2014ASCO年会摘要发布

几乎所有新药的临床数据都得到了更新，我先搬一些过来

我会尽量抽时间来翻译的，更希望懂英语的同学能够帮助翻译一下，谢谢！

这里是发布摘要的首页
http://abstracts.asco.org/144/IndexView_144.html
点进去之后选择“BROWSE Abstracts By Track”，可以根据主题的类型查看摘要
比如我要看NSCLC相关的，就可以选择“Local-regional Non-Small Cell Lung Cancer”（局部NSCLC）和“Lung Cancer - Non-Small Cell Metastatic”（转移性NSCLC）

Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC).
突变选择EGFR抑制剂AZD9291在对EGFR抑制剂耐药的NSCLC患者中的临床活性

Abstract:

Background: AZD9291 is a selective, third generation EGFR-TKI, effective against both EGFR-TKI sensitizing and resistance T790M mutations in preclinical models. We are conducting a phase I study of AZD9291 in EGFR mutant (EGFRm+) NSCLC pts.
背景：AZD9291是一种选择性的第三代EGFR-TKI，可同时作用于对EGFR-TKI敏感的和具有T790M耐药突变的临床前肿瘤模型中。我们正在进行一项将AZD9291用于具有EGFR突变的NSCLC患者的1期研究

Methods: EGFRm+ NSCLC pts, with acquired resistance to EGFR-TKIs, were enrolled in a multicenter trial (NCT01802632) into dose escalation and expansion cohorts. AZD9291 was administered orally, at doses of 20–240 mg once daily. Stable brain metastases were allowed. All pts were assessed for pharmacokinetics (PK), response to therapy, and adverse events (AEs). Prospective mandatory central T790M testing was required in the expansion cohorts and was optional for dose escalation cohorts.
背景：EGFR突变并具有对EGFR-TKI获得性耐药的NSCLC患者，在一个多中心的临床试验中（NCT01802632）入组进入剂量递增和扩展队列。给予患者每天口服一次剂量20mg至240mg的AZD9291。所有的患者都经过药代动力学，对治疗的响应，以及副作用的评估。扩展对列中的患者需要接受中心的前瞻性强制的T79M检测，这对于剂量递增队列的患者是可选的。

Results: As of 16 January 2014, 199 pts (62% female, median age 60, Asian/Caucasian 65%/32%, immediate prior EGFR-TKI therapy: 57%) were enrolled including 31 across 5 dose levels in the dose escalation and 168 in 8 dose expansion cohorts. Median number of prior EGFR therapies: 1 (range, 1-5). PK was dose proportional, median t1/2 ~50 h. Plasma exposures achieved at all doses are predicted to be efficacious in preclinical models. Among all evaluable pts to date, the confirmed+unconfirmed overall response rate (c+uORR) was 51% (91/177). RECIST responses were observed at all dose levels and in brain metastases. In 132 pts with centrally confirmed T790M, the c+uORR in 89 EGFR T790M+ pts was 64% (95% CI; 53%, 74%) and in 43 EGFR T790M- pts was 23% (95% CI; 12%, 39%).The overall disease control rate (CR+PR+SD) in T790M+ pts was 96% (85/89). Among the 60 pts with a confirmed response, 97% (58/60) were ongoing at data cut-off; longest duration of response to date >8 months. No dose limiting toxicities were observed. Most common AEs (≥15%), mostly CTCAE Grade 1, were: diarrhea (30%), rash (24%), and nausea (17%). Grade 3/4 AEs occurred in 16% of pts. Six pts (3%) had dose reductions. Five reports of ILD-like events are under investigation.
结果：截止2014年1月16日，199名患者（62%女性，中位年龄60岁，亚裔人种占65%，高加索人群占32%，57%的患者最近接受过EGFR-TKI的治疗）入组，其中有31位在剂量递增队列的患者被分配到5个剂量级别，剩余的168位患者被分配到剂量扩展队列中。之前接受过EGFR治疗种类的中位数是1种。9291的药代动力学是与剂量成正比的，中位半衰期(t1/2)约为50个小时。所有的剂量级别都达到了在临床前模型中被预测的有效血浆暴露量（曲线下面积）。在目前所有可评估的患者中，进过验证和未验证的总体缓解率（c+uORR）为51%（91/177）。RECIST响应在所有的剂量级别和脑转移患者中被观察到（这基本上可以确定9291是入脑的，只是还需要进一步的在CSF中分布数据）。在132位经过了T790M测试的患者中，9291在89位T790M阳性的患者的c+uORR为64%（95% CI; 53%, 74%），在43位T790M阴性患者中为23%（95%；12%, 39%）。对于T790M阳性患者的总体疾病控制率（CR+PR+SD）是96%（85/89）。在60位具有确定响应的患者中，97%（58/60）的患者在数据截止的时候任然继续接受治疗。截止目前，最长响应时间超过8个月。未观察到剂量限制性毒性。最常见的副作用（大于15%），大多数为CTCAE1级，包括：腹泻（30%），皮疹（24%）以及恶心呕吐（17%）。有16%的患者出现过3-4级副作用。6位患者（3%）已经降低了使用剂量。5位被报告具有类间质性肺炎事件的患者目前正在作进一步的调查。

Conclusions: AZD9291 has robust efficacy and is well tolerated in EGFRm+ NSCLC pts with acquired resistance to EGFR-TKIs. Pts with EGFR T790M+ tumors have higher ORR with AZD9291 compared with those with EGFR T790M- tumors. Clinical trial information: NCT01802632.
总结：AZD9291具有出众的效果，而且能够良好耐受于EGFR突变且具有对EGFR-TKI获得性耐药的NSCLC患者。具有EGFR T790M阳性肿瘤的患者，其总体缓解率高于T790M阴性的患者。临床研究信息：NCT01802632

First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M).
一种不可逆，作用于突变型EGFR(激活突变和T790M)的高选择性酪氨酸激酶抑制剂，CO-1686，第一次人体试验的评估

Abstract:

Background: Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition. CO-1686 is an oral, covalent TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR.
背景：现有的EGFR-TKI在NSCLC中的有效性受限于T790M突变的出现，该突变大约在60%的患者中存在，并且也受限于抑制野生型EGFR所导致的严重的皮疹和腹泻。CO-1686是一种口服的共价结合的TKI，其靶向于常见的EGFR激活突变以及T790M，同时能够避开野生型EGFR。

Methods: This is a completed dose finding study in patients with EGFR mutated advanced NSCLC. Patients were previously treated with EGFR TKI and had a tumor biopsy in screening for central EGFR genotyping. CO-1686 was administered twice daily. Endpoints included safety, pharmacokinetics (PK), and efficacy.
方法：该研究是一项在具有EGFR突变的晚期NSCLC患者中进行的完整的剂量探索研究。患者之前都接受过EGFR TKI的治疗，并且具有肿瘤活检组织样本以便进行EGFR核心基因型的筛选。CO-1686每天两次给予患者。研究终点包括安全性、药代动力学和效果。

Results: As of 17thJanuary 2014, 88 patients were treated: 57 with CO-1686 free base (up to 900 mg BID); 31 with CO-1686 HBr (500 to1000 mg BID). 10 transitioned from free base to HBr. 63% were T790M+, median age 61 years, 77% female, 76% white, and 72% ECOG 1. Median number of previous therapies was 3 (1- 7); 40% had >1 prior line of EGFR TKI. PK of the CO-1686 HBr formulation was dose proportional with three times greater exposure than the equivalent free base dose. The dose limiting toxicity (DLT) rate at all doses was <33%. Related AEs (all grades) in ≥ 20% patients were: nausea (25%), fatigue (21%), impaired glucose tolerance/hyperglycemia (21%). Hyperglycemia was well managed with oral hypoglycemics and/or dose reduction. A recommended phase 2 dose of 750 mg BID has been selected. Nine T790M+ patients treated with 900 mg BID (free base) were evaluable for response; 6 (67%) achieved PRs, 2 (22%) achieved SD, one of whom subsequently achieved a PR after transition to CO-1686 HBr. Eight of nine progressed on EGFR TKI immediately before CO-1686. PRs have occurred among patients treated with CO-1686 HBr, however the majority of patients have not reached the first restaging. Efficacy data for at least 41 patients on CO-1686 HBr will be presented at the meeting.
结果：截止到2014年1月17日，有88位患者接受了治疗：57位患者接受CO-1686自由基（剂量递增至900mg bid）；31位患者接受CO-1686氢溴酸（剂量范围为500mg到1000mg bid），10位患者从自由基转换成氢溴酸。63%的患者T790M阳性，中位年龄61岁，77%为女性，76为白色人种，72%的患者ECOG评分1分。中位前期治疗线数为3(1-7)。有40%的患者具有大于1线的前期EGFR TKI治疗历史。

Conclusions: CO-1686 has demonstrated promising efficacy against T790M+ EGFR mutant NSCLC. CO-1686 HBr delivered higher exposures than free base and was equally well tolerated. Dose-related WT-driven diarrhea and rash has not been seen. The phase 2/3 program will open in 2014. Clinical trial information: NCT01526928.

Updated efficacy and safety of the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC).
ALK抑制剂AP26113在晚期肿瘤包括ALK阳性的NSCLC患者中更新的治疗效果和安全性

Abstract:
摘要：

Background: AP26113 is a novel orally-active tyrosine kinase inhibitor with preclinical activity against ALK and all 9 clinically-identified crizotinib-resistant mutants tested.
背景：AP26113是一种口服活性的酪氨酸激酶抑制剂，其具有针对ALK突变以及所有9种临床确定的克唑替尼耐药突变的临床前活性。

Methods: The Phase (Ph) 2 portion of a Ph1/2 single arm, multicenter study in pts with advanced malignancies is underway. We report updated safety for all treated pts and efficacy data for ALK+ NSCLC pts previously treated with crizotinib. NCT01449461.
方法：这个Phase 1/2单臂临床试验的Phase 2部分的多中心研究已经在晚期肿瘤患者中展开。我们报告了对所有患者的更新了的安全性数据，以及对之前接受过克唑替尼治疗的ALK阳性(ALK+)的NSCLC患者的有效性数据。NCT01449461

Results: As of 16 Dec 2013, 114 pts were enrolled: 65 in Ph1 (30-300 mg) and 49 in Ph2 (180 mg). Baseline characteristics: 59% female, median age 57 yr; diagnoses: NSCLC n=106, other n=8. 66 pts remain on study; median follow-up for all pts is 3.6 mo (max= 21.4 mo, ongoing). The most common treatment-emergent AEs (≥20%) were nausea (38%), diarrhea (31%), fatigue (31%), cough (23%), and headache (20%), which were generally grade 1/2 in severity. Early onset of pulmonary symptoms (dyspnea with hypoxia and/or findings on imaging) observed in 6/45 (13%) pts at 180mg QD. These symptoms, requiring immediate medical attention, were not observed at 90mg QD (n=8) or in the lead-in dose cohort (n=19; initiated at 90mg QD, escalated to 180mg QD after 1 wk). Pts continue to be enrolled with this dose escalation scheme, and an additional cohort of 90mg QD without escalation will be added. Among 38 evaluable ALK+ NSCLC pts with prior crizotinib, 24 (63%) responded (23 partial response, 1 complete response). Duration of response was 1.6 - 14.7 mo (ongoing). 15 pts had confirmed responses; 5 await confirmation, 4 are unconfirmed. Among 42 evaluable pts with ALK+ NSCLC, median progression free survival is 47 wk. Independent radiological review conducted on 10 pts enrolled with untreated or progressing brain metastases showed 6/10 pts with response in brain, including 4 with undetectable brain metastases following AP26113; 2 pts had stable disease, 2 pts progressed; 8/10 remain on study (range 5-17 mo).
结果：截止到2013年12月16日，共有114位患者入组：65位患者进入Phase 1(30-300mg)，49位进入Phase 2(180mg)。基线特征为：59%为女性，中文年龄57岁；诊断结果：NSCLC患者106位，其他肿瘤患者8位。有66位患者还继续参与研究；对所有患者的中位随访时间为3.6个月(最长21.4个月，继续随访中)。最常见的治疗出现的AE(大于等于20%)为恶心(38%)、腹泻(31%)、乏力(31%)、咳嗽(23%)和头痛(20%)，严重程度通常为1-2级。

Conclusions: AP26113 has promising anti-tumor activity in pts with crizotinib-resistant ALK+ NSCLC, including pts with brain metastases. A randomized Ph2 trial evaluating 90 mg QD vs. 90mg QD escalating to 180mg QD in crizotinib-resistant ALK+ NSCLC will begin shortly. Clinical trial information: NCT01449461.

TBD

A phase II cluster study of single agent AUY922, BYL719, INC280, LDK378, and MEK162 in Chinese patients with advanced non-small cell lung cancer (NSCLC).

Abstract:

Background: Advanced NSCLC management has evolved toward individual tumor subtyping based on targetable oncogenic drivers. Most molecularly characterized lung adenocarcinoma patients (pts) could thus potentially benefit from targeted treatment. This study investigates the innovative paradigm of allocating pts to specific treatment arms based on their genetic profile. The targeted therapies AUY922 (HSP90 inhibitor), BYL719 (PI3K), LDK378 (ALK), INC280 (MET), and MEK162 (MEK) will be evaluated in different pt subgroups with appropriate confirmed molecular aberrations, in a single cluster study.

Methods: This Phase II, multiple arm, open-label study will enroll pts (aged ≥18 years, ECOG PS ≤2) with advanced (stage IIIB/IV) lung adenocarcinoma bearing different molecular alterations, who have failed prior treatment or are unsuitable for chemotherapy, and have received ≤2 prior lines of therapy. Pts must have locally obtained documentation of a relevant molecular alteration from either a new or the most recent archival tumor sample, using primary genetic profiling. Pts will be allocated to a specific treatment arm accordingly (AUY922, 70 mg/m2 QW: activating EGFR mutation and resistant to EGFR inhibitors; BYL719, 350 mg QD: PIK3CA mutation/amplification [other PI3K pathway alterations may be eligible]; INC280, 600 mg BID: MET-positive tumors [by IHC or FISH]; LDK378, 750 mg QD: ALK or ROS1 rearrangement; MEK162, 45 mg BID: KRAS, NRAS or BRAF mutation). Sample size was calculated based on a Bayesian approach using either a minimally informative prior (BYL719, INC280 and MEK162; N=20 for each) or an informative prior using relevant historical data (AUY922 [N=30] and LDK378 [N=25]). The sample size will allow detection with high likelihood, of statistically and clinically relevant antitumor activity. Each treatment arm is independent from one another and will be analyzed separately. Study treatment is given until disease progression or discontinuation. The primary endpoint is overall response rate; secondary endpoints are overall survival, progression-free survival, disease control rate, duration of response, safety, and pharmacokinetics.

Safety and efficacy of INC280 in combination with gefitinib (gef) in patients with EGFR-mutated (mut), MET-positive NSCLC: A single-arm phase lb/ll study.

Abstract:

Background: Despite high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients (pts) with EGFR-mut NSCLC ultimately relapse. Dysregulation of the MET pathway is implicated as a therapeutically tractable resistance mechanism, occurring in 15–20% of cases. INC280 is a highly selective, oral MET inhibitor with preclinical activity in EGFR-mut/MET-activated NSCLC when combined with EGFR TKIs.

Methods: This Ph Ib/II, open-label, dose-escalation study of INC280 plus gef was performed in pts (age ≥18 yrs, ECOG PS ≤2) with EGFR-mut NSCLC who progressed after prior EGFR TKI, and have confirmed MET dysregulation (amplification [FISH ≥5 CN] or overexpression [IHC 2/3+]). The primary objective (Ph Ib) was to determine the MTD/recommended Ph II dose (RP2D) of INC280 plus gef; secondary objectives were safety, efficacy, pharmacodynamics and PK. An adaptive Bayesian logistic regression model with overdose control guided dose escalation to establish the MTD.

Results: As of December 2, 2013, 41 pts were enrolled in the ongoing Ph Ib part of the study (59% female, median age 58 years). Pts were treated with INC280 at 7 dose cohorts of 100–800 mg QD and 200–600 mg BID, in combination with gef 250 mg QD. Dose-limiting toxicities (DLTs) occurred in 2 pts: dizziness (800 mg QD) and dyspnea (600 mg BID). The most frequent drug-related AEs (any grade [Gr]) were nausea (27 %), vomiting, diarrhea, and rash (all 22%). The most common drug-related Gr 3/4 AEs were increased lipase (7 %), and increased amylase (5%). For one death, causality to INC280 was not ruled out. INC280 exposure increased with dose from 100–800 mg QD and 200–400 mg BID; preliminary data show no PK interactions with gef. Partial responses were seen in 6/41 (15%) evaluable pts; 5 confirmed, 1 unconfirmed, including 3/7 pts (43%) on 400 mg BID; 5/6 responders had EGFR TKIs as a last treatment prior to study entry. All responders had high MET status.

Conclusions: Oral INC280 in combination with gef is well tolerated; the RP2D has not yet been defined. Preliminary clinical activity supports further evaluation of INC280 combined with gef in MET-positive NSCLC resistant to EGFR TKIs. Clinical trial identifier: NCT01610336. Clinical trial information: NCT01610336.

First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 status.

Abstract:

Background: The fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody nivolumab has demonstrated durable responses and tolerability in patients (pts) with previously treated advanced NSCLC. Tumor PD-1 ligand (PD-L1) expression is being studied as a potential biomarker for nivolumab. We report interim phase I results of first-line nivolumab in chemotherapy-na&#239;ve advanced NSCLC pts.

Methods: Pts with squamous (sq) or non-sq advanced NSCLC received nivolumab 3 mg/kg IV Q2W until progression or unacceptable toxicity (post-progression treatment allowed based on protocol-defined criteria). Responses (RECIST 1.1) were evaluated overall and according to tumor PD-L1 status (PD-L1+ = ≥5% tumor cells expressing PD-L1 [Dako immunohistochemistry assay]). Results on the first 20 pts are included.

Results: After ≥6 months follow up, 17 pts (85%) experienced any-grade treatment-related adverse events (AEs), managed with standard algorithms. Treatment-related grade 3-4 AEs (3 pts, 15%) were AST or ALT elevations, hyperglycemia, and rash (n=1 each). No pneumonitis (any grade) was observed. Objective response rate (ORR) was 30% (Table); 5/6 responders (83%) achieved response by first scan (wk 11). Two pts had >80% target lesion reduction at 18 wks. Of 15 evaluable tumor samples, 9 were PD-L1+. ORR was 67% in PD-L1+ pts; no responses were observed in the 6 PD-L1- pts. Responses were durable (median duration of response [mDOR] not reached [NR]; 5 ongoing responses).

Conclusions: In this phase I study, nivolumab led to early, durable responses in advanced NSCLC pts, with a tolerable safety profile. PD-L1 status appeared to correlate with ORR/progression-free survival (PFS). Follow up and responses of 30 additional treated pts will be reported. These data support further studies of first-line nivolumab monotherapy in advanced NSCLC. Clinical trial information: NCT01454102.

Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): Survival and clinical activity by subgroup analysis.

Abstract:

Background: Nivolumab, a fully human IgG4, PD-1 immune-checkpoint inhibitor antibody, has shown durable clinical activity in a large phase I trial of pts with advanced solid tumors. For NSCLC pts in this trial, we report overall survival (OS) by dose and histology and clinical activity of pt subgroups including PD-L1 tumor status.

Methods: Previously treated pts with advanced NSCLC received IV nivolumab (1, 3, or 10 mg/kg) Q2Wk for ≤96 wk with tumor evaluation by RECIST v1.0. Clinical activity by key prognostic factors was assessed. PD-L1 tumor cell membrane expression was measured in archival specimens (n=68) by a Dako immunohistochemistry assay (positive ≥5% tumor cells).

Results: Across doses and histologies, NSCLC pts (N=129, 54% with ≥3 prior therapies) hadmedian overall survival (mOS) of 9.2-14.9 mo and 1- and 2-y OS rates of 32-56% and 12-45%, respectively (Table). At the 3 mg/kg dose, mOS was 14.9 mo; 1- and 2-y OS rates were 56% and 45%. Objective response rate was 17% (22/129); median response duration was 17 mo. Clinical activity was observed across all pt subgroups, including <3 and ≥3 prior therapies and with/without EGFR or KRAS mutations. For pts with PD-L1(+) and (–) tumors, mOS was 7.8 mo (95% CI: 5.6, 21.7) and 10.5 mo (5.2, 21.2), respectively; mPFS was 3.6 mo (1.8, 7.5) and 1.8 mo (1.7, 2.3). Grade 3-4 treatment-related adverse events occurred in 14% of pts; most common was fatigue (3%).

Conclusions: Nivolumab continues to demonstrate an encouraging survival profile and clinical activity across NSCLC pt subgroups with a manageable safety profile. Ongoing phase III trials are evaluating 3 mg/kg nivolumab in NSCLC pts and PD-L1 as a potential predictor of clinical outcomes. Clinical trial information: NCT00730639.

Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: Interim phase I results.

Abstract:

Background: Nivolumab, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, and ipilimumab, an IgG1 CTLA-4 checkpoint receptor blocking antibody, have shown activity in advanced NSCLC; clinical data in melanoma showed improved responses and a manageable safety profile when combined. We report interim results from a phase I study evaluating first-line nivolumab + ipilimumab (N+I) in advanced NSCLC patients (pts).

Methods: Chemotherapy-naive pts (n=46) with squamous (sq) or non-sq NSCLC received the 3 + 1 mg/kg or 1 + 3 mg/kg combination dose IV Q3W for 4 cycles followed by nivolumab 3 mg/kg IV Q2W until progression/unacceptable toxicity. Objective response rate (ORR; RECIST 1.1) was evaluated overall and by baseline tumor PD-L1 status (Dako immunohistochemistry assay). After an amendment, a 1 + 1 mg/kg cohort was added (n=30, data immature at Dec 2013 analysis).

Results: In the 4 cohorts with ≥4 months follow up, any-grade treatment-related adverse events (managed with protocol algorithms) were reported in 39 pts (85%; grade 3–4 in 22 pts [48%]) and led to discontinuation in 16 pts. Treatment-related deaths (n=3) were due to respiratory failure, bronchopulmonary hemorrhage and toxic epidermal necrolysis. Responses occurred in all 4 cohorts (Table); overall ORRb was 22% (median duration of response [mDOR] not reached [NR]) and stable disease (SD) 33% (range 13 – 34.1+ wks); 2 pts exhibited unconventional “immune related” responses. In 29 evaluable tumor samples from the study, ORR did not correlate with PD-L1 status.

Conclusions: These interim data in pts with advanced NSCLC suggest that a nivolumab + ipilimumab immunotherapy regimen is feasible and demonstrates antitumor activity in both PD-L1+ and PD-L1– pts. Safety will be further assessed at the 1 + 1 mg/kg dose. The recommended combination dose for phase II/III evaluation has not been determined. Clinical trial information: NCT01454102.

Phase (Ph) 1/2 study of TSR-011, a potent inhibitor of ALK and TRK, including crizotinib-resistant ALK mutations.

Abstract:

Background: Ultimately, the majority of anaplastic lymphoma kinase (ALK) rearranged (+) non-small cell lung cancers (NSCLC) are either unresponsive to crizotinib or develop resistance mutations. Similarly, gene rearrangements in NTRK1 have been identified as a potentially actionable oncogenic aberration. TSR-011 inhibits ALK and tropomyosin-related kinase (TRK) A, B, and C receptor activity with IC50 values < 3 nM and exhibits inhibition of oncogenic echinoderm microtubule associated protein like 4 (EML4)-ALK and tropomyosin (TPM)-TRKA dependent tumor growth in mice.

Methods: A Ph 1-2a dose escalation and cohort expansion study is underway to evaluate safety, tolerability, PK, and preliminary efficacy of TSR-011. Ph 1 is evaluating unselected patients with advanced solid tumors and lymphomas. The recommended Ph 2 dose will be evaluated in Ph 2a in patients with ALK+ or TRK ligand/receptor + tumors (defined by immunohistochemistry or fluorescent in-situ hybridization) including those with NSCLC progressing on, or na&#239;ve to, ALK inhibitor therapy.

Results: Twenty-three patients with advanced cancer have been enrolled at oral total daily doses between 30 and 480 mg, including NSCLC (n=10, including 5 ALK+), pancreatic (3), ovarian (2), salivary gland (2) and 1 each with papillary thyroid, cholangiocarcinoma, bladder, carcinoid, colon & leiomyosarcoma. Bi-exponential PK was observed, with dose proportional Cmax and AUC and t1/2 of 12-24 h. Dose-limiting toxicities included dysaesthesia and QTc prolongation; MTD has been defined. PK modeling revealed that a fractionated dose of 60 mg daily (dose expansion cohort) minimizes peak exposure and achieves sustained trough concentrations well above the IC50 for ALK inhibition. Of 5 patients with ALK+ NSCLC, 3 (all crizotinib-resistant) achieved PR (1 met RECIST criteria and 2 had non-measurable disease, so not formally RECIST-classified) 1 is early (not imaged yet), and 1 discontinued for DLT. Stable disease was observed in ALK- papillary thyroid, pancreatic and colorectal patients.

Conclusions: TSR-011 is a well-tolerated promising second-generation agent for ALK-dependent and crizotinib resistant NSCLC, and is being explored in ALK+ and TRK+ tumors. Clinical trial information: NCT02048488.