Gilotrif (afatinib)

P2/3, N=90, Not yet recruiting, Peking University Cancer Hospital & Institute

This study represents the latest investigation of resistance mechanisms to afatinib in NSCLC patients with nonclassical mutations. The mechanism of resistance to EGFR-TKI in this study was discovered different from that of patients with classical mutations.

In this review, we highlight a case example that illustrates key treatment considerations, including balancing efficacy, toxicity, and patient preferences when selecting the optimal palliative therapy. We discuss key treatment considerations for EGFR PACC mutated NSCLC to inform the use of afatinib (the only approved therapy with an indication that includes two EGFR PACC mutations, G719X and S768I), osimertinib, or combination therapies in the upfront setting; limitations of the available data; and ongoing clinical trials specific to the EGFR PACC mutation subgroup that may further refine our understanding of treatment for patients with these tumors.

He received afatinib as first-line therapy, followed by pemetrexed/carboplatin and later a quadruple regimen of atezolizumab, bevacizumab, paclitaxel, and carboplatin. This case is the first to demonstrate a durable, near-complete response to amivantamab combined with chemotherapy in a patient harboring an uncommon EGFR G719A mutation and extensive visceral metastases. Although further studies are warranted, this report highlights amivantamab-based combination therapy as a promising salvage option for high-risk patients.

We report a 72-year-old man with stage IV squamous NSCLC harboring an EGFR mutation and PD-L1 tumor proportion score of 90% who developed persistent fever shortly after first exposure to ivonescimab combined with nab-paclitaxel and carboplatin. His prior treatments included concurrent chemoradiotherapy, osimertinib, the investigational EGFR inhibitor BH-30643, afatinib, and recent gamma knife for cerebellar metastases plus palliative radiotherapy for bone metastases...Symptoms improved with corticosteroids, tocilizumab, and desmopressin, consistent with probable arginine vasopressin deficiency (AVP-D), possibly secondary to hypophysitis-though pituitary metastasis cannot be ruled out without biopsy...Advanced age, EGFR-mutant/PD-L1-high tumor biology, recent radiotherapy, and Parkinsonism may have contributed to the inflammatory environment, though none can be proven causal in a single case and each deserves prospective study. Early recognition of persistent steroid-responsive fever, serial IL-6 monitoring, thorough endocrine workup, and timely IL-6 blockade are critical.

Our study demonstrated that both afatinib and osimertinib as first-line treatments offer favorable median OS in patients with advanced EGFR-mutant NSCLC. In addition, we recommend that patients receiving afatinib as first-line therapy undergo sequential osimertinib treatment, regardless of their T790M mutation status.

Consistently, afatinib treatment resulted in marked tumor shrinkage and suppression of EGFR signaling in the established mDEL OsiR #1/#3 in vivo. These findings establish secondary Egfr V804F/EGFR V802F as an on-target osimertinib resistance mechanism, providing a preclinical rationale for evaluating afatinib in biomarker-selected patients harboring this alteration.

Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment. Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients.

Among 56 patients who received subsequent systemic therapy, clinical outcomes were comparable between ICI plus platinum doublet and platinum doublet alone. These findings indicate that afatinib and osimertinib provide comparable survival outcomes as first-line therapies for NSCLC with UMs, with treatment effects varying by molecular subtype, while subsequent ICI-based regimens may confer limited additional benefit.

Molecular docking simulations suggested promising drug repurposing avenues, particularly with afatinib and crizotinib, for GABRD inhibition. GABRD gene may serve as a novel biomarker in the diagnosis, prognosis and immune infiltrates of CRC patients.

Additionally, the model accurately predicted patient sensitivity to specific chemotherapeutic agents like afatinib and dasatanib...We developed a signature of lncRNAs linked to crotonylation that offers dependable prognostic insights and characterizes the immune microenvironment within GC. However, additional investigation is necessary to confirm its practical applications in clinical settings.

Successful generation of a BrM-derived organoid line enabled high-throughput drug screening, which recapitulated the patient's clinical resistance to standard therapies [gemcitabine/nab-paclitaxel, 5-fluorouracil (5-FU)], and showed sensitivity to afatinib, everolimus and RMC-6236...Physicians should also be aware that KRAS wild-type pancreatic cancer with atypical amplifications is likely to exhibit unique metastatic tropisms. Finally, we suggest that patient-derived organoids pharmacotyping can mirror clinical drug responses and help evaluate therapeutic avenues for patient treatment.