9137 Background: Amivantamab (ami), an EGFR and cMET bispecific antibody with immune cell-directing activity, and lazertinib (laz), a CNS-penetrant 3 rd -generation EGFR tyrosine kinase inhibitor have shown clinical activity in biomarker-selected patients (pts) with advanced NSCLC. Antitumor activity has been suggested to be improved when the agents are given in combination (Leighl Ann Oncol 2021;32:suppl_5, 1192MO). We examined the incidence of VTE, a common adverse event (AE) among pts with lung cancer, for those receiving ami monotherapy, laz monotherapy, and ami+laz to investigate if there is elevated risk and understand potential predisposing risk factors. Methods: CHRYSALIS (NCT02609776; ami monotherapy and ami+laz), CHRYSALIS-2 (NCT04077463; ami+laz), and LASER201 (NCT04075396; laz monotherapy) are ongoing open-label studies of locally advanced/metastatic NSCLC. Two descriptive, univariate risk analyses were performed, with the primary analysis including all treatment-emergent VTE events (grouped term) and a secondary analysis that excluded VTE events occurring after progression of disease (PD) or within 30 days prior to PD. Results: This analysis included 560 pts who received ami monotherapy, 536 ami+laz, and 252 laz monotherapy, predominantly in the TKI-relapsed setting. The incidence of VTE events of any grade was numerically higher in pts who received ami+laz (21%) than those who received ami (11%) or laz (11%) monotherapy. The median time to onset of the first VTE event was 84.5 days for ami, 79 days for ami+laz, and 170 days for laz. The majority (64%) of ami+laz pts had VTE events in the first 4 months. The most common VTE events by preferred term were pulmonary embolism and deep vein thrombosis. The incidence of grade ≥3 VTE events was comparable among pts receiving ami (5%), ami+laz (6%), and laz (6%), and there were no grade 5 VTE events for ami+laz. The overall incidence of serious VTE AEs was low (ami, 3%; ami+laz, 5%; laz, 4%). There were 6 discontinuations due to VTE, 1 (0.2%) ami, 2 (0.4%) for ami+laz, and 3 (1.2%) laz. In the primary analysis, age ≥60 years was a significant risk factor ( P< 0.05). In the secondary analysis, age ≥60 years, ECOG performance status of 1 (vs 0), and response to therapy (partial response or better) were significant risk factors ( P< 0.05). Conclusions: Lung cancer diagnosis is a known risk factor for VTE. In a review across clinical trials, single-arm cohort data suggest there is a numerically higher incidence of VTE for ami+laz compared with each monotherapy. Age ≥60 years, ECOG performance status, and response to treatment are potential risk factors. The relationship between response and VTE is emerging and may reflect possible immune or inflammatory-mediated mechanisms. Further efforts to understand VTE-associated risk factors in randomized clinical trials are ongoing. Clinical trial information: NCT02609776 , NCT04077463 , NCT04075396 .
Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With <i>NTRK</i> Fusion-Positive Solid Tumors
Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With <i>NTRK</i> Fusion-Positive Solid Tumors
Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With <i>NTRK</i> Fusion-Positive Solid Tumors
<div>AbstractPurpose:<p>Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.</p>Experimental Design:<p>Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (<i>n</i> = 12). Organoids were analyzed by whole-exome sequencing (<i>n</i> = 61) and RNA sequencing (<i>n</i> = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.</p>Results:<p>PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non–small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an <i>EGFR</i> exon 19 deletion and a <i>BRAF</i> G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an <i>EGFR</i> L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against <i>ERBB2</i> exon 20 insertions and pralsetinib against <i>RET</i> fusions.</p>Conclusions:<p>We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.</p></div>
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