Dato-DXd Misses OS End Point in TROPION-Lung01 Study for NSCLC

Jacob Sands, MD

Treatment with the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (dato-DXd) did not significantly improve overall survival (OS) compared with docetaxel for patients with non–small cell lung cancer (NSCLC), according to findings from the final OS analysis of the TROPION-Lung 01 study (NCT04656652) presented at the IASLC 2024 World Conference on Lung Cancer.¹

Findings from the intent-to-treat (ITT) population from the open-label study showed a median OS of 12.9 months (95% CI, 11.0-13.9) with dato-DXd compared with 11.8 months (95% CI, 10.0-12.8) with docetaxel (HR, 0.94; 0.78-1.14; P = .530). In those with nonsquamous NSCLC, the median OS with dato-DXd was 14.6 months (95% CI, 12.4-16.0) compared with 12.3 months with docetaxel (95% CI, 10.7-14.0), representing a non-statistically significant 16% reduction in the risk of death (HR, 0.84; 95% CI, 0.68-1.05). There were significantly fewer grade 3 or greater treatment-related adverse events (TRAEs) with dato-DXd compared with docetaxel (26% vs 42%, respectively).

“Dato-DXd did not meet its OS end point, but the therapy has many positive upsides that make it an option for some patients with nonsquamous NSCLC,” lead investigator Jacob Sands, MD, oncology medical director at Dana-Farber Cancer Institute and assistant professor at Harvard Medical School, said in a statement. “The overall safety and efficacy profile of dato-DXd supports its use as a potential new therapeutic option for patients with nonsquamous NSCLC who are eligible for subsequent therapy.”

In the phase 3 TROPION-Lung01 study, patients were randomized to receive dato-DXd at 6 mg/kg every 3 weeks (Q3W; n = 299) or docetaxel at 75 mg/m² Q3W (n = 305). The study had dual primary end points of OS and progression-free survival (PFS). Secondary end points focused on response rate and safety. Actionable mutations, histology, geography, and prior immune checkpoint inhibitor treatment were stratification factors.

Patient characteristics were balanced between arms. In the dato-DXd arm, the median age was 63 years (range, 26-84), most were White (41%) or Asian (40%), and most had an ECOG performance status of 1 (70%) with others having a score of 0 (30%). The most common histology was nonsquamous (78%) and 80% of patients were current or former smokers. Actionable genomic alterations were present in 17% of those enrolled. Nearly half of patients had received at least 1 prior line of therapy (56%), with 44% having received 2 or more. Brain metastasis was present in 26% of patients at baseline in the dato-DXd arm compared with 30% of those in the docetaxel group.

The median PFS was 4.4 months with dato-DXd compared with 3.7 months for docetaxel (HR, 0.75; 95% CI, 0.62-0.91; P = .004). In those with nonsquamous NSCLC (n = 468), the median PFS was 5.5 months with dato-DXd compared with 3.6 months with docetaxel (HR, 0.63; 95% CI, 0.51-0.79). In this subgroup, the overall response rate (ORR) was 31.2% with dato-DXd compared with 12.8% with docetaxel.

In the ITT analysis, 53.8% of patients remained alive at 12 months with dato-DXd compared with 49.9% with docetaxel. At 24 months, 25.8% and 20.2% were alive in the dato-DXd and docetaxel arms, respectively. Similar findings were seen across subgroup analyses, with some non-statistical variation in hazard ratios. In those with squamous NSCLC, the median OS with dato-DXd was 7.6 months (95% CI, 5.0-11.0) compared with 9.4 months (95% CI, 7.2-12.5) with docetaxel (HR, 1.32; 95% CI, 0.91-1.92).

In those with nonsquamous histology, numerical improvements in OS were seen regardless of actionable mutation status. For those with a mutation, the median OS was 15.6 months with dato-DXd compared with 9.8 months with docetaxel (HR, 0.65; 95% CI, 0.40-1.08). In those without an actionable mutation, the median OS was 13.6 months with dato-DXd and 12.3 months with docetaxel (HR, 0.89; 95% CI, 0.70-1.13).

Sensitivity analyses were performed to examine the effect of subsequent anti-cancer therapy specifically in the nonsquamous histology subgroup, which found no meaningful impact on OS. When removing the effects of all posttreatment anti-cancer therapies in both arms, the median OS was 12.1 months (95% CI, 7.5-17.3) with dato-DXd and 9.6 months (95% CI, 7.5-13.0) with docetaxel (HR, 0.79; 95% CI, 0.54-1.15).

No late onset toxicities were observed in the final OS analysis, with an additional 11 months since the prior PFS cutoff. Serious TRAEs were seen in 11% of patients treated with dato-DXd vs 13% of those in the docetaxel arm. Fewer dose reductions were required in the dato-DXd arm (20%) compared with docetaxel (30%), and treatment discontinuations were also less common with dato-DXd (8%) compared with docetaxel (12%). The median treatment duration was 4.2 months with dato-DXd compared with 2.8 months with docetaxel.

One of the leading TRAEs of concern with dato-DXd is interstitial lung disease (ILD) or pneumonitis, which occurred in 9% of those treated with the ADC compared with 4% treated with the chemotherapy. Of these cases, 4% were deemed grade 3 or greater in the dato-DXd arm compared with 1% in the docetaxel group. The most common TRAEs were stomatitis, nausea, alopecia, and decreased appetite. Febrile neutropenia was more common in the chemotherapy arm, with 0.7% of those treated with dato-DXd experiencing this TRAE compared with 7.2% of those receiving docetaxel.

Continued investigation of dato-DXd is underway, including the investigation of a biomarker of response. Data also presented at the IASLC 2024 World Conference on Lung Cancer showed potential for using TROP2 normalized membrane ratio using quantitative continuous scoring.² Although this has not yet been applied to the OS data, in those testing positive for this biomarker, the ORR was 32.7% with dato-DXd compared with 10.3% with docetaxel and the median PFS was 6.9 months compared with 4.1 months (HR, 0.57; 95% CI, 0.41-0.79).

References

1. Sands J, Lisberg A, Okamoto I, et al. Datopotamab Deruxtecan Vs Docetaxel in Patients with Non-Small Cell Lung Cancer: Final Overall Survival from TROPIONLung01. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-11, 2024; San Diego, CA. Abstract 2640.
2. 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.