Efficacy and Safety of Rovalpituzumab Tesirine in Third-Line and Beyond Patients with DLL3-Expressing, Relapsed/Refractory Small-Cell Lung Cancer: Results From the Phase II TRINITY Study

Abstract

Purpose: Although extensive-stage small-cell lung cancer (SCLC) is highly responsive to first-line therapy, virtually all patients develop resistance with short survival. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting delta-like 3 protein (DLL3). This open-label, single-arm, phase II study (TRINITY) assessed safety and efficacy of Rova-T in patients with DLL3-expressing SCLC in the third-line and beyond (3L+) setting.

Patients and methods: Patients with DLL3-expressing SCLC (determined by mouse antibody immunohistochemistry [IHC] assay), and ≥2 prior regimens, received 0.3 mg/kg Rova-T once every 6 weeks for two cycles. During study, a rabbit antibody IHC assay was developed and used for the final analysis, with DLL3-positive and DLL3-high defined as ≥25% and ≥75% of tumor cells positive for DLL3, respectively. The primary endpoints were objective response rate (ORR) and overall survival (OS).

Results: Among 339 patients enrolled, 261 (77%) had two prior lines of therapy and 78 (23%) had ≥3. DLL3-high and DLL3-positive tumors by rabbit IHC were seen in 238 (70%) and 287 (85%) patients, respectively. The remaining 52 (15%) were DLL3-negative only by rabbit IHC or had missing results. ORR was 12.4%, 14.3%, and 13.2% in all, DLL3-high, and DLL3-positive patients, respectively. Median OS was 5.6 months in all patients and 5.7 months in DLL3-high patients. The most common adverse events (AE) were fatigue, photosensitivity reaction, and pleural effusion. Grade 3-5 AEs were seen in 213 (63%) patients.

Conclusions: Rova-T is the first targeted agent in SCLC to use DLL3, a novel biomarker. However, results demonstrate modest clinical activity in 3L+ SCLC, with associated toxicities.

Trial registration: ClinicalTrials.gov NCT02674568.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

D. Morgensztern is an employee/paid consultant for Abbvie, Bristol-Myers Squibb, Takeda, and PharmaMar. B. Besse reports receiving commercial research grants from Abbvie. R. Santana-Davila reports receiving commercial research grants from and is an advisory board member/unpaid consultant for Abbvie. N. Ready is an employee/paid consultant for Abbvie, Bristol-Myers Squibb, Merck, AstraZeneca, Celgene, G1 therapeutics, Gene-tech, EMDSerano, and Tesaro, reports receiving commercial research grants from Merck, and speakers bureau honoraria from Bristol-Myers Squibb and Celgene. C.L. Hann is an employee/paid consultant for AbbVie, Bristol-Myers Squibb, Ascentage, and Genentech, and reports receiving commercial research grants from AbbVie, Bristol-Myers Squibb, Merrimack, and GlaxoSmithKline. A.F. Farago is an employee/paid consultant for AbbVie, Stemcentrx, Pharmamar, Bristol-Myers Squibb, Loxo, Bayer, Boehringer Ingelheim, AstraZeneca, Genentech, and Roche, and reports receiving other commercial research support from AbbVie, AstraZeneca, Pharmamar, Genentech/Roche, Bayer, Amgen, Bristol-Myers Squibb, and Merck. A. Dowlati is an advisory board member/unpaid consultant for Abbvie, Takeda, Seattle Genetics, and Bristol-Myers Squibb. C.M. Rudin is an employee/paid consultant for AbbVie, Amgen, Ascentage, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, PharmaMar, Vavotek, Bridge, and Harpoon. S. Lally is an employee/paid consultant for and holds ownership interest (including patents) in AbbVie. S. Yalamanchili holds ownership interest (including patents) in AbbVie.J. Wolf is an employee/paid consultant for AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Blueprint, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Roche, and Takeda, and reports receiving commercial research grants from Bristol-Myers Squibb, Janssen, MSD, Novartis, and Pfizer. R. Govindan is an employee/paid consultant for Jounce Therapeutics and Achilles, and reports receiving speakers bureau honoraria from Genentech and Amgen. D.P. Carbone is an employee/paid consultant for AbbVie, Adaptimmune, Agenus, Amgen, Ariad, AstraZeneca, Biocept, Boehringer Ingelheim, Bristol Myers-Squibb, Celgene, EMD Serono, Foundation Medicine, Genentech/Roche, Gritstone, Guardant Health, Inovio, Merck, MSD, Novartis, Palobio-farma, Pfizer, prIME Oncology, and Takeda, and reports receiving commercial research grants from Bristol Myers-Squibb.

©2019 American Association for Cancer Research.

Figures

Figure 1.

CONSORT diagram.

Figure 2.

Survival in DLL3-high patients. A, Overall survival. B, Progression-free survival by Central Radiographic Assessment. Mo, months.

Figure 3.

Change in target lesions from baseline. Percentage of change in target lesions from baseline measured by RECIST v1.1 in 304 patients who had a baseline scan and at least one follow-up scan with an evaluable response. Dotted line at 20% indicates threshold for PD, and dotted line at −30% indicates threshold for PR. Response category determined by Central Radiographic Assessment.