TROP2 Membrane Ratio Effectively Predicts Dato-DXd Outcomes in NSCLC

Marina Chiara Garassino, MD

A novel digitally defined biomarker measuring TROP2 normalized membrane ratio (NMR) by quantitative continuous scoring (QCS) was shown to be predictive for improved overall response rate (ORR) and longer progression-free survival (PFS) in patients with non–small cell lung cancer (NSCLC) treated with datopotamab deruxtecan (dato-DXd) compared with docetaxel, according to results from an exploratory analysis from the TROPION-Lung 01 study (NCT04656652) presented at the IASLC 2024 World Conference on Lung Cancer.

In patients with tumors that tested TROP2 QCS-NMR+, the ORR with dato-DXd was 32.7% compared with 10.3% for docetaxel; the median PFS was 6.9 months compared with 4.1 months for docetaxel (HR, 0.57; 95% CI, 0.41-0.79). In the TROP2 QCS-NMR– group, the ORRs were 16.9% and 15.1%, respectively. In the TROP2 QCS-NMR– arm, the median PFS was 2.9 months with dato-DXd and 4.0 months for docetaxel (HR, 1.16; 95% CI, 0.79-1.70). The rates of adverse events (AEs) were similar regardless of the biomarker status.

“This is the first TROP2 biomarker and, of note, I think this is the first computational pathology biomarker that I recall in lung cancer,” principal investigator Marina Chiara Garassino, MD, from the University of Chicago, said during a presentation of the results. “I think this is really a breakthrough, because it's the first biomarker done with digital pathology, and it is a very easy process. This will open a new era of biomarker discovery and biomarker development in lung cancer.”

In the TROPION-Lung01 study, 299 patients were randomized to 6 mg/kg every 3 weeks (Q3W) of dato-DXd and 305 received 75 mg/m2 of docetaxel Q3W. Three hundred fifty-two patients with stage IIIB, IIIC, and IV NSCLC were assessable for QCS-NMR status in the study data. There were 107 patients with TROP2 QCS-NMR+ status in the dato-DXd arm and 107 in the docetaxel group. In the negative group, there were 65 patients in the dato-DXd group and 73 patients in the docetaxel arm.

For the analysis, an immunohistochemistry assay for TROP2 was used followed by creation of whole slide images (WSI). The WSIs were then analyzed using a pathologist-trained deep learning algorithm that measured the optical density of the membrane and cytoplasm. The optical density was then used to calculate NMR using membrane density divided by membrane density plus cytoplasm density. Positivity was considered those with 75% or more tumor cells with a TROP2 NMR of less than or equal to 0.5585.

“In order to understand the biomarker, it is important to go back to the mechanism of action of dato-DXd. The drug must bind to the membrane and then must be internalized in the cytoplasm. This way it can release the cytotoxic payload and the cytotoxic effect,” said Garassino. "This biomarker, for the time being, only applies to dato-DXd."

Baseline characteristics in the 352 patients with known TROP2 QCS-NMR status were like the 604 patients enrolled in the full TROPION-Lung01 study, with some areas of difference. In the positive group, 14% of patients had brain metastasis at baseline in the dato-DXd group compared with 17% in the docetaxel group. In the negative arm, 18% of those in the dato-DXd group had brain metastasis compared with 12% in the docetaxel group. Additionally, those receiving 3 or more prior lines of therapy were also inconsistent, with this applying to 7% of those receiving dato-DXd in the TROP2 QCS-NMR+ group versus 12% in the docetaxel group. No patients had received 3 or more prior lines of therapy in the dato-DXd group in the negative arm compared with 5% in the docetaxel group.

“I think we are aware that dato-DXd is apparently more effective in the population of nonsquamous and in fact you can see that the proportion of patients who are NMR+ in their tumor is higher in the nonsquamous compared to the squamous population," Garassino said.

In biomarker-evaluable patients with nonsquamous, non-actionable genetically altered NSCLC (n = 221), the ORR with dato-DXd was 36.8% in the TROP2 QCS-NMR+ group compared with 15.3% in the docetaxel arm. The median PFS was 7.2 months with the investigational agent compared with 4.1 months for the chemotherapy (HR, 0.52; 95% CI, 0.35-0.78). Within this same population in the TROP2 QCS-NMR– arm, the ORR was 22.5% with dato-DXd compared with 12.2% with docetaxel. The median PFS was 4.0 and 4.4 months for dato-DXd and docetaxel, respectively (HR, 1.22; 95% CI, 0.74-2.00).

In the TROP2 QCS-NMR+ group, treatment-related AEs (TRAEs) of grade 3 or higher in severity were experienced by 30% of those in the dato-DXd arm compared with 46% of those in the docetaxel group. In the negative group, grade 3 or more TRAEs were experienced by 22% of those in the dato-DXd arm compared with 27% treated with docetaxel. The most common adverse events were stomatitis, ocular surface events, and adjudicated interstitial lung disease. This was not significantly different then the full population, Garassino noted.

Outside of the TROPION-Lung01 study, the QCS-NMR biomarker was also examined in findings from the TROPION-PanTumor01 study (NCT03401385), which looked at dato-DXd across types of cancer. In this analysis reported by Garassino, among 84 patients testing positive for the marker, the ORR was 22.6% with dato-DXd compared with 3.2% in those testing negative for the marker. The median PFS in those testing positive was 5.5 months compared with 2.9 months for those who were negative (P = .00054).

“Many trials in the future will incorporate this as a biomarker, and there are a couple trials looking at this from the beginning and this will be incorporated into multiple other trials exploring dato-DXd,” said Garassino. One such trial that is currently under way is AVANZAR (NCT05687266) that is exploring dato-DXd in the frontline setting; however, Garassino felt confident this new biomarker would be added to many other trials.

Reference

1. Garassino MC, Sands J, Paz-Ares L, et al. Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung01. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-11, 2024; San Diego, CA. Abstract 4037.