Phase 1/2 Open Label Study Of Pf 06459988 (Epidermal Growth Factor Receptor T790m Inhibitor) In Patients With Advanced Epidermal Growth Factor Receptor Mutant (Del 19 Or L858r + - T790m) Non Small Cell Lung Cancer

Phase 1 - open label, multi-center, non-randomized, safety, pharmacokinetic and pharmacodynamics dose escalation study of PF-06459988 as a single agent in patients with advance EGFRm NSCLC (del 19, L858R, +/- T790M). The resulting PF-06459988 dose selected from the phase 1 portion will undergo a series of sub-studies to fully characterize the impact of food, antacid and CYP3A4 inhibitors/inducers. The PK studies are in addition to the MTD expansion and will be completed prior to the initiation of Phase 2. Phase 2 is an open label, multi-center single-arm study of PF-06459988 for the assessment of antitumor activity in patients with advanced EGFRm (del 19 or L858R) NSCLC with T790M.

Start Date01 Jan 2015

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with PF-06459988

100 Translational Medicine associated with PF-06459988

100 Patents (Medical) associated with PF-06459988

Literatures (Medical) associated with PF-06459988

13 Apr 2017·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR

Q1 · MEDICINE

Article

Author: Zhang, Chengyi ; Wang, Yuli ; Bernier, Louise ; Planken, Simon ; Almaden, Chau ; Dinh, Dac M. ; Behenna, Douglas C. ; Sach, Neal W. ; Zientek, Michael ; Vicini, Paolo ; Ballard, T. Eric ; Deal, Judith G. ; Ferre, Rose Ann ; Dalvie, Deepak ; Tseng, Elaine ; Nair, Sajiv K. ; Kania, Robert S. ; Tran, Khanh ; Zhou, Ru ; Shen, Hong ; Cho-Schultz, Sujin ; Nagata, Asako ; Orr, Suvi T. M. ; Liu, Longqing ; Matthews, Jean ; Niessen, Sherry ; Shi, Manli ; Weinrich, Scott L. ; Solowiej, James ; Luo, Yiqin ; Kath, John C. ; Edwards, Martin P. ; Gajiwala, Ketan S. ; Johnson, Theodore O. ; Bailey, Simon ; Cheng, Hengmiao ; Murray, Brion W. ; Hemkens, Michelle ; Pairish, Mason ; Xin, Shuibo ; Lafontaine, Jennifer

Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.

10 Mar 2016·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants

Q1 · MEDICINE

Article

Author: Sach, Neal ; Planken, Simon ; Hemkens, Michelle D. ; Smeal, Tod ; Behenna, Doug ; Gajiwala, Ketan S. ; Solowiej, Jim ; Wang, Shuiwang ; Kephart, Susan ; Richter, Daniel ; Liu, Zhengyu ; Cho-Schultz, Sujin ; Ryan, Kevin ; Bailey, Simon ; Niessen, Sherry ; Xu, Haiwei ; Weinrich, Scott L. ; Kania, Robert S. ; Feng, Jun Li ; Ren, Shijian ; Cheng, Hengmiao ; Orr, Suvi T. M. ; Liu, Kevin K.-C. ; Jackson-Fisher, Amy ; Nair, Sajiv K. ; Nagata, Asako ; Lafontaine, Jennifer ; Kath, John C. ; Lunney, Beth ; Zientek, Michael ; Pairish, Mason ; Yin, Min-Jean ; Sutton, Scott ; Ornelas, Martha A. ; Almaden, Chau ; Murray, Brion W. ; Jalaie, Mehran ; Baxi, Sangita ; Tseng, Elaine ; Johnson, Ted O. ; Shen, Hong ; Vernier, William ; Walls, Marlena ; Xin, Shuibo ; Dinh, Dac M. ; Zhou, Ru ; Ferre, Rose Ann ; Tran, Khanh ; Matthews, Jean ; Dalvie, Deepak ; Edwards, Martin P.

First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.

100 Deals associated with PF-06459988

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Indication	Highest Phase	Country/Location	Organization	Date
EGFR-mutated non-small Cell Lung Cancer	Phase 2	-	Pfizer Inc.	01 Jan 2015

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