2013年第38届欧洲临床肿瘤协会年会（ESMO）的相关报道

ESMO成立于1975年，是欧洲领先的专业组织，作为一个非盈利组织，ESMO一直以推动癌症护理和治疗为使命，致力于推进肿瘤医学专业，以多学科的方法来促进癌症的治疗和护理。
2013年第38届欧洲临床肿瘤协会年会（ESMO）于2013年9月27日-10月1日在荷兰阿姆斯特丹举行。
http://www.esmo.org/Conferences/European-Cancer-Congress-2013
http://www.ecco-org.eu/Amsterdam2013.aspx

ARIAD Presents Updated Phase 1/2 Data on AP26113 in Patients with Non-Small Cell Lung Cancer
The updated Phase 1/2 results are being presented this morning at the European Cancer Congress (the 38th ESMO, 32nd ESTRO, 17th ECCO conference) being held in Amsterdam.

Phase 1/2 Study Design

Patients enrolled in the Phase 1 portion of the trial had advanced solid tumors that were refractory to available therapies or had no standard or curative treatment available. The objectives of the Phase 1 portion of the trial were to characterize the safety and tolerability of AP26113, pharmacokinetics, and preliminary anti-tumor activity and to determine the recommended dose for further study of AP26113. The trial used an open-label, dose-escalating design. Anti-tumor activity was determined by serial CT scans using RECIST criteria. The study identified a recommended Phase 2 dose of 180 mg administered orally once daily.

The Phase 2 portion of the trial began in June 2013 and has enrolled 26 patients in the United States and Europe. This portion of the trial consists of five expansion cohorts: (1) ALK+ NSCLC treatment-naïve, (2) ALK+ NSCLC resistant to crizotinib, (3) epidermal growth factor receptor mutant (EGFRm) NSCLC resistant to one prior EGFR TKI with documented T790M secondary mutation, (4) cancers with AP26113 targets (including ALK, ROS1, and EGFR ineligible for Cohort 3), and (5) ALK+ NSCLC, either naïve or resistant to crizotinib, with active brain metastases.

Ninety-one patients have been enrolled in the study at seven dose levels (i.e., 30, 60, 90, 120, 180, 240 and 300 mg per day, administered orally). Fifty-four patients currently remain on study.

The updated results from the on-going Phase 1/2 trial show that AP26113 continues to exhibit anti-tumor activity in patients with TKI-naïve and crizotinib-resistant ALK-positive NSCLC, stated D. Ross Camidge, M.D., Ph.D. Associate Professor of Medicine at University of Colorado School of Medicine, the studys presenter at ESMO. Importantly, AP26113 is active in ALK-positive brain metastases, demonstrating responses of clinically meaningful duration.

Key data from the study presented at ESMO include:

Safety and Tolerability

Safety assessments show AP26113 to be generally well tolerated. The most common adverse events (AEs), regardless of treatment relationship and including all grades, were nausea (38%), fatigue (34%), and diarrhea (32%).
Adverse events grade 3 or higher were uncommon. Treatment-related events occurring in two or more patients were dyspnea (4%), fatigue (3%), diarrhea (2%), hypoxia (2%), and pneumonitis (2%).
In 3 out of 26 patients receiving 180 mg per day of AP26113 in the Phase 2 portion of the trial, early-onset pulmonary symptoms were observed after the first dose of AP26113. Similar events were observed at lower doses but less frequently and have not been observed at 90 mg per day or lower.
To lessen the infrequent early pulmonary symptoms observed, the recommended Phase 2 dose of 180 mg per day is now preceded by dosing for 1 week at 90 mg per day, for all patients receiving AP26113.
ALK+ Patients

Objective responses were observed in ALK+ NSCLC patients at the lowest dose tested (60 mg), and responses were observed in patients who were either naïve or resistant to crizotinib.
Of the 34 ALK+ NSCLC patients evaluable for response, 22 (65%) demonstrated an objective response, including 21 partial responses (PR) and one complete response (CR). Of the three TKI-naïve NSCLC patients treated with AP26113, all demonstrated an objective response, including one CR.
Objective response durations ranged from 8+ weeks to 40+ weeks. Of the 15 ALK+ NSCLC patients receiving treatment for at least 6 months, 12 (80%) remain on study. The waterfall plot analysis demonstrated tumor shrinkage in nearly all ALK+ patients.
Of particular note, eight out of ten (80%) ALK+ NSCLC patients with pre-existing brain metastases had evidence of radiographic improvement in those metastases, and seven of these patients remain on study, with duration of central nervous system (CNS) benefit ranging from 8+ to 40+ weeks.
EGFR T790M Patients

Of the 18 patients who had a history of a T790M secondary mutation, 12 were evaluable for response. Three T790M patients have been enrolled since June who met the rigorous eligibility criteria of having failed one prior EGFR TKI, documented T790M secondary mutation following disease progression on most recent EGFR TKI, and administration of AP26113 within 30 days of stopping the prior EGFR TKI. These three patients received 240 mg per day, and one patient was evaluable for response.
Of the 12 evaluable patients with a history of a T790M secondary mutation, no objective responses have been observed to date; 5 (42%) demonstrated stable disease.

摘取关键的内容翻译：
AP26113治疗非小细胞肺癌的2期临床试验纳入了1期临床实验的54个病人，1期临床实验结果推荐180mg每天的剂量，EGFR突变组新招了3名T790突变的病人，剂量为240mg每天。
AP26113耐受性良好，主要的副作用是恶心 (38%), 乏力(34%)和腹泻 (32%)，3级以上副作用少见，主要是呼吸困难 (4%), 乏力 (3%), 腹泻 (2%), 缺氧(2%)和肺炎(2%)。
26名服用180mg AP26113的病人有3名在第一个疗程出现早发性肺部症状，之前在120mg组发生过，但概率更低，在90mg及以下剂量没有发生。鉴于此副作用，AP26113的剂量暂时调整到90mg每天（一周）。
ALK+组：
（1）初始治疗或克药耐药病人在60mg组都观察到有部分病人肿瘤缓解。
（2）34名ALK+评估病人中，22名（65%）达到有效缓解，包括1名完全缓解（该病人为初次使用alk靶向药），无进展时间为8+周到40+周，15名病人超过6个月，其中的12名病人仍留在实验组内。几乎所有的ALK+病人观察到肿瘤缩小。
（3）10名脑转病人中有8名（80%）脑部肿瘤缩小，脑部获益时间为8+周到40+周，其中的7名仍留在实验组内。
EGFR T790M 组：
18名EGFR T790M病人，有12人参加评估，其中有3人是240mg每天的剂量，有效缓解率是0%，疾病稳定率是42%。
ARIAD _ESMO2013_FINAL92713.pdf (486.9 KB, 下载次数: 17)

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向老马致敬！

EGFR T790M 组：
18名EGFR T790M病人，有12人参加评估，其中有3人是240mg每天的剂量，有效缓解率是0%，疾病稳定率是42%。

有EGFR突变的人不用试了？

不考虑这药了，谢谢马哥的信息。

谢谢马老师   AP26113 EGFR的不用考虑了

— TSR-011 Identified as a Potent Dual Inhibitor of ALK and TRK Kinases

— Preliminary Clinical Activity Demonstrated in Patients with Several
Tumors, Including ALK-Positive NSCLC Patients Previously Treated with
Crizotinib

— Phase 2 Dose Selection and Cohort Expansion Into Patients With
ALK-Positive or TRK-Mutated Tumors Anticipated to Occur by Year End
AMSTERDAM, Netherlands, Sept. 29, 2013 (GLOBE NEWSWIRE) — TESARO, Inc. (Nasdaq:TSRO), an oncology-focused biopharmaceutical company, presented initial data from a Phase 1 trial of TSR-011 today at the European Cancer Congress in Amsterdam. TSR-011 is a potent inhibitor of both anaplastic lymphoma kinase (ALK) and tropomyosin-related kinases (TRK). Preliminary clinical activity has been observed in this study in one papillary thyroid carcinoma patient and one pancreatic cancer patient without ALK expression, and in three patients with ALK-positive non-small cell lung cancer (NCSLC) who progressed following prior treatment with crizotinib.

Of the three ALK-positive NSCLC patients who progressed on prior crizotinib treatment, one achieved a RECIST partial response after four weeks of treatment with TSR-011; one, with disease not evaluable by RECIST criteria, achieved an investigator-assessed partial response; and one has stable disease. Each of these three patients remains on study today. In addition, one patient with papillary thyroid carcinoma and one patient with pancreatic cancer each have long term stable disease following several cycles of TSR-011 treatment. Preliminary results after eight weeks of treatment with TSR-011 demonstrated disease control (partial responses plus stable disease) in 11 of 17 (65%) evaluable patients treated with TSR-011.

“We are very pleased with the emerging profile of TSR-011, including the adverse event profile and early demonstration of clinical activity,” said Dr. Mary Lynne Hedley, President of TESARO. “We remain on track to move into Phase 2a by the end of this year, which will allow us to further evaluate the benefit/risk profile of TSR-011 in patients with cancers that are ALK-positive or have TRK rearrangements.”

Pharmacokinetic data demonstrated rapid absorption, predictable, dose proportional plasma concentrations following oral administration and an elimination half-life of 12 to 24 hours. TSR-011 was well tolerated at therapeutic dose levels, and no drug related Grade 4 or Grade 5 adverse events have been observed to date. The most frequently occurring dose limiting toxicities included ECG changes and dysaethesia, both of which were reversible.

Phase 1/2a Trial Design

The ongoing Phase 1/2a trial is a sequential, open-label, two part study with dose escalation in Phase 1 followed by expansion into selected cohorts in Phase 2a. Following identification of a recommended Phase 2 dose and schedule, Phase 2a will be initiated to evaluate the safety and efficacy of TSR-011 in a variety of tumor settings that express ALK or TRK. The three expansion cohorts will include: (1) patients who have ALK-positive, ALK inhibitor naive non-small cell lung cancer (NSCLC); (2) ALK-positive NSCLC patients who have progressed following prior treatment with another ALK inhibitor; and (3) patients with other solid tumors or lymphomas that are either ALK-positive or have mutations of TRK genes.
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TSR-011的效果看来比较差。

Roche/Chugai update from ESMO
As of September 23, Roche’s ALK inhibitor (now called Alectinib) has been granted breakthrough therapy status by the FDA. This was based in part on the abstract below.

LATE BREAKING ABSTRACT: Safety and efficacy analysis of RO5424802/CH5424802 in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients who have failed crizotinib in a dose-finding phase I study (AF-002JG, NCT01588028)

S. Ou(1), S. Gadgeel(2), A. Chiappori(3), G. Riely(4), R. Lee(5), L. Garcia(6), M. Tatsuno(7), T. Tanaka(7), L. Gandhi(8)

Background: RO5424802 is a highly selective and potent ALK inhibitor in development for ALK+ NSCLC and inhibitors both wild-type and mutant NSCLC ALK fusion variants. While the clinical activity of RO5424802 has been published in crizotinib-naive ALK+ NSCLC patients, its clinical activity in crizotinib-refractory ALK+ NSCLC patients remained to be determined.
Materials and methods: A phase I dose escalation study of RO5424802 in crzitoinib-refractory ALK+ NSCLC patients was completed in July, 2013. Primary objective was to determine the recommended phase 2 dose (RP2D). Secondary objectives were efficacy, safety, and pharmacokinetics (PK). Key eligibility criteria included prior progression on crizotinib, ECOG PS 0-2, adequate organ functions, confirmed ALK rearrangement by a FDA-approved test. Patients with asymptomatic CNS metastases were eligible to enroll directly into where study whereas patients with symptomatic CNS metastases required radiation treatment before participation. RO5424802 was administered orally at doses of 300, 460, 600, 760, 900 mg BID until progression of lack of clinical benefit. One treatment cycle is 21 days. Efficacy was assessed by RECIST 1.1. Toxicities were evaluated by CTCAE v4.0.
Results:A total of 45 patients were enrolled from 6 US sites from 05/2012 to 07/2013. As of July 10, 2013 the median duration on study was 141 days (range 30-379+ days) and 33 patients (73%) remained on study without progression. PK analysis showed area under the curve (AUC) of 600 mg BID of RO5424802 was twice that of 300 mg BID but no difference from that achieved with 760 mg BID of RO5424802. Two DLTs (one grade 3 headache and one grade 3 neutropenia resutling in RO5424802 being held for 7 days) were observed in the 900 mg BID cohort. Two patients were dose reduced from 760 mg to 600 mg due to grade 2 fatigue and abdominal pain respectively. The RP2D was determined to be 600 mg BID. Preliminary efficacy was assessed in 37 evaluable patients across all cohorts with an overall response rate (ORR) of 59% (1 CR, 14 confirmed PR, 7 unconfirmed PR, and 11 SD). Of the 37 evaluable patients, 20 (54%) had pre-existing brain metastasis at enrollment. Sixteen (80%) out of the 20 patients remained on study for > 6.6 months without progression (4 had brain radiation 1 month prior to enrollment, 10 had remote brain RT, 2 had no prior brain RT). Of the five patients who received brain RT 1 month prior to enrollment only 1 patient treated at 300 mg BID had discontinued treatment due to progression. Four of these five patients are in cycles 19+, 12+, 7+, 6+ treated at doses of 760 mg, 600 mg, 600 mg, 900 mg respectively. Responses to untreated CNS lesions occurred as early as 3 weeks after RO5424802 initiation.
Conclusions: RO5424802 is well-tolerated with significant anti-tumor activity both extra-cranially and intra-cranially in crizotinib-refractory ALK+ NSCLC patients. The RP2D dose of RO5424802 is determined to be 600 mg BID. A global phase 2 trial of RO5424802 in crizotinib-refractory ALK+ NSCLC patients is ongoing.
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Chugai的剂量也太大了，每天要1200mg。

3 Quotes from Ariad’s ESMO conference call.

The first starts at 17:47 into the call.

Dr Camidge: “In term of your other question, which is a very pertinent question. How does this compare to the other second generation ALK inhibitors out there? Well there are differentiating features both in terms of efficacy and toxicity.
So in terms of efficacy, I think, we have a very similar picture in terms of the objective response rate in the post Crizotinib setting. If you looked at LDK their initial data had an 80% response rate, but then when you got more mature data, it fell I think to 57% [the ASCO data I am aware of was at 60%]. So things which are to good to be true usually are. I think the Chugai data which had something like a 93% response rate, that is in Crizotinib naive patients and only in Japanese patients and I would be astonished if that number stayed that high when you start to do it in a Crizotinib resistant setting, which I suspect will also fall into a similar range.

What will be interesting in terms of systemic disease control. Is in that first slide [the third slide in the PowerPoint] that I showed you whether there will some mutations which will start to become more prominent with some of these inhibitors as a mechanism of resistance that will differentiate it from 26113. So everyone gets a good initial response because your suppressing the common mutations but then you create an environment for evolution to take place and you will generate the mutations which will grow in the presence of each individual drug.

And so the drug with broadest spectrum of activity is attractive from that point of view….
So the second point on efficacy is brain metastases. So we have seen literally MRI scans showing here is a brain lesion, it’s got smaller for LDK and Chugai and probably the Astellas compound as well, but if I showed you one CT scan of a chest but no waterfall plot. You’d say where is the rest of the data. So I think a single MRI tells you nothing other than its a case report.

What we are trying to do here, and I think that is the most exciting thing, is give hard data. The number of people, you have a denominator, 8 out of 10, getting shrinkage. You’ve got a duration of response, more than 40 weeks and ongoing. When you start to get that kind of hard data, you will be able to compare between these compounds. So having a brief response in a minority of patients, you still get one MRI scan you can show. So you really be saying to the other people, show me the data regarding the CNS responses.

Let me get to the tolerability. So LDK is the one we have the best data on, in terms of its tolerability, and that is a little worrying. It has a relatively high rate of sever gastrointestinal disturbance and something like a 20 to 25% [there seems to be a mismatch between the ASCO press release 19% rate and the ASCO abstract rate of 12%, I am not aware of a more recent source] rate of grade 3 transaminitis [possibly an indicator of liver damage] at their recommended phase 2 dose. It doesn’t seem to have the pulmonary signal that we have here. It’s a different spectrum of toxicity than we are seeing. But at least in my hands, and I have treated patients with both. 26113 provided your not in that small percentage of people that have the pulmonary symptoms, and now I think we have found a way of getting round them, is amazingly well tolerated. Literally the patients say ‘I do not have any side effects.’ That is not the case with LDK and if you look in some of the data they have presented, something like 50% of patients on LDK have to be dose reduced….

In terms of the Chugai compound, I haven’t seen any data presented other than in the Japanese population and it is hard to know how to translate that into a western population.”

The second starts at 25:30 into the call.

Question: “My follow up just really quickly for Dr. Camidge, if you look at the current data for all the secondary drugs right now. Do you think 113 looks the best with regard to brain mets, or is that also to early to tell?”

Dr. Camidge: “The short answer is I think, yes. I think when you see the data you’ve got to say show me the money, show me the data. You want to see a denominator, you want to see a duration of benefit. Also you want to be real clear that they are talking about active brain mets. There may be some data presented which says ‘here are 10 people with a history of brain mets but if they’ve all had radiotherapy just before they’ve started on the drug. You can tell absolutely nothing from that.

So this is as good a data as there is out there. And therefor it is the best of all possible data, it’s the only data there is that’s good.”

The third starts At 47:50 into the call.

Dr. Camidge: “You could say why aren’t we going forward with 90 mg which seems to be a relatively clean tox signal. But you have to go back to the idea that we think that brain mets is a key area of therapeutic benefit.

And if I use the LDK as an example, if you have 50% dose reduction of 750 mg starting dose. Their really going to start drop their exposures in the brain. That is why again I go back to the idea that its not enough to show one MRI of the brain. If you drop the dose the next week, then they will progress in the brain. So you have to see the duration of response. So everything we can to get the dose up and maintain it in a safe way, is what is driving this.”