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

Daniel Morgensztern, Benjamin Besse, Laurent Greillier, Rafael Santana-Davila, Neal Ready, Christine L. Hann, Bonnie S. Glisson, Anna F. Farago, Afshin Dowlati, Charles M. Rudin, Sylvestre Le Moulec, Satwant Lally, Sreeni Yalamanchili, Jurgen Wolf, Ramaswamy Govindan, David P. Carbone

Research output: Contribution to journalArticle

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 (3Lþ) 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 3Lþ SCLC, with associated toxicities.

Original languageEnglish (US)
Pages (from-to)6958-6966
Number of pages9
JournalClinical Cancer Research
Volume25
Issue number23
DOIs
StatePublished - Dec 1 2019

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Small Cell Lung Carcinoma
Safety
Immunohistochemistry
Rabbits
delta protein
Survival
Antibodies
Pleural Effusion
Fatigue
Neoplasms
Survival Rate
Biomarkers

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Morgensztern, Daniel; Besse, Benjamin; Greillier, Laurent; Santana-Davila, Rafael; Ready, Neal; Hann, Christine L.; Glisson, Bonnie S.; Farago, Anna F.; Dowlati, Afshin; Rudin, Charles M.; Le Moulec, Sylvestre; Lally, Satwant; Yalamanchili, Sreeni; Wolf, Jurgen; Govindan, Ramaswamy; Carbone, David P.

In: Clinical Cancer Research, Vol. 25, No. 23, 01.12.2019, p. 6958-6966.

Research output: Contribution to journalArticle

Morgensztern, D, Besse, B, Greillier, L, Santana-Davila, R, Ready, N, Hann, CL, Glisson, BS, Farago, AF, Dowlati, A, Rudin, CM, Le Moulec, S, Lally, S, Yalamanchili, S, Wolf, J, Govindan, R & Carbone, DP 2019, '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', Clinical Cancer Research, vol. 25, no. 23, pp. 6958-6966. https://doi.org/10.1158/1078-0432.CCR-19-1133
Morgensztern, Daniel ; Besse, Benjamin ; Greillier, Laurent ; Santana-Davila, Rafael ; Ready, Neal ; Hann, Christine L. ; Glisson, Bonnie S. ; Farago, Anna F. ; Dowlati, Afshin ; Rudin, Charles M. ; Le Moulec, Sylvestre ; Lally, Satwant ; Yalamanchili, Sreeni ; Wolf, Jurgen ; Govindan, Ramaswamy ; Carbone, David P. / 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. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 23. pp. 6958-6966.
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title = "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{\th}) 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{\th} SCLC, with associated toxicities.",
author = "Daniel Morgensztern and Benjamin Besse and Laurent Greillier and Rafael Santana-Davila and Neal Ready and Hann, {Christine L.} and Glisson, {Bonnie S.} and Farago, {Anna F.} and Afshin Dowlati and Rudin, {Charles M.} and {Le Moulec}, Sylvestre and Satwant Lally and Sreeni Yalamanchili and Jurgen Wolf and Ramaswamy Govindan and Carbone, {David P.}",
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TY - JOUR

T1 - Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer

T2 - Results from the phase II TrINITY study

AU - Morgensztern, Daniel

AU - Besse, Benjamin

AU - Greillier, Laurent

AU - Santana-Davila, Rafael

AU - Ready, Neal

AU - Hann, Christine L.

AU - Glisson, Bonnie S.

AU - Farago, Anna F.

AU - Dowlati, Afshin

AU - Rudin, Charles M.

AU - Le Moulec, Sylvestre

AU - Lally, Satwant

AU - Yalamanchili, Sreeni

AU - Wolf, Jurgen

AU - Govindan, Ramaswamy

AU - Carbone, David P.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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 (3Lþ) 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 3Lþ SCLC, with associated toxicities.

AB - 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 (3Lþ) 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 3Lþ SCLC, with associated toxicities.

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