Pozenveo (poziotinib) / Hanmi, Luye Group, Assertio - LARVOL DELTA

Poziotinib for EGFR exon 20-insertion NSCLC: Clinical efficacy of the phase 2 ZENITH trial and differential impact of EGFR exon 20 insertion location on sensitivity. (PubMed, Nat Commun) - P1/2, P2 | "In vitro studies show that afatinib, poziotinib, and zipalertinib more potently inhibited near-loop than far-loop insertions, whereas mobocertinib has similar IC50 in both groups. In comparison, in the previously published EXCLAIM trial (NCT02716116), mobocertinib demonstrates similar activities across both groups in tumor size reduction (-38.5% vs. -34.1%, p = 0.59) and PFS (12.0 vs. 13.0 months, p = 0.99). Therefore, EGFRex20ins location differentially impacts the sensitivity of TKIs."

Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Zongertinib Has Activity Against NRG1 Fusion Positive Tumor Cells (IASLC-WCLC 2025) - "Likewise, pan-HER family TKIs, poziotinib and afatinib, showed activity against NRG1 fusion-positive cells that expressed EGFR. This preclinical activity is consistent with the clinical responses in NRG1 fusions previously reported in the phase 1A of zongertinib. Conclusions : Our findings indicate that zongertinib is a promising therapeutic approach for patients with NRG1 fusion-positive malignancies, particularly those expressing HER2 and HER3."

Tumor cell • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ERBB3 • HER-2 • NRG1 • SLC3A2

Preferential Sensitivity of the EGFR L858M/L861R Mutation to Second-Generation EGFR Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer. (PubMed, Cancer Res Treat) - "Compared to other mutations, cells expressing EGFR L858M/L861R mutation were less sensitive to first-generation EGFR TKIs (gefitinib, erlotinib) and third-generation EGFR TKIs (osimertinib, lazertinib), whereas second-generation EGFR TKIs (afatinib, poziotinib) demonstrated potent inhibitory effects. The EGFR L858M/L861R mutation drives strong oncogenic signaling and exhibits preferential sensitivity to second-generation EGFR TKIs. These findings underscore the importance of accurate molecular diagnosis for guiding effective, personalized therapeutic strategies in NSCLC."

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

Targeted Therapy in HER2 Exon 20-Mutant Non-small Cell Lung Cancer With Leptomeningeal Disease: A Case-Based Approach to Treatment Decision-Making. (PubMed, Cureus) - "In the absence of LMD-specific therapeutic guidelines for HER2-driven NSCLC, treatment was initiated with trastuzumab deruxtecan (Enhertu), based on extrapolated evidence from clinical trials in systemic NSCLC and HER2-positive breast cancer with central nervous system involvement. Other options such as poziotinib and zongertinib were considered but not pursued. This case underscores the urgent need for inclusive clinical trials addressing CNS complications in molecularly defined NSCLC and demonstrates the real-world application of precision oncology beyond trial populations."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

Efficacy of zipalertinib in NSCLC patients with EGFR exon 20 insertion mutations who received prior platinum-based chemotherapy with or without amivantamab. (ASCO 2025) - P1/2 | "Of the 51 pts with prior ami, 30 had no other ex20ins-directed therapy, while 21 had also received other ex20ins drugs (such as mobocertinib, sunvozertinib, BLU-451, or poziotinib), the cORR was 30.0% and 14.3%, respectively. Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in pts with exon20ins NSCLC who have received prior platinum-based chemotherapy and for those who received prior amivantamab, a significant and growing unmet need. BICR assessed tumor responses per RECIST v1.1.CR=complete response, PR=partial response, SD=stable disease."

Clinical • EGFR exon 20 • IO biomarker • Anemia • Dental Disorders • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Stomatitis • EGFR

Efficacy and safety outcomes of emerging EGFR‑TKIs for patients with non‑small cell lung cancer with EGFR exon 20 insertion mutations: A systematic review and meta‑analysis. (PubMed, Oncol Lett) - "Subgroup analysis revealed the following ORRs: 0.731 (95% CI, 0.560-0.901; I2=0%) for YK-029A; 0.608 (95% CI, 0.511-0.705; I2=0%) for sunvozertinib; 0.602 (95% CI, 0.440-0.764; I2=80.2%) for furmonertinib; 0.602 (95% CI, 0.486-0.718; I2=84.5%) for befotertinib; 0.566 (95% CI, 0.236-0.896; I2=96.3%) for amivantamab; 0.444 (95% CI, 0.215-0.674; I2=0%) for BEBT-109; and 0.256 (95% CI, 0.178-0.334; I2=75.0%) for poziotinib. In conclusion, the emerging EGFR-TKIs for NSCLC with EGFR exon 20 insertion have a promising treatment outcome with a manageable safety profile. However, further analysis is needed when more clinical data are released."

Journal • Retrospective data • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thrombocytopenia

Antitumor activity of YH42946, a potent tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertion mutations (AACR 2025) - "It demonstrated superior activity compared to Mobocertinib (IC50 < 30 nM for ASV and IC50 < 30 nM for SVD), Furmonertinib (IC50 < 100 nM for ASV and IC50 < 100 nM for SVD), and Zipalertinib (IC50 < 100 nM for ASV and IC50 < 100 nM for SVD), and was comparable to Poziotinib (IC50 < 10 nM for ASV and IC50 < 10 nM for SVD). YH42946 is a potent small-molecule inhibitor that selectively targets EGFR ex20ins while sparing EGFR WT in preclinical models, offering potential therapeutic benefits for NSCLC patients with EGFR ex20ins mutations. Additionally, YH42946 has demonstrated effective inhibition of the EGFR pathway. Given these robust activities against EGFR ex20ins, YH42946 is anticipated to provide a significant therapeutic option for NSCLC patients harboring EGFR ex20ins mutations."

EGFR exon 20 • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Zongertinib demonstrates potent efficacy against cancer cells harboring HER2 non-tyrosine kinase domain mutations (AACR 2025) - "While tyrosine kinase inhibitors (TKIs) such as the HER2-selective inhibitor zongertinib and the pan-HER inhibitors poziotinib, pyrotinib, and afatinib have been tested primarily in patients harboring TKD mutations, their efficacy against non-TKD mutations has been less well characterized. 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."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding. (PubMed, Commun Chem) - "We studied the structure-reactivity-activity relationships of a series of analogues of the EGFR inhibitor poziotinib with point changes in two substructural regions as well as variations in warhead reactivity and geometry...These effects include the detection of potency differences between an enantiomeric pair that differ greatly in their activity and their capacity to form a covalent bond. This difference is rationalised by X-ray crystallography and computational studies and the effect translates quantitatively into cellular mechanistic and phenotypic effects."

Journal • EGFR

The Brain-Penetrant Pan ErbB Inhibitor Poziotinib Effectively Targets HER2+ Breast Cancer Brain Metastases. (PubMed, Cancer Res) - "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."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • EGFR • ERBB3 • ERBB4 • NRG1

Clinical Impact of TP53 Mutations in Patients with Head and Neck Cancer Who Were Treated with Targeted Therapies or Immunotherapy. (PubMed, Cancer Res Treat) - "Patients were assigned to treatment groups based on genomic profiles: Group 1, alpelisib; Group 2, poziotinib; Group 3, nintedanib; and Group 4, abemaciclib. If there was no identifiable target, the patients were allocated to Group 5 (durvalumab ± tremelimumab)...Furthermore, TP53 mutations were strongly associated with poor overall survival than TP53 wild-type in all the patients (11.1 vs. 28.8 months, p=0.005) and in Group 5 (8.1 vs. 33.0 months, p=0.001). TP53 mutations were associated with aggressive clinical characteristics and poor survival, particularly in HNSCC patients treated with immunotherapy."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • TP53

Comprehensive Pan-Cancer Analysis of Oncogenic ERBB2 Fusions (AMP 2024) - "Treatment of Ba/F3 or lung cells expressing MDK::ERBB2 with ERBB2 inhibitors (afatinib, poziotinib, tucatinib) blocked phosphorylation of ERBB2 and downstream effectors, and inhibited growth of both cell lines. ERBB2 fusions are rare oncogenic drivers that are candidates for targeted therapy. The subset of recurrent ERBB2 fusions with C-terminal/3' partners may represent an alternative mechanism of fusion oncogenicity."

Pan tumor • Brain Cancer • Breast Cancer • CNS Tumor • Glioma • HER2 Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • GRB7 • HER-2 • IKZF3 • MDK • RPS6

Biochemical analysis of EGFR exon20 insertion variants insASV and insSVD and their inhibitor sensitivity. (PubMed, Proc Natl Acad Sci U S A) - "Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants."

EGFR exon 20 • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with NSCLC Harboring EGFR Exon 19 Insertions: A Report from the LC-SCRUM-Asia (IASLC-WCLC 2024) - "We also studied preclinical Ba/F3 models expressing EGFR -K745_E746insIPVAIK (Ba/F3-IPVAIK) and EGFR -delE746_A750 (Ba/F3-Del19) to investigate the sensitivity to 1st-generation (gen) (gefitinib and erlotinib), 2nd-gen (afatinib, dacomitinib, and poziotinib), 3rd-gen (osimertinib), and EGFR exon 20 insertion active TKIs (mobocertinib, sunvozertinib, and zipalertinib). The preclinical therapeutic window of Ba/F3-IPVAIK and Ba/F3-Del19 for all the 2nd generation TKIs were similarly favorable, whereas Ba/F3-IPVAIK had much unfavorable therapeutic windows to other EGFR-TKIs compared to Ba/F3-Del19. Conclusions : Our clinical and preclinical findings indicate 2nd-gen EGFR-TKIs are more effective than 1st and 3rd-gen EGFR-TKIs in patients with EGFR exon 19 insertions."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDKN2B • EGFR • FGFR • PIK3CA • TP53

Resistance mechanisms of EGFR tyrosine kinase inhibitors, in EGFR exon 20 insertion-mutant lung cancer. (PubMed, Eur J Cancer) - "Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC."

EGFR exon 20 • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MET

Pan-HER Inhibition Overcomes Feedback Adaptation Resistance to KRAS G12C Inhibition in KRAS G12C Mutant Non-Small Cell Lung Cancer (LUNG-SPORE 2024) - "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..."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ERBB3 • KRAS

Trastuzumab Deruxtecan Resistance can be Mediated by Payload Resistance or Secondary Extracellular ERBB2 Mutations but Sensitivity to HER2 Tyrosine Kinase Inhibitors is Maintained (LUNG-SPORE 2024) - "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."

Human Immunodeficiency Virus • Infectious Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2 • TOP1

Evaluating progression-free survival of EGFR exon 20ins in patients with advanced non-small lung cancer receiving EGFR inhibitors: A real-world data study. (ASCO 2024) - "EGFR inhibitors were Afatinib (13), Osimertinib (12), Furmonertinib (6), Anlotinib(6), Crizotinib (3), Poziotinib(2), Almonertinib(2), Apatinib (2), Other (8). Our exploratory analysis suggested improved PFS among female, and younger patients. No differences were observed by treatment line or treatment."

Clinical • EGFR exon 20 • Metastases • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Targeted Therapies for EGFR Exon 20 Insertion Mutation in Non-Small-Cell Lung Cancer. (PubMed, Int J Mol Sci) - "This review explores key therapeutic agents, such as Amivantamab, Mobocertinib, Poziotinib, Zipalertinib, and Sunvozertinib, which have shown promise in treating NSCLC with EGFR exon 20 insertions. 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."

EGFR exon 20 • Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MET

Detection of EGFR exon 20 insertion mutations in non-small cell lung cancer: implications for consistent nomenclature in precision medicine. (PubMed, Pathology) - "A total of 1,418 EGFR E20ins mutations were collected from six studies (FoundationInsights, Geneseeq Technology Inc, mobocertinib phase I/II trial, poziotinib phase II trial, sunvozertinib phase I trial, and Samsung Medical Center) and reorganised according to Human Genome Variation Society (HGVS) nomenclature. To ensure comprehensive coverage in real-world settings, it is essential to standardise the annotations for each variant, for example using the HGVS nomenclature. 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."

EGFR exon 20 • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

NCI-2017-00831: Poziotinib in EGFR Exon 20 Mutant Advanced NSCLC (clinicaltrials.gov) - P2 | N=93 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Sep 2024 ➔ Dec 2025 | Trial primary completion date: Sep 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

HER2 TKIs enhance the anti-tumor activity of HER2-targeting CAR-T and CAR-NK cells against NSCLC (AACR 2024) - "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."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2 • LAMP1

Trastuzumab deruxtecan resistance can be mediated by payload resistance or secondary extracellular ERBB2 mutations but sensitivity to HER2 tyrosine kinase inhibitors is maintained (AACR 2024) - "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, BI-4142, and BI-1622...Moreover, resistance to trastuzumab-based ADCs can also be mediated by secondary mutations within domain IV of HER2. However, these resistance mutations do not diminish HER2 TKI activity."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2 • TOP1

Revolutionizing cancer research, new drug screening approach with vascularized cancer organoid platform mimicking patient tumor microenvironment (AACR 2024) - "This new platform was treated with Gefitinib and Poziotinib, and after 5 days of drug treatment, the IC50 value increased compared to LCO-only culture. Taken together, the co-culture of cancer organoids and BVOs present a platform that closely mimics the in vivo TME compared to the existing cancer organoid culture method. This innovative platform demonstrates higher drug resistance than existing approaches, offering a novel method for drug screening."

Biomarker • Clinical • Tumor microenvironment • Lung Cancer • Oncology • Solid Tumor • CD31 • PDGFRB • PECAM1

EGFR and mTOR signaling facilitate RET-independent resistance to selective RET-TKIs (AACR 2024) - "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..."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCDC6 • HER-2 • KIF5B • RET