Yutaka Fujiwara

Background: Interstitial lung disease (ILD)/pneumonitis is a safety concern with trastuzumab deruxtecan (T‐DXd). We characterized post‐onset changes in ILD severity and imaging patterns, and explored potential prognostic factors for fatal T‐DXd‐related ILD in Japanese patients with breast or gastric cancer. Methods: This post hoc analysis included 381 independently adjudicated T‐DXd‐related ILD cases from two Japanese all‐patient post‐marketing surveillance studies. We described transitions from onset to worst Common Terminology Criteria for Adverse Events grade and imaging pattern changes. Exploratory tumor type‐stratified Cox proportional hazards models were used to assess factors associated with time to fatal (Grade 5) ILD. The variable with the highest hazard ratio (HR) and each of the remaining significant univariate factors ( p < 0.05 or a 95% confidence interval excluding 1) meeting the criteria were included in two‐covariate multivariable models. Results: At ILD onset, 60.1% of patients had Grade 1 ILD. Overall, 30 of the 381 adjudicated ILD cases (7.9%) progressed to fatal Grade 5, initially presenting with Grade 1 ( n = 9), 2 ( n = 5), or 3 ( n = 16); time to death was 3–173 days. Of 24 cases with imaging pattern changes, 14 transitioned from nondiffuse alveolar damage (non‐DAD) to DAD (10 were fatal). Abnormal C‐reactive protein (CRP) at onset had the highest HR in univariate analyses. In separate CRP‐adjusted two‐covariate multivariable models, preexisting ILD and several onset factors (dyspnea; abnormal SpO ₂ /lactate dehydrogenase/Krebs von den Lungen‐6; pleural/cardiac effusion; DAD pattern; traction bronchiectasis) were associated with fatal ILD. An organizing pneumonia pattern was associated with a lower hazard. Conclusions: T‐DXd‐related ILD may progress rapidly to fatal outcomes, even from low‐grade or non‐DAD presentations, and several onset factors (e.g., elevated CRP, decreased SpO ₂ , and DAD pattern) were associated with fatal ILD outcomes. These findings are exploratory and should not be used to determine whether to initiate or withhold corticosteroids. Guideline‐concordant ILD management remains essential regardless of these factors, while their potential role in identifying patients requiring closer monitoring warrants further validation. Trial Registration: The breast cancer and the gastric cancer surveys were registered at the Japan Registry of Clinical Trials ( https://jrct.mhlw.go.jp/en‐top ) under the identifiers jRCT1080225197 and jRCT2001200001, respectively

Background: Interstitial lung disease (ILD)/pneumonitis is an important adverse drug reaction associated with trastuzumab deruxtecan (T-DXd). This report comprehensively characterized clinical and imaging features of T-DXd-related ILD, systematically evaluated by an independent ILD Adjudication Committee (AC), in Japanese patients with breast/gastric cancer from all-patient post-marketing surveillance studies. Patients and Methods: This post hoc analysis evaluated independent ILD AC-adjudicated T-DXd-related ILD cases. Demographics, clinical/radiological features, time to onset, treatment interventions, and outcomes (followed up to 12 months from onset) were analyzed. Results: Among 2801 T-DXd-treated patients (breast cancer: 1731; gastric cancer: 1070), 421 potential cases were reviewed: 381 were adjudicated as T-DXd-related ILD (breast cancer: 278; gastric cancer: 103). Median age was 65.0 years, 75.1% were female, and 28.3% had a smoking history. ILD occurred throughout observation (including fatal cases ≥12 months post-initiation) with no specific onset window. Time to onset did not differ across CTCAE grades. Organizing pneumonia was the predominant imaging pattern (67.7%), followed by hypersensitivity pneumonitis (14.2%) and diffuse alveolar damage (DAD, 12.6%). Most cases (78.2%) were worst CTCAE Grade 1-2. Grade 5 ILD occurred in 30 patients (7.9%), with DAD the most common pattern (26 patients). Overall recovery was 83.5%. Corticosteroids were used in 54.6% of cases, with 79.3% responding. High-dose corticosteroids and additional immunosuppressants were ineffective in seven DAD cases. Conclusions: Most T-DXd-related ILD cases were mild/moderate and corticosteroid-responsive; DAD pattern was associated with higher mortality. These findings underscore the importance of vigilant monitoring, early recognition, and prompt corticosteroid treatment to mitigate fatal T-DXd-related ILD.

Background: Epidermal growth factor receptor (EGFR) exon 20 insertion (Ex20ins) mutations in non-small cell lung cancer (NSCLC) are largely insensitive to conventional EGFR tyrosine kinase inhibitors (TKIs) because of steric hindrance in the TKI-binding pocket. Amivantamab, an EGFR-MET bispecific antibody, has been approved for use in combination with chemotherapy as the first-line treatment for EGFR Ex20ins NSCLC. However, intracranial activity remains unknown because monoclonal antibodies are generally thought to have limited central nervous system (CNS) penetration. Case Description: We report three patients with advanced NSCLC with EGFR Ex20ins and with asymptomatic brain metastases who were treated with carboplatin, pemetrexed, and amivantamab (PAPILLON regimen). Case 1 was a 48-year-old woman with ≥10 asymptomatic brain metastases that developed during prior treatment with carboplatin, pemetrexed, and an investigational TKI targeting their EGFR ex20ins mutations; she achieved intracranial and extracranial partial responses. Case 2 was a 67-year-old man with postoperative recurrence and new brain metastases arising during another investigational EGFR-TKI monotherapy; he achieved a complete intracranial response. Case 3 was a 35-year-old man with previously untreated advanced lung adenocarcinoma and multiple asymptomatic brain metastases, which demonstrated intracranial and extracranial partial responses within two months. Conclusions: These three cases provide clinical evidence that carboplatin, pemetrexed, and amivantamab may exert clinically meaningful intracranial antitumor activity in patients with EGFR Ex20ins NSCLC harboring small, asymptomatic brain metastases. Amivantamab, a bispecific antibody, combined with carboplatin and pemetrexed may exert clinically meaningful intracranial antitumor activity.

Anti-programmed death 1 (PD-1) antibodies, a type of immune checkpoint inhibitor (ICI), have enhanced survival rates in non-small cell lung cancer (NSCLC).

Kaplan–Meier analysis of OS. A, ITT population. The 1-, 2-, 3-, 4-, and 5-year survival rates were 92.8%, 80.4%, 63.5%, 49.6%, and 36.9% in the control group and 94.4%, 81.7%, 69.9%, 49.9%, and 35.3% in the experimental group, respectively. B, Gefitinib cohort. The 1-, 2-, 3-, 4-, and 5-year survival rates were 91.5%, 78.4%, 59.5%, 46.3%, and 34.4% in the control group and 92.2%, 77.7%, 66.4%, 46.5%, and 32.9% in the experimental group, respectively. C, Osimertinib cohort. The 1-, 2-, and 3-year survival rates were 94.8%, 83.4%, and 69.8% in the control group and 97.9%, 88.3%, and 76.0% in the experimental group, respectively. D, Subgroup analysis of OS. ECOG, Eastern Clinical Oncology Group; Ex19del, EGFR exon 19 deletion; L858R, EGFR exon 21 L858 point mutation; NE; not estimable; PS, performance status.

CONSORT diagram. Flowchart of patient disposition throughout the study, including randomization, eligibility, treatment, and follow-up.

Table 3 from Randomized Phase III Study of EGFR Tyrosine Kinase Inhibitor and Intercalated Platinum-Doublet Chemotherapy for Non–Small Cell Lung Cancer Harboring EGFR Mutation

Supplementary Figure S3. Subgroup analyses of overall survival. (A) Gefitinib cohort. (B) Osimertinib cohort. Abbreviations: CI, confidence interval; EGFR, epidermal growth factor receptor; Ex19del, EGFR exon 19 deletion; L858R, EGFR exon 21 L858 point mutation; ECOG, Eastern Clinical Oncology group; PS, performance status; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; CNS, central nervous system.