【醒目】Rociletinib （CO1686）一期临床结果（ASCO2013全文）

希望早点出YL，希望4002耐药后可用。

Ohad Hammer on December 13, 2013 at 4:32 pm said:
Care – Regarding CLVS vs. AZN. I think it’s safe to say both drugs look active in T790M NSCLC even though it’s hard to predict the eventual clinical profiles of each drug. To me, the fact CLVS’ recruit patients only immediately after progression on Tarceva (or other EGFR inhibitor) makes their case more compelling. In addition, CLVS’ compound might be more wild type EGFR sparing based on some rast AZN reported.
Wit respect to PD-1, I don’t view them as a threat to EGFR inhibitors as I believe the vast majority of EGFR mutated cases will be treated with EGFR inhibitors, let alone patients with a documented T790M mutation. Combination of the two classes of drugs is very likely down the road (no overlapping toxicities).

Clovis: KOL Believes PFS Will Be Prolonged in Front-Line NSCLC Setting with CO-1686 vs. SOC; Could Drive Significant Use Even with Generic Tarceva The KOL on our recent TKI Pulse Call believes progression free survival (PFS) will be prolonged in the front-line (FL) setting with CO-1686 (1686, AZD-9291) vs. current standard of care (SOC – i.e., Tarceva) and this could drive significant use even in a long-term market (i.e., 2018-2020+) flooded with generic Tarceva. This KOL was more conservative in estimating a 1686 FL PFS benchmark of ~16-18 months driven by discounting of 1686’s superior safety profile vs. serious SOC associated toxicities experienced at most institutions.  
Positively leveraging a TKI re-sensitization effect by using 1686 FL could meaningfully prolong overall patient PFS through multiple therapies and provide an attractive and benign safety experience. For example, patients could experience ~16-month PFS benefit if they achieved a 10-month PFS benefit with FL Tarceva, along with ~80% rash at most centers, followed by a 6-month PFS with 1686 until they become resistant. Conversely, they could experience a meaningfully less toxic and prolonged PFS by receiving 1686 as the FL agent. In this example, if FL 1686 administration resulted in a 13-
month PFS (only marginally better than Tarceva) accompanied by a relatively benign safety profile, the patient could subsequently receive Chemo (possibly prolonging PFS) and then be re-challenged with 1686, with ~30% (commonly appreciated) of patients responding to retreatment driven by a potential TKI re-sensitization effect.

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First-In-Human Evaluation of CO-1686, an Irreversible, Highly Selective Tyrosine Kinase Inhibitor of Mutations of EGFR (Activating and T790M)
http://oncologypro.esmo.org/Meet ... ctivating-and-T790M
Aim

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.

Methods
This is an ongoing first-in-human dose finding study in patients with EGFR mutated recurrent, advanced NSCLC. All patients are previously treated with an EGFR TKI and must undergo tumor tissue biopsy within 28 days before study drug dosing for central EGFR genotyping. Oral CO-1686 is administered continuously in 21-day cycles. Endpoints include safety, pharmacokinetics (PK), and efficacy.

Results
As of 15th November 2013, 66 patients were treated with CO-1686; initially, 57 with CO-1686 free base, up to 900mg BID (N=19 dose expansion at 900 mg BID); then, following formulation optimization, 9 with CO-1686 HBr up to 750 mg BID). Dose escalation continues. 70% of patients are T790M+,14% are T790M unknown/pending, median age is 60 years, 80% are female, 80% are white, and 75% are ECOG 1. The median number of previous therapies was 3 (range: 1- 6); 45% had received > one line of EGFR TKI.

Treatment-related AEs (all grades) occurring in ≥20% patients were: nausea (21%) and fatigue (20%). The majority of all events were mild or moderate. Events typical of EGFR WT inhibition, in particular rash combined with diarrhea, have not been observed.

Nine T790M+ patients treated with 900 mg BID (free base) were evaluable for response; 6 (67%) achieved PRs, 2 (22%) achieved SD. One patient at a lower dose also achieved a PR. Eight of the 9 patients had progressed on an EGFR TKI immediately before initiating CO-1686.

Data for the cohorts receiving the optimized formulation are maturing and current data will be presented at the meeting.

Conclusions
CO-1686 has demonstrated good tolerability and promising efficacy against proven T790M+ EGFR mutant NSCLC. Dose-related WT-driven diarrhea and rash has not been seen. Dose escalation is continuing with CO-1686 HBr which has improved exposure and reduced PK variability.

http://abstracts.webges.com/elcc2014/myitinerary

Clovis Oncology (CLVS) announced today updated findings from the Phase 1 portion of its ongoing Phase 1/2 clinical study of CO-1686, the Company’s novel, oral, targeted covalent (irreversible) inhibitor of mutant forms of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer in patients with initial activating EGFR mutations as well as the dominant resistance mutation T790M. Interim results from the Phase 1 dose-escalation portion of this Phase 1/2 study are being presented today in an oral presentation by Dr. Heather Wakelee at the 4th European Lung Cancer Conference (ELCC) in Geneva.

“These data are completely consistent with what I have seen personally in my own patients,” said Professor Jean-Charles Soria, Professor of Medicine and Medical Oncology at Paris University XI and cancer specialist at Gustave Roussy Institute and the European lead investigator for the Phase 1/2 study of CO-1686. “CO-1686 provides meaningful and long-term benefit for patients who until now have had limited, if any, options. I am very enthusiastic about participating in the continued development of this agent.”

“One of the issues with oncogene-targeted therapies is that while initial response rates can be promising, these responses can be short-lived,” said Patrick J. Mahaffy, President and CEO of Clovis Oncology. “In contrast, as CO-1686 Phase 1 data extend and mature, we see both a consistency of response rate that is very encouraging as well as an impressive initial duration of clinical benefit. Patients in general benefit from, and stay on, CO-1686 for a prolonged period of time. We are also pleased that we can deliver this long-term benefit with very good tolerability. Given the observed durability of clinical benefit we are increasingly optimistic about the potential of CO-1686 not only to deliver impressive response rates, but also meaningful progression-free survival in both first- and second-line patients.”

The Phase 1 dose escalation portion of the study is being conducted in the United States, France and Australia in patients with metastatic or unresectable recurrent NSCLC and a documented EGFR mutation. Patients were not required to be T790M positive for the Phase 1 portion of the study but had to have progressed on prior EGFR-directed tyrosine kinase inhibitor (TKI) therapy (prior chemotherapy was also allowed).

Approximately one hundred patients have been treated with CO-1686 to date across all dosing cohorts in the Phase 1 portion of the trial. Emerging data from the first 62 patients treated with CO-1686 at efficacious doses (comprising patients treated with 900mg BID of freebase or any dose of the hydrobromide salt (HBr) formulation) were presented today at ELCC. Of these 62 patients, 22 are centrally-confirmed T790M positive, 12 are centrally-confirmed T790M negative, seven have as yet unknown T790M status and the remaining are non-evaluable, primarily because they have not yet had their first scan.

Patients on study were heavily pretreated prior to receiving CO-1686; 73 percent of patients across all doses had immediately progressed on TKI therapy prior to CO-1686 treatment. The median number of previous lines of therapy across patients at all doses was three; the median number of previous TKI lines was two.

Evidence of Activity

In the 22 evaluable T790M positive patients across efficacious dose levels, 14 RECIST partial responses (PRs) have been observed to date, for a 64 percent objective response rate (ORR). Ten of the 14 patients (71 percent) started CO-1686 therapy immediately following progression on a prior TKI. Twenty of the 22 evaluable T790M positive patients, or 91 percent, have experienced stable disease or a PR.

In a broader population of 29 evaluable T790M positive and T790M currently unknown patients, 15 RECIST PRs have been observed to date, for a 52 percent response rate. Twenty-six of the 29 evaluable 790M positive and T790M currently unknown patients, or 90 percent, have experienced stable disease or a PR. These data will be updated if and as the T790M status of the unconfirmed patients are centrally determined.

The median duration of response cannot yet be estimated in the T790M positive patients. However, PFS greater than six months has been observed in evaluable T790M positive heavily-pretreated patients and the median has not yet been reached. In contrast, PFS in T790M negative patients is shorter, with a median of three months.

Five of nine evaluable patients, or 56 percent, dosed initially with 900mg BID of freebase and now on the HBr formulation remain on drug with continuing PRs, and 35 of the 43 total patients dosed with the HBr formulation, or 81 percent, remain on drug.

Safety and Tolerability

CO-1686 is well-tolerated, with only one patient who discontinued treatment with CO-1686 due to adverse events. There was no evidence of systemic wild-type EGFR inhibition. The most common adverse events were hyperglycemia, nausea, diarrhea, decreased appetite and vomiting, and these were mostly grade 1 in severity. The most common grade 3 adverse event was hyperglycemia, which was observed in 19 percent of patients. Hyperglycemia, when observed and requiring treatment, is typically asymptomatic and managed with a commonly prescribed single oral agent.

Presentation Details

The presentation, titled “Phase 1 evaluation of CO-1686, an irreversible, mutant-selective inhibitor of EGFR mutations (activating and T790M)”, was presented on Thursday, March 27, during the session titled “Advanced Disease with Targeted Agents” from 9:00 -10:30am.

马哥哥,能开下门吗?

ELCC 2014 News: Phase I Study of CO-1686 in Patients with EGFR Mutated Recurrent, Advanced NSCLC

Evaluation of an irreversible, mutant-selective inhibitor of EGFR mutations

Date: 27 Mar 2014
Topic: Lung and other thoracic tumours / Anticancer agents & Biologic therapy
CO-1686 has demonstrated a good tolerability and promising efficacy against T790M+ epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC). It spares wild-type (wt) EGFR signalling in an early study, according to presentation of Dr Heather Wakelee of Thoracic Oncology Unit, Stanford University, USA. The findings were reported in a proffered papers session at 4th European Lung Cancer Conference (26-29 March 2014, Geneva, Switzerland).

Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients. In addition, skin rash and diarrhoea are significant problems caused by wt-EGFR inhibition. CO-1686 is a novel, oral, selective, covalent TKI that targets common activating EGFR mutations and T790M, while sparing wt-EGFR.

Phase I Study with CO-1686


Response rate above 50% observed even when patients with T790M-unknown status (for whom central testing results are awaited) are included in the analysis.
© Heather Wakelee

Dr Wakelee reported that the phase I part of phase I/II study in EGFR-mutated advanced NSCLC patients has been recently completed. The study initiated with free-base formulation and early data were presented at the 2013 World Conference on Lung Cancer. However, superior hydrobromide (HBr) salt tablet form of CO-1686 was adopted in August 2013. All free-base recipients are still on study and converted to HBr in the fall of 2013. Expansion cohorts are now comparing 500mg, 750mg and 1000mg HBr twice daily. The study is designed to support potential accelerated approval in USA.

Patients with EGFR mutated recurrent, advanced NSCLC previously treated with an EGFR TKI were enrolled. Tumour tissue biopsy was mandatory within 28 days before study drug dosing. EGFR genotyping was centrally performed. CO-1686 is administered orally, in continuous 21-day cycles.

Phase I patient characteristics indicate that approximately 75% come directly off of TKI with progressive TKI resistance. Median number of previous TKI lines is two. In total, 62 patients are included with a mean age of 59 years. Females comprise 77% of study population and Asian patients, 16%. ECOG performance status 0 was recorded in 27% of patients.

Tolerability and Efficacy

CO-1686 is very well tolerated with hyperglycaemia (grade 3 in 19%) which is typically asymptomatic and managed with a single oral agent. Etiology of hyperglycaemia is currently unknown. Other toxicities observed: nausea, diarrhoea, decreased appetite, vomiting, fatigue and myalgia were mild in most cases. Percentage of diarrhoea and rash indicate no wild-type EGFR inhibition and the compound represents truly third-generation of EGFR TKIs. QTC prolongation grade 3 was observed in 5% of patients and resolved in most cases upon dose reduction. However, only one patient has discontinued drug due to adverse events.


Durable benefit with median progression-free survival that exceeds 6 months in T790M+ patients.
© Heather Wakelee

efficacy, it is indicative that responses deepen over time. HBr shows consistent clinical benefit; the data with HBr are evolving with >80% of patients being still on drug. Efficacy is clear across dose levels in centrally-confirmed T790M+ patients with overall response rate of 64%. Response rate remains above 50% even when patients with currently T790M-unknown status are included. Median progression-free survival exceeds six months in T790M+ patients.

Dr Wakelee reported the phase II/III registration trials are planned to enrol the patients this year. TIGER1 is a phase II/III study in newly diagnosed EGFR-mutated NSCLC, that foreseen 1:1 randomisation for CO-1686 and erlotinib; primary endpoint is progression-free survival. TIGER2 is a phase II study planned for patients progressing upon first and only TKI treatment and biopsy-proven T790M+ disease; primary endpoint is overall response rate. TIGER3 is a phase III study in patients who progress upon doublet chemotherapy or TKI in T790M+ and T790M- setting. Randomisation is foreseen to CO-1686 versus chemotherapy. TIGER4 is a phase II study in plasma T790M+ setting and patient population like in the TIGER2 trial.  

Dr Wakelle concluded that CO-1686 is a novel, oral, selective, covalent inhibitor of EGFR mutant NSCLC that inhibits key activating and T790M resistance mutations. It spares wild-type EGFR signalling and is generally well-tolerated. Promising activity is seen across all dose levels with durable benefit.

Dr Tony Mok, who discussed the study results, compared CO1686 characteristics as a third generation TKI inhibitor with characteristics of first generation TKIs (gefitinib and erlotinib) and second generation TKIs (afatinib, dacomitinib). He characterised the response rate observed with CO1686 as impressive, and emphasised the need to develop T790M as a companion biomarker. As unanswered questions, he wonders if CO1686 works in T790M negative tumours and if yes, why. He also asked if a T790M EGFR TKI should be used as first line treatment for patients with only sensitising EFGR mutation.

Reference

Abstract 93O: First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M).