A randomized phase 2 trial of MM-121, a fully human monoclonal antibody targeting ErbB3, in combination with erlotinib in EGFR wild-type NSCLC patients.

Sequist, Lecia V.; López-Chávez, Ariel; Gray, Jhanelle E.; Harb, Wael A.; Modiano, Manuel; Jackman, David M.; Baggstrom, Maria Q.; Atmaca, Akin; Felip, Enriqueta; Provencio, Mariano; Cobo, Manuel; Kripas, Christopher J.; MacBeath, Gavin; Czibere, Akos; Cho, Byoung Chul; Park, Keunchil; Shepherd, Frances A.

doi:10.1200/jco.2014.32.15_suppl.8051

Cited by 26 publications

(20 citation statements)

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“…The addition of lumretuzumab may have caused an increase in the incidence of diarrhea compared with the incidence for cetuximab monotherapy [77.6% (any grade) and 12.2% (grade !3) compared with 12.7% (any grade) and 1.2% (grade !3) for cetuximab monotherapy (35)] and erlotinib monotherapy [76.1% (any grade) and 15.5% (grade !3) compared with 55% (any grade) and 6% (grade !3) for erlotinib monotherapy (36)]. The severity of diarrhea seemed increased at the highest lumretuzumab doses tested, that is, at 1,600 and 2,000 mg. A similar diarrhea side effect profile as in the current study was seen for combination treatments of other HER3-targeting antibodies with cetuximab (37,38) and erlotinib (38)(39)(40) in early clinical studies. Effects might be caused by a disinhibition of HER-modulated chloride channels in colonic epithelial cells leading to secretory diarrhea (41,42).…”

Section: Discussionsupporting

confidence: 81%

Phase Ib Study of Lumretuzumab Plus Cetuximab or Erlotinib in Solid Tumor Patients and Evaluation of HER3 and Heregulin as Potential Biomarkers of Clinical Activity

Meulendijks

Jacob

Voest

et al. 2017

Clinical Cancer Research

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This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas. The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of mRNA and mRNA and protein expression were investigated in a dedicated extension cohort of squamous non-small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib. Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor and mRNA levels were associated with a numerically higher disease control rate but not ORR. The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher mRNA expression levels..

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Section: Discussionsupporting

confidence: 81%

Phase Ib Study of Lumretuzumab Plus Cetuximab or Erlotinib in Solid Tumor Patients and Evaluation of HER3 and Heregulin as Potential Biomarkers of Clinical Activity

Meulendijks

Jacob

Voest

et al. 2017

Clinical Cancer Research

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“…28 Most recently, evidence from phase 2 clinical trials has suggested that adding an anti-HER3 antibody to other systemic anticancer agents leads to increased progression-free survival in various tumor types, including ovarian, 29 breast, 30 and non-small cell lung cancer. [31][32][33] These data clearly support the role of heregulin and anti-HER3 targeting in patients with HNSCC. However, to the best of our knowledge, there currently is very little information regarding the prognostic value of heregulin in patients with HNSCC.…”

Section: Introductionsupporting

confidence: 60%

“…Several clinical trials have now linked heregulin expression with rapid disease progression during the receipt of standard therapy as well as an improved response to HER3-targeted therapies in various tumor types, including ovarian, breast, and non-small cell lung cancers. [29][30][31][32][33] In preclinical models of HNSCC, we found that seribantumab (MM-121), a fully human antibody that blocks heregulin binding to HER3, exhibits an antitumor activity either alone or in combination with cetuximab. 27 Collectively, these findings strongly support the clinical investigation of HER3directed therapy in patients with HNSCC whose tumors exhibit high levels of heregulin mRNA.…”

Section: Discussionmentioning

confidence: 99%

Heregulin and HER3 are prognostic biomarkers in oropharyngeal squamous cell carcinoma

Qian

Jiang

Wang

et al. 2015

Cancer

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BACKGROUND Although heregulin and HER3 are frequently expressed at high levels in head and neck cancer, their prognostic value remains unclear. We explored the prognostic significance of heregulin/HER3 expression in patients with oropharyngeal squamous cell carcinoma (OPSCC), taking into account other HER family members as well as p16 status. METHODS Ninety-six primary tumor specimens from OPSCC patients were retrospectively collected and analyzed for heregulin mRNA by in situ hybridization and for HER3, EGFR, and HER2 by quantitative immunohistochemistry. Heregulin and HER3 mRNA levels were also examined among different tumor types using The Cancer Genome Atlas (TCGA) database. RESULTS High heregulin mRNA (> median) correlated significantly with poor OS (HR: 8.48; 95% CI: 2.17–33.17; P = 0.002) but not DFS (HR: 1.52; 95% CI: 0.64–3.65; P = 0.344), in OPSCC patients. Heregulin mRNA correlated negatively with OS in both p16-positive (P = 0.049) and p16-negative (P = 0.091) OPSCC patients on univariate analysis. High HER3 (> median) also correlated with poor OS (HR: 4.68; 95%CI: 1.47–14.90; P = 0.009) on multivariate analysis. EGFR levels independently correlated with DFS (P = 0.025) and inversely correlate with p16 status (P = 0.012). In addition, TCGA data showed that head and neck squamous cell carcinoma exhibits higher heregulin expression compared to other solid tumor types examined. CONCLUSION: High heregulin mRNA and high HER3 protein levels independently correlate with poor OS in OPSCC. These data support targeting HER3 in heregulin-high OPSCC and warrant further clinical investigation.

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“…Many therapeutic agents targeting HER3 have demonstrated promising results in preclinical studies, whereas the clinical use of those agents has not resulted in meaningful benefits . In contrast, the U3‐1402 anti‐HER3 antibody (patritumab) conjugated with topoisomerase demonstrated impressive efficacy with a 48% response rate in patients with HER3‐positive pretreated breast cancer .…”

Section: Discussionmentioning

confidence: 99%

“…We reported that its efficacy depends on heregulin level in cancer cells, as is generally observed for anti‐HER3 agents . Furthermore, some studies on anti‐HER3 antibodies such as seribantumab demonstrated their efficacy in patients with heregulin‐positive cancer; however, other clinical trials on anti‐HER3 antibodies did not report obvious relationships between efficacy and heregulin levels . Therefore, the clinical relationship between anti‐HER3 efficacy and heregulin expression is still controversial.…”

Section: Introductionmentioning

confidence: 94%

Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer

et al. 2019

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HER2‐targeted therapy, especially the anti‐HER2 antibody trastuzumab, is standard for HER2‐positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)‐dependent HER2‐HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2‐positive breast cancer. The anti‐HER2 antibody pertuzumab and anti‐HER3 antibody patritumab both target this heregulin–HER3‐HER2 complex in different ways. This study examined the anticancer efficacy of dual HER2 and HER3 blockade in trastuzumab‐resistant HER2‐positive breast cancer. HER2‐positive SKBR3 or BT474 cells overexpressing heregulin (SKBR3‐HRG, BT474‐HRG) were used to evaluate the efficacy of trastuzumab, pertuzumab, and patritumab in vitro by performing cell viability, immunoblotting, and clonogenic assays. The effects of these agents were then evaluated in vivo using BT474‐HRG and an intrinsic heregulin‐expressing and HER2‐positive JIMT‐1 xenograft models. SKBR3‐HRG and BT474‐HRG cells lost sensitivity to trastuzumab, which was accompanied by Akt activation. Unexpectedly, trastuzumab in combination with pertuzumab or patritumab also showed limited efficacy toward these cells. In contrast, trastuzumab/pertuzumab/patritumab triple treatment demonstrated potent anticancer efficacy, concomitant with strong repression of Akt. Finally, in heregulin‐expressing BT474‐HRG and JIMT‐1 xenograft models, the addition of pertuzumab and patritumab to trastuzumab also enhanced antitumor efficacy leading to tumor regression. The current study found that triple blockade of HER2 and HER3 using trastuzumab, pertuzumab, and patritumab could overcome resistance to trastuzumab therapy in heregulin‐expressing and HER2‐positive breast cancer, which could be exploited clinically.

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A randomized phase 2 trial of MM-121, a fully human monoclonal antibody targeting ErbB3, in combination with erlotinib in EGFR wild-type NSCLC patients.

Cited by 26 publications

References 0 publications

Phase Ib Study of Lumretuzumab Plus Cetuximab or Erlotinib in Solid Tumor Patients and Evaluation of HER3 and Heregulin as Potential Biomarkers of Clinical Activity

Phase Ib Study of Lumretuzumab Plus Cetuximab or Erlotinib in Solid Tumor Patients and Evaluation of HER3 and Heregulin as Potential Biomarkers of Clinical Activity

Heregulin and HER3 are prognostic biomarkers in oropharyngeal squamous cell carcinoma

Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer

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