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Background: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade =3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. Patients and methods: Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. Results: Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}. Conclusions: Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Background MET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) occurring via over activation of downstream signaling pathways such as PI3K and MAPK. METamp occurs in ≈10% of patients receiving erlotinib, gefitinib, afatinib, or icotinib, and is the most common resistance mechanism to osimertinib in phase III trials, occurring in ≈19% of patients. Tepotinib, an oral once daily potent and selective MET inhibitor, is associated with improved survival in combination with gefitinib in patients with EGFR-mutant MET-amplified NSCLC with EGFR TKI resistance compared with standard chemotherapy in the INSIGHT study (NCT01982955): investigator-reported progression free survival (PFS) was 21.2 vs 4.2 months (HR 0.13; 90% CI 0.04, 0.43) and overall survival, (OS) was 37.3 vs. 13.1 months (HR 0.08; 90% CI 0.01, 0.51). Trial design INSIGHT 2 (NCT03940703) is a global single-arm, open-label, phase II trial of tepotinib in patients with advanced (stage IIIB/IV) NSCLC with resistance to 1st–3rd generation EGFR TKIs driven by METamp. Eligibility criteria include patients aged ≥18 years with advanced EGFR-mutant NSCLC and known T790M status, having acquired resistance to EGFR TKIs, and are METamp positive by plasma 'liquid' biopsy, with an ECOG PS of 0 or 1 and normal organ function. Prior immunotherapy is permitted but prior MET pathway-targeted therapy is not. Tepotinib (500 mg orally once daily) in combination with osimertinib (80 mg once daily) will be administered until disease progression, unacceptable toxicity, or withdrawal of consent. An initial safety run-in will comprise 6 patients (endpoint; dose-limiting toxicities); anticipated full enrollment is 90 patients. The primary endpoint is objective response rate (ORR) by independent review committee (RECIST v1.1). Secondary objectives include investigator-assessed ORR, duration of response, disease control, PFS, OS, pharmacokinetics, health-related quality of life, tolerability, and safety (NCI-CTCAE v5.0). Recruitment is ongoing and approximately 80 study sites in 17 countries in Europe, Asia, and North America are expected to participate in this study. Clinical trial identification NCT03940703. Legal entity responsible for the study Merck Healthcare KGaA. Funding Merck Healthcare KGaA. Disclosure J.C-H. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche/Genentech/Chugai; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Yuhan Pharmaceuticals; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo ; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda Oncology; Honoraria (self), Advisory / Consultancy: Blueprint Medicines; Honoraria (self), Advisory / Consultancy: Hansoh Pharmaceuticals. B. Ellers-Lenz: Full / Part-time employment: Merck Healthcare KGaA. J. Straub: Full / Part-time employment: Merck Healthcare KGaA. A. Johne: Full / Part-time employment: Merck Healthcare KGaA. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Sanofi. [ABSTRACT FROM AUTHOR]

BACKGROUND Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. RESULTS A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; PcO.OOl). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy -- a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. CONCLUSIONS First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. [ABSTRACT FROM AUTHOR]

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of metastatic non-small-cell lung cancer (NSCLC) was published in 2016. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Chinese Society of Clinical Oncology (CSCO) to convene a special guidelines meeting immediately after the Chinese Thoracic Oncology Group Annual Meeting 2018, in Guangzhou, China. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic NSCLC cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic NSCLC representing the oncological societies of China (CSCO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the six participating Asian countries. During the review process, the updated ESMO 2018 Clinical Practice Guidelines for metastatic NSCLC were released and were also considered, during the final stages of the development of the Pan-Asian adapted Clinical Practice Guidelines. [ABSTRACT FROM AUTHOR]

BACKGROUND Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear. METHODS In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred. RESULTS A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median followup was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted. CONCLUSIONS Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501.). [ABSTRACT FROM AUTHOR]

Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ~213 OS events and&#880532-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases. Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66-1.12, P=0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58-1.17, P=0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62-1.36, P=0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a thirdgeneration EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. [ABSTRACT FROM AUTHOR]

Background: The PI3K/AKT pathway is one of the key pathways of EGFR signaling in NSCLC.We hypothesize that combination of gefitinib with MK-2206, an allosteric oral AKT inhibitor, will overcome the development of EGFR TKI resistance and further increase the therapeutic efficacy of gefitinib. Preclinical data support the synergistic effect of this combination. The purpose of this study (NCT01147211) is to define the MTD of MK-2206 when combined with gefitinib in NSCLC. Methods: The main eligibility criteria include metastatic NSCLC patients who previously failed and progressed through more than 3 months’ use of EGFR TKI (e.g. erlotinib, gefitinib, afatinib) and >1 line of chemotherapy. Cohorts of 3 + 3 patients will be enrolled on escalating doses (level -1, 90 mg; level 1, 135 mg; level 2 200 mg QW) of MK-2206 administered followed by gefitinib (250 mg QD). Dose-limiting toxicity (DLT) is Gr 4 ANC >7 d, Gr >3 febrile neutropenia, Gr 4 platelets; Gr >3 non-hematologic toxicity except inadequately treated vomiting, diarrhea, asymptomatic uncomplicated hyperglycemia without Gr >3 electrolytes (but AC >250 mg/dL, PC >500 mg/dL), hypersensitivity, ALT >1 wk; and toxicity leading to a dose modification or causing a >3 wk delay. Results: A total of 14 patients (median age 62, range 35 – 84; median prior treatments 4, range 2 – 6) who had been treated with gefitinib (n = 4), erlotinib (alone or with afatinib; n = 7), or both (n = 2) were enrolled, starting at MK-2206 QW 135 mg (n = 3) with 1 DLT (grade 3 vomiting). MK-2206 was de-escalated to 90 mg (n = 3) without DLT. MK-2206 was then escalated to 135 mg (n = 5) with 1 DLT (grade 2 erythema multiforme). No DLTs were observed at 200 mg (n = 3) QW. The most common toxicities of all grades for the combination of gefitinib and MK-2206 were eosinophil increase (n = 9), rash (n =9), diarrhea (n = 7), hyperglycemia (n = 4), and mucositis (n = 4). The RP2D identified was gefitinib 250 mg QD and MK-2206 200 mg QW. Two pts with MK-2206 200 mg QW had minor responses (-18, -20%) with symptomatic improvement for 8 and 27 wks, respectively. Conclusions: Gefitinib combined with MK-2206 is well tolerated and had shown preliminary activity in NSCLC patients with acquired resistance to EGFR TKIs. [ABSTRACT FROM AUTHOR]

Background In the first preplanned interim analysis (IA) from ALTA-1L (NCT02737501; median follow-up BRG/CRZ: 11.0/9.3 mo, 99 PFS events), BRG demonstrated superior BIRC-assessed PFS and improved patient-reported quality of life vs CRZ. We report results of the second IA planned at 75% of 198 expected events. Methods Patients (pts) with ALK inhibitor–naive advanced ALK+ NSCLC and ECOG PS 0–2 were enrolled. One prior chemotherapy for advanced NSCLC was allowed. Asymptomatic CNS metastases were allowed. Pts were stratified by baseline (BL) brain metastases and prior chemotherapy. All pts had brain MRI at each tumor assessment. Pts were randomized 1:1 to BRG 180 mg QD (with 7-day lead-in at 90 mg) or CRZ 250 mg BID. Pts in the CRZ arm were offered BRG at progression. Primary endpoint: BIRC-assessed PFS (RECIST v1.1). Secondary endpoints included confirmed ORR, confirmed iORR, iPFS by BIRC, OS, and safety. Results 275 pts were randomized (BRG/CRZ, n = 137/138); median age 58/60 y. 26%/27% received prior chemotherapy; 29%/30% had BL brain metastases. As of 28 Jun 2019, median follow-up was BRG/CRZ: 24.9/15.2 mo, with 150 PFS events. HR of BIRC-assessed PFS was 0.49 (95% CI 0.35–0.68, log-rank P < 0.0001); BRG mPFS was 24.0 mo (95% CI 18.5–NE) vs CRZ 11.0 mo (95% CI 9.2–12.9). Investigator-assessed PFS HR was 0.43 (95% CI 0.31–0.61, median 29.4 vs 9.2 mo). OS was immature (total events: 33/37, BRG/CRZ). In pts with BL brain metastases, the PFS HR was 0.25. Data were less mature in pts without BL brain metastases treated with BRG. Table shows additional efficacy data. Most common TEAEs grade ≥3: BRG: increased CPK (24.3%) and lipase (14.0%), hypertension (11.8%); CRZ: increased ALT (10.2%), AST (6.6%), and lipase (6.6%). Any grade ILD/pneumonitis (BRG/CRZ): 5.1%/2.2%; discontinuations due to AE (BRG/CRZ): 12.5%/8.8%. Table: LBA1 BIRC-Assessed Efficacy  BRG  CRZ  P Value  All pts (ITT), n  137  138    ORR a , %  79 (71–85 b)  75 (67–82 b)  0.4376 c   Confirmed ORR, %  74 (66–81 b)  62 (53–70 b)  0.0342 c   mDoR d , mo  NE (19–NE b)  14 (9–21 b)    PFS events, n (%)  63 (46)  87 (63)    mPFS, mo  24.0 (18.5–NE b)  11.0 (9.2–12.9 b)    PFS HR  0.49 (0.35–0.68 b)  <0.0001 e   Any BL brain metastases, n  40 f   41 f     PFS events, n (%)  20 (50)  30 (73)    PFS HR  0.25 (0.14–0.46 b)  <0.0001 e     47 g   49 g     iPFS events, n (%)  21 (45)  32 (65)    iPFS HR  0.31 (0.17–0.56 b)  <0.0001 e   No BL brain metastases f , n  97  97    PFS events, n (%)  43 (44)  57 (59)    PFS HR  0.65 (0.44–0.97 b)  0.0298 e   BL measurable brain metastases, n  18  23    iORR a , %  78 (52–94 b)  30 (13–53 b)  0.0036 c   Confirmed iORR, %  78 (52–94 b)  26 (10–48 b)  0.0014 c   Median iDoR d , mo  NE (6–NE b)  9 (4–9 b)    BIRC-Assessed Efficacy  BRG  CRZ  P Value  All pts (ITT), n  137  138    ORR a , %  79 (71–85 b)  75 (67–82 b)  0.4376 c   Confirmed ORR, %  74 (66–81 b)  62 (53–70 b)  0.0342 c   mDoR d , mo  NE (19–NE b)  14 (9–21 b)    PFS events, n (%)  63 (46)  87 (63)    mPFS, mo  24.0 (18.5–NE b)  11.0 (9.2–12.9 b)    PFS HR  0.49 (0.35–0.68 b)  <0.0001 e   Any BL brain metastases, n  40 f   41 f     PFS events, n (%)  20 (50)  30 (73)    PFS HR  0.25 (0.14–0.46 b)  <0.0001 e     47 g   49 g     iPFS events, n (%)  21 (45)  32 (65)    iPFS HR  0.31 (0.17–0.56 b)  <0.0001 e   No BL brain metastases f , n  97  97    PFS events, n (%)  43 (44)  57 (59)    PFS HR  0.65 (0.44–0.97 b)  0.0298 e   BL measurable brain metastases, n  18  23    iORR a , %  78 (52–94 b)  30 (13–53 b)  0.0036 c   Confirmed iORR, %  78 (52–94 b)  26 (10–48 b)  0.0014 c   Median iDoR d , mo  NE (6–NE b)  9 (4–9 b)    BIRC, blinded independent review committee; DoR, duration of response; iDoR, intracranial DoR; iORR, intracranial ORR; iPFS, intracranial PFS; ITT, intent-to-treat; mDoR, median DoR; NE, not estimable; ORR, objective response rate; PFS, progression-free survival. a Response, ≥1 assessment; b 95% CI; c Cochran-Mantel-Haenszel test; d Confirmed responders; e Log-rank; f Per investigator assessment; g Per BIRC assessment. Table: LBA1 BIRC-Assessed Efficacy  BRG  CRZ  P Value  All pts (ITT), n  137  138    ORR a , %  79 (71–85 b)  75 (67–82 b)  0.4376 c   Confirmed ORR, %  74 (66–81 b)  62 (53–70 b)  0.0342 c   mDoR d , mo  NE (19–NE b)  14 (9–21 b)    PFS events, n (%)  63 (46)  87 (63)    mPFS, mo  24.0 (18.5–NE b)  11.0 (9.2–12.9 b)    PFS HR  0.49 (0.35–0.68 b)  <0.0001 e   Any BL brain metastases, n  40 f   41 f     PFS events, n (%)  20 (50)  30 (73)    PFS HR  0.25 (0.14–0.46 b)  <0.0001 e     47 g   49 g     iPFS events, n (%)  21 (45)  32 (65)    iPFS HR  0.31 (0.17–0.56 b)  <0.0001 e   No BL brain metastases f , n  97  97    PFS events, n (%)  43 (44)  57 (59)    PFS HR  0.65 (0.44–0.97 b)  0.0298 e   BL measurable brain metastases, n  18  23    iORR a , %  78 (52–94 b)  30 (13–53 b)  0.0036 c   Confirmed iORR, %  78 (52–94 b)  26 (10–48 b)  0.0014 c   Median iDoR d , mo  NE (6–NE b)  9 (4–9 b)    BIRC-Assessed Efficacy  BRG  CRZ  P Value  All pts (ITT), n  137  138    ORR a , %  79 (71–85 b)  75 (67–82 b)  0.4376 c   Confirmed ORR, %  74 (66–81 b)  62 (53–70 b)  0.0342 c   mDoR d , mo  NE (19–NE b)  14 (9–21 b)    PFS events, n (%)  63 (46)  87 (63)    mPFS, mo  24.0 (18.5–NE b)  11.0 (9.2–12.9 b)    PFS HR  0.49 (0.35–0.68 b)  <0.0001 e   Any BL brain metastases, n  40 f   41 f     PFS events, n (%)  20 (50)  30 (73)    PFS HR  0.25 (0.14–0.46 b)  <0.0001 e     47 g   49 g     iPFS events, n (%)  21 (45)  32 (65)    iPFS HR  0.31 (0.17–0.56 b)  <0.0001 e   No BL brain metastases f , n  97  97    PFS events, n (%)  43 (44)  57 (59)    PFS HR  0.65 (0.44–0.97 b)  0.0298 e   BL measurable brain metastases, n  18  23    iORR a , %  78 (52–94 b)  30 (13–53 b)  0.0036 c   Confirmed iORR, %  78 (52–94 b)  26 (10–48 b)  0.0014 c   Median iDoR d , mo  NE (6–NE b)  9 (4–9 b)    BIRC, blinded independent review committee; DoR, duration of response; iDoR, intracranial DoR; iORR, intracranial ORR; iPFS, intracranial PFS; ITT, intent-to-treat; mDoR, median DoR; NE, not estimable; ORR, objective response rate; PFS, progression-free survival. a Response, ≥1 assessment; b 95% CI; c Cochran-Mantel-Haenszel test; d Confirmed responders; e Log-rank; f Per investigator assessment; g Per BIRC assessment. Conclusions BRG showed durable PFS superiority vs CRZ in ALK inhibitor–naive ALK+ NSCLC. Clinical trial identification NCT02737501. Editorial acknowledgement Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and funded by Millennium Pharmaceuticals, Inc. a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Legal entity responsible for the study ARIAD Pharmaceuticals, Inc. a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Funding ARIAD Pharmaceuticals, Inc. a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Disclosure R. Camidge: Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Takeda; Honoraria (self): Arrys/Kyn; Honoraria (self): Novartis; Honoraria (self): Celgene; Honoraria (self): Clovis; Honoraria (self): Orion; Honoraria (self): Revolution Med; Honoraria (self): Lycera; Honoraria (self): Bio-Thera DSMB; Honoraria (self): Hansoh SRC; Honoraria (self): Daichi Sankyo; Honoraria (self): Ignyta; Honoraria (self): Roche/Genentech; Honoraria (self): Mersana Therapeutics; Honoraria (self): G1 Therapeutics; Honoraria (self): Genoptix. H.R. Kim: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. M. Ahn: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis. J.C. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche/Genentech/Chugai; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Yuhan Pharmaceuticals; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Hansoh Pharmaceuticals. J. Han: Research grant / Funding (self): Roche. M.J. Hochmair: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self): Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Takeda; Advisory / Consultancy: Novartis. K.H. Lee: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. A. Delmonte: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim. M.R. Garcia Campelo: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Ariad; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim. F. Griesinger: Advisory / Consultancy: Ariad; Advisory / Consultancy: Takeda; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer. E. Felip: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Takeda; Advisory / Consultancy: Merck. R. Califano: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Novartis. A. Spira: Advisory / Consultancy: Ariad; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. S. Gettinger: Advisory / Consultancy, Research grant / Funding (self): Ariad; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy: Janssen; Research grant / Funding (self): AstraZeneca/MedImmune; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Incyte; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Roche/Genentech. M. Tiseo: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Otsuka; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. Q. Ni: Full / Part-time employment: Takeda. P. Zhang: Full / Part-time employment: Takeda. S. Popat: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Research grant / Funding (institution): Epizyme; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution): Clovis Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Chugai Pharma; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: AbbVie. [ABSTRACT FROM AUTHOR]

Background Preliminary data from TATTON (NCT02143466, a multi-arm, multi-drug combination study) suggested that adding savolitinib (AZD6094, HMPL-504, volitinib), a potent and highly selective MET TKI, to osimertinib, a 3rd generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), which selectively inhibits EGFR TKI sensitising (EGFRm) and T790M resistance mutations, may overcome MET-driven resistance to EGFR TKIs. We present updated data from TATTON Part B and data from Part D, for the first time. Methods Pts were ≥18 years (Japan ≥20 years), mainly Asian, with locally advanced/metastatic, MET-positive, EGFRm NSCLC and disease progression on prior therapy. Pts enrolled based on MET status by local fluorescent in-situ hybridisation (MET gene copy ≥5 or MET/CEP7 ratio ≥2), next-generation sequencing or immunohistochemistry (+3 in ≥ 50% of tumour cells), with retrospective central confirmation. Pts in Part B received osimertinib 80 mg + savolitinib 600 mg or 300 mg orally (PO) once daily (QD). Pts in Part D received osimertinib 80 mg + savolitinib 300 mg PO QD, were T790M negative and had received no prior 3rd generation EGFR TKI. Primary endpoints: safety and tolerability; secondary endpoints included objective response rate and progression-free survival. Results In Parts B (N = 138) and D (N = 42); Grade ≥3 AEs reported by 57% and 38%, respectively; serious AEs reported by 45% and 26%, respectively. AEs possibly related to treatment, led to discontinuation of savolitinib in 38 (28%) vs 9 (21%) and osimertinib in 14 (10%) vs 2 (5%), for Parts B and D, respectively. Efficacy data: Table. Table: LBA2 Efficacy endpoints   Part B   Part D  Endpoint  Previously treated with a 3G EGFR TKI  No prior 3G EGFR TKI, T790M-negative  No prior 3G EGFR TKI, T790M-positive  Total  No prior 3G EGFR TKI, T790M-negative  Best response  n = 69  n = 51  n = 18  n = 138  n = 36 *   ORR † , n (%) [95% CI]  21 (30) [20–43]  33 (65) [50–78]  12 (67) [41–87]  66 (48) [39–56]  23 (64) [46–79]  PFS  n = 69  n = 51  n = 18  n = 138  n = 42  Median PFS, months  5·4  9·0  11·0  7·6  9·1  [95% CI]  [4·1–8·0]  [5·5–11·9]  [4·0–NR]  [5·5–9·2]  [5·4–12·9]  Total events, n (%)  43 (62)  33 (65)  10 (56)  86 (62)  17 (40)    Part B   Part D  Endpoint  Previously treated with a 3G EGFR TKI  No prior 3G EGFR TKI, T790M-negative  No prior 3G EGFR TKI, T790M-positive  Total  No prior 3G EGFR TKI, T790M-negative  Best response  n = 69  n = 51  n = 18  n = 138  n = 36 *   ORR † , n (%) [95% CI]  21 (30) [20–43]  33 (65) [50–78]  12 (67) [41–87]  66 (48) [39–56]  23 (64) [46–79]  PFS  n = 69  n = 51  n = 18  n = 138  n = 42  Median PFS, months  5·4  9·0  11·0  7·6  9·1  [95% CI]  [4·1–8·0]  [5·5–11·9]  [4·0–NR]  [5·5–9·2]  [5·4–12·9]  Total events, n (%)  43 (62)  33 (65)  10 (56)  86 (62)  17 (40)  * Best response data are for patients who had an opportunity to have two follow-up scans. † All confirmed responses were partial response. Table: LBA2 Efficacy endpoints   Part B   Part D  Endpoint  Previously treated with a 3G EGFR TKI  No prior 3G EGFR TKI, T790M-negative  No prior 3G EGFR TKI, T790M-positive  Total  No prior 3G EGFR TKI, T790M-negative  Best response  n = 69  n = 51  n = 18  n = 138  n = 36 *   ORR † , n (%) [95% CI]  21 (30) [20–43]  33 (65) [50–78]  12 (67) [41–87]  66 (48) [39–56]  23 (64) [46–79]  PFS  n = 69  n = 51  n = 18  n = 138  n = 42  Median PFS, months  5·4  9·0  11·0  7·6  9·1  [95% CI]  [4·1–8·0]  [5·5–11·9]  [4·0–NR]  [5·5–9·2]  [5·4–12·9]  Total events, n (%)  43 (62)  33 (65)  10 (56)  86 (62)  17 (40)    Part B   Part D  Endpoint  Previously treated with a 3G EGFR TKI  No prior 3G EGFR TKI, T790M-negative  No prior 3G EGFR TKI, T790M-positive  Total  No prior 3G EGFR TKI, T790M-negative  Best response  n = 69  n = 51  n = 18  n = 138  n = 36 *   ORR † , n (%) [95% CI]  21 (30) [20–43]  33 (65) [50–78]  12 (67) [41–87]  66 (48) [39–56]  23 (64) [46–79]  PFS  n = 69  n = 51  n = 18  n = 138  n = 42  Median PFS, months  5·4  9·0  11·0  7·6  9·1  [95% CI]  [4·1–8·0]  [5·5–11·9]  [4·0–NR]  [5·5–9·2]  [5·4–12·9]  Total events, n (%)  43 (62)  33 (65)  10 (56)  86 (62)  17 (40)  * Best response data are for patients who had an opportunity to have two follow-up scans. † All confirmed responses were partial response. Conclusions Our results support that osimertinib + savolitinib may overcome MET-driven resistance to EGFR TKIs, and warrant further exploration of the osimertinib 80 mg + savolitinib 300 mg combination in the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies. Clinical trial identification NCT02143466. Editorial acknowledgement Laura Crocker, BMedSci, of iMed Comms, an Ashfield Company, funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure J. Han: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Research grant / Funding (self): ONO; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Takeda. L.V. Sequist: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Janssen; Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Merrimack Pharmaceuticals; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): LOXO; Honoraria (self), Research grant / Funding (institution): Blueprint Medicines; Honoraria (self), Research grant / Funding (institution): Genentech. M. Ahn: Honoraria (self), Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, Roche; Advisory / Consultancy: Takeda, Alpha Pharmaceutical. B.C. Cho: Research grant / Funding (institution): Novartis, Bayer, AstraZeneca, Mogam Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics; Licensing / Royalties, Patent with royalties paid: Champions Oncology. H. Yu: Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): AstraZeneca, Lilly, Pfizer, Daiichi, Novartis, Astellas. S. Kim: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. J.C. Yang: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, MSD, Pfizer, Novartis, Bristol-Myers Squibb, Ono Pharmaceuticals; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol-Myers Squibb, Ono Pharmaceuticals, Daiichi Sankyo, Hansoh, Takeda, Blueprint. M. Cantarini: Shareholder / Stockholder / Stock options, Full / Part-time employment, Full time Contractor: AstraZeneca. R.B. Verheijen: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: Aduro Biotech. A. Mellemgaard: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Frewer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. X. Ou: Full / Part-time employment, Full time Contractor: AstraZeneca. G. Oxnard: Honoraria (self): Chugai Pharma, Bio-Rad, Sysmex, Guardant Health, Foundation Medicine; Advisory / Consultancy: AstraZeneca, Inviata, Takeda, Loxo, Ignyta, DropWorks, GRAIL, Illumina, Janssen; Licensing / Royalties, Patent pending: DFCI. [ABSTRACT FROM AUTHOR]

Background Pembrolizumab, a PD-1 inhibitor combined with platinum-based Ctx is standard therapy for eligible pts without a targetable mutation, stage IIIB/IV NSCLC. Currently, there is no data to guide treatment following progression on sequential/concomitant use of platinum-based Ctx and PD-1 inhibitors. Activation of inflammation and elevated baseline c-reactive protein (CRP) levels are associated with a lower response to immunotherapies. Canakinumab is a high-affinity anti-IL-1β monoclonal antibody that showed a significant reduction in the incidence of fatal and nonfatal lung cancer in myocardial infarction pts with increased CRP levels (CANTOS study). Trial design CANOPY-2 (NCT03626545) is a multicenter, phase 3 study evaluating the safety and efficacy of docetaxel ± canakinumab in pts with squamous/non-squamous, stage IIIB-IV NSCLC. This study includes a safety run-in part (part 1 – open-label) to confirm recommended phase 3 regimen (RP3R) to be used in the randomized phase 3 part (part 2 – double-blind, placebo-controlled). Key inclusion criteria: adult pts pretreated with one prior platinum-based Ctx and one prior PD-(L)1 inhibitor therapy for locally advanced or metastatic disease, either together/sequentially and then progressed; ECOG PS 0-1. In part 1, ∼9 pts will be enrolled to have at least 6 evaluable pts and ∼226 pts will be randomized (1:1, stratified by the number of prior lines of therapy and histology) in part 2 to docetaxel ± canakinumab. Primary objectives: to confirm RP3R of canakinumab + docetaxel, as determined by the incidence of dose-limiting toxicity in the first 42 days of administration (part 1) and overall survival (part 2). Secondary objectives: overall response rate, disease control rate, duration of response, time to response, progression-free survival by investigator (RECIST v1.1), safety, PK, immunogenicity of canakinumab, and patient-reported outcomes. Part 1 is completed and part 2 is ongoing after confirming canakinumab 300 mg Q3W as RP3R. Clinical trial identification ACZ885V2301/NCT03626545. Legal entity responsible for the study Novartis. Funding Novartis. Disclosure D. Lim: Advisory / Consultancy: MSD, Novartis, Astra-Zeneca, Boerhinger-Ingelheim; Honoraria (self): MSD, Novartis, Boehringer-Ingelheim. Y. Goto: Speaker Bureau / Expert testimony: AstraZeneca, Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, MSD, Shionogi Pharma, Novartis; Advisory / Consultancy: Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Glaxo Smith Kline; Research grant / Funding (self): AbbVie, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Pfizer, Novartis, Kyorin. B.C. Cho: Honoraria (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD; Research grant / Funding (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Licensing / Royalties: Champions Oncology. H. Kaneda: Honoraria (self): Novartis; Advisory / Consultancy: Novartis. J-H. Kang: Honoraria (self): Roche, AZ, Merck ; Advisory / Consultancy: AZ, MSD, Takeda; Research grant / Funding (self): AZ, Yuhan, CKD, Astellas. S-W. Kim: Advisory / Consultancy: AstraZeneca; Research grant / Funding (self): AstraZeneca, Lilly, Boehringer Ingelheim. C-H. Chiu: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche. J.C-H. Yang: Honoraria (self): Novartis, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, personal fees from Roche/Genentech, personal fees from Chugai, personal fees from MSD, personal fees from Pfizer, personal fees from Novartis, personal fees from BMS, persona; Advisory / Consultancy: Novartis, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, personal fees from Bayer, personal fees from Roche/Genentech, personal fees from Astellas, personal fees from MSD, personal fees from Merck Serono, personal fees from Pfizer. W-C. Su: Travel / Accommodation / Expenses: BI, BMS. K. Obyrne: Advisory / Consultancy: Boehringer Ingelheim, Merck Sharpe and Dohme, Eli Lilly, AstraZeneca, Roche, Pfizer, Bristol-Myers Squibb, and Novartis. V. Papadimitrakopoulou: Advisory / Consultancy: Nektar Therapeutics, AstraZeneca, Arrys Therapeutics, Merck, LOXO Oncology, Araxes Pharma, F Hoffman-La Roche, Janssen Research Foundation, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Novartis, Takeda, AbbVie, TRM Oncology, Tesaro, Exelixis, Gritsto; Honoraria (self): F Hoffman-La Roche; Research grant / Funding (self): Eli Lilly, Novartis, Merck, AstraZeneca, F Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, Incyte (to institution). M. Reck: Speaker Bureau / Expert testimony: AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Advisory / Consultancy: AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Honoraria (self): AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Officer / Board of Directors: IASLC BOD, Member of Scientific Committee. I. Malet: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis. B. Mookerjee: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis, Glaxo Smith Kine, Incyte, AstraZeneca. Z. Zewen: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis. L. Paz-Ares Rodriguez: Advisory / Consultancy: Roche, Lilly, Novartis, Pfizer, BMS, MSD, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Celgene; Honoraria (self): Roche, Lilly, Novartis, Pfizer, BMS, MSD, Amgen, Merck, Sanofi, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, PharmaMar, Celgene. [ABSTRACT FROM AUTHOR]

Background Overexpression of interleukin (IL)-1β has been described in solid tumors, including lung. IL-1β can promote angiogenesis, tumor invasiveness, and induces tumor-associated immunosuppression through myeloid-derived suppressor cell (MDSC) accumulation in tumors. Pre-clinical data has shown that IL-1β inhibition reduced tumor growth, by limiting pro-tumorigenic inflammation and polarization of MDSCs into M1 phenotype. Canakinumab is a human monoclonal antibody with high affinity and specificity for IL-1β. Recently, it was found that canakinumab was associated with a significant and dose-dependent reduction in incidence and mortality from lung cancer based on CANTOS study. Trial design CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab vs placebo in pts with surgically resected NSCLC. This trial will enroll adult pts, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T > 5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 pts will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or pt, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. In the amended protocol, a sub-study was included to determine the biomarker levels in the blood at pre- and post-surgery, and to establish their association with canakinumab efficacy. The primary objective is disease-free survival (per investigator assessment). Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and pt-reported outcomes. Enrollment is ongoing. Clinical trial identification CACZ885T2301. Legal entity responsible for the study Novartis. Funding Novartis. Disclosure B.C. Cho: Honoraria (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD; Research grant / Funding (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Licensing / Royalties: Champions Oncology. G-C. Chang: Honoraria (self): F. Hoffmann–La Roche, Ltd, Eli Lilly and Company Oncology, AstraZeneca, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Merck Sharp & Dohme. Y-C. Kim: Honoraria (self): AstraZeneca, Roche, Boehringer Ingelheim; Research grant / Funding (self): AstraZeneca, Roche, Boehringer Ingelheim. S. Geater: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Roche; Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, Roche, MSD; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Roche. S. Saeteng: Honoraria (self): AstraZeneca, Novartis : Speaker. Y. Goto: Speaker Bureau / Expert testimony: AstraZeneca, Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, MSD, Shionogi Pharma, Novartis; Advisory / Consultancy: Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Glaxo Smith Kline; Research grant / Funding (self): AbbVie, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Pfizer, Novartis, Kyorin. S. Lu: Research grant / Funding (self): AstraZeneca, Hutchison, Roche; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Hutchison MediPharma, Simcere, Roche; Honoraria (self): AstraZeneca, Roche. A. Ardizzoni: Advisory / Consultancy: MDS, Roche; Honoraria (self): MSD, BMS, Pfizer, Lilly; Research grant / Funding (self): BMS, Celgene, Roche; Leadership role: Member Educational Committee. F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology,. P. De Marchi: Advisory / Consultancy: Roche, Bayer, Msd, BMS, Pfizer, AstraZeneca; Speaker Bureau / Expert Testimony: Roche, Bayer, MSD, BMS, Pfizer, AstraZeneca; Travel / Accommodation / Expenses: Roche, MSD, BMS, AstraZeneca. L. Paz-Ares: Advisory / Consultancy: Roche, Lilly, Novartis, Pfizer, BMS, MSD, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Celgene; Honoraria (self): Roche, Lilly, Novartis, Pfizer, BMS, MSD, Amgen, Merck, Sanofi, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, PharmaMar, Celgene. D.R. Spigel: Advisory / Consultancy: AbbVie (Inst); Amgen (Inst); AstraZeneca (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Evelo Therapeutics (Inst); Foundation Medicine (Inst); Genentech/Roche (Inst); GlaxoSmithKline (Inst); Illumina (Inst); Lilly (Inst); Research grant / Funding (institution): AbbVie (Inst); Acerta Pharma (Inst); Aeglea Biotherapeutics (Inst); Amgen (Inst); ARMO BioSciences (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Celldex (Inst); Clovis Oncolog; Travel / Accommodation / Expenses: AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; EMD Serono; Genentech; Genzyme; Intuitive Surgical; Lilly; Merck; Pfizer; Purdue Pharma; Spectrum Pharmaceuticals; Sysmex. M. Thomas: Advisory / Consultancy: Novartis, Lilly, Pfizer, Bristol-Myers Squibb, Roche, AstraZeneca, Boehringer Ingelheim, MSD; Honoraria (self): Roche, Bristol-Myers Squibb, Lilly, AstraZeneca, Novartis, Pfizer, Boehringer Ingelheim, MSD; Research grant / Funding (self): Roche, BMS, MSD, AstraZeneca, Takeda. E.B. Garon: Advisory / Consultancy: Dracen, EMD Serono; Research grant / Funding (self): AstraZeneca, BMS, Eli Lilly, Genentech, Merck, Novartis, Neon, Iovance, Dynavax, Mirati. M. Leung: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis. J. Baum: Shareholder / Stockholder / Stock options: Novartis stock; Full / Part-time employment: Novartis. Spouse (Lauren Baum) – Abbot Laboratories. Z. Zewen: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis. B. Mookerjee: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis, GlaxoSmithKline, Incyte, AstraZeneca. J.C-H. Yang: Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai Pharmaceutical, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi-Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals, Bluep; Honoraria (self): Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai Pharmaceutical, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi-Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals, Bluep; Leadership role: IASLC CME activity: Author/Board of Directors/Presenter/Reviewer. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Identifying the optimal sequence of EGFR TKIs is important to maximise survival in EGFR mutation-positive (EGFRm+) NSCLC. The observational GioTag study (NCT03370770) investigated outcomes in patients (pts) with EGFRm+ NSCLC who were treated with sequential afatinib and osimertinib in a 'real-world' clinical setting, including pts with poor prognosis (ECOG PS ≥ 2: 15%; stable brain metastases: 10%).1 In the primary analysis, time to treatment failure (TTF) was 27.6 months in the overall population, 30.3 months in Del19-positive pts, and 46.7 months in Asians. Here we report overall survival (OS) and updated TTF. Methods Data were retrospectively collected from Dec 2017–June 2018 for 203 pts with EGFRm + (Del19, L858R) NSCLC who were T790M positive after first-line afatinib and subsequently received osimertinib. TTF was the primary outcome; OS analysis was exploratory. Data were collected from electronic health records (EHRs; n = 126) or medical charts (n = 77). For logistical reasons, this interim analysis includes updated data (at April 2019) from pts with available EHRs (all USA; n = 94); final analysis with updated data from manual chart reviews is anticipated in early 2020. Results After median follow-up of 30.3 months, median OS was 41.3 months (90% CI: 36.8–46.3) in the overall dataset (n = 203) and 45.7 months (90% CI: 45.3–51.5) in Del19-positive pts (n = 149); 2-year OS was 80%. OS in Asians was immature. Updated median TTF was 28.1 months (90% CI: 26.8–30.3) in all pts, and 30.6 months (90% CI: 27.6–32.0) in Del19-positive pts. Median TTF with osimertinib was 15.6 months (90% CI: 13.8–17.1) in the overall dataset, and 16.4 months (90% CI: 14.9–17.9) in Del19-positive pts. Median time from osimertinib discontinuation to death was 8 months. In 168 pts starting on afatinib 40 mg, median OS was 45.3 months (90% CI: 37.6–47.6); median TTF was 28.1 months (90% CI: 26.8–30.6). Conclusions Encouraging OS and TTF was seen in pts with EGFR T790M-positive NSCLC with sequential afatinib and osimertinib, especially Del19-positive pts. Of note, prior afatinib treatment did not preclude prolonged TTF with second-line osimertinib. 1. Hochmair MJ, et al. Future Oncol. 2018;14:2861–74. Clinical trial identification NCT03370770. Editorial acknowledgement Lynn Pritchard of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure M.J. Hochmair: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self): Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis. A. Morabito: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp and Dohme. D. Hao: Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca. R.A. Soo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Ignyta; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Yuhan. J.C-H. Yang: Honoraria (self): Merck Sharp and Dohme; Advisory / Consultancy: Merck Serono; Honoraria (self): Novartis; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Yuhan Pharmaceuticals; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ono pharmaceuticals; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Hansoh Pharmaceuticals; Advisory / Consultancy: Takeda Pharmaceuticals; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: G1 Therapeutics; Honoraria (self): Pfizer. B. Halmos: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp and Dohme; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Advisory / Consultancy: Genentech; Advisory / Consultancy: Spectrum; Advisory / Consultancy: Ignyta; Research grant / Funding (self): Takeda; Research grant / Funding (self): Guardant Health; Research grant / Funding (self): Mirati; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Novartis; Research grant / Funding (self): GSK; Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Guardant Health. L. Wang: Full / Part-time employment: Boehringer Ingelheim. A. Märten: Full / Part-time employment: Boehringer Ingelheim. T. Cufer: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background In patients with EGFR-mutant NSCLC, MET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKI). In the randomized phase Ib/II INSIGHT study (NCT01982955) that halted full enrolment due to low recruitment, tepotinib (TEP), a potent, selective MET TKI, plus gefitinib (GEF) improved progression-free survival (PFS) and objective response rate (ORR) vs chemotherapy (CTx) in patients with EGFR-mutant NSCLC and resistance to 1st-line EGFR TKIs due to METamp (≥6-month follow-up). We now present long-term survival outcomes (≥18-month follow-up) for this predefined analysis. Methods Patients were randomized to TEP 500 mg + GEF 250 mg orally once daily (until progressive disease, intolerable toxicity or other withdrawal) or platinum + pemetrexed IV (≤6 x 21-day cycles). METamp was defined as GCN ≥5 and/or MET/CEP7 ratio ≥2. Primary endpoint was investigator-assessed (INV) PFS. Secondary endpoints included overall survival (OS), ORR, PFS by independent review (IRC), safety. Results From 04/24/15 to 06/12/17, 55 patients enrolled in the INSIGHT study and 19 were METamp (TEP+GEF 12; CTx 7); this predefined subgroup is analysed here. Median GCN was 8.8 (range 4.8–29.5); 18 patients had GCN ≥5, 13 had MET/CEP7 ratio ≥2. At data cutoff (12/12/18), median treatment duration (weeks [range]) for TEP+GEF was 49 (4.6–110.9; 3 patients still ongoing for ≥24 months), pemetrexed was 18.0 (5.9–60.4), cisplatin 12.0 (6.6–25.1) or carboplatin 12.8 (5.9–19.7), all CTx patients discontinued. TEP+GEF compared with CTx improved PFS (INV mPFS 21.2 vs 4.2 months, HR [90% CI] 0.13 [0.04, 0.43]; IRC mPFS 19.3 vs 5.5 months; 0.18 [0.06, 0.61]) and OS (mOS 37.3 vs 13.1 months, 0.08 [0.01, 0.51]), as well as ORR (INV 66.7 v 42.9%; OR 2.67 [0.37, 19.56]; IRC 75.0 vs 42.9%; OR 4.00 [0.51, 31.38]). Grade ≥3 treatment-related AEs in METamp patients (≥15% in either arm, TEP+GEF vs CTx) were amylase or lipase increased (both 33.3% vs 0%), anemia, neutrophil or WBC count decreased (all 0 vs 28.6%). Conclusions TEP+GEF improved survival of patients with EGFR TKI-resistant NSCLC due to METamp. TEP + osmertinib is currently being investigated in patients with METamp, EGFR-mutant NSCLC with acquired EGFR TKI resistance (NCT03940703). Clinical trial identification NCT01982955. Editorial acknowledgement Medical writing assistance was provided by Lisa Jolly, Bioscript, Macclesfield, UK, and funded by Merck KGaA, Darmstadt, Germany. Legal entity responsible for the study Merck KGaA, Darmstadt, Germany. Funding Merck KGaA, Darmstadt, Germany. Disclosure K. Park: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Clovis; Elli Lilly; Hanmi; ONO; Roche; Novartis. R.A. Soo: Honoraria (self): BMS, Celgene, Ignyta, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. R. Bruns: Full / Part-time employment: Merck KGaA. J. Straub: Full / Part-time employment: Merck KGaA. A. Johne: Full / Part-time employment: Merck KGaA. J. Scheele: Full / Part-time employment: Merck KGaA. J.C-H. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical, Daiichi Sankyo and AstraZeneca, Takeda Oncology, Blueprint Medicines, Hansoh Pharmaceu. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim ; Advisory / Consultancy: Merck; Honoraria (self): Eli Lilly, Pierre Fabre, Pfizer, Sanofi. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background There is an expanding list of therapeutically relevant biomarkers for NSCLC and effective molecular profiling is paramount. We sought to comprehensively and prospectively evaluate the molecular epidemiology of NSCLC in Asia and ascertain the extent of access to relevant therapies. The study is being conducted by the Asian Thoracic Oncology Research Group (ATORG) – an academic co-operative lung cancer trials group in Asia. Methods ATORG-001 is a prospective, multi-centre study of NSCLC patients (pts) throughout Asia. Eligible pts must have good performance status (ECOG ≤2), adequate organ function and ≤3 prior lines of cytotoxic chemotherapy. Archival tissue specimens are sent to a central laboratory in Singapore (Singapore General Hospital) for profiling, consisting of NGS with the Oncomine Focus Assay (52 gene panel including fusions) and PD-L1 immunohistochemistry. Results are returned to investigators in a clinically relevant timeframe. Baseline demographics, pre-existing molecular profile and prior treatment details are collected. Treatment and pt outcomes are followed for 2 years. Recruitment commenced in Jan 2019 in 3 sites (National Cancer Centre Singapore, Chinese University of Hong Kong, University Malaya Medical Centre). We report an interim analysis for the first 27 of a planned 500 pts. Results As of 01 Jul 2019, 27 pts have enrolled with median age 67 yrs (range 46-79), 59% male, 81% adenocarcinoma, 52% stage IV, 37% non-smokers, median lines of prior therapy 1 (range 0-6) and 85% with no known oncogenic driver. Pre-existing mutation status was known in 89% for EGFR and 63% for ALK. Median turnaround time from tissue acquisition to profiling results was 22 days (range 15-74). New alterations were most common in KRAS (19%), MYC (15%), CDK4 (7%) and ERBB2 (7%). Potentially actionable new alterations were found in 7 (26%) pts, including KRAS G12C mutation (7%), BRAF G469A mutation (4%), ERBB2 exon 20 insertion (4%), ERBB2 amplification (4%), FGFR2 amplification (4%) and MET exon 14 skipping mutation (4%). Conclusions Enrolment is ongoing with additional sites and countries planned to comprehensively evaluate the molecular epidemiology of NSCLC in Asia. Legal entity responsible for the study Asian Thoracic Oncology Research Group. Funding Asian Thoracic Oncology Research Group, Novartis. Disclosure A.C. Tan: Travel / Accommodation / Expenses: ASLAN Pharmaceuticals. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]