2014ASCO年会摘要发布

二师兄 · 发表于 2014-5-16 11:12:01

版主，有关于PF06463922的消息么，还有CH5424802的

lzf285 · 发表于 2014-5-16 11:24:42

版主辛苦了

2300 · 发表于 2014-5-16 13:03:06

正在9291中很重要的信息感谢楼主

costa_na · 发表于 2014-5-16 13:17:12

Updated efficacy and safety of the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC).

Abstract:

Background: AP26113 is a novel orally-active tyrosine kinase inhibitor with preclinical activity against ALK and all 9 clinically-identified crizotinib-resistant mutants tested.

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.

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).

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.

costa_na · 发表于 2014-5-16 13:20:14

二师兄发表于 2014-5-16 11:12
版主，有关于PF06463922的消息么，还有CH5424802的

Antitumor activity of alectinib (CH5424802/RO5424802) for ALK-rearranged NSCLC with or without prior crizotinib treatment in bioequivalence study.

Abstract:

Background: Alectinib, a potent highly selective ALK inhibitor, shows good efficacy and safety for crizotinib-naïve and -resistant patients (pts) with ALK-rearranged non-small cell lung cancer (NSCLC). However, each dose required 8 capsules (caps). Thus, a higher strength formulation was developed.

Methods: This 2-arm crossover study (JP28927) evaluated the bioequivalence of alectinib 300 mg b.i.d. with 20 and 40 mg caps vs. 150 mg caps at steady state in ALK-rearranged NSCLC pts. Primary objectives were to evaluate bioequivalence between drug formulations and food effect with 150 mg caps; secondary objectives were to evaluate efficacy and safety. Arm 1 of Cycle 1 (30 d) consisted of 300 mg b.i.d. with 20/40 mg caps for 10 d, 150 mg caps for the next 10 d, and 150 mg caps after meals for the last 10 d. The order was different in arm 2: 150 mg caps for 10 d, 20/40 mg caps for the next 10 d, and 150 mg caps after meals for the last 10 d. After Cycle 1, to evaluate bioequivalence, pts continued alectinib 300 mg b.i.d. with 150 mg caps until the investigator determined lack of clinical benefit. Tumors were assessed on Day 31 and 59, and then every 56 d.

Results: As of Dec 16, 2013, 35 ALK-rearranged NSCLC pts were enrolled. The exposure between formulations was similar, and no food effect was seen with 150 mg caps. Safety (median follow-up period, 4 months) was acceptable: no pt discontinued treatment due to AEs; AEs were mostly Grade 1 or 2. Preliminary efficacy was observed with 63.3% partial response (PR) (including 9 unconfirmed PR) by investigator’s assessment in the 30 pts with target lesions. Among 20 crizotinib-resistant pts with target lesions (median duration from last dose of crizotinib, 18.5 d [15–361]), response rate was 60.0% (including 5 unconfirmed PR) and median time to response was 36 d (29–119). In 2 pts, non-irradiated brain metastases over 10 mm had complete response at first assessment (Day 34 and 36).

Conclusions: The exposure of 20/40 mg and 150 mg caps was similar, and no food effect was seen with 150 mg caps. Alectinib in 150 mg caps was efficacious for ALK-rearranged NSCLC pts regardless of crizotinib treatment history, with quick and high efficacy and good safety. Clinical trial information: JapicCTI-132186.

costa_na · 发表于 2014-5-16 13:23:43

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 naïve 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.