Metastatic non-small cell lung cancer (NSCLC) poses a significant challenge in treatment, with a majority of cases being diagnosed at an advanced stage. Even among patients initially diagnosed at an earlier stage, a considerable proportion will eventually progress to metastatic disease within five years. DelveInsight 2023 estimates that there are roughly 200,000 NSCLC annual cases in the  United States with an estimated market opportunity of roughly USD 14 billion. This underscores the substantial burden of metastatic NSCLC on patients along with the excessive growth opportunity this particular indication has for pharmaceutical companies.

In addressing the unmet medical need for metastatic NSCLC patients who have progressed after platinum-based chemotherapy and anti-PD-(L)1 therapy, the EVOKE-01 trial holds significance as one of the pioneering ADC studies in this context. This trial compares TRODELVY (sacituzumab govitecan-hziy) against docetaxel, focusing on patients with disease progression during or after platinum-based treatment plus a checkpoint inhibitor.

According to findings presented at ASCO 2024, as of November 2023, a total of 603 patients had been randomized. The median follow-up was 12.7 months. Although the study did not reach statistical significance for overall survival (OS), notable findings emerged. Sacituzumab govitecan demonstrated a numerical improvement in OS, particularly in patients with both squamous and nonsquamous histology. In patients with high unmet medical needs whose tumors did not respond to the last anti-PD-(L)1-containing treatment, a meaningful OS improvement of 3.5 months was seen when treated with TRODELVY vs. docetaxel (mOS: 11.8 vs. 8.3 months). Patient-reported outcomes (PROs) were also favorable with sacituzumab govitecan compared to docetaxel. In terms of safety, sacituzumab govitecan exhibited a lower incidence of Grade ≥3 treatment-emergent adverse events (TEAE) compared to docetaxel, and fewer treatment-related adverse events led to discontinuation.

The insights gained from EVOKE-01 have implications not only for the TROP-2 ADC class but also for Gilead's development plan for sacituzumab govitecan in NSCLC. These findings offer promise for the advancement of safe and effective treatment options for metastatic NSCLC patients, addressing a critical gap in current therapeutic strategies.

KOL insights

“Treating patients with metastatic NSCLC who have progressed on available treatments continues to be a challenge. After progression, the standard of care for most patients is limited to single-agent chemotherapy, which offers modest benefits. The data, including the meaningful benefit observed in the sub-group of patients, are encouraging and warrants further investigation as these patients have a great unmet need.” –Expert Opinion.

“The data in metastatic NSCLC demonstrating TRODELVY’S activity continue to advance understanding of the potential to build on the impact for the patient.”–Expert Opinion.

Conclusion-

Despite significant strides in NSCLC treatment with immune checkpoint inhibitors (ICIs), challenges persist, especially for patients experiencing disease progression after initial ICI therapy. TROP2 has emerged as a promising target, yet leading antibody-drug conjugates (ADCs) in trials have shown suboptimal outcomes, necessitating further investigation.

Disappointing results were observed with datopotamab deruxtecan (Dato-dxd) in the TROPION-Lung01 trial. However, sacituzumab govitecan, another anti-TROP2 ADC, is currently undergoing late-phase trials for first-line NSCLC treatment. Although not achieving statistical significance, sacituzumab govitecan demonstrated numerical improvement in overall survival (OS) compared to docetaxel, with consistent results across major subgroups, including histology. Notably, sacituzumab govitecan showed clinically meaningful OS improvement in patients who did not respond to prior PD(L)-1inhibitors (IO) therapy and was better tolerated than docetaxel, with an observed safety profile consistent with expectations.