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9109 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions have been identified as oncogenic drivers in a diverse array of tumor types including lung cancer. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of adult and pediatric patients (pts) with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). Here, we report the updated data on pts with lung cancer treated with larotrectinib. Methods: Pts with lung cancer harboring a NTRK gene fusion enrolled in two clinical trials (NCT02576431 and NCT02122913) were identified for this analysis. Larotrectinib 100 mg PO BID was administered on a continuous 28-day schedule until disease progression, withdrawal, or unacceptable toxicity. Response was assessed by the investigator per RECIST v1.1. Results: As of July 20, 2020, a total of 20 pts with TRK fusion-positive lung cancer (19 with non-small cell lung cancer and 1 with small cell lung cancer) were enrolled. Median age was 48.5 years (range 25.0–76.0). The gene fusions involved NTRK1 (n = 16; 80%) or NTRK3 (n = 4; 20%). Pts were heavily pre-treated with a median of 3 systemic therapies (range 0–6). Among 15 evaluable pts, the confirmed ORR was 73% (95% CI 45–92): 1 complete response, 10 partial responses (PR), 3 stable disease (SD) and 1 progressive disease (PD). The median time to response was 1.8 months. Among 8 evaluable pts with baseline measurable and non-measurable CNS metastases, the ORR was 63% (95% CI 25–91): 5 PR, 2 SD, and 1 PD. In all evaluable pts, the 12-month rates for duration of response and progression-free survival were 81% and 65%, respectively. Median overall survival was 40.7 months (95% CI 17.2 to not estimable) at a median follow-up of 16.2 months. Duration of treatment ranged from 0.03+ to 51.55+ months. Adverse events (AEs) were predominantly Grade 1–2. Treatment-related AEs were reported in 16 pts, of which 2 experienced Grade 3 events (myalgia, hypersensitivity, weight increase). There were no treatment discontinuations due to AEs. Conclusions: These data confirm that larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in pts with advanced lung cancer harboring NTRK gene fusions, including in pts with CNS metastases. These results underscore the importance of screening for NTRK gene fusions in pts with lung cancer. Clinical trial information: NCT02576431 and NCT02122913.

9056 Background: Capmatinib, a potent, selective MET inhibitor, showed substantial antitumor activity and manageable tolerability in patients with METex14-mutated advanced non-small cell lung cancer (aNSCLC) in the GEOMETRY mono-1 trial (NCT02414139). Patient-reported outcomes (PROs) from this study are reported here. Methods: GEOMETRY mono-1 enrolled patients ≥18 years with METex14-mutated or MET-amplified, ALK-negative and EGFR wild-type, treatment-naïve (1L) or pre-treated (2L+) aNSCLC, to receive capmatinib orally 400 mg bid during 21-day treatment cycles. Here we report results for patients with METex14 mutations. PROs (EORTC QLQ-C30, QLQ-LC13 and EQ-5D-5L) were collected at baseline (BL) and every 6 weeks (Wks) until end of treatment. Key PROs (in patients with BL and ≥1 post-BL value) included change from BL in QLQ-C30 global health status (GHS), QLQ-LC13 symptoms (cough, chest pain and dyspnea), and EQ-5D-5L visual analogue scale (VAS), with a ≥10-point change from BL considered clinically meaningful. Time to definitive deterioration (TTDD) in QLQ-LC13 symptoms (time from treatment initiation to first date of ≥10% symptom change from BL with no later reduction) was assessed using Kaplan-Meier. QLQ-LC13 symptoms over time were explored by BIRC-assessed clinical response to capmatinib. Results: By Jan 6, 2020 cut-off, median capmatinib exposure was 48.2 (4.0 117.4) Wks and 22.1 (0.4 136.0) Wks for 1L and 2L+ patients, respectively. A total of 27/28 1L patients and 65/69 2L+ patients completed PROs at BL, and completion rate remained high (mostly > 70%) through treatment cycles. Mean [SD] BL PRO scores were moderate-to-high in 1L and 2L+ patients (GHS: 64.7 [21.6] and 58.8 [21.0.]; cough: 35.9 [32.6] and 28.7 [28.2]; chest pain: 12.8 [23.2] and 17.2 [22.7]; dyspnea: 23.5 [23.4] and 22.2 [20.8]; VAS: 67.7 [20.8] and 61.9 [18.8], respectively). Overall change from BL in PROs was maintained over time. Cough improved early, with meaningful improvements observed through cycles, notably in 1L patients (mean change from BL [SD] at Wk 7: 1L -13.0 [39.9], 2L+ -8.2 [28.4]; Wk 25: 1L -15.6 [33.0], 2L+ -6.0 [31.5]; Wk 43: 1L -28.2 [26.7], 2L+ -10.5 [27.3]). Median TTDD in GHS was 16.6 months (95% CI: 9.7, NE [not estimated]) and 12.4 months (95% CI: 4.2, 19.4) in 1L and 2L+ patients, respectively. Median TTDD for cough and chest pain was NE in both 1L and 2L+ patients, and for dyspnea was 19.4 months (95% CI: 12.4, NE) and 22.1 months (95% CI: 9.9, NE), respectively. QLQ-LC13 symptoms improved at all cycles in patients achieving clinical complete response or partial response, while symptom worsening was seen in those with no clinical response. Conclusions: Capmatinib was associated with clinically meaningful improvements in cough, delayed time to lung symptom deterioration, and preserved QoL, supporting its use as a treatment option in patients with METex14-mutated aNSCLC. Clinical trial information: NCT02414139.

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.

3005 Background: SHP2 transduces signals from activated receptor tyrosine kinases to downstream pathways including MAPK. TNO155 is a selective, allosteric, oral inhibitor of SHP2. Methods: CTNO155X2101 (NCT03114319) is an ongoing first-in-human, open-label dose escalation/expansion trial of TNO155 in adults with advanced solid tumors. The primary objective is to characterize the safety and tolerability of TNO155 and identify regimen(s) for future study. Secondary assessments included pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy. Here we present data from TNO155 single agent escalation. Results: As of 10/26/2020, 118 patients received TNO155 in variable schedules: once (QD; 1.5–70 mg; n = 55) or twice daily (BID; 30–50 mg; n = 25) in a 2 weeks on/1 week off (2w/1w) cycle; or QD in a 3w/1w cycle (30–60 mg; n = 32), or continuously (40 or 50 mg QD; n = 6). The most common cancer diagnoses treated were colorectal (54%), gastrointestinal stromal tumor (16%), non-small cell lung (12%), and head & neck (8%). The median number of prior antineoplastic therapies was 4 (range 1–10). Overall 109 patients (92%) have discontinued study treatment, 94 (80%) for progressive disease and 6 (5%) for adverse events (AEs). TNO155 showed rapid absorption (median day 1 Tmax ̃1.1 hours), an effective median T½ of ̃34 hours, and near dose-proportional exposure at day 14 (power model: AUCτ beta = 1.09 [90% CI 1.02–1.16]). AEs were mostly Grade 1/2 and generally consistent with on-target effects of SHP2 inhibition. The most common treatment-related AEs (all grades) were increased blood creatine phosphokinase (n = 33, 28%), peripheral edema (n = 31, 26%), diarrhea (n = 31, 26%), and acneiform dermatitis (n = 27, 23%). The most common treatment-related Grade ≥3 AEs were decreased platelets (n = 5, 4%), increased aspartate aminotransferase, diarrhea, and decreased neutrophils (each n = 4, 3%). The best observed response was stable disease (SD) per RECIST 1.1, reported in 24 (20%) patients, with a median duration of SD of 4.9 months (range 1.7–29.3). Evidence of SHP2 inhibition, as measured by change in DUSP6 expression by qPCR in paired pre- vs. on-treatment tumor samples, was seen in the majority of patients treated with TNO155 doses ≥20 mg/day (≥25% reduction, 38/42 [90%]; ≥50% reduction, 25/42 [60%]). Analysis of tumor whole-transcriptome RNA sequencing data is ongoing. Conclusions: TNO155 shows favorable pharmacokinetic properties and promising early safety and tolerability data at doses with evidence of target inhibition. The optimal dose using several schedules is still under evaluation. Studies of TNO155 in combination with other agents, including nazartinib (mutant-selective EGFR inhibitor[i]), adagrasib (KRAS G12Ci), spartalizumab (anti-PD-1 antibody), ribociclib (CDK4/6i), and dabrafenib (BRAFi) with LTT462 (ERKi), are ongoing (NCT03114319, NCT04330664, NCT04000529, NCT04294160). Clinical trial information: NCT03114319.

9089 Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]

9065 Background: Selpercatinib, a first-in-class highly selective and potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Here we report an update of efficacy and safety results which provide a longer follow up and increased number of patients (safety population: N = 345 vs N = 329). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, ongoing LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites) were included in this analysis. Pts with the opportunity to be followed ≥6 months from their first dose were included in the efficacy-evaluable population for these analyses. Integrated analysis set (IAS) included 218 NSCLC pts with prior platinum-chemotherapy. Primary analysis set (PAS) was a subset of the IAS and included the first 105 consecutively enrolled pts. The treatment-naïve population included 48 efficacy-evaluable pts. Primary endpoint was objective response rate (ORR, RECIST v1.1) by independent review committee (IRC). Secondary endpoints included ORR by investigator, duration of response (DoR), progression-free survival (PFS), clinical benefit rate (CBR; CR+PR+SD ≥16 weeks), and safety. Safety population (N = 345) included all pts with NSCLC who received ≥1 selpercatinib dose by data cutoff (30 Mar 2020). Results: In pts with prior treatment (N = 218) and treatment-naïve (N = 48) pts, 56% and 60% were female, with a median pt age of 61 and 64 years, respectively. The ORR with selpercatinib was 57% in the IAS, 64% in the PAS, and 85% in the treatment-naïve population (Table). In both the IAS and PAS, the median DoR was 17.5 months, median PFS was 19.3 months at median follow-up of 12.0 and 15.7 months, respectively (Table). The most common treatment-emergent adverse events (TEAEs) reported in ≥25% of pts were dry mouth, diarrhea, hypertension, increased ALT/AST, edema peripheral, and fatigue. Twenty-five pts (7%) permanently discontinued due to TEAEs, with 10 pts (3%) discontinuing selpercatinib due to treatment-related AEs as per investigator. Conclusions: In this updated data set, selpercatinib continued to demonstrate durable antitumor activity in pts with RET-fusion+ NSCLC. Selpercatinib was well-tolerated with a safety profile consistent with previous reports. A global, randomized, phase 3 trial (LIBRETTO-431) evaluating selpercatinib compared with standard frontline therapy is ongoing. Clinical trial information: NCT03157128. [Table: see text]

9048 Background: Primary findings from the phase 1b/2 study (NCT01610336) demonstrated clinical activity of combination therapy with capmatinib, a potent and selective MET inhibitor, and gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in heavily pre-treated patients with EGFR-mutated and MET dysregulated non-small cell lung cancer (NSCLC). The objective response rate (ORR) was 27% in patients across phase 1b/2 of the study. At the recommended phase 2 dose (R2PD) of capmatinib 400 mg twice-daily (bid) and gefitinib 250 mg once-daily (qd), the ORR was 47% in patients with high MET-amplified tumors ( MET gene copy number ≥6). Here, we report the updated data on the efficacy and safety from the NCT01610336 study. Methods: Patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletion or L858R mutation with a recorded clinical benefit on prior single-agent EGFR-TKI before progression and confirmed dysregulated MET pathway after progression on EGFR TKIs were included. Patients in phase 1b received capmatinib 100 to 800-mg capsules qd or 200 to 600-mg capsules or tablets bid, plus gefitinib 250 mg qd. Patients in phase 2 received the R2PD dose. Data on the overall survival (OS) and cumulative safety endpoints are reported in this final analysis. Results: Overall, 161 patients received the combination treatment in this study; phase 1b (n = 61) and phase 2 (n = 100). The median age of patients was 60.0 years, mostly Asian (67.1%) with an Eastern Cooperative Oncology Group performance status of 0/1: 18.0%/78.3%. At data cut-off on May 27, 2020, all patients had discontinued the study; 82 out of the 100 patients in phase 2 had died and 18 were censored (mostly lost to follow-up [n = 15]). One patient was still on treatment with a partial response and rolled over to another study. The median (range) follow-up time for OS was 12.2 (0.9-70.2) months. The median OS was 13.9 months (95% confidence interval, 11.6-15.7 months). The median (range) duration of exposure for capmatinib plus gefitinib was 16 weeks (0.4-209.7 weeks) during phase 1b and 18.5 weeks (0.4-268.0 weeks) during phase 2. Majority of the patients (98.8%) experienced ≥1 adverse event (AE); 87% of the patients had treatment-related AEs. Most common treatment-related AEs (reported in ≥20%) were nausea (28.0%), peripheral edema (23%), rash (21.7%), and decreased appetite (21.1%). Grade 3 or 4 treatment-related AEs occurred in 51 patients (31.7%) across both phases, of which, the most frequent (reported in ≥5%) were increased amylase and increased lipase (6.2% each) and peripheral edema (5%). Conclusions: Capmatinib 400 mg bid in combination with gefitinib 250 mg qd was well-tolerated and showed encouraging clinical activity in patients with EGFR-mutant and MET-dysregulated NSCLC. Clinical trial information: NCT01610336.

9032 Background: Selpercatinib, a first-in-class highly selective, potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Selpercatinib demonstrated durable antitumor activity in previously treated pts with RET fusion+ NSCLC in an ongoing Phase 1/2 trial, LIBRETTO-001 (Besse et al., ASCO 2021). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites). Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival, duration of response, and safety. This post-hoc intrapatient analysis was based on a 30 March 2020 data cutoff date. Historical physician-reported best overall response (BOR) from last systemic therapy received prior to enrollment was compared with selpercatinib BOR by independent review committee per RECIST v1.1, with each patient serving as his/her own control. Results: In efficacy-evaluable pts (N = 218) who previously received platinum-based chemotherapy (chemo), median pt age was 61 years, the majority with ECOG of 0/1 (37%/61%), with a median of 2 (range: 1-15) prior systemic therapies. Overall, 57% of patients responded to selpercatinib while 16% responded to the immediate prior therapy. ORR improvements with selpercatinib were observed regardless of prior therapy: chemotherapy + immune checkpoint inhibitor (ICI) (57% vs 14%), single-agent ICI (48% vs 3%), or chemotherapy (58% vs 15%). A total of 108 patients (49%) did not respond to immediate prior therapy but responded to selpercatinib. Fewer patients had progressive disease as their BOR with selpercatinib (2%) compared to the immediate prior therapy (28%). The median duration of therapy for selpercatinib was notably extended compared with that of the immediate prior therapy (11.8 vs. 3.4 months, respectively). Conclusions: In pts with RET fusion+ NSCLC treated on LIBRETTO-001, systemic therapies administered prior to enrollment achieved less meaningful clinical benefit than selpercatinib. Selpercatinib demonstrated consistent efficacy regardless of the type of prior therapy. Clinical trial information: NCT03157128.

9111 Background: Capmatinib, a highly selective and potent MET inhibitor, was approved for patients (pts) with advanced MET exon 14 skipping mutation (METex14) NSCLC in the US and Japan, with the FoundationOne CDx (tissue NGS assay), based on results of the ongoing GEOMETRY mono-1 study (NCT02414139). Here, we report efficacy findings in pts from GEOMETRY mono-1, who were identified as METex14 using a next-generation sequencing (NGS)-based liquid biopsy test (LDx), which detects METex14 in circulating tumor (ct)DNA. Methods: During the GEOMETRY mono-1 study, pts were screened for METex14 status using a METex14 RT-PCR clinical trial assay (CTA) on FFPE tissue. Clinical validation of the LDx was performed using plasma samples from pts enrolled in the GEOMETRY mono-1 study, which include METex14-positive samples from Cohort (C)4 (pretreated) and C5b (treatment-naïve), in addition to METex14-negative samples from C1b, C2, and C3, and 21 tissue-matched NSCLC plasma samples from commercial sources to supplement the total number of METex14 deletion negative patients. Concordance of the CTA and LDx were evaluated by positive percent agreement (PPA) and negative percent agreement (NPA). This retrospective analysis reports overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS), all by BIRC, and overall survival (OS) in pts identified as METex14 by the LDx (data cutoff: Sep 18, 2020). Results: Of the 97 pts with METex14 NSCLC in C4 (n = 69) and C5b (n = 28), 88 pts had plasma volume ≥2.5 mL and cell free DNA ≥20 ng (minimum input); of these 57 were LDx positive (C4, n = 41; C5b, n = 16), 26 were negative; 5 had invalid sequencing results. Of the 97 CTA METex14-negative patients who met minimum input requirements, 88 were LDx negative and 9 had invalid sequencing results; none of the CTA METex14-negative pts (N = 97) were reported as positive by the LDx. The PPA and NPA for these were 68.7% (95% CI: 57.6%, 78.4%) and 100% (95% CI: 95.9%, 100%), respectively, when excluding LDx invalid results. In pts identified as METex14 positive by LDx, the ORR (95% CI) was 81.3% (54.4‒96.0; n = 16) in C5b and 48.8% (32.9‒64.9; n = 41) in C4; median DOR (95% CI) was 20.3 (4.2, NE; n = 13) months in C5b and 9.8 (4.2‒19.5; n = 20) months in C4; median PFS (95% CI) was 12.4 (4.5‒NE; n = 16) months in C5b and 5.4 (4.0‒6.6; n = 41) months in C4; median OS was 17.9 (9.8‒NE; n = 16) months in C5b and 13.6 (6.6‒23.3; n = 41) months in C4. Clinical findings in those identified as METex14 positive by LDx were comparable with those identified by the CTA. Conclusions: Current findings from the GEOMETRY mono-1 study support the activity of capmatinib in advanced NSCLC pts with METex14 identified using LDx. For pts identified as METex14-negative by the LDx, further testing should be performed on tissue samples, as a negative LDx result does not preclude a positive result by tissue biopsy. Clinical trial information: NCT02414139.

OBJECTIVES We have previously identified and validated a panel of molecular prognostic markers (ATP13A3, SSR3, and ANO1) for Head and Neck Squamous Cell Carcinoma (HNSCC). The aim of this study was to investigate the consequence of ATP13A3 dysregulation on signaling pathways, to aid in formulating a therapeutic strategy targeting ATP13A3-overexpressing HNSCC. MATERIALS AND METHODS Gene Set Enrichment Analysis (GSEA) was performed on HNSCC microarray expression data (Internal local dataset [n = 92], TCGA [n = 232], EMBL [n = 81]) to identify pathways associated with high expression of ATP13A3. Validation was performed using immunohistochemistry (IHC) on tissue microarrays (TMAs) of head and neck cancers (n = 333), staining for ATP13A3 and phosphorylated Aurora kinase A (phospho-T288). Short interfering RNA was used to knockdown ATP13A3 expression in patient derived HNSCC cell lines. Protein expression of ATP13A3 and Aurora kinase A was then assessed by immunoblotting. RESULTS GSEA identified Aurora kinase pathway to be associated with high expression of ATP13A3 (p = 0.026). The Aurora kinase pathway was also associated with a trend towards poor prognosis and tumor aggressiveness (p = 0.086, 0.094, respectively). Furthermore, the immunohistochemical staining results revealed a significant association between Aurora kinase activity and high ATP13A3 expression (p

Lung cancer is a leading cause of cancer-related mortality worldwide, and is classically divided into two major histological subtypes: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although NSCLC and SCLC are considered distinct entities with different genomic landscapes, emerging evidence highlights a convergence in therapeutically relevant targets for both histologies. In adenocarcinomas with defined alterations such as EGFR mutations and ALK translocations, targeted therapies are now first-line standard of care. By contrast, many experimental and targeted agents remain largely unsuccessful for SCLC. Intense preclinical research and clinical trials are underway to exploit unique traits of lung cancer, such as oncogene dependency, DNA damage response, angiogenesis, and cellular plasticity arising from presence of cancer stem cell lineages. In addition, the promising clinical activity observed in NSCLC in response to immune checkpoint blockade has spurred great interest in the field of immunooncology, with the scope to develop a diverse repertoire of synergistic and personalised immunotherapeutics. In this Review, we discuss novel therapeutic agents for lung cancer that are in early-stage development, and how prospective clinical trials and drug development may be shaped by a deeper understanding of this heterogeneous disease.

Targeted next-generation sequencing is becoming increasingly common as a clinical diagnostic and prognostic test for patient- and tumor-specific genetic profiles as well as to optimally select targeted therapies. Here, we describe a custom-developed, next-generation sequencing test for detecting single-nucleotide variants (SNVs) and short insertions and deletions (indels) in 93 genes related to gastrointestinal cancer from routine formalin-fixed, paraffin-embedded clinical specimens. We implemented a validation strategy, based on the College of American Pathologists requirements, using reference DNA mixtures from cell lines with known genetic variants, which model a broad range of allele frequencies. Test sensitivity achieved >99% for both SNVs and indels, with allele frequencies >10%, with high specificity (97.4% for SNVs and 93.6% for indels). We further confirmed test accuracies using primary formalin-fixed, paraffin-embedded colorectal cancer specimens characterized by alternative and conventional clinical diagnostic technologies. Robust performance was observed on the formalin-fixed, paraffin-embedded specimens: sensitivity was 97.2% and specificity was 99.2%. We also observed high intrarun and inter-run reproducibility, as well as a low cross-contamination rate. Overall assessment using cell line samples and formalin-fixed, paraffin-embedded samples showed that our custom next-generation sequencing assay has consistent detection sensitivity down to 10% variant frequency.

Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) is routinely evaluated by fluorescent in-situ hybridization (FISH) testing on biopsy tissues. Testing can be challenging however, when suitable tissue samples are unavailable. We examined the relevance of circulating tumor cells (CTC) as a surrogate for biopsy-based FISH testing. We assessed paired tumor and CTC samples from patients with ALK rearranged lung cancer (n = 14), ALK-negative lung cancer (n = 12), and healthy controls (n = 5) to derive discriminant CTC counts, and to compare ALK rearrangement patterns. Blood samples were enriched for CTCs to be used for ALK FISH testing. ALK-positive CTCs counts were higher in ALK-positive NSCLC patients (3-15 cells/1.88 mL of blood) compared with ALK-negative NSCLC patients and healthy donors (0-2 cells/1.88 mL of blood). The latter range was validated as the 'false positive' cutoff for ALK FISH testing of CTCs. ALK FISH signal patterns observed on tumor biopsies were recapitulated in CTCs in all cases. Sequential CTC counts in an index case of lung cancer with no evaluable tumor tissue treated with crizotinib showed six, three and eleven ALK-positive CTCs per 1.88 mL blood at baseline, partial response and post-progression time points, respectively. Furthermore, ALK FISH rearrangement suggestive of gene copy number increase was observed in CTCs following progression. Recapitulation of ALK rearrangement patterns in the tumor on CTCs, suggested that CTCs might be used to complement tissue-based ALK testing in NSCLC to guide ALK-targeted therapy when suitable tissue biopsy samples are unavailable for testing.

Tumor heterogeneity is a major hindrance in cancer classification, diagnosis and treatment. Recent technological advances have begun to reveal the true extent of its heterogeneity. Single-cell analysis (SCA) is emerging as an important approach to detect variations in morphology, genetic or proteomic expression. In this review, we revisit the issue of inter- and intra-tumor heterogeneity, and list various modes of SCA techniques (cell-based, nucleic acid-based, protein-based, metabolite-based and lipid-based) presently used for cancer characterization. We further discuss the advantages of SCA over pooled cell analysis, as well as the limitations of conventional techniques. Emerging trends, such as high-throughput sequencing, are also mentioned as improved means for cancer profiling. Collectively, these applications have the potential for breakthroughs in cancer treatment.

Introduction Reflex molecular testing plays a critical role in identifying actionable targets and allocating patients to appropriate treatment. We report the clinicopathologic features and treatment outcomes of non-squamous non-small cell lung cancer (NSCLC) patients who underwent reflex testing for EGFR and ALK . Methods We analyzed the data of NSCLC patients diagnosed from 2010 to 2014 who underwent reflex testing for EGFR (from 2010) and ALK (from 2012) alterations and compared the outcome of those positive for the alterations against those who were wild-type (WT). Using multivariate cox regression, we determined the significant prognostic clinical factors that predicted for an improved survival outcome. Results EGFR mutation was more prevalent among females and never-smokers. The median OS (months) for the positive group was 24.8 versus 13.3 for the WT group (p EGFR tyrosine kinase inhibitor (TKI) treatment (all p ALK fusion was more prevalent among Malay patients (p=0.031). There were no significant survival differences in OS between positive and WT groups. Prognostic factors include gender, ethnicity, ECOG status, treatment intent, number of palliative treatment and metastatic sites (all p ALK TKI treatment (p=0.06). Conclusion This study found significant differences in demographic and clinical characteristics, and treatment outcomes between positive and WT patients for EGFR and ALK profiles, reinforcing the importance of reflex testing in patient management.

9520 Background: Capmatinib (INC280) has shown promising efficacy in patients (pts) with MET exon 14 ( METex14)–mutated NSCLC who were pretreated (cohort 4) or treatment (tx)-naïve (cohort 5b) in the ongoing, multicohort, phase 2 GEOMETRY mono-1 study. We report the results for pts enrolled in the expansion cohort 6 with either high-level MET amplification (gene copy number [GCN] ≥10) or METex14 mutation (any MET GCN) whose disease progressed on 1 prior line of systemic therapy. Methods: Adult pts (≥18 years), ECOG PS 0–1 who had ALK and EGFR wt, stage IIIB/IV NSCLC (any histology) received capmatinib tablets 400 mg twice daily (with or without food). Key efficacy endpoints were overall response rate (ORR) and duration of response (DOR) by blinded independent review committee (BIRC) per RECIST v1.1. Other secondary endpoints included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival (PFS; BIRC and investigator assessment) and safety. Results: As of Jan 6, 2020, 34 NSCLC pts with METex14 mutation (n = 31) or high-level MET amplification (n = 3) were included in this analysis. Tx was ongoing for 38.2% of pts. In METex14-mutated NSCLC pts, per BIRC assessment: ORR was 48.4%, median DOR was 6.93 months (mo, not yet mature, 95% CI: 4.17–NE) and median PFS was 8.11 mo (not yet mature, 95% CI: 4.17–9.86). Investigator-assessed responses were similar to BIRC assessment (Table). Only 3 pts with high-level MET amplification were included in this cohort due to challenges in enrollment. All 3 pts had stable disease per BIRC assessment and were on treatment for 48, 85 and 97 days. Most common AEs (≥25%, all grades, N = 34) were peripheral edema (64.7%), nausea (35.3%), fatigue (29.4%), back pain (26.5%) and vomiting (26.5%). Data for pts with brain metastasis will be presented at the ASCO 2020 meeting. Conclusions: Capmatinib was confirmed to be efficacious in 2nd line, METex14-mutated NSCLC pts. This is the first cohort where capmatinib has been administered without fasting restriction and data confirm the favorable safety profile. Clinical trial information: NCT02414139 . [Table: see text]

3640 Background: LTT462 is an investigational small molecule inhibitor of ERK1/2, which has demonstrated preclinical activity in multiple MAPK activated cancer cells and xenograft models. This first-in-human study was designed to evaluate the safety and tolerability of LTT462 in advanced solid tumors harboring MAPK pathway alterations (NCT02711345). Methods: The dose-escalation part of this Phase I, open-label study, enrolled adult and adolescent pts with advanced solid tumors harboring ≥1 documented MAPK pathway alteration with progressive disease (PD) despite standard therapy, or for whom there is no effective standard treatment. Oral LTT462 was given once daily (QD) at 45–600 mg or twice daily (BID) at 150 mg or 200 mg. Objectives were to determine the maximum tolerated dose (MTD) using a Bayesian hierarchical logistic regression model guided by escalation with overdose control, and characterize safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of LTT462. Results: Sixty-five pts (median age 60 years) including 1 pt aged 15 were enrolled in the dose-escalation; most pts (22%) had 3 prior therapies. Most common primary sites for cancer were in the colon (n = 21; 32%), ovary (n = 9; 14%), and pancreas (n = 7; 11%). All pts discontinued, the majority due to PD (n = 44; 68%). Eleven pts experienced DLTs; 6 pts experienced Grade 3 eye disorder DLTs (4 pts retinopathy, 2 pts chorioretinopathy). Treatment-related adverse events (TRAEs) were reported for 89% of pts, most commonly ( > 30%) diarrhea (n = 25; 38%) and nausea (n = 22; 34%). Grade 3/4 TRAEs were reported in 29% of pts; most common was retinopathy (n = 4; 6%). MTD of LTT462 was 400 mg QD and 150 mg BID. Overall, 8 pts (12%) had stable disease (SD) and 35 pts (54%) had PD. An unconfirmed partial response was reported in a pt with cholangiocarcinoma with BRAF mutation; best change in sum of target lesions per RECIST 1.1 was -33.9%. LTT462 increased plasma peak drug concentration and drug exposure at increasing doses between 45–450 mg QD. Exposure at LTT462 600 mg QD was lower than anticipated, indicating potential saturation of absorption at this dose. LTT462 inhibited ERK1/2 and reduced DUSP6 expression relative to baseline in most pts evaluated. Conclusions: LTT462 is well tolerated. Limited clinical activity was reported with single agent LTT462; best overall response was SD. An ongoing study is investigating LTT462 in combination with the RAF inhibitor, LXH254, in NSCLC and melanoma. Clinical trial information: NCT02711345 .

3594 Background: Selpercatinib (LOXO-292) is a highly selective and potent small molecule RET kinase inhibitor. Here we report an update on the efficacy and safety of selpercatinib in RET-mutant medullary thyroid cancer (MTC). Methods: Patients with RET-mutant MTC were enrolled to the Phase 1/2 LIBRETTO-001 trial (NCT03157128), a global, multicenter trial (16 countries, 89 sites). Following the Phase 1 dose escalation portion of the trial, patients received the recommended dose of 160 mg orally twice daily. Each cycle was 28 days. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. Per health authority agreement, the primary analysis set was defined as the first 55 consecutively enrolled patients previously treated with multikinase inhibitors cabozantinib and/or vandetanib. Patients naïve to cabozantinib and vandetanib treatment were analyzed separately. All analyses were based on a 16-Dec-2019 data cutoff date. Results: In the primary analysis set of prior cabozantinib and/or vandetanib-treated patients with MTC (n = 55), the ORR by investigator assessment was 62% (95% CI 47.7–74.6, n = 34/55) and the median DoR was not reached (95% CI 18.4 months–not estimable) despite a median follow-up of 14.8 months. In cabozantinib/vandetanib treatment-naïve patients (n = 88), the ORR by investigator assessment was 69% (95% CI 58.6–78.7, n = 61/88, including 2 responses pending confirmation). Of the 59 confirmed responding patients, with a median follow-up of 8 months, responses were ongoing for 57 responders at the time of the analysis. In the safety analysis set consisting of all selpercatinib dosed patients (N = 702), the most common treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were dry mouth (33.3%), increased AST (24.5%), increased ALT (23.8%), hypertension (23.2%), diarrhea (19.7%), and fatigue (16.8%). Only 2% (14 of 702) of patients discontinued selpercatinib for TRAEs. Conclusions: Selpercatinib use was associated with marked and durable antitumor activity in prior cabozantinib and/or vandetanib-treated patients and in cabozantinib/vandetanib-naïve patients with RET-mutant MTC, with the majority of responses ongoing in both cohorts. Selpercatinib was well tolerated. Efficacy data assessed by independent review committee based on the 16-Dec-2019 data cutoff date will be presented. Clinical trial information: NCT03157128 .

9516 Background: Patients with RET fusion-positive NSCLC have an ~50% lifetime prevalence of developing central nervous system (CNS) metastases. Selpercatinib is a highly selective oral RET inhibitor with CNS penetration. Its intracranial antitumor activity was previously demonstrated in an orthotopic RET fusion-positive preclinical model. The activity of selpercatinib in RET fusion-positive NSCLC patients with CNS metastases was evaluated as a prespecified subgroup analysis in LIBRETTO-001, a registrational phase 1/2 trial (NCT03157128). Methods: This global (89 sites, 16 countries) trial enrolled patients with advanced RET-altered solid tumors, including patients with RET fusion-positive advanced NSCLC with baseline CNS metastases. The selpercatinib recommended phase 2 dose was 160 mg twice daily, dosed orally in 28-day cycles. CNS metastases were assessed by MRI/CT scan at baseline, then every 8 weeks for 1 year, and every 12 weeks thereafter. The primary endpoint for this analysis was intracranial objective response rate (ORR, confirmed; RECIST v1.1) as assessed by independent review committee (IRC). Secondary endpoints included intracranial duration of response (DoR) by IRC. To be included in the efficacy analysis, patients were required to have adequate follow-up time (opportunity for ≥6 months follow-up from the first dose). Analyses were based on 17Jun2019 data cutoff date. Results: 79 patients with RET fusion-positive NSCLC and baseline CNS metastases were enrolled. Per IRC, 22 of 79 patients had measurable (≥10 mm) CNS disease; 14 of the 22 patients had adequate follow-up time for analysis. This efficacy-evaluable population had a median age of 64 yrs (range 43-80), ECOG PS 0/1 = 21% / 79%, and all had prior systemic therapy. 5 of the 14 patients received prior intracranial radiotherapy; all radiotherapy was completed > 2 months prior to selpercatinib. The intracranial ORR in the 14 patients was 93% (n = 13; 95% CI = 66.1 – 99.8), including 2 complete responses (14%) and 11 partial responses (79%). The median intracranial DoR was 10.1 months (95% CI = 6.7 – NE), with CNS progression events (n = 5) or death (n = 1) reported in 6 of 13 responders. The remaining responders (n = 7) were ongoing and censored. Presentation will include updated IRC data as of 16Dec2019. Conclusions: Selpercatinib had marked intracranial anti-tumor activity in RET fusion-positive NSCLC patients with CNS metastases. Tumor responses were durable, independently-confirmed, and observed in patients with prior systemic chemotherapy. Clinical trial information: NCT03157128 .

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.

9574 Background: Prior data from a phase I/II study showed durable responses, including efficacy in brain lesions, and a tolerable safety profile with nazartinib in treatment (tx)-naïve patients (pts) with EGFR-mutant (mut), locally advanced (adv)/metastatic NSCLC. Here we report updated phase II results, including overall survival (OS). Methods: Tx-naïve adult pts with activating EGFR-mut (L858R or ex19del), stage IIIB/IV adv NSCLC with neurologically stable and controlled brain metastasis (BM) received oral nazartinib 150 mg once daily (continuous schedule). Primary endpoint: overall response rate (ORR) by BIRC per RECIST v1.1; secondary endpoints: disease control rate (DCR), duration of response (DOR), time to response, progression-free survival (PFS), OS, and safety. Results: At data cut-off (Nov 1, 2019), 45 pts were enrolled (median [range] age: 64 [28–83] years; 26 pts [58%] ECOG PS 1; 18 pts [40%] had baseline BM). EGFR mutations: 56% ex19del, 40% L858R, 4% other. 26/45 pts (58%) discontinued tx, with the primary reason being progressive disease in 19 pts (42%); 2 pts (4%) discontinued tx due to AEs. Median (range) follow-up for OS: 25 (0–33) months (mo); and for PFS: 17 (0–33) mo. ORR by BIRC: 69%; median PFS by BIRC: 18 mo; median OS was NE and at 33 mo, 56% of pts were alive (Table). BIRC results by baseline BM are shown in the Table. Median (range) duration of exposure: 24 (0–34) mo. Most frequent AEs (≥20% all grade, all causality): diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough and stomatitis (27% each), decreased appetite and pruritus (24% each), and dermatitis acneiform (22%). Most frequent grade 3/4 AEs (≥10%, all causality): maculopapular rash (5 pts [11%]; all grade 3) and increased lipase (5 pts [11%]; 1 pt with grade 4; no clinical pancreatitis AE was observed). Conclusions: After additional follow-up, median OS was still not reached and the safety profile was manageable. Nazartinib is a promising 3rd generation EGFR TKI for tx-naïve pts with adv EGFR-mut NSCLC, including pts with baseline BM. Clinical trial information: NCT02108964 . [Table: see text]

3584 Background: Selpercatinib (LOXO-292) is a highly selective and potent small molecule RET kinase inhibitor. Here we report an update on the efficacy and safety of selpercatinib in RET-fusion+ non-small-cell lung cancer (NSCLC). Methods: Patients with RET-fusion+ NSCLC were enrolled to the Phase 1/2 LIBRETTO-001 trial (NCT03157128), a global, multicenter trial (16 countries, 89 sites). Following the Phase 1 dose escalation portion of the trial, patients received the recommended dose of 160 mg orally twice daily. Each cycle was 28 days. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. Per health authority agreement, the primary analysis set was defined as the first 105 consecutively enrolled patients previously treated with platinum-based chemotherapy. Treatment-naïve patients were analyzed separately. All analyses were based on a 16-Dec-2019 data cutoff date. Results: In the primary analysis set of platinum-treated patients (median of 3 prior systemic regimens; range 1-15), the ORR by investigator assessment was 70% (95% CI 59.8–78.1, n = 73/105). Responses did not differ by fusion partner or number or type of prior therapies, including anti-PD-1/PD-L1 agents and off-label multikinase inhibitor use. The median DoR was 20.3 months (95% CI 15.6–24.0) with 45 of 73 (62%) responders censored at a median follow-up of 14.8 months. Among 39 treatment-naïve patients, the ORR by investigator assessment was 90% (95% CI 75.8–97.1, n = 35/39, including 2 responses pending confirmation). Median DoR was not reached with 27 of 33 (82%) confirmed responses ongoing at a median follow-up of 7.4 months. In the safety analysis set consisting of all selpercatinib dosed patients (N = 702), the most common treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were dry mouth (33.3%), increased AST (24.5%), increased ALT (23.8%), hypertension (23.2%), diarrhea (19.7%), and fatigue (16.8%). Only 2% (14 of 702) of patients discontinued selpercatinib for TRAEs. Conclusions: Selpercatinib achieved marked and durable antitumor activity in patients with RET-fusion+ NSCLC. Selpercatinib was well tolerated. Efficacy data assessed by independent review committee based on the 16-Dec-2019 data cutoff date will be presented. Clinical trial information: NCT03157128 .

9515 Background: Pralsetinib is an investigational, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations. We provide the registrational dataset for pts with RET fusion+ NSCLC with and without prior treatment from the global ARROW study. Methods: ARROW (75 sites in 11 countries; NCT03037385) consists of a phase I dose escalation to establish recommended phase II dose (400 mg once daily [QD] orally) and phase II expansion cohorts defined by tumor type and/or RET alteration. Primary objectives were overall response rate (ORR; blinded independent central review per RECIST v1.1) and safety. Efficacy analyses are shown for response-evaluable pts (REP) with RET fusion+ NSCLC who initiated 400 mg QD pralsetinib by July 11 2019 and safety for all pts (regardless of diagnosis) treated with 400 mg QD. Results: As of November 18 2019, 354 pts with advanced solid tumors had received pralsetinib at starting dose of 400 mg QD with median follow-up 8.8 months. ORR, disease control rate (DCR), and % of pts with tumor size reduction are shown in the table for pts with metastatic RET fusion+ NSCLC (n=116; 72% KIF5B; 16% CCDC6; 12% other/fusion present but type unknown) and with prior platinum treatment (n=80) or without prior systemic treatment (n=26). ORR was similar regardless of RET fusion partner, prior therapies, or central nervous system involvement. Overall there were 7 (6%) complete responses, 4 (5%) in prior platinum pts and 3 (12%) in treatment naïve pts; median time to response overall was 1.8 months and median duration of response (DOR) was not reached (95% CI, 11.3–NR). In the safety population (n=354), most treatment-related adverse events (TRAEs) were grade 1-2, and included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%) and hypertension (20%). 4% of pts in the safety population (all tumor types) discontinued due to TRAEs. Conclusions: Updated, registrational, centrally reviewed data demonstrate that pralsetinib has rapid, potent, and durable clinical activity in pts with advanced RET fusion+ NSCLC regardless of RET fusion genotype or prior therapies, and QD oral dosing is well-tolerated. Clinical trial information: NCT03037385 . [Table: see text]

3610 Background: The highly selective TRK inhibitor larotrectinib is approved for the treatment of adult and pediatric cancers that harbor NTRK gene fusions; it achieves a 79% overall response rate (ORR) in this population (Hong et al., Lancet Oncol, 2020). The activity of larotrectinib in adults alone was further characterized in this update with a larger series of patients and more mature durability data. Methods: Adults (aged ≥18 y) with TRK fusion cancer treated in three larotrectinib clinical trials (NCT02122913, NCT02576431, and NCT02637687) were analyzed. Larotrectinib was administered 100 mg BID until disease progression, withdrawal, or unacceptable toxicity. ORR was investigator-assessed (RECIST v1.1). Compared to previously presented data on 74 patients, this expanded data set includes an additional 42 patients (data cutoff: July 15, 2019). Results: 116 adults (median age: 56 y, range 19–84 y; 53% female) with TRK fusion cancer were treated. Tumor types included thyroid cancer (22%), salivary gland cancer (19%), soft tissue sarcoma (16%), lung cancer (12%), colon cancer (7%), melanoma (5%), breast cancer (5%), GIST (3%), and 9 other types (≤2% each). NTRK fusions involved NTRK1 (43%), NTRK2 (3%), and NTRK3 (54%). 78% of patients had received prior systemic therapy (with 68% of those receiving ≥2 prior therapies). The ORR was 71% (95% CI 62–79): 10% complete response, 60% partial response (2% pending confirmation), 16% stable disease, 9% progressive disease, 3% not determined. In patients with brain metastases, the ORR was 71% (95% CI 42–92; 10 of 14 patients, all partial responses). Median duration of response for the overall data set (n = 116) was 35.2 mo (95% CI 21.6–not estimable [NE]). Median progression-free survival was 25.8 mo (95% CI 15.2–NE). Median overall survival was not reached (range 0.5+ to 51.6+ mo) at a median follow-up of 15.8 mo. Duration of treatment ranged from 0.10 to 51.6+ mo. 12% of patients had dose reductions. One patient (1%) discontinued due to a larotrectinib-related adverse event (AE). AEs were mostly grade 1–2; no new unexpected AEs were reported. Conclusions: In an expanded data set of adults with TRK fusion cancer, larotrectinib demonstrated robust and durable tumor-agnostic efficacy and favorable safety, supporting NTRK gene fusion testing in patients with solid tumors of any type. Clinical trial information: NTC02122913, NCT02576431, NCT02637687 .

527 Background: Aberrant activation of the fibroblast growth factor receptor (FGFR) pathway is implicated in many cancers, including UC. In a recent Phase I dose-escalation study, rogaratinib, an oral pan-FGFR1-4 inhibitor, demonstrated favorable efficacy and safety in pts with solid cancers selected based on FGFR1-3 mRNA overexpression. We report results from the Phase I expansion cohort with rogaratinib in pts with UC selected by FGFR1-3 mRNA overexpression and/or FGFR3-activating mutations (NCT01976741). Methods: Pts with advanced/metastatic UC were screened for FGFR1-3 mRNA overexpression using RNA in situ hybridization (RNAscope) and NanoString assay in fresh or archival tumor samples. Pts received rogaratinib 800 mg po BID continuously. Tumor response and safety were assessed. Results: 74 pts with UC were treated with rogaratinib; 73.0% were male, median age was 66 years (range 45-85), and 93.2% had stage IV disease. Rogaratinib was well tolerated, with adverse events being mostly mild or moderate. The most common treatment-emergent adverse events (TEAEs) are shown in the Table. The most common drug-related TEAEs (any grade) were diarrhea (52.7%), increased blood phosphorus (41.9%), and decreased appetite and dry mouth (31.1% each). No ocular toxicities were reported. Increased blood creatinine and acute kidney injury (AKI), regardless of relatedness, were reported in 16.2% and 2.7% of pts, respectively; 1 case of AKI was confirmed as acute tubular necrosis. Of 72 evaluable pts, 15 (20.8%) achieved an objective response; complete and partial responses were observed in 1 (1.4%) and 14 (19.4%) pts, respectively. Stable disease was achieved by 34 pts (47.2%), with a disease control rate of 68.1%. Conclusions: Rogaratinib demonstrated a favorable safety and efficacy profile in pts with tumor FGFR1-3 mRNA-positive UC. TEAEs observed in >25% of pts. Clinical trial information: NCT01976741. [Table: see text]

730 Background: Tumoral KRAS mutations (KRAS mt) are detected in ~80% of APC and associated with a negative prognosis. Digital droplet PCR (ddPCR) has high sensitivity for circulating KRASmtbut narrower gene coverage. NGS using hybrid-capture methods has reported ctDNA KRASmtin ~30% of patients (pt). We previously presented clinical results of the Phase I trial of OXIRI (GI ASCO 18 #411). We now present the first prospective evaluation of ctDNA in APC by an amplicon-based NGS approach in this Phase I trial. Methods: Paired ctDNA and CA19-9 samples were taken at baseline, C2D1, C3D1 and end of trial. A targeted panel with error-correction (Lucence Diagnostics) was used to detect for mtin KRAS, TP53, SMAD4, CDKN2A, CTNNB1, GNAS, APC and MYC. CT scans were performed every 2 cycles. Survival curves by Kaplan Meier were compared by mutational status, ctDNA and CA19-9 response using the log-rank test. Spearman correlation of ctDNA and CA19-9 changes was performed. Results: ctDNA mtwas detected at baseline in 19/23 (83%) samples, comprising KRAS 17/23 (73%), TP53 (61%), SMAD4 (48%) and CDKN2A (30%). KRAS mtand SMAD4 mt conferred a negative prognosis for overall survival with a hazard ratio of 4.2 (CI: 1.6-10.4; p = 0.01) and 2.8 (CI: 0.9-8.65; p = 0.01) respectively. Drop in ctDNA and CA19-9 was associated with a trend for longer progression free survival at C2D1 (both) and C3D1 (ctDNA only). Radiological partial response (PR) was associated with lower ctDNA in 5/5 pt and CA 19-9 in 4/5 pt. Decrease in ctDNA and CA19-9 was associated with disease control (PR/SD) at C2D1 in 11/14 pt and 10/10 pt; at C3D1 in 11/12 pt and 6/7 respectively. No significant correlation between the amplitude of CA19-9 and ctDNA changes was found. Conclusions: ctDNA could be detected in 83% of pts of whom KRAS mtrates were similar to reports using tissue NGS. Determination of RAS mtand SMAD4 mtin ctDNA may aid in the prognostication of pts and decrease in ctDNA levels may predict for treatment benefit, similar in extent to CA 19-9. This may be particularly useful in non-CA19-9 secreting APC as an adjunct to imaging. Clinical trial information: NCT02368860.

BACKGROUND The comeasurement of both genomic and transcriptomic signatures in single cells is of fundamental importance to accurately assess how the genetic information correlates with the transcriptomic phenotype. However, existing technologies have low throughput and laborious work flows. METHODS We developed a new method for concurrent sequencing of the transcriptome and targeted genomic regions (CORTAD-seq) within the same single cell on an automated microfluidic platform. The method was compatible with the downstream library preparation, allowing easy integration into existing next-generation sequencing work flows. We incorporated a single-cell bioinformatics pipeline for transcriptome and mutation analysis. RESULTS As proof of principle, we applied CORTAD-seq to lung cancer cell lines to dissect the cellular consequences of mutations that result in resistance to targeted therapy. We obtained a mean detection of 6000 expressed genes and an exonic rate of 50%. The targeted DNA-sequencing data achieved a 97.8% detection rate for mutations and allowed for the identification of copy number variations and haplotype construction. We detected expression signatures of tyrosine kinase inhibitor (TKI) resistance, epidermal growth factor receptor (EGFR) amplification, and expansion of the T790M mutation among resistant cells. We also identified characteristics for TKI resistance that were independent of EGFR T790M, indicating that other alterations are required for resistance in this context. CONCLUSIONS CORTAD-seq allows assessment of the interconnection between genetic and transcriptomic changes in single cells. It is operated on an automated, commercially available single-cell isolation platform, making its implementation straightforward.

Mutational signatures can reveal the history of mutagenic processes that cells were exposed to prior to and during tumourigenesis. We expect that as-yet-undiscovered mutational processes will shed further light on mutagenesis leading to carcinogenesis. With this in mind, we analyzed the mutational spectra of 36 Asian oral squamous cell carcinomas. The mutational spectra of two samples from patients who presented with oral bacterial infections, showed novel mutational signatures. One of these novel signatures, SBS_AnT, is characterized by a preponderance of thymine mutations, strong transcriptional strand bias, and striking enrichment for adenines in the 4 base pairs 5’ of mutation sites. Examination of publicly available sequencing data revealed SBS_AnT in 25 tumours from several mucosal tissue types, all of which harbour human symbionts or are adjacent to tissues that harbour symbionts. Data in a preprint released while this manuscript was in revision strongly suggest that the bacterial compound colibactin causes SBS_AnT.

BackgroundMucinous epithelial ovarian cancers (mEOCs) respond poorly to conventional chemotherapy and have a poor prognosis in advanced stages. The genomic landscape for mEOC in the Asian settings is ill defined. We seek to identify various mutational aberrations present in mEOC and correlate them with clinical outcomes.MethodsA total of 199 cases of mEOC were identified from a prospectively maintained gynecologic oncology tumor database. DNA was extracted and analyzed for KRAS mutations by using Sanger sequencing. Further MassArray sequencing was performed on 45 samples. Clinicopathologic correlation was performed with the results obtained.FindingsKRAS mutation status was evaluable in 124 cases. Fifty-five percent (68/124) were KRAS negative, whereas 45% (56/124) harbored a KRAS mutation, lower than that in Western populations. Successful ascertainment of both KRAS and HER2 statuses by Sanger sequencing occurred for 105 cases. The proportion of the double-positive subtype (HER2+ and KRAS positive) was 8% (8/105); double-negative subtype (HER2− and KRAS negative), 34% (36/105); and cases with mutation in either KRAS or HER2, 58% (61/105). The KRAS mutation rate was 44%, 50%, and 29% among Chinese, Indians, and Malays, respectively. There was no significant difference in overall survival (P = 0.952) or progression-free survival (P = 0.635) between KRAS-positive and KRAS-negative patients. Similar results were observed for progression-free survival (P = 0.206) and overall survival (P = 0.440) when outcomes were examined between the 4 groups based on KRAS and HER2 mutation. Patients in the double-negative mutation subgroup had higher risk for death/progression compared with patients in the other 3 mutation subgroups. Further MassARRAY multiplexed profiling was performed in patients with sufficient DNA material (n = 45) and yielded KRAS mutations (n = 16), PDGFRA mutations (n = 3), PIK3CA (n = 1) and KIT (n = 1), and HRAS, FGFR, MET, and NRAS (n = 1 each).ConclusionsOur study provides further knowledge about the mutational aberrations in mEOC in Asian populations. Neither the presence of KRAS mutation nor their correlation with HER2 mutations influenced outcomes.

Background In the randomized, double-blind, phase 3 trial SOLO1, olaparib (OLA) in the maintenance setting demonstrated a 70% lower risk of disease progression or death than placebo in women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation. This study aimed to evaluate the cost-effectiveness of OLA maintenance therapy versus routine surveillance (RS) after response to first-line platinum-based chemotherapy in this population in Singapore. Methods A three-state partitioned survival model was developed to simulate the lifetime (50 years) incremental cost-effectiveness ratio (ICER) of OLA versus RS from a healthcare payer perspective. Progression-free and overall survival curves were estimated using data from SOLO1 and extrapolated beyond the trial period using parametric survival models. Any patient who remained progression-free at year 7 was assumed to be a long-term survivor and no longer at risk of progression. Mortality rates for this group were modelled on all-cause mortality from the general population adjusted for BRCA1/2 mutation status. These assumptions were validated with local clinicians. Health state utilities and adverse event frequencies were obtained from SOLO1. Drug costs were sourced from local public healthcare institutions. Healthcare resource usage and costs were based on local clinician input and publications. A 3% discount rate was applied to costs and outcomes. Deterministic and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of results. Results The base-case analysis of OLA maintenance therapy versus RS resulted in an ICER of SGD17,326 per quality-adjusted life year (QALY) gained. The ICER was most sensitive to variations in the discount rate and mortality risk in long-term survivors. PSA demonstrated that OLA was associated with an 81% probability of being cost-effective at a willingness-to-pay threshold of SGD50,000 per QALY gained. Conclusions OLA has a high potential of being a cost-effective maintenance therapy versus RS for patients with BRCA1/2 mutated advanced ovarian cancer after response to first-line chemotherapy in Singapore. Legal entity responsible for the study AstraZeneca Singapore Pte Ltd. Funding AstraZeneca Singapore Pte Ltd. Disclosure D.S. Tan: Honoraria (self): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Bayer; Honoraria (self): Genmab; Honoraria (self): Tessa Therapeutics; Honoraria (self): Merck Serono ; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche (Foundation Medicine); Research grant / Funding (self): National Medical Research Council Singapore Clinician Scientist Award; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: ETC/D3 Singapore; Advisory / Consultancy: Tessa Therapeutics; Advisory / Consultancy: Genmab. J.J. Chan: Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Merck Sharp & Dohme; Advisory / Consultancy: Eisai; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): OncoQuest Inc; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: Synthon; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Celgene. J.K. Loke: Full / Part-time employment: AstraZeneca. R. Hettle: Full / Part-time employment: AstraZeneca. C.C. Yu: Full / Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.

Background In global phase III ASCEND-4 study (NCT01283516), ceritinib 750 mg/day (fasted), demonstrated statistically significant and clinically meaningful improvement in PFS by BIRC (median, 16.6 mos [95% CI: 12.6, 27.2] vs 8.1 mos [95% CI: 5.8, 11.1]; HR = 0.55; p Methods Pts with stage IIIB/IV, ALK + (centrally tested IHC), nonsquamous NSCLC, ≥1 measurable lesion per RECIST v1.1, and WHO PS 0–2 were eligible. Efficacy and safety were evaluated in Asian pts who had not received prior systemic anticancer therapy except neo-/adjuvant therapy. Data cutoff: June 24, 2016. Results Among 376 pts randomized (1:1) in the study, 158 pts were Asian, with 76 in ceritinib arm and 82 in chemotherapy arm. Of these, 25 pts (32.9%) in ceritinib arm and 21 (25.6%) in chemotherapy arm had brain metastases at baseline. Median duration of treatment exposure: 64.5 wks (ceritinib, N = 76) and 35.0 wks (chemotherapy, N = 75). Median duration from randomization to data cutoff: 18.3 mos. Ceritinib demonstrated superior PFS by BIRC (median, 26.3 mos; 95% CI: 8.6, NE; HR = 0.66) compared to chemotherapy (Table). Most common (≥50%; all grades; all-causality) AEs in ceritinib arm: diarrhea (85.5%), ALT increased (73.7%), vomiting (73.7%), AST increased (69.7%), and nausea (69.7%). Incidence of grade 3/4 AEs was Table . 1473P By BIRC (N * =158) Ceritinib 750mg N = 76 Chemotherapy N = 82 Overall response rate (ORR), % [95% CI] 65.8 [54.0, 76.3] 29.3 [19.7, 40.4] Best overall response, n (%) Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD) Non-CR/Non-PD Unknown 0 50 (65.8) 11 (14.5) 11 (14.5) 2 (2.6) 2 (2.6) 0 24 (29.3) 38 (46.3) 6 (7.3) 3 (3.7) 11 (13.4) Disease control rate (DCR), % [95% CI] 82.9 [72.5, 90.6] 79.3 [68.9, 87.4] M ‡ =50 M ‡ =24 Median DOR, months [95% CI] NE [24.7, NE] 16.4 [7.8, NE] n/N (%) 14/50 (28.0) 8/24 (33.3) % Event-free probability estimates [95% CI] 9 months 81.2 [67.0, 89.8] 76.1 [48.0, 90.4] 12 months 79.0 [64.5, 88.1] 50.8 [22.5, 73.5] 15 months 70.4 [54.0, 81.9] 50.8 [22.5, 73.5] Median PFS, months [95% CI] 26.3 [8.6, NE] 10.6 [6.7, 15.0] n/N (%) 32/76 (42.1) 45/82 (54.9) % Event-free probability estimates [95% CI] 9 months 61.0 [48.4, 71.5] 54.7 [41.8, 65.8] 12 months 61.0 [48.4, 71.5] 49.8 [37.1, 61.2] 15 months 55.9 [43.2, 66.9] 39.0 [26.9, 51.0] * Total number of patients included in the full analysis set. ‡ Total number of patients with confirmed complete response or partial response. n: Total number of events included in the analysis. N: Total number of patients included in the analysis. Conclusions In Asian pts with ALK+ NSCLC, ceritinib demonstrated durable and clinically meaningful efficacy and a safety profile consistent with overall ASCEND-4 study results. Clinical trial identification NCT01828099. Editorial acknowledgement Shilpa Garg, Novartis Healthcare Pvt Ltd. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure D.S. Tan: Honoraria (self): Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda; Advisory / Consultancy: Novartis, Bayer, Boehringer Ingelheim, Celgene, AstraZeneca, Eli-lily, Loxo; Research grant / Funding (self): Novartis, AstraZeneca, GlaxoSmithKline, Bayer, Pfizer; Travel / Accommodation / Expenses: Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche,Takeda. S. Geater: Advisory / Consultancy: Boehringer Ingelheim; Honoraria (institution): AstraZeneca, Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Roche, Novartis, Boehringer Ingelheim; Full / Part-time employment: Prince of Songkla Univerisity. C.J. Yu: Honoraria (self): Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim; Advisory / Consultancy: Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim. T.C. Hsia: Advisory / Consultancy: Norvatis, Lilly, AZ, Roche local speaker. M.C. Lin: Advisory / Consultancy: AZ, Novartis, BI, Roche. V. Sriuranpong: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Novartis, Roche, Pfizer, Eisai, Boehringer, Taiho, MSD, BMS, Amgen; Research grant / Funding (institution): AstraZeneca, Novartis, Roche, Pfizer, Boehringer, Eisai, Taiho, Lilly, MSD. P. Sen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. F. Branle: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. M. Shi: Shareholder / Stockholder / Stock options: Novartis stock; Full / Part-time employment: Novartis. Y.L. Wu: Honoraria (self): AZ, Roche, Eli Lilly, Pfizer, MSD, BMS, BI; Advisory / Consultancy: AZ, Roche, BI; Research grant / Funding (institution): AZ, Roche. All other authors have declared no conflicts of interest.

Background Genomic rearrangements involving NTRK1/2/3 result in constitutively active TRK fusion proteins that are oncogenic drivers in multiple pediatric and adult cancers. Larotrectinib is a selective TRK inhibitor approved by the FDA in 2018 for the treatment of any TRK fusion cancer based on a primary analysis in 55 patients from 3 clinical trials [Drilon et al. NEJM 2018]. For the first time, we now report median duration of response (DOR) data in this primary cohort, as well as updated data in an expanded cohort of 159 total TRK fusion patients treated with larotrectinib, with 153 (55 primary + 98 supplemental) evaluable for efficacy. Methods Patients with TRK fusion cancer detected by local molecular profiling were treated with larotrectinib across 3 studies (NCT02122913, NCT02637687, and NCT02576431). Disease status was assessed by investigators using RECIST 1.1. Data cut-off was 19 February 2019. Results In the primary cohort of 55 patients with a median follow-up of 26 months, the median DOR in 44 patients with complete or partial responses was 35.2 months (95% CI 21.2–NE), with 17 progression events and 27 responses ongoing (range 1.6–44 months). The median PFS in the primary cohort was 25.8 months (95% CI 9.9–NE), with 27 patients having progressed. In the expanded combined dataset, the most common tumor types included soft tissue sarcoma (n = 36), infantile fibrosarcoma (n = 29), thyroid carcinoma (n = 26), salivary gland carcinoma (n = 21), and lung cancer (n = 12). The median age was 43 years, ranging from Conclusions These data confirm the marked tissue-agnostic efficacy and long durability of response in patients with TRK fusion cancer treated with larotrectinib. Larotrectinib continued to demonstrate a favorable long-term safety profile. Screening patients for NTRK gene fusions should be actively considered. Clinical trial identification NCT02122913, NCT02637687, NCT02576431. Editorial acknowledgement Editorial assistance was provided by Michael Sheldon, PhD, of Scion, London, UK, funded by Bayer. Legal entity responsible for the study Bayer. Funding Bayer. Disclosure D.M. Hyman: Advisory / Consultancy: Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer Pharmaceuticals, Genentech / F. Hoffmann-La Roche; Research grant / Funding (self): Loxo Oncology, Bayer Pharmaceuticals, PUMA Biotechnology, AstraZeneca. C.M. van Tilburg: Advisory / Consultancy: Novartis, Bayer. D.S.W. Tan: Advisory / Consultancy: Novartis, Merck Loxo AstraZeneca Roche Pfizer; Travel / Accommodation / Expenses: Pfizer Boehringer Ingelheim Roche; Honoraria (self): BMS, Takeda, Novartis, Roche, Pfizer; Research grant / Funding (self): Novartis, GSK, AstraZeneca. A.F. Farago: Research grant / Funding (self): Bayer, Loxo Oncology; Advisory / Consultancy: Bayer, Loxo Oncology. T.W. Laetsch: Advisory / Consultancy: Novartis, Bayer, Loxo, Lill; Research grant / Funding (self): Pfizer Novartis Bayer Loxo Abbvie Amgen Atara Biotherapeutics BMS Lilly Epizyme GSK Janssen Jubilant Pharmaceuticals Novella Clinical, Servier. S. Kummar: Honoraria (self): Bayer; Advisory / Consultancy: Bayer; Travel / Accommodation / Expenses: Bayer. F. Doz: Research grant / Funding (institution): BMS, Celgene; Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Bayer, BMS, Celgene, Loxo Oncology, Servier. U.N. Lassen: Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer. S.G. DuBois: Advisory / Consultancy: Loxo; Travel / Accommodation / Expenses: Loxo, Roche; Honoraria (self): Loxo; Research grant / Funding (self): Millennium, Merck, Novartis Roche Lilly Lilly Loxo BMS. R. McDermott: Travel / Accommodation / Expenses: Janssen-Cilag, Pfizer; Honoraria (self): Bayer, Sanofi, Janssen, Astellas, BMS, MSD, Pfizer, Novartis, Clovis; Research grant / Funding (self): Sanofi, Janssen, Bayer, Astellas. L. Mascarenhas: Research grant / Funding (institution): AstraZeneca, Eli Lilly. J.D. Berlin: Research grant / Funding (institution): PsiOxus, Bayer, EMD Serono, Symphogen, Roche/Genentech, Immunomedics, Novartis, Taiho, AbbVie (pharamcyclics), Boston Biomedical, FivePrime, Loxo, Incyte, Macrogenics; Honoraria (self): Nestle; Advisory / Consultancy: Rafeal, Seattle Genetics, EMD Serono, Bayer, eisai, Taiho, Armo,Gritstone, AstraZeneca, Celgene, Erytech. E.R. Rudzinski: Advisory / Consultancy: Bayer. M.C. Cox: Full / Part-time employment: Loxo Oncology. S. Nanda: Full / Part-time employment: Loxo Oncology. B.H. Childs: Full / Part-time employment: Bayer. A. Drilon: Advisory / Consultancy: Loxo Oncology/Bayer, Ignyta, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda/Ariad/Millenium, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Bayer, Tyra; Research grant / Funding (self): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Honoraria (institution): Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho; Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: MORE Health. D.S. Hong: Research grant / Funding (self): AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seatt; Travel / Accommodation / Expenses: Loxo, MiRNA, ASCO, AACR, SITC, Genmab; Advisory / Consultancy: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics; Shareholder / Stockholder / Stock options: Molecular Match, OncoResponse, Presagia Inc. All other authors have declared no conflicts of interest.

Lung cancer has the highest cancer associated mortality rate in many countries across the world. In contrast to western populations, approximately half of lung adenocarcinoma cases in Singapore harbour activating epidermal growth factor receptor (EGFR) mutations, with preponderance for never smokers and female gender. Although EGFR tyrosine kinase inhibitors (TKIs) confer high response rates of up to 70%, drug resistance invariably ensues - most commonly through the “acquisition” of EGFR T790M mutation. While the extent and pattern of intratumoral heterogeneity (ITH) in non-small cell lung cancer (NSCLC) were recently described, these studies examined histologically and molecularly diverse cohort of patients, majority being current or ex-smokers. Here we report ITH in eight never-smoker EGFR mutant lung adenocarcinoma cases of Asian ethnicity. All eight patients had no prior treatment history and harboured an activating EGFR mutation (5 L858R, 2 exon 19 deletion, 1 exon 20 insertion). They underwent lobectomy for Stage IA, IB NSCLC. Tumors were harvested using a systematic sectoring protocol according to standard operation procedures, with tissue banked for exome sequencing, RNA-sequencing and SNP array. A total of 46 tumor sectors (at least 4 regions from each of the 8 tumors) were subject to whole exome sequencing, with matched normal samples. With an average sequencing depth of 100x, we identified 860 somatic exonic SNVs (601 being non-synonymous) and 49 indels across all samples. The median number of SNVs per patient was 112 and per sector was 49. Notably, activating EGFR mutations were identified across all tumor sectors of all but two patients (for whom it was identified in 3 of 5 and 5 of 7 sectors respectively). In addition, we did not identify the EGFR T790M mutation in any of the sequenced tumor sectors, suggesting that, this resistance mutation is not present at detectable frequencies even as a branch or subclonal event in a treatment naïve scenario. Of 20 genes that were significantly mutated across 46 individual tumor sectors, only two overlapped with published recurrently mutated genes in NSCLC. In conclusion, we show that activating EGFR mutations are ubiquitous truncal events in 6 of 8 Asian never-smoker lung adenocarcinoma – consistent with its role as a therapeutically tractable driver gene. The T790M mutation commonly associated with TKI resistance was not detected as a subclonal event in treatment naïve patients. Further, our study reveals the unique mutation spectra of Asian EGFR mutant lung adenocarcinoma, highlighting the value of multi-region sequencing in characterising the genomic architecture of defined molecular subsets of NSCLC from different ethnic backgrounds. Citation Format: Rahul Nahar, Weiwei Zhai, Angela Takano, Alexis Jiaying Khng, Xingliang Liu, Chong Hee Lim, Audrey S.M. Teo, Cheryl Xueli Chan, Apoorva Gogna, Kiat-Hon Lim, Tina Koh, Huay Mei Poh, Yin Yeng Lee, Liang He Chen, Tong Zhang, Vidhya Gomathi Krishnan, N Gopalakrishna Iyer, Pauline Ng, Wan Teck Lim, Bing Lim, Eng-Huat Tan, Daniel S.W. Tan, Axel M. Hillmer. Intratumor heterogeneity in never-smoker Asian EGFR mutant lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-25.

Background To date, biomarkers to predict benefit from anti-angiogenic therapy are still lacking. Sorafenib and metronomic oral vinorelbine combination was studied and changes in blood and DCE-MRI parameters were investigated as biomarkers for benefit. Material and methods Patients with advanced NSCLC were recruited to 3 successive cohorts. Each cohort was given a fixed metronomic (3 times a week) dose of oral vinorelbine at 60 mg/week, 90 mg/week, or 120 mg/week respectively. Within each cohort, patients received a starting dose of sorafenib at 200 mg bid for 4 weeks. In the absence of dose-limiting toxicities, each patient's dose of sorafenib was escalated to 400 mg bid for 4 weeks, 600 mg bid for 4 weeks and finally 800 mg bid. Biomarkers measured include DCE-MRI parameters, circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and plasma thrombospondin (TSP-1). Results 48 evaluable patients were analyzed. There were 4 (8.9%) patients with partial response (PR) and 7 (15.2%) with cavitary response (CaR). Two subpopulations of CECs (CEChi, CEClo) were identified that trended in opposite directions during treatment, with CEChi demonstrating an upward trend in contrast to CEClo. Higher baseline CEChi and lower baseline blood flow (F) and fractional intravascular blood volume (V1) predicted for response. Multivariate analysis revealed a lower baseline V1, and dynamic changes of CEC during treatment (CEC increase, sum of CEChi and CEClo) predicted for improved survival. Conclusions Sorafenib and metronomic oral vinorelbine is active in advanced NSCLC. Baseline levels and changes in DCE parameters and CEC may be useful predictive biomarkers.

Development of pulmonary infiltrates with respiratory symptoms in patients with advanced cancer presents a diagnostic challenge. We describe a case of a patient who developed progressive respiratory failure and bilateral lung infiltrates whilst receiving docetaxel chemotherapy for advanced lung cancer. After excluding other aetiologies, he was treated for docetaxel-related pneumonitis with corticosteroid therapy. Interstitial pneumonitis is a rare complication of Docetaxel chemotherapy but needs to be recognised and treated early, as it is associated with high mortality rates. We describe the presentation, differential diagnoses and possible mechanisms associated with drug-related pneumonitis.

BACKGROUND The current study was performed to report the long-term results of a trial comparing concurrent chemotherapy and radiotherapy (CCRT) with surgery and adjuvant radiotherapy (RT) in patients with stage III/IV nonmetastatic head and neck squamous cell carcinoma. METHODS Patients with stage III/IV resectable head and neck squamous cell carcinoma were randomized to surgery followed by RT or CCRT. The trial was halted prematurely due to poor accrual. Human papillomavirus status was tested on archival material using polymerase chain reaction sequencing. RESULTS Of the total of 119 patients, 60 patients were randomized to primary surgery (S arm) and 59 patients were randomized to CCRT (C arm). Human papillomavirus status was tested in 75 patients, and only 3 were found to be positive. The median follow-up for surviving patients was 13 years. Analysis of the entire cohort demonstrated no statistically significant difference in overall survival and disease-specific survival (DSS): 5-year rates were 45% versus 35% for overall survival (P = .262) and 56% versus 46% for DSS (P = .637) for the S arm and C arm, respectively. Analysis by subsites indicated that this difference favoring the S arm was mainly driven by survival data among patients with cancers of the oral cavity and maxillary sinus. For patients with oral cavity cancer, survival was significantly better in those who underwent primary surgery compared with CCRT; the 5-year DSS rate was 68% versus 12% for the S arm and C arm, respectively (P = .038). For patients with cancers of the maxillary sinus, the 5-year DSS rate was 71% for patients on the S arm and 0% for patients on the C arm (P = .05). CONCLUSIONS These long-term results demonstrate a significant advantage for primary surgery in patients with cancers of the oral cavity or maxillary sinus, providing strong support for primary surgery as the main modality of treatment for these subsites. In other subsites, CCRT and surgery with adjuvant RT were found to demonstrate similar efficacy for survival in patients with advanced resectable tumors. Cancer 2015;121:1599–1607. © 2015 American Cancer Society.

The gene encoding the receptor-tyrosine kinase RET was first discovered more than three decades ago, and activating RET rearrangements and mutations have since been identified as actionable drivers of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET-rearranged lung cancers and RET-mutant thyroid cancers. Nevertheless, response rates to RET-directed therapy are modest compared with those achieved using targeted therapies matched to other oncogenic drivers of solid tumours, such as sensitizing EGFR or BRAF(V600E) mutations, or ALK or ROS1 rearrangements. To date, no RET-directed targeted therapeutic has received regulatory approval for the treatment of molecularly-defined populations of patients with RET-mutant or RET-rearranged solid tumours. In this Review, we discuss how emerging data have informed the debate over whether the limited success of multikinase inhibitors with activity against RET can be attributed to the tractability of RET as a drug target, or the lack, until 2017, of highly specific inhibitors of this oncoprotein in the clinic. We emphasize that novel approaches to targeting RET-dependent tumours are necessary to improve the clinical efficacy of single-agent multikinase inhibition and, thus, hasten approvals of RET-directed targeted therapies.

It is not known whether clinicopathologic characteristics, treatment, and survival of never-smokers among lung cancer incident cases have changed over time. We assessed the trend and overall survival (OS) of these patients within our institution during a 10-year period.We reviewed 2 cohorts of non-small-cell lung cancer patients with a diagnosis from 1999 to 2002 and from 2008 to 2011. The patient characteristics and OS were compared by smoking status within each cohort and between the 2 cohorts over time.Of the 992 patients in the 1999-2002 cohort and the 1318 patients in the 2008-2011 cohort, 902 and 1272 had a known smoking status, respectively. The proportion of never-smokers increased from 31% in 1999-2002 to 48% in 2008-2011 (P .001). Within both cohorts, the differences in characteristics among never-, former-, and current-smokers have remained largely constant over time. A greater proportion of never-smokers had Eastern Cooperative Oncology Group performance status 0 to 1 and adenocarcinoma. The median OS increased from 15.5 months in 1999-2002 to 24.9 months in 2008-2011 (P = .001) for never-smokers, 12.3 to 15.9 months (P = .150) for former-smokers, and 10.5 to 13.9 months (P = .011) for current-smokers. The larger survival improvement among never-smokers was likely accounted for by the larger increase in never-smokers who were treated with tyrosine kinase inhibitors and pemetrexed over time.We found an increasing trend of never-smokers among incident lung cancer cases and improved survival for these patients during a 10-year period. The documentation of smoking status in any national cancer registry is vital to estimate the true incidence of lung cancer among never-smokers over time.

The advent of targeted therapies has established new standards of care for defined molecular subsets of non-small cell lung cancer (NSCLC). Not only has this led to significant changes in the routine clinical management of lung cancer e.g., multiplexed genomic testing, but it has provided important principles and benchmarks for determining "actionability". At present, the clinical paradigms are most evolved for EGFR mutations and ALK rearrangements, where multiple randomized phase III trials have determined optimal treatment strategies in both treatment naive and resistant settings. However, this may not always be feasible with low prevalence alterations e.g., ROS1 and BRAF mutations. Another emerging observation is that not all targets are equally "actionable", necessitating a rigorous preclinical, clinical and translational framework to prosecute new targets and drug candidates. In this review, we will cover the role of targeted therapies for NSCLC harbouring BRAF, MET, HER2 and RET alterations, all of which have shown promise in non-squamous non-small cell lung cancer (ns-NSCLC). We further review some early epigenetic targets in NSCLC, an area of emerging interest. With increased molecular segmentation of lung cancer, we discuss the upcoming challenges in drug development and implementation of precision oncology approaches, especially in light of the complex and rapidly evolving therapeutic landscape.

Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket. However pooled analysis of two recent clinical trials LUX-3 and LUX-6 demonstrated an unprecedented overall survival benefit of afatinib over chemotherapy for the EGFR 19del , but not the EGFR L858R . In the current study we use modelling and simulations to show that structural constraints in EGFR 19del deletion result in significantly attenuated flexibilities in the binding pocket resulting in strong hydrogen and halogen bonds with afatinib in the EGFR 19del ; these constraints are modulated by buried water and result in the differential affinities of afatinib for the different mutants. SNP analysis of residues surrounding the buried water points to the likelihood of further differential effects of afatinib and provides a compelling case for investigating the effects of the SNPs towards further stratification of patients for ensuring the most effective use of afatinib.

Hepatocyte growth factor (HGF)/c‐Met pathway dysregulation is a mechanism for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Ficlatuzumab (AV‐299; SCH 900105), a humanized IgG1κ HGF inhibitory monoclonal antibody, prevents HGF/c‐Met pathway ligand–mediated activation. This phase 1b study assessed the safety/tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of ficlatuzumab plus gefitinib in Asian patients with previously treated advanced non–small cell lung cancer (NSCLC). Patients received intravenous ficlatuzumab either 10 mg/kg (cohort 1; n = 3) or 20 mg/kg (cohort 2; n = 12) every 2 weeks plus oral gefitinib 250 mg daily. Patients tolerated the drug combination well. Four treatment‐related grade 3/4 adverse events were reported in 3 patients (cohort 2). Pharmacokinetic profiles for ficlatuzumab and gefitinib were consistent with prior single‐agent trials. Partial responses were achieved in 5 patients (4 confirmed), all in cohort 2; objective response rate (ORR) was 33% (duration, 1.9–6.4 months). Responding patients had no prior EGFR TKI treatment, 2 without an EGFR mutation. Four additional patients had disease stabilization (cohort 2; duration, 2.7–9.1 months; 42% ORR). The recommended phase 2 dose for ficlatuzumab plus gefitinib 250 mg/day was 20 mg/kg every 2 weeks. This drug combination has shown preliminary dose‐related antitumor activity in advanced NSCLC.