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LBA8507 Background: Atezo, in combination with CE, was the first cancer immunotherapy approved for 1L treatment of ES-SCLC. However, most pts eventually experience disease progression. TIGIT is a novel inhibitory immune checkpoint present on activated T cells and NK cells. Tira (anti-TIGIT) may synergise with other immunotherapies, such as PD-L1/PD-1 inhibitors, and further amplify the immune response to improve clinical outcomes. SKYSCRAPER-02 (NCT04256421) evaluates whether the antitumor effect and survival benefits of the combination of atezo + CE could be enhanced by adding tira in pts with ES-SCLC. Methods: Eligible pts with untreated ES-SCLC (asymptomatic treated or untreated brain metastases [BM] permitted) were randomized 1:1 to receive induction tira 600 mg IV or placebo (pbo) combined with atezo 1200 mg IV + CE for 4 x 21-day cycles followed by maintenance tira or placebo combined with atezo every 3 weeks until disease progression or loss of clinical benefit. Stratification factors include ECOG PS (0 vs 1); presence/history of BM (yes vs no); LDH (≤upper limit of normal [ULN] vs >ULN). Co-primary endpoints were investigator-assessed PFS and OS in all randomized pts without the history/presence of BM at baseline (primary analysis set [PAS]). Additional endpoints include PFS and OS in all randomized pts regardless of BM status (full analysis set [FAS]), objective response rate, duration of response, and safety. Results: A total of 490 patients were randomized (tira + atezo + CE, n=243; pbo + atezo + CE, n=247). As of 6 Feb 2022, median duration of follow-up was 13.9 months (mo); data represent final analysis for PFS and interim analysis for OS. In the PAS, no additional benefit was seen for tira + atezo + CE in PFS or OS compared with pbo + atezo + CE (Table). PFS and OS in the FAS were consistent with those observed in the PAS (Table). Grade 3/4 TRAEs occurred in 52.3% (tira + atezo + CE) and 55.7% (pbo + atezo + CE) and Grade 5 TRAEs occurred in 0.4% (tira + atezo + CE) and 2.0% (pbo + atezo + CE). TRAEs leading to any treatment discontinuation occurred in 5.0% and 5.3% with tira + atezo + CE and pbo + atezo + CE, respectively. Conclusions: The addition of tira to atezo + CE did not provide benefit over atezo + CE in pts with untreated ES-SCLC with or without BM. The combination was well tolerated, and no new safety signals were identified. The study will continue to planned final OS analysis. Clinical trial information: NCT04256421. [Table: see text]

2547 Background: Immune checkpoint inhibitors (ICIs) have ushered in a unique entity known as immune-related adverse events (IrAEs) that can be debilitating and challenging for physicians. Given that genomic variation underlies both disease susceptibility and drug response, there is reasonable cause to believe that genomic markers are predictive of IrAEs. We perform a pioneering pharmacogenomic study to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: Since March 2018, we recruited cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital. IrAEs were clinical characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. DNA was extracted and genotyped by Infinium Global Screening Array (700K markers). Statistical analyses were performed using SVS/HelixTree. Genetic association was performed by logistic regression. Bonferroni corrected P < 7.1E-08 was considered statistically significant. Results: We conducted a pilot pharmacogenomic genome-wide association study (GWAS) on 307 patients of Asian Ancestry. Median age was 62. Majority were male (68.1%), Chinese (75.9%), ECOG PS 0-1 (91.6%), stage IV cancer at diagnosis (64.6%). Non-small cell lung cancer (36.2%), renal cell carcinoma (12.4%) and hepatocellular carcinoma (7.2%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, atezolizumab and durvalumab, respectively (44.6%, 26.1%, 10.1% and 10.1% respectively). Nine percent of patients received dual ICIs concurrently. Median duration of treatment was 152 days and median follow up was 212 days. IrAEs were seen in 50.5% of patients. Skin (21.8%), endocrine (6.8%) and hepatotoxicity (5.9%) were the most common IrAEs. Eight percent of patients had CTCAEv5 grade ≥3 toxicity, of which hepatotoxicity (2.6%), skin (1.6%) and pulmonary toxicities (1.3%) were the most common. A preliminary pharmacogenomic investigation revealed one potential novel genetic locus associated with IrAEs: LOC105373202 rs5915369; Unadjusted P= 6.6E-08, OR (95%CI) = 27.8 (3.7-206.5), minor allele = A, 10.7% in cases vs 0.4% in controls. We also identified an additional 3 independent SNPs (rs167609, rs2341687, DMDrs5928214) with nominal significance (7.1E-0-8≤ P< 5.0E-7). Conclusions: This pilot pharmacogenomics GWAS uncovered 4 potential novel genetic loci predictive of IrAEs from ICIs amongst Asian patients. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing to identify specific genomic biomarkers that predispose individual patients to IrAEs.

9007 Background: EGFR ins20-mutant NSCLC has historically been challenging to treat. While new agents targeting EGFR ins20 have recently been approved, adverse events (AEs), particularly wild type (WT) EGFR-related AEs are common. CLN-081 is a novel EGFR tyrosine kinase inhibitor (TKI) with broad activity against EGFR mutations, including ins20, and increased selectivity for ins20 versus WT EGFR. CLN-081 has been granted FDA Breakthrough Therapy Designation for the treatment of pts with EGFR ins20 NSCLC. We present updated results of the initial multicenter Ph1/2a study of CLN-081 in pts with advanced, EGFR ins20-mutant NSCLC, including 39 pts treated in an expanded cohort at the dose of 100 mg twice daily (BID). Methods: Ph1 dose escalation utilized an accelerated titration (AT) and rolling six design. Individual cohorts were expanded in Phase 1 and 2a based on prespecified protocol criteria. Pts were required to have received prior platinum-based chemotherapy. Stable, treated brain metastasis (mets) were allowed. CLN-081 is dosed in 21-day cycles. Results: As of 13 December 2021, 73 pts [median age: 65 (36-82), median lines of prior therapy: 2 (1-9), 28 (39%) with a history of brain mets] received CLN-081 at 30 mg (8), 45 mg (1), 65 mg (14), 100 mg (39), and 150 mg (11), all BID. Treatment-related AEs in ≥ 15% of pts were rash (74%), diarrhea (27%), paronychia (25%), fatigue (19%), anemia (18%), dry skin (18%), nausea (16%). Treatment-related Gr ≥ 3 AEs in ≥ 4 % of pts included anemia (10%), increased ALT (4%), and increased AST (4%). Gr 3 rash and Gr 3 diarrhea were observed in 1 and 2 pts, respectively, at 150 mg BID, while no pts treated at ≤ 100 mg BID experienced Gr 3 rash or diarrhea. Treatment-related dose reductions and discontinuations across all dose levels occurred in 10 pts (14%) and 5 pts (7%) respectively. Among 70 response-evaluable pts across all dose levels, 25 (36%) had a confirmed partial response (PR), 34 (49%) had stable disease (SD), and 3 (4%) had progressive disease as a best response. Seven pts (10%) had a PR that remained unconfirmed; 1 (1%) pt was pending a confirmatory scan. Of 36 response-evaluable pts at 100 mg BID, 14 (39%) had a confirmed PR, 17 (47%) had SD, and 1 (3%) had PD. Three pts had a PR that remained unconfirmed (8%); 1 (3%) pt was pending a confirmatory scan. Notably, among Ph1 pts treated at 100 mg BID (N = 13) in whom longer follow-up is available, the mDOR and mPFS (estimated by Kaplan-Meier) was > 15 months and 12 months, respectively. Disease control (SD ≥ 6 months or any PR) was observed in 12/13 pts (92%). Updated data with additional follow-up will be presented. Conclusions: In pts with heavily-pretreated advanced EGFR ins20 NSCLC, CLN-081 has a manageable safety profile, with anti-tumor activity across the range of doses tested. Further, CLN-081 has demonstrated a favorable clinical profile at the dose of 100 mg BID, with an encouraging objective response rate, response durability, and no Gr 3 rash or diarrhea. Clinical trial information: NCT04036682.

9011 Background: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, significantly improved progression-free survival (PFS) and overall/intracranial responses vs crizotinib in patients (pts) with previously untreated ALK-positive advanced non-small cell lung cancer (NSCLC) in the ongoing randomized Phase 3 CROWN study (NCT03052608). To identify whether additional molecular biomarker analysis correlated with efficacy, we evaluated early ctDNA dynamics compared with clinical outcomes. Methods: Plasma samples were prospectively collected at screening (SC), week 4 (cycle 2, day 1 [C2D1]), week 24 (C7D1), and end of treatment for ctDNA analysis. ctDNA was analyzed using Guardant360CDx (Guardant Health, Inc., Redwood City, CA, USA). Mean variant allele fraction (VAF) of ALK alterations (fusions and/or mutations) and overall detected alterations at each time point and longitudinal mean change (dVAF) as (VAFC2D1) – (VAFSC) were calculated; dVAF

9077 Background: NSCLC with EGFR ins20 represents a significant area of unmet need, with no approved targeted therapies. While several agents targeting EGFR ins20 are in development, wild-type (WT) EGFR-related adverse events (AEs) have been common and challenging to manage. CLN-081 is a novel oral EGFR TKI with broad activity against clinically relevant EGFR mutations, including ins20, and has attenuated activity against WT EGFR relative to EGFR ins20 in vitro, suggesting that CLN-081 may have a more favorable clinical therapeutic window. We present interim results of a multicenter, Phase (Ph) 1/2a trial evaluating CLN-081 in advanced, EGFR ins20 NSCLC (NCT04036682). Methods: Patients (pts) with EGFR ins20 previously treated with platinum-based therapy (tx) were eligible to enroll. Ph 1 dose escalation in this adaptive trial began with an accelerated titration (AT) design, and converted to a rolling six design based upon pre-specified safety criteria or at clinically active doses. Cohort expansion in Ph 1 occurred at any dose where responses were seen. Transition from Ph 1 to 2a was based on a Simon-Two Stage design. Prior tx with EGFR ins20-specific inhibitors was allowed in AT cohorts only. CLN-081 was dosed twice daily (BID) in 21-day cycles. Results: As of 10 November 2020, 37 pts [median age 64 years (44-82); median 2 (1-9) prior lines of tx] received CLN-081 at doses of 30 mg (n = 8), 45 mg (1), 65 mg (12), 100 mg (13), and 150 mg (3) BID. The most common all-grade (gr) treatment-related AEs (TRAEs) were rash (49%), diarrhea (24%), paronychia (16%), nausea (14%), stomatitis (14%), and dry skin (11%). Gr 3 TRAEs included anemia (5%), diarrhea (3%), and increased alkaline phosphatase (ALP) (3%). There was 1 DLT, gr 3 diarrhea at 150 mg BID. No gr ≥ 3 rash or gr 4/5 TRAEs were reported. Four pts (11%) required dose reductions for rash (2), diarrhea (1), and increased ALP (1). Two pts (5%) discontinued tx due to TRAEs of gr 2 hypersensitivity reaction (1) and gr 2 pneumonitis (1); the latter also experienced pneumonitis while receiving prior osimertinib. Among the 25 response evaluable pts (RECIST 1.1), 10 (40 %) had a partial response (PR) (6 confirmed, 2 pending confirmation, 2 unconfirmed), 14 (56%) had stable disease (SD), and 1 (4%) had progressive disease as best response. Of the 4 pts that received prior EGFR ins20 inhibitors, 2 had PR and 2 SD. Of pts with SD or PR as best response, 20/24 (83 %) experienced tumor regression [median regression: -18 % (-100 to +3)]. Enrollment is ongoing and updated data will be presented. Conclusions: CLN-081 has an acceptable safety profile, including diarrhea in < 25% of pts treated to date. CLN-081 has demonstrated encouraging preliminary anti-tumor activity across the full dose range tested, in multiple distinct EGFR ins20 variants, and in heavily pre-treated pts that are either naïve or refractory to other EGFR ins20 inhibitors. Since the time of the data cut, a Ph 2a expansion has been initiated at 100 mg BID. Clinical trial information: NCT04036682.

6535 Background: Epstein-Barr virus (EBV) is associated with non-keratinising (NK) NPC, a disease prevalent in Southeast Asia, and provides a potential target for dendritic cell (DC) vaccine therapy. CD137 ligand (CD137L) expressed on antigen presenting cells costimulates CD137 expressing T cells upon receptor/ligand interaction. CD137L signalling differentiates monocytes to CD137L-DC, a novel type of DC, which are more potent than classical DC in stimulating autologous T cells. Here, we explore the safety and efficacy of autologous CD137L-DC pulsed with EBV peptides spanning Epstein Barr nuclear antigen 1, latent membrane protein 1 (LMP1) and LMP2 (CD137L-DC-EBV-VAX) in patients with locally recurrent or metastatic NPC. Methods: In this single centre, phase I study, eligible patients (pts) with locally recurrent or metastatic NK-NPC and clinical benefit (CB) from their prior treatment (stable disease [SD], partial [PR] or complete response[CR]), underwent apheresis to isolate monocytes which were differentiated to CD137L-DC through CD137L agonist exposure. CD137L-DC were pulsed with EBV antigens during maturation to obtain CD137L-DC-EBV-VAX which was administered intradermally every 2 weeks (w) for up to 7 injections following site preconditioning with Tetanus and Diphtheria vaccine. Results: 14 pts were enrolled of which 2 progressed rapidly and did not begin treatment. Mean age was 58 years. Median lines of prior treatment for metastatic NPC was 1 (range 1-6), the most common being cisplatin and gemcitabine. 9 pts received 7 vaccine doses (range 2-7) with a mean administered cell count of 23.9x106. CB was seen in 5 cases (42%) with 1 PR and 4 SD beyond 1 year. Median progression free survival (mPFS) was 26w (95% CI, 23-43). The lowest PFS (8w) was in a pt with 6 prior lines of treatment including a checkpoint inhibitor. Mean pretreatment neutrophil: lymphocyte ratio (NLR) was 3.4 and a value of less than 3 was associated with prolonged mPFS (42 vs 14w, p = 0.01). Enzyme linked immune absorbent spot (ELISPOT) analysis in 5 pts with CB showed a rise in interferon-γ secreting peripheral T cells prior to the 3rd vaccine versus baseline. Treatment was well tolerated with only 4 cases of grade 1 related adverse events reported, most commonly injection site reaction (3pts). Conclusions: CD137L-DC-EBV-VAX is safe and exhibits promising efficacy when administered following CB from chemotherapy. A rise in activated peripheral blood mononuclear cells after 2 vaccinations in selected patients showing benefit suggests immunological correlates with efficacy. Clinical trial information: NCT03282617 .

1019 Background: Preclinical studies show cross talk between RET and estrogen receptor, with at least additive treatment (Tx) effect of Len, a RET inhibitor, with Let. Our previous work concluded a recommended phase 2 dose (RP2D) of Len 14mg daily and Let 2.5mg daily (Lim, ASCO 2019). We present efficacy data from dose escalation and expansion cohorts. Methods: Safety, tolerability and efficacy data of MBC patients in both dose escalation (Len dose level 1 [DL]:20mg, DL -1:16mg and DL -2:14mg) and expansion (Len 14mg) cohort of this phase Ib/II study of combination Len+Let study was analysed. Patients were treated with single-agent Len for 2 weeks, followed by Len+Let until disease progression (PD). Serial tumor biopsies at baseline, after Len alone, 4 weeks post Len+Let, and upon PD, were sequenced for 440 genes with the ACTOnco+ platform. Results: A total of 33 pts (DL1 6pts, DL-1 6pts, DL-2 + expansion 21pts) with median 5 lines of prior Tx (range 0-11) were enrolled; 87.9%, 75.8%, and 75.8% had prior endocrine therapy (ET), ET+CDK4/6 inhibitor (i), and chemotherapy (CT) respectively. Objective response rate (ORR), disease control rate (DCR) ≥6 months (m), median duration of response (DOR), and percentage progression-free (PPF) at 12m were 33.3%, 45.5%, 11.5m (range 6.3-22.4), and 27.2% respectively. Among patients who previously progressed on CDK4/6i (n = 25), ORR, DCR ≥6m, median DOR, and PPF at 12m were 24.0%, 40.0%, 13.7m (range 6.3-18.2), and 12.0% respectively. Of note, 3/25 (12%) patients had durable response to Len+Let lasting ≥12m, despite having only modest PFS on ET+CDK4/6i (3, 7, and 12 months respectively). Most frequent all-grade toxicities (tox) were HTN (n = 15, G3:15), hypothyroidism (n = 20, G3:0) and fatigue (n = 13, G3:2), with no G4/5 tox. No new toxicity signals were observed compared to dose escalation phase. Pre-treatment tumor molecular profiling showed responders to be more likely to harbor NEFH, USH2A and PTCH1 mutations, while non-responders were more likely to carry PIK3R1, APC and PALB2 mutations. Sequencing of serial biopsies showed downregulation of BRD4, PTCH1, KIT, NTRK1 and CREBBP after Len treatment. Conclusions: Len+Let showed significant anti-tumor activity with meaningful duration of response, even in pts who failed prior CT or ET+CDK4/6i. The results support further investigation in randomized studies. Tumor profiling identified mutations associated with response and insights on molecular effects of lenvatinib. Clinical trial information: NCT02562118 .

3561 Background: Somatic profiling of MBC has highlighted actionable mutations and driven trials of matched targeted therapy (tx). Previous phase I studies have reported improved outcomes following matched therapies with tumour molecular profiles. Here, we review next generation sequencing (NGS) and treatment outcomes of Asian MBC patients (pts) in the phase I unit of a tertiary centre. Methods: Pts with MBC referred to a phase I unit underwent NGS (n = 152). Tumour tissue was sequenced via the amplicon based Ion Ampliseq Cancer (IAC) v2 (50 genes) platform from 2014-2017 prior to institutional change to Foundation Medicine 1 (FM1) (324 genes) 2017-2019. Patients were counselled on findings and enrolled onto matched therapeutic trials where available. Results: NGS was successfully performed in 107 pts (IAC 46%, FM1 54%) of which tumour subtypes include hormone receptor positive 63%, triple negative breast cancer (TNBC) 28% and Her2 positive 19%. Median lines of prior tx for MBC was 4 (range 0-12). 89% had prior chemotherapy (CT), 57% prior endocrine therapy (ET). 72/107 (67%) sequenced patients had further treatment and 18 (25%) were matched to tx based on NGS findings (15 clinical trial, 3 off trial). Matching rates on both NGS platforms were similar (IAC 22% vs FM1 28%). Mutated pathways with potential matched tx included PIK3CA/AKT/PTEN (52%), DNA damage response (DRR) (15%), and FGFR (11%) pathways. PIK3 mutations were seen in 43% and associated with higher number of metastatic sites (p = 0.03); most prevalent aberrations were PIK3CA H1047R (41%) and PIK3CA E542K (13%). Matched cases were more heavily pretreated (mean lines of prior tx 5.3 matched vs 3.7, unmatched p = 0.05), and showed a median progression free survival (mPFS) of 24 weeks [w] and clinical benefit rate (complete/partial response or stable disease ≥ 12 weeks) of 53% on matched tx. Comparison by NGS platform showed improved mPFS for matched vs unmatched pts sequenced on FM1 vs IAC (FM1: 26 vs 19w, HR = 0.76 [95% CI: 0.3-1.9]; IAC: 8 vs 12w; HR = 1.21 [95% CI: 0.5-2.8]). Interestingly, 1 pt with SMARCB mutation, reportedly associated with the FGFR pathway, had a PFS of 70w on tx with a pan-FGFR inhibitor after progressing on 3 prior lines of tx (ET and CT). Conclusions: Molecular profiling of MBC in a phase I unit led to matched tx in 25% of cases. Matched pts showed encouraging mPFS with a suggestion of benefit in those matched after sequencing on a broader gene panel (FM1).

9043 Background: Stage III NSCLC is a heterogeneous disease requiring a multimodality approach. We conducted a global study to characterise the patients (pts), treatment patterns and their associated outcomes for this disease in a real-world setting in the pre-IO era. Methods: KINDLE is a retrospective, multi-country, multi-centre study capturing data on patient and disease characteristics, treatments and outcomes. The study included pts with stage III NSCLC diagnosed between January 1st, 2013 and December 31st, 2017 and with at least 9 months of documented follow-up. Descriptive statistics were used to describe patient demographics, disease characteristics and treatment modalities. Inferential statistics was used to correlate various clinical and treatment variables with progression free survival (PFS) and overall survival (OS). Results: 3151 patients were enrolled at 125 centres in three geographical regions; 1046 pts in Middle East and North Africa, 1874 pts in Asia and 231 pts in Latin America. Median age was 63 years (range 21-92); 76.5% were male; 69.2% with a smoking history; 55.9% were staged as IIIA (AJCC 7th ed.); 53.7% had adenocarcinoma and 36.6% squamous cell, and 31.7% were known to have an EGFR mutation. 21.4% of patients underwent curative surgical resection. First line therapy included more than 25 different regimens, the most common being concurrent chemo-radiotherapy (cCRT) in 29.4%, chemotherapy (CT) alone in 17%, sequential chemo-radiotherapy (sCRT) in 10.4%, and radiotherapy (RT) alone in 8.5%. Median PFS for the whole cohort was 12.5 mos (95% CI; 12.06 – 13.14) and median OS 34.9 mos (95% CI; 32.00 – 38.01). Stage IIIA patients who were eligible for and underwent surgery + CT, had longer OS than patients who did not undergo surgery, receiving other treatments. Non-surgical approaches included CT, RT, and CRT. In stage IIIB, OS was significantly improved for cCRT vs. CT alone (p = 0.0015) or RT alone (p = < 0.0001) or sCRT (p = 0.0216). Improved survival was observed with sCRT compared with RT alone and chemotherapy vs RT alone. Conclusions: KINDLE, a large multi-country observational study, reveals the diversity of treatment practices that exist in stage III NSCLC and provides insights on the outcomes in a real-world setting. The unmet medical need remains high and approaches are required to optimize patient outcomes including implementation of guidelines, physician education and improved access to innovative medicines and quality care.

e19385 Background: Pembrolizumab has dramatically improved the survival of patients with non-small cell lung cancer (NSCLC) and is considered the standard of care for first line treatment of NSCLC who do not harbour oncogenic drivers. The fixed dose of 200mg was approved by the US Food and Drug Administration. The dose of 200mg was based on pharmacokinetic analysis. Studies have demonstrated equivalent efficacy with weight-based dosing 2mg/kg. An average Asian weighs 50-60kg. We aimed to look at the efficacy of pembrolizumab at a low fixed dose compared to the standard dosing. Methods: A review of all consecutive patients receiving pembrolizumab for advanced NSCLC from January 2016 to December 2019 in a large, high-volume academic medical centre, the National University Hospital, Singapore was conducted. Data fields collected include patient’s demographics, treatment doses and clinical characteristics. Time on treatment and overall survival were analysed using the Kaplan Meier method. Results: In total, 92 ECOG 0-2 patients with advanced NSCLC were treated with pembrolizumab. Median age was 69 years (Range, 29-92). Most were males (76%) and Chinese race (68%). Of the 92 patients, 46 (50%) and 46 (50%) received 100mg (Pem100) and 200mg (Pem200) of pembrolizumab respectively. Pembrolizumab was prescribed as first line in 73 (79%) and second line in 19 patients (21%). The average dose of pembrolizumab received in the low dose group was 1.87mg/kg (Range, 1.24mg/kg – 2.70mg/kg). 88 patients were included in the survival analysis. 4 were excluded due to the presence of an oncogenic driver. Patients were followed up for a median of 13.2 months. There was no difference in progression free survival between Pem100 and Pem200 for first-line single agent and when combined with chemotherapy (PFS: NR versus 5.3months, HR 2.17, 95% CI 0.76-6.16, p = 0.15 and NR vs 16.9 months, HR 2.89, 95% CI 0.35-25.16, p = 0.33 respectively). For patients who received pembrolizumab in the first line setting, the response rate was 56% vs 20% (p = 0.07), 67% vs 52% (p = 0.69) for Pem100 and Pem200 as a single agent and when combined with chemotherapy respectively. The median number of cycles received was 8.9 (Range, 1-60 cycles), translating to estimated cost savings of SGD 45 395 (~ USD 32 664) per patient who received Pem100. Conclusions: A lower fixed dose of pembrolizumab at 100mg showed no difference in progression free survival and response rate in an Asian cohort with significant cost savings. A further randomised controlled trial in an Asian population should be carried out.

1045 Background: Endocrine blockade (EB) is standard of care for patients (pts) with HR+ LABC/MBC. RET over-expression (RET+) occurs in up to 75% of HR+ breast cancers and is a postulated mechanism of endocrine resistance. Preclinical studies show cross talk between RET and estrogen receptor, and at least additive treatment (Tx) effect of Len+EB. Methods: We performed a phase Ib trial (3+3 dose escalation) to study safety, tolerability, pharmacodynamics and efficacy of Len+Let. Both drugs were given as continuous daily dosing with 2 weeks (wks) of Len alone, followed by Len+Let for 12 wks then surgery (LABC), or till disease progression (PD) (MBC). Serial tumor biopsies (n = 15) were done at baseline, after Len alone, 4 wks post Len+Let, and at surgery [LABC] / upon PD [MBC]. Results: 16 pts were treated (4 LABC, 12 MBC); Among MBC pts, median lines of prior Tx was 3 (range 0-10); 84.6%, 66.7%, and 58.3% had prior EB, EB+CDK4/6 inhibitor (i), and chemotherapy (CT) respectively. At dose level (DL) 1, 2/4 pts had dose-limiting toxicities (DLT). There was no DLT at DL-1, but 6/6 pts needed dose reductions (DR), with 4/6 DR within 6 wks of Len+Let (3 G3 hypertension [HTN], 1 G3 wound pain), deeming DL-1 intolerable. At DL-2, 0/6 pts had DLT; this was declared recommended phase 2 dose (RP2D). Most frequent G3 toxicities (tox) were HTN (6/16), proteinuria (2/16) and palmar-plantar erythrodysesthesia (PPE) (2/16), with no G4/5 tox. Len+Let was active with 93.8% overall disease control rate (DCR) (50.0% partial response [PR], 43.8% stable disease [SD]). Among MBCts (8/12 had prior EB+CDK4/6i), DCR ≥12 wks was 91.7%; 1 pt had sustained PR for 48 wks and 1 ongoing PR at 40 wks. 9/16 pts had RET+ tumors on immunohistochemistry at baseline, and 66.7% showed down-regulation with Tx (RECIST: 4 PR, 2 SD). Conclusions: Len+Let showed significant anti-tumor activity, even in pts who failed prior CT or EB+CDK4/6i. RP2D of 14mg Len and 2.5mg Let is tolerated with efficacy; dose expansion is currently underway. Clinical trial information: NCT02562118. [Table: see text]

9019 Background: Lorlatinib is a selective, potent, brain-penetrant, 3rd generation (gen) ALK/ROS1 TKI approved for pts with advanced ALK+ NSCLC previously treated with a 2nd gen ALK TKI. We recently showed that ALK mutation tumor genotyping after failure of a 2nd gen ALK TKI may identify pts more likely to respond to lorlatinib.1 To identify other molecular response correlates, we evaluated if early ctDNA dynamics predict clinical outcome on lorlatinib. Methods: In pts enrolled on the ongoing ph 2 study (NCT01970865), plasma samples were prospectively collected for ctDNA analysis at baseline (BL), cycle 3 day 1 (C3D1, or 6 weeks) and end of treatment. Plasma DNA was analyzed using Guardant360. Change in variant allele fraction (dVAF)2 of ALK alterations (fusions and/or mutations) was calculated as (mean VAFC3D1) – (mean VAFBL); dVAF < 0 indicated decreased ctDNA at C3D1. BOR, PFS and OS were evaluated according to dVAF. Results: Of 121 paired BL/C3D1 samples collected from 158 ALK+ pts previously treated with one or more 2nd gen ALK TKIs, 57 (47%) harbored a detectable ALK alteration at BL. At C3D1, mean VAF of ALK fusions and/or mutations was significantly decreased compared to BL (-1.07, p = 0.0014). Mean tumor volume was reduced by 26% in pts with dVAF < 0 (n = 40), but only by 12% in pts with dVAF ≥0 (n = 13) (p = 0.049). Mean dVAF at C3D1 was significantly decreased compared to BL for pts with CR/PR, while there was no significant difference with SD or PD/IND; mean dVAF -1.84, -0.74, and +0.35 in pts with CR/PR, SD, or PD/IND, respectively (p = 0.0011, 0.1444 and 0.3383). Median PFS was 6.6 months (mo) in pts with dVAF < 0 (n = 44) and 2.6 mo in pts with dVAF ≥0 (n = 13) (HR = 2.6, 95% CI: 1.2, 5.8). Median OS was 18.0 mo in pts with dVAF < 0 (n = 34) and 8.6 mo in pts with dVAF ≥0 (n = 13) (HR 2.0, 95% CI, HR 0.9–4.6). Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in ALK+ NSCLC, with decreased ctDNA at 6 wks associated with better response and longer PFS. Further studies are needed to validate these findings and to determine whether early intervention based on dynamic ctDNA monitoring may improve outcome. References: 1. Shaw, et al. J Clin Oncol. 2019. 2. Raja, et al. Clin Cancer Res. 2018. Clinical trial information: NCT01970865.

e20661 Background: FGFR1 gene amplifications are observed in squamous (sq) non-small cell lung cancer (NSCLC) and may suggest tractable oncogenic dependency. However, their value in predicting clinical activity of FGFR inhibitors is unclear. We explored tumor FGFR1-3 mRNA expression levels to select patients (pts) for treatment with rogaratinib, an oral, potent, small-molecule inhibitor of FGFR1-4. The first-in-human study of rogaratinib included pts with all NSCLC histologies. Methods: Pts with refractory advanced NSCLC were screened for elevated FGFR1-3 mRNA levels by RNA in situ hybridization (RNAscope) and NanoString assay in fresh or archival tumor samples, and FGFR1-3 overexpression was defined by pre-specified cut-offs. Pts received rogaratinib 800 mg BID on a continuous 21-day cycle. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1 after cycles 2, 5, and 8. Results: 260 NSCLC biopsies were screened for FGFR1-3 tumor mRNA expression; 244 (93.8%) were evaluable. FGFR1-3 mRNA overexpression was found in 47% of sq NSCLC, and only 14% of non-sq NSCLC, with FGFR3 being the most commonly overexpressed subtype. 40 FGFR mRNA-positive pts were enrolled and treated. Rogaratinib was well tolerated; hyperphosphatemia (75%), diarrhea (53%), and decreased appetite (35%) were the most frequent treatment-emergent adverse events. Events were mostly mild or moderate. 36 treated pts were evaluable for response. The overall response rate was 5.6% (2 partial responses, 1 lasting for > 16 months). Disease control rate was 64%. Disease stabilization was seen in pts with mRNA overexpression across all FGFR subtypes and also in pts who failed prior lines of therapy, including anti-PD-L1. Molecular studies are ongoing to identify additional predictors of response to improve pt selection. Conclusions: Rogaratinib has a favorable safety and tolerability profile and clinical activity in pts with refractory FGFR1-3 tumor mRNA-positive NSCLC. It has potential for further exploration in combination with other agents. A clinical trial is currently enrolling FGFR mRNA-overexpressing pts with advanced and pre-treated sq NSCLC. Clinical trial information: NCT03762122.

Purpose To investigate the frequency and the prognostic role of fibroblast growth factor receptor 1 (FGFR1) amplification in patients with surgically resected squamous cell carcinoma of the lung (SCCL) and the association between smoking and FGFR1 amplification. Patients and Methods Gene copy number of FGFR1 was investigated in microarrayed tumors from 262 patients with SCCL who had tumor tissue as well as smoking and survival data available. Gene copy number was evaluated by fluorescent in situ hybridization, and an FGFR1-amplified tumor (FGFR1 amp+) was prespecified as a tumor with nine or more copies of FGFR1. Results Among 262 patients, the frequency of FGFR1 amp+ was 13.0%. Patients with FGFR1 amp+ had significantly shorter disease-free survival (DFS; 26.9 v 94.6 months; P < .001) as well as shorter overall survival (OS; 51.2 v 115.0 months; P = .002) than those without FGFR1 amp+. Multivariate modeling confirmed that patients with FGFR1 amp+ had a significantly greater risk of recurrence and death than those without FGFR1 amp+ after adjusting for sex, smoking status, pathologic stage, and adjuvant chemotherapy (DFS: adjusted hazard ratio [AHR], 2.24; 95% CI, 1.45 to 3.45; P < .001; OS: AHR, 1.83; 95% CI, 1.15 to 2.89; P = .01). The frequency of FGFR1 amp+ was significantly higher in current smokers than in former smokers and never-smokers (28.9% v 2.5% v 0%; Ptrend < .001). As the smoking dosage increased, so did the incidence of FGFR1 amp+ (Ptrend = .002). Conclusion FGFR1 amplification is an independent negative prognostic factor in surgically resected SCCL and is associated with cigarette smoking in a dose-dependent manner. FGFR1 amplification is a relevant therapeutic target in Asian patients with SCCL.

LBA9000 Background: Atezolizumab (atezo; anti–PD-L1) demonstrated OS benefit vs docetaxel in 2L+ NSCLC regardless of PD-L1 status or tumor histology. Because cytotoxic agents can exhibit positive immunomodulatory effects, combining atezo with chemotherapy may further improve outcomes. IMpower131 (NCT02367794) was designed to evaluate atezo + carboplatin (carbo) + paclitaxel (pac) or nab-paclitaxel (nab-pac) in 1L stage IV squamous NSCLC. Methods: Patients (pts) were randomized 1:1:1 to Arm A (atezo 1200 mg q3w + carbo AUC 6 q3w + pac 200 mg/m2 q3w), Arm B (atezo + carbo + nab-pac 100 mg/m2 weekly) or Arm C (carbo + nab-pac). Pts received chemotherapy for 4 or 6 cycles and atezo until loss of clinical benefit. We present the primary analysis of investigator (INV)-assessed PFS per RECIST v1.1 in the ITT population for Arm B vs Arm C. Data cutoff: 22 January 2018. Results: 338 pts (Arm A), 343 pts (Arm B) and 340 pts (Arm C) were enrolled. Minimum follow-up was 9.8 mo. INV-assessed median PFS was 6.3 mo in Arm B vs 5.6 mo in Arm C (HR, 0.715; 95% CI: 0.603, 0.848; P = 0.0001). PFS benefit was enriched in all PD-L1–positive IHC subgroups and was most pronounced in TC3 or IC3. AEs related to any treatment (TRAEs) were 91.3% (Arm A), 94.6% (Arm B) and 90.7% (Arm C); Grade 3-4 TRAEs were 42.8% (Arm A), 68.0% (Arm B) and 56.9% (Arm C); serious TRAEs were 22.3% (Arm A), 20.4% (Arm B) and 10.5% (Arm C). Preliminary OS data will be presented. Conclusions: IMpower131 met its co-primary endpoint of INV-assessed PFS in the ITT population in Arm B vs Arm C. The safety profile of atezo + carbo + nab-pac or pac was consistent with the known risks of the individual treatment components; no new safety signals were identified. Clinical trial information: NCT02367794. [Table: see text]

2588Background: Varlitinib (V) is a reversible inhibitor of HER1/HER2/HER4. This is a phase 1b dose confirmation study to determine safety and early efficacy signals of V ± T combined with weekly P...

9058Background: The Phase 2 ATLANTIC study investigated the anti-PD-L1 antibody durvalumab in heavily pretreated pts with advanced NSCLC. Here we report updated results for two of the three pt coho...

9032Background: Despite advancement of 2nd generation (gen) ALK tyrosine kinase inhibitors (TKIs), ALK+ NSCLC pts continue to develop resistance and CNS metastases (mets) become more difficult to m...

3012Background: LAG525 and spartalizumab (PDR001), humanized IgG4 mAbs, block binding of LAG-3 to MHC class II and PD-1 to PD-L1 and PD-L2, respectively. Preclinical studies show synergistic anti-t...

e18748Background: Patient selection for phase I (P1) trials in oncology is challenging. A typical inclusion criterion for P1 studies is 'life expectancy > 3 months', however overall survival (OS) o...

2550 Background: Genomic profiling of single core biopsies (bx) are confounded intratumoral heterogeneity, resulting in sampling bias. We explored the use of a novel technique to obtain multiple bx from single metastatic lesion in pts to evaluate heterogeneity and identify therapeutic ATM. Methods: 15 pts (5 NSCLC; 3 ovarian; 2 colon, 2 uterine and 1 breast, cervix and HCC) with biopsiable lesions were identified. Using a single pass radiologically guided percutaneous bx technique, we obtained multiple spatially distinct core bx samples from a single metastatic lesion. Each bx underwent DNA extraction and WES using the NextSeq500. Results: Median of 4 core bx were obtained from each lesion. Complication rate utilizing this technique was 0%. 2 pts were omitted from analysis due to poor quality DNA with 13 pts successfully sequenced. In 1 pt, only 2 of 4 cores were successfully sequenced. The median amounts of total and non-synonymous variants were 137 (27-1286) and 66 (10-649) respectively. The median (range) filtered variants detected in 1/4, 2/4, 3/4, and 4/4 bx cores was 63(16-91)%, 5(1-65)%, 4(0-30)% and 26(0-63)% respectively, suggesting significant subclonal diversity within a single lesion. ATMs were identitified in 8/13 pts. 4/13 pts (31%) had no ATM across all 4 cores. 3 pts received therapy with inhibitors targeting ATMs. A pt with AKT1_E17K ATM received an AKT inhibitor with 21% tumour shrinkage and PFS 6.1 mths. 2 NSCLC pts harbouring an EGFR_T790M ATM were treated with an EGFRT790M specific TKI. 1 withdrew due to toxicity after 2mths and another had PFS > 16.5 mths. Tumour mutational burden (TMB) was consistent across multiple bx from each lesion. A NSCLC pt with the highest TMB received a checkpoint inhibitor with ongoing > 4 mths stable disease. Conclusions: Utilizing a single pass radiologically guided techniqueto obtainmultiple bx is feasible, safe and informative. This allows reconstruction of a tumour’s subclonal genomic architecture, providing insights into mutational heterogeneity and help guide therapy.

8547 Background: Patients (pts) with NSCLC that is initially responsive to EGFR tyrosine kinase inhibitors (EGFR TKI) typically develop resistance, often associated with aberrant c-Met activity. Dual inhibition of EGFR and c-Met is therefore a rational option to treat c-Met+ EGFR TKI-resistant NSCLC. Tepotinib is a highly selective c-Met inhibitor with good tolerability and promising activity against solid tumors. We report final data from a phase Ib trial of tepotinib + gefitinib in pts with c-Met+/EGFR-mutant NSCLC conducted in Asia. Methods: Eligible pts were adults with locally advanced/metastatic NSCLC and ECOG PS 0–1. Tumors had to express EGFR with an activating mutation be resistant to EGFR TKI therapy and be c-Met+ by IHC. Pts received tepotinib 300 or 500 mg QD combined with gefitinib 250 mg QD (T300G250 or T500G250). The primary objective was to determine the recommended phase II dose (RP2D) of tepotinib in combination with gefitinib; secondary objectives included pharmacokinetics (PK), safety, and antitumor activity. Results: 18 pts were enrolled (median age 65 [41–78]; 8 male); 6 received T300G250, 12 T500G250. No dose-limiting toxicities were observed, and tepotinib 500 mg QD was confirmed as the RP2D. 17 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), mostly grade ≤2 and most commonly diarrhea (12), rash (8), and amylase increase (6). Grade ≥3 TRTEAEs were increased amylase (n = 4), increased lipase (3), neutropenia (1), and hyperglycemia (1). The best overall response was partial response in 6 pts; 4/7 pts with IHC 3+ tumors responded (all treated with T500G250) vs 2/11 with IHC 2+ tumors. Response durations of pts with PR were 4.2–12.5 months. 4/18 pts (IHC 2+, n = 3) had stable disease. 8 pts experienced progression free survival > 5 months, 3 pts > 10 months. PK were as expected from previous studies. Conclusions: Tepotinib in combination with gefitinib was well tolerated. The RP2D of tepotinib for use in combination with gefitinib in NSCLC is 500 mg QD. T500G250 showed signs of activity against c-Met+ tumors. A phase II trial is randomizing ≈156 pts with c-Met+/T790M– tumors who have failed first-line EFGR TKI 2:1 to tepotinib + gefitinib or pemetrexed + cisplatin/carboplatin. Clinical trial information: NCT02864992.

9006 Background: Lorlatinib is a selective, potent, brain-penetrant, next generation ALK/ROS1 TKI active against most known resistance mutations. In Ph I of this Ph I/II study, lorlatinib showed robust clinical activity in ALK+ or ROS1+ advanced NSCLC pts, most of whom had CNS metastases (mets) and were heavily pre-treated. In Ph II of this study, efficacy was explored based on prior ALK TKI tx as well as safety across all patients treated at the recommended Ph II dose. Methods: In this ongoing Ph II study (NCT01970865), pts with ALK+ or ROS1+ NSCLC, ± asymptomatic untreated or treated CNS mets, were enrolled into 6 expansion cohorts (EXP) based on prior tx (EXP 1-5, ALK+) and rearrangement status (EXP 6, ROS1+). Pts received lorlatinib 100mg QD. Primary objective was ORR and intracranial ORR (IC-ORR) by independent central review (ICR). Results: Efficacy (ALK+ pts with prior tx): At data cut-off (15 Aug 2016), 82 ALK+ pts were enrolled in cohorts EXP 2-5, received C1 no later than 31 Mar 2016 and were evaluated for ORR (ITT population); 52 were evaluated for IC-ORR and 35 were evaluated for IC-ORR response based on target lesions only (≥5mm; no prior radiotherapy or progression post prior radiotherapy). Confirmed response rates by ICR are reported in the table below. Safety (all pts): 116 ALK/ROS1+ pts were evaluated for safety at data cut-off. Most common tx-related AEs (TRAEs) and grade 3/4 TRAEs were hypercholesterolemia (90%, 17%) and hypertriglyceridemia (72%, 17%). Dose interruptions and reductions due to TRAEs were reported in 29% and 20% of pts, respectively. 14% of pts had tx-related SAEs. 5 pts (4%) discontinued tx due to TRAEs and there were no tx-related deaths. 74/116 pts (64%) remain on tx. Conclusions: Lorlatinib showed compelling clinical activity, with substantial IC activity, in ALK+ pts who received ≥1 prior ALK TKI, many of whom were heavily pre-treated. Clinical trial information: NCT01970865. [Table: see text]

e14124Background: Low dose, short course anti-angiogenic agents may normalize tumor vasculature to improve drug delivery. We previously showed 12.5mg sunitinib (Su) for 7 days before neoadjuvant do...

e20501Background: Patients (pts) with NSCLC treated with EGFR inhibitors (EGFRi) ultimately develop resistance, often through c-Met activation. Dual EGFR and c-Met inhibition is therefore a rationa...

6034Background: NPC is chemo- and radiosensitive but relapse rate is high and progression free survival (PFS) short for stage 4 disease. Almost all NPCs overexpress VEGF that promotes immature vasc...

2542 Background: SXR is an orally administered potent XPO1 inhibitor that forces nuclear retention and activation of multiple tumor suppressor proteins resulting in tumor cell death. SXR was evalua...

e22162 Background: Low-dose computed tomography screening has been shown to reduce lung cancer-specific mortality, but has a high false-positive detection rate. The discovery of biomarkers for lung...

8028 Background: STAT3, a signal transduction protein of growth factor receptors including EGFR, is constitutively activated in many solid malignancies, leading to tumor angiogenesis, cell prolifer...

2625 Background: Significant progress in therapy of non SCC of the lung has been made through genomic profiling and subtyping according to oncogenic drivers. In SCC, cisplatin-based therapy remains...

11125 Background: Current evidence has highlighted the potential role for tumor infiltrating lymphocytes (TILs) in determining the survival of non-small cell lung cancer (NSCLC) patients. Whilst multiple studies have investigated the prognostic role of various subtypes of TILs, data is limited on the co-expression of TILs subpopulations and its clinical relevance. Identifying immune prognostic markers may help select postoperative NSCLC patients with a poorer prognosis for treatment with immunotherapy. We aim to identify NSCLC subgroups according to combined immunophenotypes and investigate their clinical relevance. Methods: A tissue microarray was constructed from 105 cases of resected NSCLC. Immunohistochemistry for TILs with CD3, CD8, FoxP3 and Granzyme B (GZMB) Ab was performed with an autostainer. TILs were quantified using the Vectra Automated Multispectral Imaging System. Low (-) and high (+) densities of TILs were dichotomised by the medians. EGFR and KRAS mutations were determined with Sanger seq...

7565 Background: EGFR and ALK are important driver mutations in NS. While we reported the significant association of increased ETS with EGFR mutations in Japanese cohort (Kawaguchi, Clin Cancer Res, 2011), ETS association with ALK has not been reported. Methods: ETS exposure on NS with NSCLC was evaluated using the standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was defined as a sum of the number of the exposure years in childhood and in adulthood, and was treated as a continuous variable or quintile. EGFR mutations and ALK rearrangements were tested by PCR-based detection and fluorescence in situ hybridization, respectively. Multivariate analyses were done using the generalized linear mixed model (GLIMMIX procedure, SAS v9.3). Results: From March 2008 to December 2012, 498 NS with NSCLC were registered with the following patient characteristics: ethnicity (nationality) of Asian/ Caucasian/ others, 425 (Japanese 250, Korean 102, Chinese 46, others 2)/ 48/ 25; male/female, 114/384; age =65, 286/212. EGFR status was wild type 43.6%, exon 19 deletion 25.3%, L858R 21.5% and other mutations 9.6%. ALK status was wild type 52.0%, rearranged 10.6% and unknown 37.3%. Average CETS (years) of NS with EGFR (+), ALK (+) and wild type tumors were 45.4, 26.9 and 37.7, respectively. In multivariate generalized linear mixed model, incidence of activating EGFR mutations, not ALK rearrangements, was significantly associated with the increment of CETS in female, not in male gender. Odds ratios (OR) for EGFR mutations in female (n=384) were 1.084 (95% CI, 1.003-1.171; p=0.0422) for each increment of 10 years in CETS while OR in male (n=114) were not significant (OR 0.890; 95% CI, 0.725-1.093; p=0.2627). OR for ALK rearrangements in female (n=238) and those in male gender (n=74) were 0.930 (0.791-1.094; p=0.3814) and 0.854 (0.620-1.178; p=0.3319). Conclusions: Increased ETS exposure was closely associated with EGFR mutations in NS with female gender and NSCLC in the expanded multinational cohort. However, the association of ETS and ALK rearrangements in NS with NSCLC was not significant.

2551 Background: Thymidylate synthase (TYMS) is the target of fluoropyrimidines (FP). TYMS 3R3R is the predominant genotype in East Asian (EA) patients and is associated with increased TYMS expression, reduced FP related toxicity and relative FP resistance. Dose finding studies for FP were developed in Caucasians, a population that typically harbors TYMS 2R2R and 2R3R genotypes. We hypothesize the recommended phase II dose (RP2D) of capecitabine is higher in 3R3R and similar for 2R allele carriers compared to the FDA approved dose. Objectives 1) To determine the maximal tolerated dose (MTD) and RP2D of capecitabine in EA patients with advanced stage malignancy 2) To determine the safety and toxicity of this regimen and 3) To perform plasma pharmacokinetics (PK) of capecitabine and its metabolites. Methods: EA patients with advanced stage cancer were prospectively allocated into two cohorts: Group A (3R3R) and Group B (2R3R, 2R2R). In each cohort, dose escalation followed a standard phase I 3+3 design. Additional patients were treated at the R2P2 dose level (DL). Initial dose was 1250/m2 bd for 14 days q3w (DL 1) with 125 mg/m2 bd increments subsequently. Pharmacokinetics (PK) of capecitabine and its metabolites were performed using a LC-MS/MS method. Results: 23 patients (Group A=18; group B=5) received 94 cycles (median 2.5, range 1-8). Median age was 58 (range 34-74) years. Median turnaround time for TYMS genotyping was 1 day. In group A, grade 3-4 DLTs were seen in 3 patients: diarhoea, neutropenic fever, hand-foot syndrome, and mucositis. MTD was at DL 4 (1625mg/m2 bd) and the RP2D was 1500mg/m2 bd (DL 3). DL 3 was expanded to n=9. At DL 3, day 1 mean (± SD) capecitabine and 5FU Cmax was 12.3 ± 9.9 and 0.91 ± 0.73 µg/mL, respectively and AUC0 – t was 9.84 ± 5.53 and 1.21 ± 0.54 h*µg/mL, respectively. Compared with DL1, Cmax for capecitabine and 5FU was 2 and 2.02 fold higher and AUC 0-t was 1.49 and 1.59 fold higher at DL3. Accrual in group B was ceased at DL2 due to lack of patient enrolment; no DLT was seen. By ROC analysis, day 1 5FU AUC0 – t of 1.74 h*µg/mL predicted for DLT (p=0.022, sensitivity 100%, specificity 90%). Conclusions: In EA patients with TSER 3R3R, the RP2D was 1500 mg/m2 bd. The D1 5FU AUC0 – t at RP2D was 59% more than the FDA approved dose (DL1).

e13002 Background: CPT-11 has complex PK and PD; genotyping of UGT1A1 is recommended for higher doses in *28 carriers (Caucasian) and *6 carriers (Asian) because of a higher risk of toxicity. Raltegravir is mainly metabolized to raltegravir glucuronide by UGT1A1. CPT-11 is mainly eliminated by cytochrome P450 isoform 3A (CYP3A)-mediated oxidation and by esterase cleavage to form SN-38, which is further conjugated by uridine-diphosphate glucuronosyltransferase (UGT) isozymes to the inactive SN-38 glucuronide. We prospectively explored the correlation of midazolam and raltegravir PK with CPT-11 clearance (CL) and SN-38 levels respectively and toxicity in patients undergoing chemotherapy with CPT-11. Methods: Twenty-five Asian patients with advanced cancer received CPT-11 as a 2-weekly 90-minute infusion (180 mg/m2) as part of the FOLFIRI regimen. Subjects were administered raltegravir 400 mg orally (as a UGT1A1 probe) and intravenous midazolam 1 mg (as a CYP3A4 probe) one day before the first dose of their chemotherapy. Blood sampling for drug concentrations was performed for 2 days after probe drug administration. Non-compartmental PK analyses were performed using WinNonLin. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1*6. Results: One patient developed grade 3 diarrhea and 16 developed grade 3-4 neutropenia. The mean CPT-11 CL was 21.9 + 7.8L/h. SN-38G/SN-38 AUC ratio was highly correlated with Raltegravir glucuronide/ Raltegravir AUC ratio (r=0.784 p10Nadir Absolute Neutrophil Count (ANC) (r=-0.397 p10 Nadir ANC. Of the 24 patients with genotyping of UGT1A1*6 done, 17 were wild type (GG), 7 heterozygotes (AG) and 0 were mutant (AA). No differences in toxicity or SN38 pharmacokinetics were observed in the UGT1A1*6 variants. Conclusions: Raltegravir glucuronide ratio is a good predictor of SN-38 glucuronidation, and has potential to predict neutropenia from FOLFIRI treatment. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize CPT-11 therapy.

3002 Background: STAT3 is constitutively activated by growth signaling pathways in many malignancies; in many cell lines inhibition of STAT3 leads to cell death. OPB51602 is a small molecule inhibitor of STAT3 phosphorylation (Tyr705) and activation. Methods: A phase I study of OPB51602 administered for 2 weeks every 3 weeks was initiated to determine the maximum tolerable dose (MTD), evaluate pharmacokinetics (PK), and assess pharmacodynamics effects on STAT3 in peripheral blood mononuclear cells (PBMCs). The starting dose was 2mg/day, and dose escalations to 5mg/d, 10mg/d, 20mg/d, were planned. Single dose PK was done on the first day of administration for 4 days. Dose escalation was based on the “3+3” design, MTD was defined as the dose with at least 2/6 dose limiting toxicities (DLTs) in the first cycle and toxicities were graded by NCICTCv4.0. Results: 32 patients (pt) were treated at doses of 2mg/d (n=7), 4mg/d (n=18), 5mg/d (n=7). The main toxicities observed included nausea/vomiting, diarrhea, peripheral neuropathy and fatigue. 5 mg/d was the MTD, where cycle 1 DLTs of grade 3 diarrhea/dehydration and hyponatremia occurred in 1 patient respectively. One pt developed grade 3 peripheral neuropathy at 4mg/d cohort. PK showed maximal drug levels 2-3 hours after administration, bi-exponential decay, with mean oral clearance of 316.5 +/- 638.9 L/h and long terminal mean half-life of 61.8 +/- 15.9 h on day 17. STAT3 phosphorylation in PBMCs assessed in 6 pts receiving 4mg/d was reduced from 67.4 +/- 17.4% at baseline to 53.0 +/- 18.1% (p=0.001) after administration on day 1. Interestingly, reduction in tumor metabolism by PET CT on day 15 was observed in 4/8 pts receiving 4mg/d. A pt with heavily pretreated adenocarcinoma of lung at 5mg/d dose had partial response; another pt with metastatic endometrial cancer at 4mg/d dose experienced stable disease for 6 cycles. Conclusions: OPB51602 has an MTD of 5mg/d on this schedule, demonstrates inhibition of STAT3 phosphorylation, and evidence of clinical activity. Further proof of concept studies of OPB51602 are warranted.

e13061 Background: Antigen (Ag)-specific cancer immunotherapy is based on induction of immune responses (humoral and cell-mediated) specifically targeting Ags expressed by tumor cells. This may be achieved by delivering the Ag as a recombinant protein combined with potent immunostimulants. PRAME and MAGE-A3 are tumor Ags with distinct tumor expression patterns, both under investigation as targets for immunotherapy in NSCLC and malignant melanoma. For additional clinical development of these immunotherapies in other cancer types, expression of PRAME and MAGE-A3 in these cancers must be investigated taking into account patient ethnicity and tumor characteristics. Methods: 4 retrospective studies were performed, each including all tumor stages: NSCLC pts (in Asia and Europe); bladder cancer pts in Europe; HCC pts in Asia. Formalin-fixed paraffin embedded tumor tissues were tested for PRAME and MAGE-A3 expression by quantitative RT-PCR using an expression cut-off value for positivity. Exploratory analyses of possible associations with patient and tumor characteristics were done to identify factors that may impact Ag expression. Results: The overall Ag expression rates are shown in the table below. In NSCLC, both Ags were expressed less frequently in Asian than in European patients (the histological distribution was the same). NSCLC tumors more frequently expressed PRAME than MAGE-A3 while the reverse tendency was seen for bladder tumors and HCC. In the NSCLC studies, squamous cell carcinomas expressed both Ags more frequently than adenocarcinomas. No study found any association between tumor stage and Ag expression. Some 60% of the tumors express at least one of the Ags. Conclusions: The expression rates of PRAME and MAGE-A3 are sufficiently high to consider these Ags as targets for immunotherapy against NSCLC, bladder cancer and HCC. [Table: see text]

7512 Background: Linifanib is a potent and selective inhibitor of VEGF and PDGF receptors with modest single-agent activity in NSCLC. We evaluated the combination of linifanib with carboplatin (C) and paclitaxel (P) for first-line therapy of advanced non-squamous NSCLC. Methods: Patients (pts) with stage IIIB/IV, non-squamous NSCLC, stratified by ECOG PS and gender, were randomized to receive up to six 3-wk cycles of C (AUC 6 mg/ml/min) and P (200 mg/m2) with daily placebo (Arm A), linifanib 7.5 mg (Arm B), or linifanib 12.5 mg (Arm C). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), 12 m survival rate, and objective response rate (ORR). Safety was assessed by NCI-CTCAE v3.0. Results: 138 pts were randomized at 37 sites in 6 countries. Baseline characteristics were: median age, 61 y; men, 57%; smoker, 84%. Efficacy results are shown in the table. Thrombocytopenia was the only Grade 3/4 AE significantly higher on linifanib (Arm B: 16.7%; Arm C: 29.8%) vs. placebo (2.1%). Other adverse events (AEs) related to the dose of linifanib were diarrhea, thrombocytopenia, hypertension, weight loss, palmar-plantar erythrodysaesthesia syndrome, and hypothyroidism. Analysis of samples for predictive biomarkers including serum VEGF and placental growth factor are underway. Conclusions: The addition of linifanib to chemotherapy was tolerable at the doses tested and resulted in a significant improvement in PFS, with a modest survival improvement for Arm C in first-line therapy of advanced non-squamous NSCLC. [Table: see text]

7590 Background: Linifanib (ABT-869), a novel orally active VEGF/PDGF RTK inhibitor, had single-agent activity in pts with advanced solid tumors including NSCLC. Methods: This open-label multicente...

3053 Background: Linifanib (ABT-869) is an orally bioavailable, potent, selective VEGF and PDGF RTK inhibitor. Activity was observed in a phase I trial of patients (pts) with advanced solid tumors ...

2526 Background: Use of concomitant medications that inhibit drug metabolizing enzymes such as Cyp3A4 is common and may affect chemotherapy PK/PD. We studied the effects of Cyp3A4 inhibition with ketoconazole on docetaxel PK/PD in 3 Asian ethnic groups. Methods: Two cohorts of chemonaive breast cancer patients were compared. The first cohort comprised of 95 patients (62 Chinese, 26 Malay, 7 Indian) treated with 75mg/m2 docetaxel unmodulated by ketoconazole, while the second cohort comprised of 31 patients (14 Chinese, 14 Malay, 3 Indian) treated with docetaxel 70mg flat dose modulated by oral ketoconazole, a regimen we previously reported to result in comparable docetaxel AUC as 75mg/m2 docetaxel. Plasma docetaxel concentrations were obtained at 0, 0.5, 1, 2, 5, 7 and 24 hours, and blood counts monitored on days 8 and 15 of cycle 1. Results: No significant differences in docetaxel PK or neutropenia between the races were observed in response to 75mg/m2 docetaxel unmodulated by ketoconazole (docetaxel clearance 36.4±16.9, 34.3±12.5, 44.2±27.7L/h, p=0.702; docetaxel AUC 3.6±2.7, 3.5±1.2, 2.9±1.3mg/L h, p=0.418; day 8 neutrophil count 0.5±0.6, 0.8±0.8, 0.4±0.3x109/L, p=0.138; grade 4 neutropenia 66%, 50%, 86%, p=0.157). In contrast, when docetaxel was administered with ketoconazole to inhibit Cyp3A4, inter-ethnic differences in docetaxel PK/PD were observed, with Chinese having the lowest docetaxel clearance and highest docetaxel AUC, followed by Malays and Indians (docetaxel clearance 18.6±5.7, 23.7±9.3, 30.6±6.7L/h, p=0.048; p=0.017 trend test; docetaxel AUC 4.2±1.4, 4.1±3.9, 2.4±0.5 mg/L h, p=0.048, p=0.017 trend test), although there were no statistically significant differences in body weight or surface area between the races. In concordance, Chinese patients experienced greatest degree of myelosuppression, followed by Malays and Indians (day 8 neutrophil count 0.8±0.8, 1.5±1.1, 1.7±1.1x109/L, p=0.046, p=0.013 trend test), and were more likely to develop grade 4 neutropenia (57%, 14%, 0%, p=0.024) from docetaxel + ketoconazole. Conclusions: Inter-ethnic differences in CYP3A inhibition by ketoconazole exist, and are important when evaluating the impact of concomitant medications with chemotherapy that may inhibit Cyp3A4. No significant financial relationships to disclose.

3514 Background: The distributed parameter (DP) model is a DCE-MRI model that enables derivation of blood flow and capillary permeability-surface area product (PS). We aim to compare the DP model t...

2507 Background: S-1 is an oral fixed combination drug composed of a prodrug of 5-FU (tegafur [FT]), a dihydropyrimidine dehydrogenase inhibitor (gimeracil [CDHP]), and an inhibitor primarily in the lower GI tract of 5-FU phosphorylation (Oxo). FT is primarily converted to 5-FU via CYP2A6. The purpose of this study was to compare S-1 PK and CYP2A6 activity of Asian and Caucasian patients. Methods: Asian and Caucasian patients with advanced solid tumors were enrolled in Singapore and the US and received S-1 30 mg/m2 bid for 14 consecutive days every 3 weeks. Blood samples for determination of S-1 components and metabolites were collected on Day 14 of cycle 1 at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 30 and 48 hrs post-dose. CYP2A6 activity was determined using ratio of plasma cotinine and nicotine concentrations after chewing nicotine gum. Results: Of 18 Asian (15 Chinese, 3 Malay) and 19 Caucasian patients enrolled, 11 Asian and 10 Caucasian patients with mean BSA 1.63 m2 and 1.89 m2, respectively, were evalu...

14535 Background: ABT-869, an orally administered, potent small molecule inhibitor of VEGF receptors 1–3 and platelet derived growth factor, is active in solid malignancies. Consistent with similar...

14109 Background: Transfer constant (Ktrans) and IAUC60 normalized with arterial input function are commonly used dynamic contrast enhanced magnetic resonance imaging (DCE MRI) parameters. The distributed parameters model (DP) is a DCE MRI model that enables derivation of blood flow and capillary permeability-surface area product (PS). We aim to study the distributed parameters model as an alternative method of angiogenesis assessment and correlate the above parameters to drug exposure and patient outcome in a Phase I anti- angiogenic trial. Methods: Fifteen evaluable patients from an on-going Phase I trial (ABT 869) with 3 dose escalations formed the study population. Pharmacokinetic study was performed on Day 1 and the area under the concentration time curve extrapolated to infinity (AUCinfinity) was used as an indicator of drug exposure. All patients underwent DCE MRI at baseline, Day 3 and Day 15 with temporal resolution of 4 seconds. Gadolinium concentrations were estimated using a dual flip angle method. Patients demonstrating progressive disease in first 2 evaluation scans (cycle 2 or 4) based on RECIST criteria were considered progressors and all other patients non-progressors. Receiver operating curve (ROC) analysis was performed. Correlation with AUCinfinity was analyzed. Results: There is good correlation (Spearman’s coefficient -0.67, p = 0.008) between AUCinfinity and DP derived PS and less strong correlation with normalized IAUC60 (Spearman’s coefficient -0.57, p = 0.03). There is no correlation for Ktrans (Spearman’s coefficient 0.04). ROC analysis for predicting progressors versus non-progressors showed a higher ROC area for PS compared to Ktrans (0.83 versus 0.47, p = 0.037). Normalized IAUC60 showed a slightly lower area compared to PS (0.77 versus 0.83) but the difference is not significant (p = 0.58). Conclusions: PS derived from DP model shows better correlation with drug exposure and may predict patient outcome better than Ktrans. [Table: see text]

18104 Background: Asian NSCLC patients are known to have higher response rates to the EGFR TKI gefitinib (G) and erlotinib (E). Anecdotal reports suggest some activity for a second EGFR TKI after failure of the first. Methods: A retrospective review of the electronic pharmacy records, clinical and radiographic records of patients with advanced NSCLC at the National University Hospital who received both G and E in the previous 2 years was conducted. Objectives were to assess the disease control (response/stable disease) of the second TKI after failure of the first and characterize the clinical, pathological and molecular features of patients benefiting from a 2nd TKI. Results: 14 patients with advanced NSCLC who received a 2nd EGFR TKI after progression on the 1st TKI were identified. Patient characteristics: Chinese 12, female 10, and non-smokers 13. Histologic subtype: adenocarcinoma 7, bronchioloalveolar carcinoma (BAC) 3, squamous-cell carcinoma 1, NSCLC unspecified 3. 12 patients received cytotoxic chemotherapy with a median of 2 lines, (range 1–5). G and E was used as 1st/2nd/3rd/=4th line treatment in 8/2/2/2 and 0/4/2/8 patients respectively. G was used before E in 13 cases and disease control was seen in 8/14 (57%) patients. With a 2nd TKI after disease progression, disease control was seen 4/14 (28%) patients. Patient characteristics were: adenocarcinoma 3, BAC 1, all were never smokers and all received and responded to prior G. Median duration of control in these 4 patients for G was 8 (range 7–12) months, and subsequently to E was 2.5 (range 2–8) months. Disease control was associated with symptomatic improvement. Conclusion: This study documents disease control in 28% of Asian NSCLC patients treated with a second EGFR TKI after failure of a first. The molecular basis for these observations is currently being investigated. No significant financial relationships to disclose.

2008 Background: Genotypic variation for drug metabolising enzymes, targets and transporters is associated with inter-patient and inter-ethnic variability in toxicity and efficacy. Gemcitabine is a nucleoside anti-metabolite used in a range of solid tumors. Aims: 1) to determine genotype distribution of genes involved in gemcitabine pharmacology pathway in ethnic groups; 2) to evaluate the association between genotypes and treatment related outcomes in patients with chemo-naive, advanced NSCLC receiving gemcitabine based chemotherapy on a prospective study. Methods: Candidate genes involved in gemcitabine pharmacology were identified from a comprehensive search of public databases (NCBI, PharmGKB), and publications. 25 variants of 9 candidate genes (RRM-1, SLC28A1, SLC28A2, SLC28A3, SLC29A2, POLA2, DCTD, CDA, TS) were genotyped from blood in 94 healthy donors and 76 cancer patients (breast 22, NSCLC 54) with pyrosequencing. Chi-squared, Kruskall-Wallis, and Kaplan-Meier analysis were used to evaluate associations between genotypes and ethnic groups and clinical end points. Results: Significant differences in genotype distribution between Chinese, Malay and Indian were seen in 5/25 loci (see table ). In NSCLC patients, POLA2 2089 (G > A) was associated with neutropenia (p = 0.022), SLC28A1-1576 (C > T) with neutropenia nadir (p = 0.030) and thrombocytopenia nadir (p = 0.037), RRM-1 -524 (T > C) with neutropenia (p = 0.024) and SLC28A2–283 (CA 18.3 vs CC 8.5 months, p = 0.004), and SLC28A2–22 (CC 8.0 vs CT 18.3 months, p = 0.002) with survival. Conclusions: Our results suggest there is significant genotypic variability among ethnic groups. Variants in gemcitabine transporters and targets may be useful indicators of gemcitabine related toxicity and survival. Further studies should be performed to confirm these preliminary findings. [Table: see text] No significant financial relationships to disclose.

3145 Cyclin dependent kinase (CDK) inhibition mimics tumor suppressor protein function and induces cell cycle arrest and apoptosis in cancer cell lines. Seliciclib, an orally administered inhibitor...