Outcomes of osimertinib rechallenge after osimertinib-induced interstitial lung disease in metastatic EGFR-mutated NSCLC: Systematic review and meta-analysis.

Abstract

e20732 Background: Osimertinib is standard therapy for metastatic EGFR-mutated (mEGFR+) NSCLC but rarely causes pneumonitis/interstitial lung disease (ILD). After recovery, rechallenge may allow continued benefit, but the safety of rechallenge varies between studies and remains unknown. Methods: We conducted a systematic review & meta-analysis (PROSPERO: CRD420261290112). MEDLINE and Embase were searched from inception to July 17, 2025. Eligible studies were cohorts or case series (≥2 patients) of adults with mEGFR+ NSCLC who developed osimertinib-associated ILD and were subsequently rechallenged with osimertinib after improvement or resolution. Comparators, when reported, included switching to other EGFR-TKIs or other treatments (i.e. chemotherapy). Primary outcomes were recurrent ILD, grade ≥3 ILD, or fatal (grade 5) ILD recurrence. Random-effects meta-analyses of proportions and risk ratios were performed in R. When individual patient data (IPD) was available, time to recurrent ILD was summarized descriptively. We also explored the association between initial ILD grade and severe recurrence (grade ≥3) using Fisher’s exact test. Results: Seven studies were included: 98 patients rechallenged with osimertinib and 96 switched to another EGFR-TKI. Median ages ranged from 64-75 years, and 60.4% were female. Of studies that reported initial ILD severity, 50% (32) were Grade 1, 32.8% (21) were Grade 2, 14.1% (9) were Grade 3, and 3.1% (2) were Grade 4. Pooled recurrent ILD after osimertinib rechallenge was 32.2% (95%CI, 20.2–47.2) versus 15.6% (95%CI, 9.6–24.3) after EGFR-TKI switch (RR 2.01, 95%CI 1.10–3.68, I 2 = 5.8%, p = 0.02). Three fatal ILD recurrences occurred after osimertinib rechallenge, all from a study with 50% of patients with initial ILD grade ≥3. One fatality was reported after alternative EGFR-TKI in the same study. Of 18 patients with a recorded time to recurrent ILD, the median time to recurrence was 2.05 months (IQR 1.00-4.25). In exploratory IPD, severe initial ILD predicted severe recurrence (initial grade 3–4: 4/4 with recurrent grade ≥3 vs initial grade 1–2: 1/11 with recurrent grade ≥3; Fisher p≈0.004). Conclusions: Osimertinib rechallenge after osimertinib-induced ILD carries a substantial recurrence risk and approximately double the recurrence versus switching to non osimertinib EGFR-TKI, with events occurring early. These data support that rechallenge may be reasonable after low-grade ILD in carefully selected patients, but should likely be avoided after high-grade initial ILD, given the risk of severe or fatal recurrence.