- |||||||||| zongertinib (BI 1810631) / Boehringer Ingelheim
Zongertinib demonstrates potent efficacy against cancer cells harboring HER2 non-tyrosine kinase domain mutations (Section 35; Poster Board No: 26) - Mar 25, 2025 - Abstract #AACR2025AACR_8999;
Consistent with our results obtained using Ba/F3 models, HCC4006 HER2 V659E cells were sensitive to HER2 inhibition with zongertinib. Our findings indicate that zongertinib demonstrates comparable or more potent inhibitory activity for HER2 non-TKD mutants (e.g TMD and JMD) as HER2 TKD mutations, providing a potential therapeutic option for patients with these HER2 non-TKD mutant cancers.
- |||||||||| Pozenveo (poziotinib) / Assertio
Journal: The Brain-Penetrant Pan ErbB Inhibitor Poziotinib Effectively Targets HER2+ Breast Cancer Brain Metastases. (Pubmed Central) - Feb 11, 2025
Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with trastuzumab and HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM)...The clinical receptor tyrosine kinase inhibitor (RTKi) lapatinib blocked phosphorylation of all ErbB receptors (ErbB1-4) and induced the intrinsic apoptosis pathway in BCBM94...Two weeks of poziotinib treatment successfully ablated BCBM94 and BT474 HER2+ brain tumors in vivo. In conclusion, this study established a patient-derived HER2+ BCBM model and identified poziotinib as highly efficacious RTKi with excellent brain penetrability that eliminated HER2+ BCBM.
- |||||||||| Pozenveo (poziotinib) / Assertio, Exkivity (mobocertinib) / Takeda, Rybrevant (amivantamab-vmjw) / J&J
Journal, EGFR exon 20: Resistance mechanisms of EGFR tyrosine kinase inhibitors, in EGFR exon 20 insertion-mutant lung cancer. (Pubmed Central) - Aug 10, 2024
However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants. Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC.
- |||||||||| Krazati (adagrasib) / BMS, Pozenveo (poziotinib) / Assertio, Lumakras (sotorasib) / Amgen
Pan-HER Inhibition Overcomes Feedback Adaptation Resistance to KRAS G12C Inhibition in KRAS G12C Mutant Non-Small Cell Lung Cancer (Grace Murray Hopper Auditorium, Yale West Campus Conference Center) - Jun 23, 2024 - Abstract #LUNGSPORE2024LUNG_SPORE_66;
KRAS G12C inhibitors sotorasib and adagrasib are FDA approved for advanced/metastatic KRAS G12C-positive NSCLC, although the duration of benefit from these drugs is relatively modest and therapeutic resistance typically emerges relatively quickly to these drugs...We observed that in combination with KRAS G12C inhibitors pan-HER TKIs such as poziotinib yielded a synergistic effect compared to HER2 TKI treatment...The combination of pan-HER TKIs with KRAS G12C inhibitor suppressed tumor growth significantly as compared to KRAS G12C inhibitor alone with a tolerable toxicity profile in KRAS G12C mutant patients derived xenograft models. Collectively, our findings indicate that the adaptive feedback activation of HER family members, including not only EGFR but also HER2 and HER3, diminishes the efficacy of KRAS G12C inhibitors against KRAS G12C-positive NSCLC tumor cells, and that the combination of pan-HER TKIs with KRAS G12C inhibitors may be more effective than KRAS G12C inhibitors alone.
- |||||||||| Enhertu (fam-trastuzumab deruxtecan-nxki) / Daiichi Sankyo, AstraZeneca
Trastuzumab Deruxtecan Resistance can be Mediated by Payload Resistance or Secondary Extracellular ERBB2 Mutations but Sensitivity to HER2 Tyrosine Kinase Inhibitors is Maintained (Grace Murray Hopper Auditorium, Yale West Campus Conference Center) - Jun 23, 2024 - Abstract #LUNGSPORE2024LUNG_SPORE_65;
T-DXd resistant cell lines were sensitive to payloads with alternate mechanisms of action including maytansine and likewise retained sensitivity to the HER2 ADC trastuzumab emtansine (T-DM1) which utilizes DM1 as a payload...T-DXd resistant cells remained highly sensitive to HER2 TKIs including poziotinib, afatinib, and zongertinib...Moreover, resistance to trastuzumab-based ADCs can also be mediated by secondary mutations within domain IV of HER2 or loss of the extracellular terminal of HER2. However, these alterations do not diminish HER2 TKI activity.
- |||||||||| Review, Journal, EGFR exon 20: Targeted Therapies for EGFR Exon 20 Insertion Mutation in Non-Small-Cell Lung Cancer. (Pubmed Central) - Jun 19, 2024
Despite these advances, challenges in overcoming resistance mutations and improving central nervous system penetration remain. Future research should focus on optimizing first-line combination therapies and enhancing diagnostic strategies for comprehensive mutation profiling.
- |||||||||| Pozenveo (poziotinib) / Assertio
Trial completion date, Trial primary completion date, EGFR exon 20, HER2 exon 20, Metastases: NCI-2017-00831: Poziotinib in EGFR Exon 20 Mutant Advanced NSCLC (clinicaltrials.gov) - May 23, 2024
P2, N=93, Active, not recruiting,
The accurate classification and analysis of drug responsiveness in EGFR E20ins necessitate consideration of the nomenclature, particularly with respect to the locations where the actual mutations occur. Trial completion date: Sep 2024 --> Dec 2025 | Trial primary completion date: Sep 2024 --> Dec 2025
- |||||||||| Pozenveo (poziotinib) / Assertio, Enhertu (fam-trastuzumab deruxtecan-nxki) / Daiichi Sankyo, AstraZeneca, Perjeta (pertuzumab) / Roche
HER2 TKIs enhance the anti-tumor activity of HER2-targeting CAR-T and CAR-NK cells against NSCLC (Section 2) - Mar 5, 2024 - Abstract #AACR2024AACR_6967;
Current HER2-targeting approaches, including antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan, have shown promising response rates...We engineered a series of HER2 CAR constructs utilizing scFvs derived from trastuzumab, pertuzumab, and FRP5, recognizing distinct domains of HER2...Using a HER2 YVMA duplication patient-derived xenograft (PDX) NSCLC model, we observed that the in vivo combination of poziotinib with HER2 CAR-NK cells exhibited superior anti-tumor activity as compared to poziotinib treatment alone. In conclusion, HER2 CAR-T and CAR-NK cells effectively target HER2-mutant and HER2-positive NSCLC, and their combination with HER2 TKIs enhances vulnerability to HER2-targeting strategies.
- |||||||||| EGFR and mTOR signaling facilitate RET-independent resistance to selective RET-TKIs (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_4117;
To determine whether EGFR or MET signaling facilitate RET inhibitor resistance, LC-2/ad and NCCE-TH1101 (KIF5B-RET) NSCLC cells were treated with increasing concentrations of selpercatinib or pralsetinib with or without ligands for these receptors, EGF or HGF respectively, and after five days cell viability was measured by CellTiter Glo...Next, to evaluate whether blockade of EGFR or MET signaling could enhance the activity of RET inhibitors, we treated LC-2/ad and NCCE-TH1101 cells with RET TKIs alone or in combination with the EGFR TKI erlotinib or poziotinib, or the MET inhibitor SU11274...We observed that treatment of LC-2/ad and NCCE-TH1101 cells with an mTOR inhibitor (everolimus) or a MEK inhibitor (trametinib) in combination with RET TKIs increased the anti-tumor activity or RET inhibitors...RET TKI resistant cells were sensitive to mTOR or MEK inhibitors in combination with RET TKIs. Collectively, our findings indicate that in RET-fusion positive NSCLC tumor cells, activation of bypass pathways including the EGFR, MAPK, mTOR pathways may facilitate RET inhibitor resistance and that blockade of bypass pathways may enhance the efficacy of selective RET inhibitors and overcome acquired RET TKI resistance.
- |||||||||| Pozenveo (poziotinib) / Assertio
Trial completion date, Trial termination, EGFR exon 20, HER2 exon 20, Metastases: ZENITH20: Phase 2 Study of Poziotinib in Participants With NSCLC Having EGFR or HER2 Exon 20 Insertion Mutation (clinicaltrials.gov) - Jan 25, 2024
P2, N=648, Terminated,
Collectively, our findings indicate that in RET-fusion positive NSCLC tumor cells, activation of bypass pathways including the EGFR, MAPK, mTOR pathways may facilitate RET inhibitor resistance and that blockade of bypass pathways may enhance the efficacy of selective RET inhibitors and overcome acquired RET TKI resistance. Trial completion date: Dec 2023 --> Apr 2023 | Active, not recruiting --> Terminated; Strategic business decision (unrelated to safety)
- |||||||||| Journal, EGFR exon 20: The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors. (Pubmed Central) - Jan 17, 2024
This report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance-robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance.
- |||||||||| Pozenveo (poziotinib) / Spectrum Pharma, Luye Group, foretinib (GSK1363089) / Exelixis, pexmetinib (ARRY-614) / Pfizer
Preclinical, Journal, IO biomarker: Screening of potent RIPK3 inhibitors to attenuate necroptosis and inflammation in mouse traumatic brain injury models. (Pubmed Central) - Jan 3, 2024
In our study, we explored the role of NBCs in neuroprotection after traumatic brain injury. It's effectiveness in traumatic brain injury animal models and favorable safety profiles make it a potential candidate for the advances of new therapies for necroptosis-associated neuroinflammatory disorders.
- |||||||||| Review, Journal: Management of Brain Metastases: A Review of Novel Therapies. (Pubmed Central) - Nov 28, 2023
Novel systemic therapies with intracranial utility include new anaplastic lymphoma kinase inhibitors like brigatinib and ensartinib; selective "rearranged during transfection" inhibitors like selpercatinib and pralsetinib; B-raf proto-oncogene inhibitors like encorafenib and vemurafenib; Kirsten rat sarcoma viral oncogene inhibitors like sotorasib and adagrasib; ROS1 gene rearrangement (ROS1) inhibitors, anti-neurotrophic tyrosine receptor kinase agents like larotrectinib and entrectinib; anti-human epidermal growth factor receptor 2/epidermal growth factor receptor exon 20 agent like poziotinib; and antibody-drug conjugates like trastuzumab-emtansine and trastuzumab-deruxtecan. This review highlights the modern multidisciplinary management of BM, emphasizing the integration of systemic and local therapies.
- |||||||||| Pozenveo (poziotinib) / Spectrum Pharma, Luye Group, Nerlynx (neratinib) / Puma, Knight Therap, Pierre Fabre
Journal: The uncharted role of HER2 mutant alleles in breast cancer. (Pubmed Central) - Nov 5, 2023
Herein, we discuss the under-explored effects of individual HER2 mutant alleles on therapeutic response, a role for HER2 mutation in metastatic propensity, and differences in patient outcomes in ER+ invasive lobular carcinoma (ILC) versus invasive ductal carcinoma (IDC). The preclinical efficacy of additional agents is also discussed, particularly the pan-HER inhibitor poziotinib.
- |||||||||| Exkivity (mobocertinib) / Takeda, Rybrevant (amivantamab-vmjw) / Genmab, J&J, Tagrisso (osimertinib) / AstraZeneca
Adding Amivantamab as a Salvage Strategy Post EGFR TKI (Osimertinib/Mobocertinib) in EGFRm+ NSCLC (Exhibit Hall) - Aug 16, 2023 - Abstract #IASLCWCLC2023IASLC_WCLC_2593;
Incorporating amivantamab to prior EGFR TKI treatment appears to be a feasible option, although osimertinib stands out as the most well-tolerated TKI with clinical efficacy. Further studies should aim to identify patient subgroups and confirm these findings through prospective analysis.
- |||||||||| Irene (pyrotinib) / Jiangsu Hengrui Pharma
Journal: Treatment of Non-Small Cell Lung Cancer with HER2 Alterations (Pubmed Central) - Jul 31, 2023
There have been few effective treatments for NSCLC with HER2 alterations, but in recent years, TKIs such as pyrotinib and poziotinib, and ADCs such as trastuzumab-deruxtecan(T-Dxd)have shown meaningful anti-tumor efficacy. In particular, T-Dxd received FDA approval in August 2022 for NSCLC patients with certain types of mutations in HER2 gene, and is expected to provide new treatment options in the future.
- |||||||||| Pozenveo (poziotinib) / Spectrum Pharma, Luye Group
Efficacy of poziotinib in HER2 exon 20 insertion NSCLC patients who received prior platinum-based and HER2 targeted therapies () - Jul 27, 2023 - Abstract #ESMO2023ESMO_2882;
P2
Of these, 35 patients (25 16 mg QD; 10 8 mg BID) had prior HER2 therapy such as trastuzumab, TDM1, and T-DXd...ORRs were 30% with PLT+any systemic therapy; 30% with PLT+docetaxel and 43% with PLT+TKI...Conclusions Poziotinib demonstrated clinically meaningful efficacy in patients who received prior 2+ lines of therapy including HER2 therapy. ZENITH20 study provides a large dataset in the 3rd or later line setting of HER2 exon 20 mutations in NSCLC who have very limited treatment options.
- |||||||||| Exkivity (mobocertinib) / Takeda, Tagrisso (osimertinib) / AstraZeneca
Amivantimab as a salvage strategy post TKI (osimertinib/mobocertinib) in EGFRm NSCLC () - Jul 27, 2023 - Abstract #ESMO2023ESMO_2836;
Conclusions Incorporating amivantamab to prior EGFR TKI treatment appears to be a feasible option, although osimertinib stands out as the most well-tolerated TKI with clinical efficacy. Further studies should aim to identify patient subgroups and confirm these findings through prospective analysis.
- |||||||||| Pozenveo (poziotinib) / Assertio
Enrollment change, Trial completion date, Trial termination, Trial primary completion date, HER2 exon 20, Metastases: Study of Poziotinib in Japanese Patients With NSCLC (clinicaltrials.gov) - Jul 14, 2023
P1/2, N=42, Terminated,
No new safety signal was detected in this patient population. N=76 --> 42 | Trial completion date: Mar 2025 --> May 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Feb 2023; Business decision, not related to safety.
- |||||||||| Pozenveo (poziotinib) / Spectrum Pharma, Luye Group, Exkivity (mobocertinib) / Takeda, Nerlynx (neratinib) / Puma, Knight Therap, Pierre Fabre
Journal: Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in breast cancer. (Pubmed Central) - Jul 5, 2023
Double-mutant cells showed enhanced MEK/ERK signaling, which was blocked by combined inhibition of HER2 and MEK. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer.
- |||||||||| Pozenveo (poziotinib) / Assertio
Enrollment change, Trial completion date, Trial termination, Trial primary completion date: A Study to Allow Continued Dosing and/or Follow-up of Patients Who Have Had Previous Exposure to Poziotinib (clinicaltrials.gov) - May 25, 2023
P2, N=7, Terminated,
Comparative studies with more extensive patient follow-up, larger sample size and better design are needed to reliably quantify the effect of these drugs. N=20 --> 7 | Trial completion date: Apr 2026 --> Mar 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Oct 2023 --> Mar 2023; Business reasons, not related to safety.
- |||||||||| Pozenveo (poziotinib) / Assertio
Trial completion date, Trial primary completion date, EGFR exon 20, HER2 exon 20, Metastases: NCI-2017-00831: Poziotinib in EGFR Exon 20 Mutant Advanced NSCLC (clinicaltrials.gov) - Apr 5, 2023
P2, N=116, Active, not recruiting,
Thus, particular attention should be paid when poziotinib is taken together with Schisandrins in clinical practice. Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024
- |||||||||| Pozenveo (poziotinib) / Spectrum Pharma, Luye Group
P2 data, Journal, HER2 exon 20: Poziotinib in Treatment-Na (Pubmed Central) - Mar 25, 2023
Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024 Poziotinib demonstrated clinically meaningful efficacy with a manageable toxicity profile for treatment-na
- |||||||||| Role of individual HER family members and pan-HER targeting treatment strategy in NRG1 fusion positive cancer (Section 21; Poster Board #16) - Mar 14, 2023 - Abstract #AACR2023AACR_6231;
Treatment with cetuximab, an antibody that targets EGFR, in combination with trastuzumab and pertuzumab yielded a synergistic effect on tumor cell killing. These data indicate that HER4 and EGFR can play a role in NRG1 fusion-driven signaling through crosstalk with HER2/HER3 and thus, pan-HER/EGFR inhibitors are more effective than EGFR/HER2 or HER2/HER4-selective inhibitors, highlighting the therapeutic potential of targeting multiple members of the HER family in NRG1 fusion driven cancers.
- |||||||||| TAS2940 / Otsuka
TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models (Section 20; Poster Board #14) - Mar 14, 2023 - Abstract #AACR2023AACR_6207;
P1
Here, we demonstrate that TAS2940 induces downregulation of phosphorylated HER2/EGFR, reduces tumor burden, and promotes a significant increase in survival in intracranial xenograft mouse models with HER2-amplification (BC), HER2-Exon20 insertion mutation (NSCLC), and EGFR-amplification (GBM). These promising preclinical data highlight potential novel therapeutic strategies for patients with EGFR-aberrant GBM and brain metastases harboring HER2/EGFR alterations, and may help support the advancement of the ongoing first-in-human clinical trial (NCT04982926) for TAS2940 in solid tumors with EGFR and/or HER2 alterations.
- |||||||||| Biochemical inhibition profiles of 370 wild type human kinases provide a basis for selecting alternative combinations of EGFR and VEGFR inhibitors (Section 14; Poster Board #1) - Mar 14, 2023 - Abstract #AACR2023AACR_4887;
Kinase inhibition profiles were measured for 7 agents that were candidate alternatives for cediranib or erlotinib, including: vandetanib, erdafitinib, axitinib, lenvatinib, cabozantinib, poziotinib, and mobocertinib (note: Cmax values varied 58-fold among the drugs)...This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I.
- |||||||||| Pozenveo (poziotinib) / Spectrum Pharma, Luye Group, Tagrisso (osimertinib) / AstraZeneca
CD70-targeting CAR-T and CAR-NK cells demonstrate potent activity against NSCLC drug-tolerant persister cells (Section 37; Poster Board #6) - Mar 14, 2023 - Abstract #AACR2023AACR_2272;
Furthermore, we determined that CD70-targeting CAR-T and CAR-NK cells showed promising in vitro activity against the DTPCs of osimertinib-treated EGFR mutant NSCLC. These results demonstrate CAR-based cellular therapy as an effective approach to target DTPCs and identify CD70 as a novel therapeutic target for combatting DTPCs in NSCLC.
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