Brain metastases are relatively common in patients with NSCLC that have spread to other parts of the body. Patients with brain mets may not live as long as those without.

Dato-DXd is a TROP-2 directed antibody-drug conjugate (ADC), designed using Daiichi Sankyo’s proprietary DXd ADC technology. It comprises a humanized anti-TROP2 IgG1 monoclonal antibody, attached to several topoisomerase I inhibitor payloads, an exatecan derivative, via tetrapeptide-based cleavable linkers.

The data presented at ESMO 2024 from TROPION-Lung01 trial, among 468 patients with NSQ NSCLC, 84 had brain metastases (43 on Dato-DXd, 41 on Docetaxel), and 384 did not. Baseline characteristics were generally balanced. For patients with brain metastases, the median age was 61 for Dato-DXd and 58 for Docetaxel, with 63% and 68% male, respectively. For those without brain metastases, the median age was 64 for Dato-DXd and 54 for Docetaxel, with 56% and 63% male, respectively.

Dato-DXd showed improved outcomes compared to Docetaxel. Median overall survival (OS) was 12.9 months with Dato-DXd vs. 8.9 months with Docetaxel in patients with brain metastases, and 14.8 months vs. 12.6 months in those without. Dato-DXd also significantly prolonged progression-free survival (PFS) compared to Docetaxel: 4.9 vs. 3.6 months in patients with brain metastases (HR 0.59) and 5.7 vs. 3.7 months in those without (HR 0.64). The objective response rate (ORR) was higher with Dato-DXd in both groups: 30% vs. 12% in patients with brain metastases, and 31% vs. 13% in those without. Additionally, 31% of patients with brain metastases on Dato-DXd had a duration of response (DOR) exceeding six months, compared to 20% with Docetaxel. Among patients without brain metastases, 8% on Dato-DXd had a DOR exceeding nine months, while none on Docetaxel did. Dato-DXd also resulted in fewer grade ≥3 serious treatment-related adverse events (TRAEs) and dose reductions or discontinuations compared to Docetaxel, regardless of brain metastasis status.

KOL insights

“There are two TROP-2 directed ADCs currently in development for patients with NSCLC. One is sacituzumab govitecan, this agent was in lung cancer back in 2017 and efforts to utilize it in the second line and the first line are being reignited. Dato-DXd also has been looked at as a single agent in a highly pretreated group of patients with NSCLC. We now have Phase III data looking at Dato-DXd versus docetaxel in the second line and data showing a PFS advantage in patients with non-squamous histology. Both TROP-2-directed ADCs have activity in the second line. Both have been looked at in the first line in small datasets and showed meaningful activity” - MD, US

Conclusion 

The results of Dato-DXd from TROPION-Lung01 presented at the ESMO 2024 showed that the Patients with NSQ NSCLC who received Dato-DXd tended to survive longer after the start of treatment with progression free survival, and overall survival compared with those who received docetaxel, regardless of whether they had brain metastasis at baseline. The safety of Dato-DXd was manageable in patients with NSQ NSCLC with and without baseline brain metastasis. The findings suggest that Dato-DXd can benefit patients with advanced NSQ NSCLC with or without brain mets.

The competition in the TROP2 ADC in NSCLC is getting more fierce. At present Gilead, and Daiichi Sankyo/AstraZeneca are at the forefront of the competition. In advanced NSCLC that had received prior treatment, Dato-DXd exhibited an improvement in overall survival that was clinically meaningful but not statistically significant. Gilead’s TRODELVY also failed in Phase III EVOKE-01 lung cancer study (not able to show a statistically meaningful OS benefit). At present, there is no clarity when the company is planning to file for approval in second-line setting. The company has not disclosed any timelines for filing. The Phase III TROPION-Lung01 study (NCT04656652) presented at ESMO 2024 supported the Biologics License Applications (BLA) of Dato-DXd, and a Prescription Drug User Fee Act (PDUFA) target action date is expected on December 20, 2024. Even though the PDUFA is set for the fourth quarter of 2024, the launch could be delayed. 

Dato-DXd is a better tolerated medication, despite some apparent differences in its toxicity profile. For patients with advanced non-squamous NSCLC eligible for second-line chemotherapy, it seems to be a -potentially useful new treatment. Looking at the current scenario, it can be expected that Dato-DXd is likely to become the first TROP2 ADC to enter the NSCLC market. Tapping into the broader NSCLC market, both with or without actionable genomic alterations, is Daiichi Sankyo/AstraZeneca's ambition. At present, Dato-DXd with or without Osimertinib is also being explored in TROPION-Lung14 (NCT06350097), and TROPION-Lung15 (NCT06417814) studies for the treatment of EGFRm locally advanced or metastatic NSCLC. Growth potential for Dato-DXd in NSCLC may be further accelerated by expansion in EGFR NSCLC. With these advancements, Dato-DXd stands out as a therapy that every other pharma company should keep an eye on.