Non-15n-del) have also yielded conflicting results regarding PFS and OS [10, 18, 22]

The gap

Evidence profile

Sourced from the discussion and future work of the source papers, classified as general, drawn from work published between 2025 and 2026, spanning 3 journals. Those papers have been cited 7 times in total.

Supporting evidence — 3 representative gaps

• Sensitivity of different epidermal growth factor receptor (EGFR) exon 19 deletion subtypes to first-line osimertinib in Chinese non-small cell lung cancer patients (2026) · BMC Cancer · doi

  non-15n-del) have also yielded conflicting results regarding PFS and OS [10, 18, 22]. Collectively, these inconsistent findings highlight the ongoing controversy and underscore the need for further investigation, particularly with newer-generation TKIs. Limited studies either focused on osimertinib as second-line treatment, had insufficient sample sizes, or exclusively targeted spe- cific subtypes of rare mutations, lacking larger sample cohorts to explore the efficacy of first-line osimertinib in various EGFR 19del subtypes.

  generaldiscussion
  Keywords: osimertinib line sample subtypes yielded conflicting regarding collectively inconsistent highlight ongoing controversy underscore need further
• Anti-TROP2 Antibody Drug Conjugates in EGFR-Mutant Non-Small Cell Lung Cancer: Biological Rationale and Clinical Challenges (2026) · Pharmaceutics · doi

  Overall, the summarized biological and clinical data suggest a future role for TROP2- targeted ADCs in the treatment of EGFR-mutated NSCLC. From a biological point of view, the framework for the use of TROP2-directed ADCs to eradicate residual and drug-tolerant clones in EGFR-mutated NSCLC includes target enrichment under selective pressure, preserved cell surface accessibility, and bystander- mediated coverage of heterogeneous tumor populations [21,30]. On the other hand, current clinical data already support a role for these agents in patients progressing on first-line Osimertinib, as confirmed by a recent meta-analysis [47]. even though randomized data in non-Asian populations are still awaited. In this context, the ORCHARD study as well as recent evidence from the COMPEL clinical trial support, from a clinical standpoint, the biological rationale for continuing EGFR inhibition beyond progression on first-line TKI [31,58]. The association of Osimertinib beyond progression and anti-TROP2 ADC is also corroborated by translational findings showing that TROP2 cell surface levels are affected by Osimertinib administration, therefore suggesting synergism in efficacy [16]. In this evolving context, defining the optimal positioning of TROP2-directed ADCs across lines of therapy becomes a priority. The therapeutic scenario is getting crowded, and TROP-directed ADCs are likely to become one potential standard in second line setting, together with other options including both strategies driven by the specific resistance mechanism and strategies designed for unselected patients. These competing options include distinct drug classes. Among non-ADC antibody strategies, the EGFR–MET bispecific amivantamab plus chemotherapy was the first reg- imen to improve PFS over chemotherapy after osimertinib progression in the phase III MARIPOSA-2 trial (median PFS 6.3 vs. 4.2 months; HR 0.48), albeit with substantial EGFR/MET-related toxicity [59]. The PD-1 × VEGF bispecific ivonescimab plus chemother- https://doi.org/10.3390/pharmaceutics18080905 Pharmaceutics 2026, 18, 905 16 of 21 apy improved PFS over chemotherapy in EGFR-mutant patients progressing after a third- generation TKI in the phase III HARMONi-A trial (median PFS 7.06 vs. 4.80 months; HR 0.46) [60]. ADCs directed at targets other than TROP2 are also under investigation. Patri- tumab deruxtecan (HER3-DXd), which shares the deruxtecan payload and a tetrapeptide cleavable linker with Dato-DXd, produced durable responses in the phase II HERTHENA- Lung01 study (confirmed ORR 29.8%), but failed to improve OS versus chemotherapy in the phase III HERTHENA-Lung02 trial (median OS 16.0 vs. 15.9 months; HR 0.98), leading to withdrawal of its biologics license application [61,62]. The EGFR × HER3 bispecific ADC izalontamab brengitecan (Iza-bren) showed activity in an exploratory pooled analysis of phase I/II trials in EGFR-mutant NSCLC after TKI progression (confirmed ORR 47.4%, median PFS 6.9 months), al

  generalfuture work
  Keywords: egfr trop adcs phase clinical directed osimertinib trial progression chemotherapy median months biological nsclc patients
• Possibilities of Overcoming Resistance to Osimertinib in NSCLC Patients with Mutations in the EGFR Gene (2025) · Cancers · cited 7× · doi

  To conclude, patients with EGFR mutations have mainly been treated with osimertinib during the last few years. The high ORR and prolonged PFS and OS justify this care standard, but most patients will eventually experience progression. Understanding the mechanism of progression is crucial as it drives important clinical decisions concerning the subsequent therapy. In the first step, patients should be evaluated after progression to identify the resistance mechanism and confirm the on-target or off-target aberrations. The methods to establish this diagnosis are not standardised, with the possibility of applying NGS and CGP rather than WES or WGS in the clinical setting. Single-gene tests are not encouraged except for some clinical trial enrollment, which is still recommended in this group of patients. Outside clinical trials, amivantamab plus chemotherapy for patients with mutations in exon 19 or L858R substitutions in exon 21 of the EGFR gene is the best available option in osimertinib-resistant patients, based on MARIPOSA-2 trial results. The PALOMA-3 study showed reduced toxicity of amivantamab with subcutaneous administration, which also limits the healthcare system load. Since immunotherapy has shown inconsistent results, it is not recommended in patients with EGFR mutations based on available data. However, further progress is expected as many compounds are tested, with promising results for MET TKIs (savolitinib and tepotinib), next-generation EGFR TKIs (BLU-945 targeting the C797S mutation), and ADCs (patritumab deruxtecan and datopotomab deruxtecan). Author Contributions: Conceptualization, M.N. and P.K.; literature review, M.N., A.S.-B., E.K. and P.K.; formal analysis, M.N. and A.S.-B.; resources, M.N., A.S.-B., E.K. and P.K.; data curation, M.N.; writing—original draft preparation, M.N., A.S.-B., E.K. and P.K.; writing—review and editing, M.N. and P.K.; visualization, M.N.; supervision, M.N. and P.K.; project administration, M.N. and P.K. All authors have read and agreed to the published version of the manuscript. Funding: The research was supported by the statutory activity of the Medical University of Lublin (DS392). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflicts of interest.

  generalfuture work
  Keywords: patients egfr clinical mutations progression review statement applicable osimertinib mechanism target gene trial recommended amivantamab

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