Conference Coverage

ADCs show early promise in NSCLC



Antibody-drug conjugates (ADC) link a tumor-targeted antibody to a cytotoxic drug through a chemical linker and hold the promise of high potency. This has led to a burgeoning interest in solid tumors, with over 100 clinical trials in progress. Non–small cell lung cancer (NSCLC) is no exception. In 2022, the Food and Drug Administration approved trastuzumab DXd for pretreated NSCLC patients with HER2-mutant tumors. Two others have lung cancer breakthrough therapy designations from the FDA, including patritumab deruxtecan (HER3-DXd) for EGFR-mutant NSCLC and telisotuzumab vedotin for NSCLC that overexpresses c-Met.

At the annual World Conference on Lung Cancer, researchers outlined some of the latest developments in ADCs targeting the antigens HER3, trophoblast cell-surface antigen 2 (TROP-2), and the B7-H3 immunoregulatory protein, as single agents or in combination with immunotherapy. Following the presentations, discussant Helena Linardou, MD, PhD, emphasized the need for pharmacogenomics to predict toxicity and studies to understand resistance mechanisms. “ADCs are a new, rapidly evolving class of therapeutics, and I think that we will all have to be prepared for the future that is coming,” said Dr. Linardou, who is director of the 4th oncology department and the Comprehensive Clinical Trials Center at Metropolitan Hospital in Athens.

Researchers presented four ADC clinical trial updates.

Patritumab deruxtecan

Patritumab deruxtecan (Daiichi Sankyo) links a HER3 antibody to the topoisomerase I inhibitor deruxtecan (HER3-DXd). In the open-label, phase 2 HERTHENA-Lung01 trial, it was tested in patients with NSCLC EGFR-activation mutations, which occurs in 14%-38% of NSCLC cases. There are few options for these patients following failure of EGFR tyrosine kinase inhibitor therapy.

The study included 225 patients previously treated with EGFR tyrosine kinase inhibitors and platinum-based chemotherapy who received 5.6 mg/kg of HER3-DXd every 3 weeks. Over a median follow-up of 13.1 months and a median treatment duration of 5.5 months), 29.8% had a confirmed overall response (95% confidence interval, 23.9%-36.2%) with a median duration of 6.4 months (95% CI, 4.9-7.8). The median progression-free survival was 5.5 months (95% CI, 5.1-5.9), and the median OS was 11.9 months (95% CI, 11.2-13.1). The researchers noted similar outcomes among patients with different mechanisms of EGFR TKI resistance. The frequency of adverse events was similar to previous studies, with drug-related adverse events linked to treatment discontinuation of 7.1% interstitial lung disease in 5.3%. Among 30 patients with brain metastases, the confirmed intracranial response rate was 33.3% (95% CI, 17.3%-52.8%).

The study was published simultaneously online in the Journal of Clinical Oncology. (Abstract)

Datopotamab deruxtecan

PD-1/PD-L1 inhibitors are the first-line therapy for metastatic NSCLC, but there are efforts to improve outcomes through combination therapy. Datopotamab deruxtecan (Dato-DXd, Daiichi Sankyo, AstraZeneca) is an ADC targeting TROP2, and it has been shown in preclinical studies to enhance tumor responses to PD-1/PD-L1 inhibitors. The ADC improved progression-free survival (PFS), compared with docetaxel, in previously treated advanced or metastatic NSCLC.

In an interim analysis of the phase 1b TROPION-Lung04 study, researchers reported results from the combination of Dato-DXd with durvalumab with or without carboplatin. The study included 38 patients, some of whom had previously undergone treatment with immune checkpoint inhibitors. Nineteen patients received the doublet, and 14 received the carboplatin triplet. Grade 3 or higher treatment-emergent adverse events occurred in 42.1% of the doublet group and 71.4% of the triplet group. Interstitial lung disease occurred in 15.8% and 7.1% of the two groups, respectively. The objective response rate was 50.0% in the doublet group and 76.9% in the triplet group. The disease control rate was 92.9% and 92.3%, respectively. Durable responses occurred in both the first-line setting and the overall population. (Abstract)


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