mavelertinib (PF-06747775) / Pfizer - LARVOL DELTA

Next-generation NSCLC drug development powered by PDCs and PDOs: Mimicking real responses (AACR 2025) - "The models response to afatinib sensitively. Another example is YUO-143, which harbors EGFR mutations E19del/T790M/C797S and was derived from a patient resistant to gefitinib and mavelertinib. YUO-143 was used in the development of the 4th gen TKI, BLU-945, and showed an IC50 of 43 nM.Conclusions : Patient-derived models could serve as a crucial tool in developing novel therapeutic strategies and next-generation drugs for NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • CD74 • EML4 • KRAS • MET • ROS1

Patient-derived cells (PDCs) and organoids (PDOs) as critical platforms for developing next therapeutic strategies for NSCLC (AACR 2024) - "IC50 of YUO-139 and YU-1092 to afatinib were 2.1 nM and 23.8 nM respectively. YUO-143 is a PDO model that harbors EGFR E19del/T790M/C797S which was derived from gefitinib and mavelertinib resistant patient revealed sensitivity to BLU-945 (IC50, 43 nM), a novel fourth-generation EGFR-TKI.Conclusions : Patient derived models could be a critical tool for developing therapeutic strategies for NSCLC."

Clinical • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • MET

First-in-human phase I study of PF-06747775, a third-generation mutant selective EGFR tyrosine kinase inhibitor (TKI) in metastatic EGFR mutant NSCLC after progression on a first-line EGFR TKI (ESMO 2017) - P1/2; "PF-7775 is well tolerated at 200 mg dose in EGFRm+ NSCLC pts with acquired resistance to first-line EGFR-TKIs. Data relating mutational status to response rate in plasma is ongoing."

P1 data • Retrospective data • Non Small Cell Lung Cancer

Repurposing the Kinase Inhibitor Mavelertinib for Giardiasis Therapy. (PubMed, Antimicrob Agents Chemother) - "Mavelertinib, dosed as low as 5 mg/kg of body weight or as high as 50 mg/kg, was efficacious in the acute murine Giardia infection model. These results suggest that mavelertinib merits consideration for repurposing and advancement to giardiasis clinical trials while its analogues are further developed."

Journal • Infectious Disease • EGFR

A phase 1b/2 study of PF-06747775 as monotherapy or in combination with Palbociclib in patients with epidermal growth factor receptor mutant advanced non-small cell lung cancer. (PubMed, Expert Opin Investig Drugs) - P1/2 | "Median progression-free survival (90% CI) was 8.1 (5.4-23.3) months. PF-06747775 had a manageable safety profile and the study design highlights important considerations for future anti-EGFR agent development."

Combination therapy • Journal • Monotherapy • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) (clinicaltrials.gov) - P1/2; N=65; Terminated; Sponsor: Pfizer; Phase classification: P2 ➔ P1/2

Clinical • Phase classification • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands. (PubMed, ACS Med Chem Lett) - "Here, we present the first complex crystal structures of mutant EGFR in complex with third-generation inhibitors such as osimertinib and mavelertinib in the presence of simultaneously bound allosteric inhibitors. These structures highlight the possibility of further combinations targeting EGFR and lay the foundation for hybrid inhibitors as next-generation TKIs."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) (clinicaltrials.gov) - P2; N=65; Terminated; Sponsor: Pfizer; Completed ➔ Terminated; The study was ended for strategic reasons and changes in the external environment. The safety profile and risk benefit ratio for PF-0674775 remained unchanged.

Clinical • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) (clinicaltrials.gov) - P2; N=65; Completed; Sponsor: Pfizer; Active, not recruiting ➔ Completed

Clinical • Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) (clinicaltrials.gov) - P1/2; N=60; Not yet recruiting; Sponsor: Pfizer

Clinical • New P1/2 trial

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) (clinicaltrials.gov) - P2; N=65; Active, not recruiting; Sponsor: Pfizer; Trial primary completion date: Jan 2019 ➔ Feb 2020

Clinical • Trial primary completion date

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer. (PubMed, Cancer Res) - "The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance...Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010...Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance."

Journal • Review

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) (clinicaltrials.gov) - P2; N=65; Active, not recruiting; Sponsor: Pfizer; Trial primary completion date: Dec 2019 ➔ Jan 2019

Clinical • PD(L)-1 Biomarker • Trial primary completion date

Identification of a lung adenocarcinoma cell line addicted to ERBB4, an actionable target for cancer therapy (AACR 2019) - "...These activated kinases would be an ideal target for cancer therapy and indeed imatinib and gefitinib displayed good clinical benefits to the patients in these diseases...Of note, we found four of the cells responding to a series of EGFR family tyrosine kinase inhibitors (TKIs) including gefitinib and lapatinib...Consistent with this observation, in vitro kinase assay revealed that sapitinib and PF-7775 exhibited ~10-fold higher ERBB4-inhibitory effect than gefitinib did while GW583340 displayed selective inhibition on ERBB4, with ~10-fold higher activity than that on activated EGFR. In conclusion, we identified NCI-H522 as an ERBB4-dependent cell line, and found ERBB4 as a novel therapeutic cancer target that could be attacked by ERBB4-directing TKIs."

Preclinical