DS-1062 Elicits Intriguing Early-Phase Data in Advanced NSCLC

Rebecca S. Heist, MD, MPH

The investigational Trop-2—targeting antibody-drug conjugate (ADC) DS-1062 demonstrated antitumor activity in unselected patients with unresectable, advanced non–small cell lung cancer (NSCLC) who are refractory to or relapsed following standard therapy or for whom no standard treatment is available, according to updated phase I findings presented at the 2019 World Conference on Lung Cancer.^1,2

Dose-escalation data demonstrated that the ADC elicited 12 partial responses (PRs) that were observed in a dose-dependent manner, which also included 5 confirmed PRs in 7 patients who received the drug at 8 mg/kg. Moreover, there was a trend toward response in patients whose tumors had Trop-2 expression, and the agent was also found to be well tolerated.

"There is a need for new treatment options to help patients with advanced non—small cell lung cancer that continues to progress on standard therapies, and these findings with DS-1062 in heavily pretreated patients are encouraging," study investigator Rebecca S. Heist, MD, MPH, medical oncologist, Massachusetts General Hospital Cancer Center, stated in a press release. "Further study in more patients at the recommended expansion dose will help further assess the potential for targeting Trop-2 with DS-1062 in NSCLC."

DS-1062, which has a drug-to-antibody ratio of 4, is an ADC designed to target and deliver chemotherapy inside cancer cells that express Trop-2 as a cell surface antigen. Preclinical data have shown that DS-1062 selectively binds to the Trop-2 receptor on tumor cell surface, and is then brought inside the cancer cell where lysosomal enzymes break down the tetrapeptide-based linker and release the DXd payload.

In the first-in-human open-label, phase I study (NCT03401385), investigators evaluated the safety and tolerability of DS-1062 in patients with unresectable relapsed/refractory advanced NSCLC who progressed on standard treatment or for whom no standard treatment is available. The dose-escalation phase of the trial assessed the safety and tolerability of increasing doses of DS-1062 with a goal to determine the maximum-tolerated dose (MTD) and recommended dose for expansion. The dose-expansion phase is evaluating the safety and tolerability of DS-1062 at the recommended dose for expansion and will enroll 40 additional patients with advanced NSCLC.

Patients who were eligible for enrollment had received prior therapy, including immune checkpoint inhibitors (86.5%), as well as EGFR inhibitors and ALK inhibitors. The data cutoff date was July 3, 2019, and 35 patients were ongoing in the trial as of August 20, 2019.

The primary endpoint is safety, and other endpoints include pharmacokinetics, objective response rate, duration of response, disease control rate, time to response, progression-free survival, overall survival, biomarker analysis, and immunogenicity.

Preliminary data from the trial, which were presented at the 2019 ASCO Annual Meeting, comprised efficacy findings for 35 evaluable patients who received DS-1062 at the dose levels between 0.27 mg/kg and 8.0 mg/kg.³ At the time of data cutoff date of April 12, 2019, results showed 3 confirmed PRs and 4 not yet confirmed PRs.

The updated efficacy data included 46 evaluable patients who received DS-1062 at 1 of 8 doses ranging from 0.27 mg/kg to 10.0 mg/kg, which showed 12 PRs—10 of which were confirmed and 2 that were early that were observed in a dose-dependent manner. Five of the confirmed PRs were observed among 7 patients (71.4%) at the 8 mg/kg dose, which was determined to be the recommended expansion dose. The other 2 patients receiving the 8 mg/kg dose experienced stable disease, and 6 of the 7 patients are continuing on the study.

Additionally, 35 patients were evaluable for Trop-2 expression via immunohistochemistry. Trop-2 expression trended higher in patients who had a PR. Following DS-1062 treatment, a genomic analysis also suggested a correlation with tumor reduction and SLFN11 expression, which was previously associated with topoisomerase I inhibitors response. Results also demonstrated a decrease in cell-free DNA in patients who had a PR and stable disease.

Regarding safety, there were updated findings for 52 patients who were evaluable for safety. DS-1062 was found to be well tolerated in doses up to the MTD and recommended expansion dose.

The most common, any-grade, treatment-emergent adverse events (TEAEs; ≥30%) included fatigue (36.5%) and nausea (36.5%), and 22 patients (42.3%) experienced at least 1 grade ≥3 TEAE. Dose-limiting toxicities (mucosal inflammation and stomatitis; n = 1 each) occurred in 2 patients at the 10 mg/kg dose and in 1 patient (rash maculopapular) at the 6 mg/kg dose. Two patients (3.8%) had to discontinue treatment due to TEAEs.

Serious TEAEs occurred in 14 patients (26.9%) regardless of causality. Moreover, 1 patient (1.9%) with disease progression who was treated at the 6.0 mg/kg dose developed an adverse event of special interest, which was grade 5 respiratory failure. However, the case was not determined to be interstitial lung disease (ILD). Since the data cutoff, 4 potential cases of ILD have been reported and are pending adjudication: one grade 2 pneumonitis (6.0 mg/kg dose), one grade 2 organizing pneumonia (8.0 mg/kg), one grade 2 pneumonitis (8.0 mg/kg), and one grade 5 respiratory failure in a patient with disease progression (8.0 mg/kg).

"These findings support DS-1062 as a potential Trop-2—targeting therapy for NSCLC and further reinforce the strength and flexibility of our DXd ADC platform, which enables each of our ADCs to be custom designed to potentially provide an optimal balance of safety and efficacy," Eric Slosberg, PhD, head, Global Translational Development, Oncology Research and Development, Daiichi Sankyo, the developer of the ADC, stated in the press release. "As the study advances, we will continue with our translational research to help uncover underlying factors contributing to patient response and identify patients most likely to respond to DS-1062."

The study is currently enrolling patients in the United States and Japan.

References

1. Heist RS, Sands J, Shimizu, et al. First-in-human phase 1 study of DS-1062a (TROP2 antibody-drug conjugate) in patients with advanced non-small cell lung cancer. Presented at: 2019 International Association for the Study of Lung Cancer World Conference on Lung Cancer; September 7 to 10, 2019; Barcelona, Spain. Abstract MA25.10.
2. Updated Clinical Results and New Biomarker Analyses Presented for Daiichi Sankyo's DS-1062 in Patients with Advanced NSCLC at 2019 World Conference on Lung Cancer. Daiichi Sankyo Company, Limited. Published September 10, 2019. https://bit.ly/2kwSC3H. Accessed September 10, 2019.
3. Daiichi Sankyo Presents Preliminary Phase 1 Data for TROP2 Targeting ADC DS-1062 in Patients with Non-Small Cell Lung Cancer at 2019 ASCO Annual Meeting. Daiichi Sankyo Company, Limited. Published June 3, 2019. https://bit.ly/2kGEuop. Accessed June 3, 2019.