Utilization of Target Lesion Heterogeneity For Treatment Efficacy assessment in Late Stage Lung Cancer

RATIONALE: Recent studies have discovered several unique tumor response subgroups outside of response classification by Response Evaluation Criteria for Solid Tumors (RECIST), such as mixed response and oligometastasis. These subtypes have a distinctive property, lesion heterogeneity defined as diversity of tumor growth profiles in RECIST target lesions. Furthermore, many cancer clinical trials have been activated to evaluate various treatment options for heterogeneity-related subgroups (e.g., 29 trials so far listed in clinicaltrials.gov for cancer patients with oligometastasis). Some of the trials have shown survival benefit by tailored treatment strategies. This evidence presents the unmet need to incorporate lesion heterogeneity to improve RECIST response classification. METHOD: An approach for Lesion Heterogeneity Classification (LeHeC) was developed using a contemporary statistical approach to assess target lesion variation, characterize patient treatment response, and translate informative evidence to improving treatment strategy. A mixed effect linear model was used to determine lesion heterogeneity. Further analysis was conducted to classify various types of lesion variation and incorporate with RECIST to enhance response classification. A study cohort of 110 target lesions from 36 lung cancer patients was used for evaluation. RESULTS: Due to small sample size issue, the result was exploratory in nature. By analyzing RECIST target lesion data, the LeHeC approach detected a high prevalence (n = 21; 58%) of lesion heterogeneity. Subgroup classification revealed several informative distinct subsets in a descending order of lesion heterogeneity: mix of progression and regression (n = 7), mix of progression and stability (n = 9), mix of regression and stability (n = 5), and non-heterogeneity (n = 15). Evaluation for association of lesion heterogeneity and RECIST best response classification showed lesion heterogeneity commonly occurred in each response group (stable disease: 16/27; 59%; partial response: 3/5; 60%; progression disease: 2/4; 50%). Survival analysis showed a differential trend of overall survival between heterogeneity and non-heterogeneity in RECIST response groups. CONCLUSION: This is the first study to evaluate lesion heterogeneity, an underappreciated metric, for RECIST application in oncology clinical trials. Results indicated lesion heterogeneity is not an uncommon event. The LeHeC approach could enhance RECIST response classification by utilizing granular lesion level discovery of heterogeneity

Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer

BackgroundHuman epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively.MethodsWe conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.ResultsA total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.ConclusionsTrastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.)