Afatinib 30 mg daily was well tolerated and demonstrated encouraging efficacy, with a 6-month PFS of 93.2%, suggesting outcomes comparable to standard dosing.

P1/2, N=29, Active, not recruiting, West China Hospital | Recruiting --> Active, not recruiting

P2, N=98, Completed, West China Hospital | Recruiting --> Completed

This study suggests that a 30-mg starting dose of dacomitinib may provide similar efficacy with improved tolerability compared with 45 mg. Prospective noninferiority studies are warranted to confirm these findings.

P2, N=50, Recruiting, Yale University | Trial completion date: Jul 2028 --> Dec 2028 | Trial primary completion date: Jul 2026 --> Dec 2026

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.

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.

Initial low-dose dacomitinib demonstrated promising efficacy with an improved safety profile in patients with EGFR exon 21-mutated NSCLC. These findings support the feasibility of a dose-optimization strategy, although further prospective studies are warranted.

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.