Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer

Lecia V. Sequist, Jhanelle Elaine Gray, Wael A. Harb, Ariel Lopez-Chavez, Robert C. Doebele, Manuel R. Modiano, David Michael Jackman, Maria Quintos Baggstrom, Akin Atmaca, Enriqueta Felip, Mariano Provencio, Manuel Cobo, Bambang Adiwijaya, Geoffrey Kuesters, Walid S. Kamoun, Karen Andreas, J. Marc Pipas, Sergio Santillana, Byoung Chul Cho, Keunchil ParkFrances A. Shepherd

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Abstract

Background: Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non-small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG. Materials and Methods: Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. Results: One hundred twenty-nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression-free survival (PFS) in the unselected intent-to-treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37–1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p =.1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16–0.76; p =.008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97–4.76; p =.059, HRG-by-treatment interaction, p value =.0016). Conclusion: The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). Implications for Practice: The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.

Original languageEnglish
Pages (from-to)1095-1102
Number of pages8
JournalOncologist
Volume24
Issue number8
DOIs
Publication statusPublished - 2019 Jan 1

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Non-Small Cell Lung Carcinoma
docetaxel
Neuregulin-1
Confidence Intervals
Safety
Erlotinib Hydrochloride
seribantumab
Messenger RNA
Disease-Free Survival
Neoplasms
Biomarkers
Large-Core Needle Biopsy
Therapeutics
histidine-rich proteins
Epidermal Growth Factor Receptor
Population
Adenocarcinoma
Down-Regulation
Immunoglobulin G
Monoclonal Antibodies

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Sequist, L. V., Gray, J. E., Harb, W. A., Lopez-Chavez, A., Doebele, R. C., Modiano, M. R., ... Shepherd, F. A. (2019). Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer. Oncologist, 24(8), 1095-1102. https://doi.org/10.1634/theoncologist.2018-0695
Sequist, Lecia V. ; Gray, Jhanelle Elaine ; Harb, Wael A. ; Lopez-Chavez, Ariel ; Doebele, Robert C. ; Modiano, Manuel R. ; Jackman, David Michael ; Baggstrom, Maria Quintos ; Atmaca, Akin ; Felip, Enriqueta ; Provencio, Mariano ; Cobo, Manuel ; Adiwijaya, Bambang ; Kuesters, Geoffrey ; Kamoun, Walid S. ; Andreas, Karen ; Pipas, J. Marc ; Santillana, Sergio ; Cho, Byoung Chul ; Park, Keunchil ; Shepherd, Frances A. / Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer. In: Oncologist. 2019 ; Vol. 24, No. 8. pp. 1095-1102.
@article{05e2d8c1fd4540b88fba06022b3c5609,
title = "Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer",
abstract = "Background: Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non-small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG. Materials and Methods: Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. Results: One hundred twenty-nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression-free survival (PFS) in the unselected intent-to-treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95{\%} confidence interval [CI], 0.37–1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95{\%} CI, 0.846 to 2.301; p =.1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95{\%} CI, 0.16–0.76; p =.008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95{\%} CI, 0.97–4.76; p =.059, HRG-by-treatment interaction, p value =.0016). Conclusion: The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). Implications for Practice: The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.",
author = "Sequist, {Lecia V.} and Gray, {Jhanelle Elaine} and Harb, {Wael A.} and Ariel Lopez-Chavez and Doebele, {Robert C.} and Modiano, {Manuel R.} and Jackman, {David Michael} and Baggstrom, {Maria Quintos} and Akin Atmaca and Enriqueta Felip and Mariano Provencio and Manuel Cobo and Bambang Adiwijaya and Geoffrey Kuesters and Kamoun, {Walid S.} and Karen Andreas and Pipas, {J. Marc} and Sergio Santillana and Cho, {Byoung Chul} and Keunchil Park and Shepherd, {Frances A.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1634/theoncologist.2018-0695",
language = "English",
volume = "24",
pages = "1095--1102",
journal = "Oncologist",
issn = "1083-7159",
publisher = "AlphaMed Press",
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Sequist, LV, Gray, JE, Harb, WA, Lopez-Chavez, A, Doebele, RC, Modiano, MR, Jackman, DM, Baggstrom, MQ, Atmaca, A, Felip, E, Provencio, M, Cobo, M, Adiwijaya, B, Kuesters, G, Kamoun, WS, Andreas, K, Pipas, JM, Santillana, S, Cho, BC, Park, K & Shepherd, FA 2019, 'Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer', Oncologist, vol. 24, no. 8, pp. 1095-1102. https://doi.org/10.1634/theoncologist.2018-0695

Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer. / Sequist, Lecia V.; Gray, Jhanelle Elaine; Harb, Wael A.; Lopez-Chavez, Ariel; Doebele, Robert C.; Modiano, Manuel R.; Jackman, David Michael; Baggstrom, Maria Quintos; Atmaca, Akin; Felip, Enriqueta; Provencio, Mariano; Cobo, Manuel; Adiwijaya, Bambang; Kuesters, Geoffrey; Kamoun, Walid S.; Andreas, Karen; Pipas, J. Marc; Santillana, Sergio; Cho, Byoung Chul; Park, Keunchil; Shepherd, Frances A.

In: Oncologist, Vol. 24, No. 8, 01.01.2019, p. 1095-1102.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer

AU - Sequist, Lecia V.

AU - Gray, Jhanelle Elaine

AU - Harb, Wael A.

AU - Lopez-Chavez, Ariel

AU - Doebele, Robert C.

AU - Modiano, Manuel R.

AU - Jackman, David Michael

AU - Baggstrom, Maria Quintos

AU - Atmaca, Akin

AU - Felip, Enriqueta

AU - Provencio, Mariano

AU - Cobo, Manuel

AU - Adiwijaya, Bambang

AU - Kuesters, Geoffrey

AU - Kamoun, Walid S.

AU - Andreas, Karen

AU - Pipas, J. Marc

AU - Santillana, Sergio

AU - Cho, Byoung Chul

AU - Park, Keunchil

AU - Shepherd, Frances A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non-small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG. Materials and Methods: Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. Results: One hundred twenty-nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression-free survival (PFS) in the unselected intent-to-treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37–1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p =.1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16–0.76; p =.008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97–4.76; p =.059, HRG-by-treatment interaction, p value =.0016). Conclusion: The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). Implications for Practice: The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.

AB - Background: Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non-small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG. Materials and Methods: Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. Results: One hundred twenty-nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression-free survival (PFS) in the unselected intent-to-treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37–1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p =.1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16–0.76; p =.008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97–4.76; p =.059, HRG-by-treatment interaction, p value =.0016). Conclusion: The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). Implications for Practice: The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.

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