lorlatinib treatment showed CM improvement from baseline in global QOL that was maintained over time. Additionally, there were improvements in physical, emotional, social, and role functioning. Improvements were shown in appetite loss and key symptoms such as pain, dyspnea, cough and fatigue; a worsening in peripheral neuropathy was noted

Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): An open-label randomised controlled phase 3 trial

PubMed ID: 26156651Background: There is a major unmet need for effective treatments in patients with squamous cell carcinoma of the lung. LUX-Lung 8 compared afatinib (an irreversible ErbB family blocker) with erlotinib (a reversible EGFR tyrosine kinase inhibitor), as second-line treatment for patients with advanced squamous cell carcinoma of the lung. Methods: We did this open-label, phase 3 randomised controlled trial at 183 cancer centres in 23 countries worldwide. We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum-based-chemotherapy. Participants were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. The randomisation was done centrally with an interactive voice or web-based response system and stratified by ethnic origin (eastern Asian vs non-eastern Asian). Clinicians and patients were not masked to treatment allocation. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). The key secondary endpoint was overall survival. This trial is registered with ClinicalTrials.gov, NCT01523587. Findings: 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). Median follow-up at the time of the primary analysis of progression-free survival was 6·7 months (IQR 3·1-10·2), at which point enrolment was not complete. Progression free-survival at the primary analysis was significantly longer with afatinib than with erlotinib (median 2·4 months [95% CI 1·9-2·9] vs 1·9 months [1·9-2·2]; hazard ratio [HR] 0·82 [95% CI 0·68-1·00], p=0·0427). At the time of the primary analysis of overall survival (median follow-up 18·4 months [IQR 13·8-22·4]), overall survival was significantly greater in the afatinib group than in the erloinib group (median 7·9 months [95% CI 7·2-8·7] vs 6·8 months [5·9-7·8]; HR 0·81 [95% CI 0·69-0·95], p=0·0077), as were progression-free survival (median 2·6 months [95% CI 2·0-2·9] vs 1·9 months [1·9-2·1]; HR 0·81 [95% CI 0·69-0·96], p=0·0103) and disease control (201 [51%] of 398 patients vs 157 [40%] of 397; p=0·0020). The proportion of patients with an objective response did not differ significantly between groups (22 [6%] vs 11 [3%]; p=0·0551). Tumour shrinkage occurred in 103 (26%) of 398 patients versus 90 (23%) of 397 patients. Adverse event profiles were similar in each group: 224 (57%) of 392 patients in the afatinib group versus 227 (57%) of 395 in the erlotinib group had grade 3 or higher adverse events. We recorded higher incidences of treatment-related grade 3 diarrhoea with afatinib (39 [10%] vs nine [2%]), of grade 3 stomatitis with afatinib (16 [4%] vs none), and of grade 3 rash or acne with erlotinib (23 [6%] vs 41 [10%]). Interpretation: The significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib, along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung. Funding: Boehringer Ingelheim. © 2015 Elsevier Ltd.Boehringer IngelheimTo date, LUX-Lung 8 is the largest prospective trial comparing two established tyrosine kinase inhibitors for second-line treatment of patients with squamous cell carcinoma of the lung. The trial achieved its primary endpoint of progression-free survival and key secondary endpoint of overall survival. To the best of our knowledge, afatinib is the first agent to show a significant survival benefit in the second-line treatment setting for patients with squamous histology non-small-cell lung cancer compared with an approved EGFR tyrosine kinase inhibitor. Whether the 1·1 month improvement in median overall survival noted with afatinib is clinically significant could be debated, but it was encouraging that longer-term survival at 12 months and 18 months was significantly improved with afatinib. In one of the most genetically complex and difficult-to-treat human cancers, these improvements can be clinically important. Afatinib was also associated with modest improvements in objective response, disease control, patient-reported outcomes, and disease-related symptoms compared with erlotinib. The pattern of adverse events was similar between treatments and consistent with their mechanistic and safety profile. Adverse events were predictable and manageable. Based on available clinical data and its similar route of administration, we used erlotinib rather than docetaxel as the comparator. A meta-analysis of trials that assessed second-line treatment with EGFR tyrosine kinase inhibitors versus chemotherapy demonstrated better tolerability in the EGFR tyrosine kinase group and confirmed comparable overall survival between groups, both in unselected patients with non-small-cell lung cancer and in an EGFR wild-type population. 31 Furthermore, subgroup analysis of the phase 3 BR.21 trial 13 showed that erlotinib improves progression-free survival and overall survival in patients with lung cancers of squamous histology, compared with placebo (HR 0·66, p=0·009), with similar benefits to docetaxel. 32 Although results of the phase 3 TAILOR trial 33 suggested that second-line docetaxel is superior to erlotinib in patients with non-small-cell lung cancer and wild-type EGFR, this benefit seemed to be driven by patients with adenocarcinoma histology; overall survival in patients with squamous histology did not differ between groups (HR 0·9, 95% CI 0·49–1·65). Because EGFR mutations are rare (2 months [presumed treatment benefit; n=144] plus a control group with progression-free survival ?2 months [treatment refractory; n=94]), the overall proportion of patients with EGFR mutation was low (14 [6%]). Furthermore, EGFR amplification was present in only 15 patients (6%; nine on afatinib and six on erlotinib). Based on these preliminary findings, it is unlikely that the improved survival outcomes we detected with afatinib in this study were driven by molecular aberrations of EGFR. These improvements might be a result of afatinib's higher potency and broader irreversible ErbB blockade in this setting compared with EGFR inhibition alone. Indeed, these receptors have been implicated in the pathobiology of squamous cell carcinoma of the lung. Up to 20% of squamous cell carcinoma express HER2, with substantial overexpression in roughly 5% of cases, 17–19 and roughly 30% of squamous cell carcinomas overexpress HER3. 34 Furthermore, a comprehensive analysis 20 of squamous cell tumours identified genetic aberrations in HER2 (4%) and HER3 (2%), in several signalling molecules downstream of the ErbB receptors: KRAS (3%), HRAS (3%), BRAF (4%), RASA1 (4%), and NF1 (11%), and in NRG1 . Based on these findings, we postulated that afatinib inactivates multiple aberrant signalling cascades downstream of ErbB receptors in patients with squamous cell carcinoma of the lung, possibly via its ability to inhibit dimerisation. 35 Several other drugs have shown promising activity in patients with squamous cell carcinoma of the lung, particularly immunotherapeutic drugs such as nivolumab and pembrolizumab. 7,36 In a phase 2 single-group study, 7 15% of patients given nivolumab, a PD-1 inhibitor, had an objective response, with a median progression-free survival of 1·9 months (95% CI 1·8–3·2), and median overall survival of 8·2 months (6·1–10·9). This study included 117 heavily pretreated patients (?two previous treatments) with advanced squamous cell carcinoma of the lung. CheckMate-017, a phase 3 trial 8 comparing second-line nivolumab (n=135) with docetaxel (n=137) in patients with squamous cell carcinoma of the lung, was stopped early because its primary endpoint of overall survival was met (median 9·2 vs 6·0 months; HR 0·59, 95% CI 0·44–0·79; p<0·001). Based on these data, nivolumab was approved by the US Food and Drug Administration for patients with metastatic squamous non-small cell carcinoma of the lung with progression during or after platinum-based chemotherapy. Median overall survival achieved with docetaxel in CheckMate-017 was lower than that previously reported in patients with squamous cell carcinoma of the lung (roughly 7·5 months). 5 Ongoing biomarker analysis in CheckMate-017 might help identify which drug is most suitable for individual patients. Ramucirumab (an anti-VEGFR-2 antibody) plus docetaxel has also been approved for non-small-cell lung cancer including squamous cell carcinoma. In a subanalysis of the phase 3 REVEL trial, 6 median overall survival in 171 patients with squamous cell carcinoma was 9·5 months (95% CI 4·4–17·6) with ramucirumab plus docetaxel and 8·2 months (95% CI 3·6–14·9, HR 0·88 [95% CI 0·69–1·13]) with docetaxel alone. 6 However, this study was not powered for subgroup analysis. The safety of afatinib has been well characterised based on an extensive clinical trial programme involving nearly 6600 patients, and post-marketing data. The adverse event profile of afatinib in LUX-Lung 8 was consistent with previous studies with no unexpected safety concerns. 23,24,26,37 The most common adverse events were class-related gastrointestinal and dermatological events. The few discontinuations because of adverse events, including the common class-related adverse events of diarrhoea and rash or acne, suggest that the recommended dose reduction scheme and supportive care measures were generally sufficient to enable patients to remain on afatinib treatment for as long as they had clinical benefit. Based on our findings, afatinib could be an additional option for the treatment of squamous cell carcinoma of the lung. Contributors J-CS, EF, SL, KS, VG, WL, AA, SMG, BW, VKC, and GDG designed the study. J-CS, EF, MC, SL, KS, KHL, EG, VG, WL, DI, SZG, AM, YJM, AA, SMG, and GDG recruited participants. EF, SL, KS, KHL, EG, WL, DI, SZG, and SMG collected data. J-CS, EF, SL, KHL, WL, DI, AM, YJM, AA, SMG, BW, VKC, and GDG analysed and interpreted data. All authors drafted and reviewed of the report, and approved the final version for submission. Declaration of interests J-CS has received personal fees for advisory boards from Boehringer Ingelheim and Roche. EF has received consulting fees from Eli Lilly, Pfizer, Roche, and Boehringer Ingelheim, and fees for speaker's bureaus from AstraZeneca and Novartis. SL has received consulting fees from Boehringer Ingelheim. AM has received personal fees from Roche, AstraZeneca, Boehringer Ingelheim, Pfizer, and Bayer. AA has received honoraria and consultation fees from Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb, and MSD. SMG has received fees for advisory board participation from Boehringer Ingelheim. BW is an employee of Boehringer Ingelheim. VKC is an employee of Boehringer Ingelheim. The other authors declare no competing interests. Acknowledgments This trial was funded by Boehringer Ingelheim. We thank the patients, their families, and all of the investigators who participated in this study. Medical writing assistance was provided by Lynn Pritchard, of GeoMed, an Ashfield Company, and was supported financially by Boehringer Ingelheim during the preparation of this report. -- -- -- -- -- -

Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study.

At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34-0.65, p &lt; 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017). Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant. Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32-0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib. Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant