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

Personalized Biomarker-Based Umbrella Trial for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: KCSG HN 15-16 TRIUMPH Trial. (PubMed, J Clin Oncol) - "To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable."

Biomarker • IO biomarker • Journal • Metastases • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR • FGFR • PIK3CA

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

Efficacy and Safety of Poziotinib in HER2 Exon 20 Insertion NSCLC Patients who Received at Least 2 Previous Systemic Therapies (IASLC-WCLC 2023) - "Introduction: HER2 mutation is a newly established actionable target in non-small cell lung cancer (NSCLC) with trastuzumab-deruxtecan (T-DXd) as the only approved targeted therapy for patients as 2nd line therapy...ORRs were 31.3% with platinum+any systemic therapy; 30.8% with platinum+docetaxel; 24.0% with platinum+HER2 antibody-based therapy; 54.5% with platinum+TKI... Poziotinib demonstrated clinically meaningful efficacy in patients who received and progressed on prior 2+ lines of therapy regardless of types and sequence of treatment. ZENITH20 study provides a large dataset in the 3rd or later line setting of HER2 exon 20 mutations NSCLC patients who have very limited treatment options. No new safety signal was detected in this patient population."

Clinical • HER2 exon 20 • IO biomarker • Lung Cancer • Mucositis • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

On-Target Acquired Resistance to Zongertinib and Strategy to Overcome It - in Vitro Study usingHER2ex20 Insertion Models (IASLC-WCLC 2026) - "Methods : We examined efficacy of zongertinib, sevabertinib and other TKIs with HER2 inhibitory activity (erlotinib, afatinib, poziotinib, mobocertinib, and osimertinib) using murine pro-B-cell line (Ba/F3) models harboring one of three most common HER2 exon 20 insertions (A775_G776insYVMA (YVMA), G776delinsVC (VC) and P780_Y781insGSP (GSP)). Conclusions : These findings indicate that distinct compound mutations confer differential resistance to HER2-TKIs depending on the original HER2 exon 20 insertion. Zongertinib-resistant mutations, such as YVMA+S783A and GSP+G776C, remained sensitive to poziotinib, whereas compound mutations associated with poziotinib resistance, including YVMA+C805S and VC+C805S, were effectively inhibited by sevabertinib."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Early Clinical Outcomes of VRN101099 in ERBB2-Mutated Advanced Non-Small Cell Lung Cancer: A Case Series From a Phase 1A Study (IASLC-WCLC 2026) - P1 | "Trastuzumab deruxtecan (T-DXd) has shown activity in HER2-mutant NSCLC but with limited durability; poziotinib and pyrotinib provide incomplete mutational coverage with dose-limiting toxicities; and current agents exhibit poor CNS penetration...All had progressed on prior HER2-targeted therapies including T-DXd (n=3) and tucatinib/trastuzumab (n=1)...Conclusions : In this Phase 1a case series, VRN101099 demonstrated preliminary antitumor activity across multiple ERBB2 mutation types and tumor histologies, including patients with CNS disease and those refractory to prior HER2-targeted therapies. These findings support the continued evaluation in planned dose-expansion cohorts to further characterize the efficacy and safety of VRN101099 in ERBB2-mutant malignancies."

Clinical • Clinical data • Metastases • P1 data • Breast Cancer • CNS Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HER-2 • KRAS • PIK3CA • TP53

Efficacy and Safety of TKI Versus ADC in Advanced or Metastatic HER2 Mutant Non-Small Cell Lung Cancer: A Metanalysis (IASLC-WCLC 2026) - "Notably, newer selective TKIs such as Zongertinib (ORR 71%) and Sevabertinib (ORR 64%) demonstrated superior efficacy compared to older pan-HER TKIs, such as Poziotinib (ORR 28-39%) and Pyrotinib (ORR 30%). However, ADCs were associated with a higher incidence of ILD/pneumonitis, whereas TKIs were more likely to cause diarrhea. These findings support the potential of newer HER2-specific TKIs as promising therapeutic options for HER2-mutant NSCLC, with an improved safety profile and efficacy."

ADC • Clinical • Metastases • Interstitial Lung Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • HER-2

Poziotinib in Treatment-Naïve Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Mutations: ZENITH20-4, A Multicenter, Multicohort, Open-label Phase 2 Trial (Cohort 4). (PubMed, J Thorac Oncol) - "Poziotinib demonstrated clinically meaningful efficacy with a manageable toxicity profile for treatment-naïve NSCLC patients harboring HER2 exon 20 mutations."

HER2 exon 20 • Journal • P2 data • Dental Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Stomatitis • HER-2 • TYK2

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

High activity of poziotinib in G778_P780dup HER2 exon 20 insertion mutations in non-small cell lung cancer (NSCLC) (ESMO 2022) - P2 | "Conclusions Poziotinib is highly active in G778, a common HER2 ex20ins alteration, in both treatment-naïve and previously treated patients with NSCLC. The AE profile was typical of a TKI."

HER2 exon 20 • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

The counterparty to the technology transfer agreements for the Non-small cell lung cancer (NSCLC) drug "poziotinib" and the neutropenia treatment "rolontis" under Hanmi Pharmaceutica…has changed from U.S.-based Assertio Holdings to Indian pharmaceutical company Zydus Lifesciences. (Chosun Biz) - "Hanmi Pharmaceutical said on the 21st that it corrected its disclosure on key management matters for investment judgment related to poziotinib and rolontis and would change the counterparty to the technology transfer agreements from Assertio to Zydus. The change comes after Zydus acquired 100% equity in Assertio. Zydus will also assume the rights and obligations related to development and sales within the contracted territories for the two treatments that Assertio had held."

Licensing / partnership • Neutropenia • Non Small Cell Lung Cancer

Global evolution of HER2-targeted clinical trials across solid tumors: Shifts in tumor representation, biomarker definitions, therapeutic modalities, and geographic leadership. (ASCO 2026) - "Trials were identified using HER2/ERBB2 terms, HER2-low and HER2-mutant criteria, and HER2-directed agents (trastuzumab, pertuzumab, T-DM1, T-DXd, tucatinib, neratinib, lapatinib, pyrotinib, poziotinib). The global HER2-targeted trial landscape has shifted dramatically from a breast-focused, monoclonal-antibody era to a broad, biomarker-driven, and therapeutically diverse ecosystem across many solid tumors. Three major trends stand out: (1) rapid growth of HER2-low and HER2-mutant trial programs(2) ADCs becoming the dominant driver of HER2 drug development (3) Asia emerging as the global leader in TKI innovation. These shifts highlight the need for clearer biomarker standards, especially for HER2-low, and for coordinated development of pan-tumor HER2-directed strategies."

Biomarker • Clinical • IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

The efficacy of trastuzumab deruxtecan after HER2-TKI exposure in HER2 exon 20 insertion–positive non–small cell lung cancer: Results from a large-scale nationwide genomic screening (LC-SCRUM-Asia). (ASCO 2026) - "Clinical outcomes (ORR, DCR, and PFS) were evaluated across three groups based on prior HER2-TKI therapy: (1) HER2-TKI-naïve patients (naïve cohort), (2) those treated with selective HER2-TKIs (zongertinib or severtinib) (selective TKI cohort), and (3) those treated with non-selective pan-HER2-TKIs (such as poziotinib, afatinib, and others) (non-selective TKI cohort). Although prior HER2-TKI exposure, particularly selective HER2-TKIs, may attenuate the efficacy of T-DXd in HER2 exon 20 insertion–positive NSCLC compared with HER2-TKI–naïve patients, T-DXd retained clinically meaningful activity in a subset of patients, including those who did not achieve objective responses to prior HER2-TKIs."

Clinical • HER2 exon 20 • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

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

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

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."

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

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

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

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

NCI-2017-00831: Poziotinib in EGFR Exon 20 Mutant Advanced NSCLC (clinicaltrials.gov) - P2 | N=93 | Terminated | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2027 ➔ Feb 2026 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2027 ➔ Feb 2026; <75% participation

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

Loss of payload sensitivity and other mechanisms of resistance to T-DXd in HER2-mutant NSCLC: implications for subsequent responsiveness to HER2 TKIs. (PubMed, J Thorac Oncol) - "In HER2 mutant NSCLC patients, loss of HER2 is not a universal mechanism of T-DXd resistance. Collectively, these data highlight multiple mechanisms of resistance to T-DXd that do not result in loss of HER2 TKI responsiveness."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCC1 • HER-2

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: Dec 2025 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2027

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

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