Since the last decade, there has been tremendous development for patients expressing PD-L1 tumors without mutation. The new area of development includes TROP-2-directed ADC’s, T cell Immunoreceptors with Ig and ITIM domains (TIGIT), and LAG-3 inhibitors majorly being targeted by the researchers, and the big companies such as AstraZeneca, Daiichi Sankyo, Beigene, Hoffmann-La Roche, Gilead Sciences, and others have their potential candidates in late stages of development. 

Among 40 patients, the overall response rate (ORR) reached 57.5%, including one complete response and 22 partial responses. The disease control rate (DCR) was notably high at 95%. Responses were observed across both squamous (45.5%) and nonsquamous (62.1%) subtypes, as well as across all PD-L1 expression levels. The median duration of response was 5.8 months (4.5 to NR).

Safety outcomes were consistent with the known profiles of both agents, with no new safety concerns identified. Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 60% of patients. The most frequent severe TEAEs included pneumonia (10%), pneumonitis (7.5%), and various events at 2.5% each, such as anemia, decreased appetite, increased amylase, musculoskeletal pain, rash, and stomatitis. Interstitial lung disease (ILD) was observed in five patients—three with Grade 2 and two with Grade 3 events—deemed treatment-related by an independent review committee.

KOL insights

Acquired resistance to frontline therapies and, ultimately, disease progression are unfortunate realities for most patients with advanced EGFR-mutated NSCLC. Treating patients with advanced EGFR-mutated NSCLC presents a significant challenge due to the limited efficacy of available treatments once the disease has progressed following frontline therapies, including the use of an EGFR. If approved, Dato-DXd could become the first TROP2-directed ADC for lung cancer, providing a promising option for patients.” – Expert Opinion.

Conclusion

TROP-2-directed ADCs including Dato-DXd, sacituzumab tirumotecan, and TRODELVY, are designed to deliver targeted cytotoxic therapy to tumors overexpressing TROP-2, a surface glycoprotein commonly found in NSCLC. Initially, Dato-DXd was expected to lead the field, with anticipated first-line approval and a potential advantage over competitors like TRODELVY. Owing to recent setbacks, it is reasonable to assume that TROP2-directed therapies may not be good for all patients in the second line and beyond NSCLC. AstraZeneca and Daiichi Sankyo have withdrawn their marketing application for Dato-DXd in NSCLC but in January 2025, the companies had announced that the FDa granted a Prescription Drug User Fee Act (PDUFA) date and decision is expected by July 12, 2025. As a result, the product will initially be introduced for the treatment of EGFR-mutated NSCLC. Meanwhile, first-line trials combining ADCs with checkpoint inhibitors (e.g., EVOKE-02 and EVOKE-03) are showing early signs of benefit, keeping the potential of TROP-2 ADCs alive. 

Dato-DXd + rilvegostomig had encouraging activity as first-line treatment for patients with mNSCLC without actionable genomic alterations, with responses seen in both histologies and across all PD-L1 levels. The next few years will be important in showing whether TROP-2 ADCs can become a lasting part of NSCLC treatment or stay limited to smaller, specific patient groups.