Table 1.
Monoclonal antibodies against HER3 under clinical development
| Study population | Clinical Trial, phase | Adverse events | Status, conclusion (references) |
|---|---|---|---|
| Lumretuzumab (RG7116, RO5479599, GE-huMab-HER3) | |||
| Advanced or metastatic NSCLC | NCT02204345, phase I + II | Gastrointestinal, hematological and nervous system toxicities, but generally mild and manageable |
Terminated. No results posted Efficacy of lumretuzumab + carboplatin + paclitaxel is like chemotherapy alone [83] |
| Metastatic BC expressing HER3 and HER2 | NCT01918254, phase Ib | Diarrhea and hypokalemia |
Completed. No results posted Lumretuzumab + pertuzumab + paclitaxel was related with a serious incidence of diarrhea that cannot warrant further clinical development [84] |
| Metastatic and/or locally advanced malignant HER3 + solid tumors of epithelial cell origin | NCT01482377, phase I | Gastrointestinal and skin toxicities |
Completed. No results posted Moderate clinical activity was observed with toxicity manageable [85, 86] |
| ISU104 | |||
|
Advanced solid tumors Dose escalation study (PART I) Dose-expansion study (PART II) |
NCT03552406, phase I |
PART I: Oral mucositis, pruritus, diarrhea and fatigue PART II: anorexia, mucositis oral and diarrhea in monotherapy and diarrhea and acneiform rash in combination with cetuximab |
Active, not recruiting PART I: ISU104 was well tolerated up to 20 mg/kg/day without DLT and showed disease control rate of 60% [87] PART II: ISU104 monotherapy or with cetuximab was safe with promising clinical outcomes in recurrent or metastatic HNSCC treated with the combination [88] |
| CDX-3379 (KTN3379) | |||
| Advanced cancer | NCT02014909, phase I | Diarrhea, fatigue, nausea and rash |
Completed. No results posted CDX-3379 can be combined in safety with cetuximab, erlotinib, vemurafenib or trastuzumab at 15 to 20 mg/kg [89] |
| HNSCC | NCT02473731, phase I | Diarrhea, fatigue and acneiform dermatitis, but mild or moderate |
Completed. No results posted CDX-3379 was well tolerated and associated with tumor regression [90] |
| Advanced Stage NRAS mutant and BRAF/NRAS wildtype melanoma | NCT03580382, phase I + II | Terminated (Per regulatory coordinator, the sponsor is no longer supporting the study). Study results available online | |
| Advanced HNSCC | NCT03254927, phase II |
Completed. Resulted submitted CDX-3379 in combination with cetuximab is well tolerated with signs of antitumor activity [91] |
|
| Thyroid cancer | NCT02456701, phase I |
Completed. No results posted Vemurafenib + CDX-3379 is safe and enhance efficacy for RAI uptake [92] |
|
| AV-203 (CAN017) | |||
| Metastatic or advanced solid tumors | NCT01603979, phase I |
Completed. No results posted AV-203 was well tolerated. RP2D is 20 mg/kg IV every 2 weeks. The PR in a patient with squamous NSCLC guarantees future testing of AV-203 in this indication [93] |
|
| GSK2849330 | |||
| Advanced HER3 + solid tumors | NCT01966445, phase I | Drug tolerated with no major issues |
Completed. Study results available online GSK2849330 has durable response in an exceptional responder with an advanced CD74–NRG1-rearranged IMA [94] |
| Advanced HER3 + solid tumors | NCT02345174, phase I | Decreased appetite and diarrhea |
Completed. No results posted Immuno-positron emission tomography reveals good tumor uptake in all evaluable patients. Despite the restricted number of patients, an exploratory ID50 of 2 mg/kg and ID90 of 18 mg/kg have been reported [95] |
| Seribantumab (MM-121, SAR256212) | |||
| Advanced NSCLC | NCT00994123, phase I + II | Diarrhea, rash, decreased appetite, fatigue and nausea |
Completed. Study results available online Phase I: No maximum tolerated dose was determined and the AE profile was similar between comparative treatment Phase II: there was no significant difference in PFS between monotherapy or combination therapy. However, retrospective analyses suggest that detectable NRG mRNA levels identified patients who may benefit from MM-121 [96] |
| NSCLC expressing NRG | NCT02387216, phase II | Diarrhea, fatigue and neutropenia in the combination treatment |
Terminated (Based on the preliminary results seen during interim analysis, which were confirmed in the final analysis, the Sponsor terminated the study) Seribantumab does not improve PFS when added to docetaxel [97] |
| CRC, HNSCC, NSCLC, TNBC and other tumors with EGFR dependence | NCT01451632, phase I |
Part 1: fatigue, dermatitis acneiform, hypomagnesemia, diarrhea, decreased appetite and hypokalemia Part 2: diarrhea, hypokalemia, nausea, fatigue, hypomagnesemia, decreased appetite, dermatitis acneiform, mucosal inflammation, dehydration and weight decrease |
Completed. Study results available online Unlike doublet treatment, seribantumab + cetuximab + irinotecan was difficult to tolerate. However, MM121 + cetuximab with and without irinotecan had no activity in the vast majority patients with prior exposure to EGFR directed therapy [98, 99] |
| Advanced gynecologic and breast cancers | NCT01209195, phase I | Completed. Study results available online | |
| ER + , HER2- BC and TNBC | NCT01421472, phase II | Completed. Study results available online | |
| Platinum resistant or refractory recurrent/advanced ovarian cancers | NCT01447706, phase II | Diarrhea, vomiting, stomatitis and mucosal inflammation |
Completed. Study results available online MM-121 + paclitaxel was no more effective than paclitaxel alone in prolonging nor OS neither PFS [100]. Exploratory analyses suggest that patients with detectable NRG and low HER2 might benefit from this combination [101] |
| Locally advanced or metastatic ER + and/or PR + and HER2- BC | NCT01151046, phase II | Diarrhea, nausea, fatigue and arthralgia |
Completed. Study results available online The addition of MM-121 to exemestane did not significantly prolong PFS in the unselected population [102] |
| CRC, NSCLC and HNSCC | NCT02538627, phase I | Terminated (Sponsor decision). No results posted | |
| Advanced solid tumors | NCT00734305, phase I | Completed. Study results available online | |
| Advanced solid tumors | NCT01447225, phase I | Diarrhea, nausea, fatigue, anemia, vomiting, hypokalemia, decreased appetite, thrombocytopenia, peripheral edema, neutropenia and constipation |
Completed. Study results available online MM-121 can be administrated with gemcitabine, pemetrexed, cabazitaxel and carboplatin [103] |
| Postmenopausal women with metastatic BC | NCT03241810, phase II | Terminated (Merrimack Inc. terminated the trial early due to business decision). Study results available online | |
| Locally advanced or metastatic solid tumors | NCT01436565, phase I | Completed. No results posted | |
| NRG1 gene fusion positive advanced solid tumors | NCT04383210, phase II | Recruiting | |
| An NRG1 fusion positive metastatic pancreatic cancer patient | NCT04790695, phase II | Completed. No results posted | |
| Patritumab (AMG-888, U3-1287) | |||
| Advanced, refractory solid tumors | NCT01957280, phase I | The most frequently reported treatment-related AEs were gastrointestinal |
Completed. No results posted Patritumab produced by a new manufacturing process was well tolerated with no anti–patritumab neutralizing antibodies formation and with normal bioavailability [104] |
| EGFR wild-type subjects with locally advanced or metastatic NSCLC who have progressed on at least one prior systemic therapy | NCT02134015, phase III | In placebo + erlotinib the most frequent AEs were rash, diarrhea and fatigue, in patritumab + erlotinib were diarrhea, rash and decreased appetite |
Terminated (Pre-defined criteria for continuation were not reached). Study results available online Patritumab + erlotinib apparently do not get better results of placebo + erlotinib |
| Recurrent or metastatic HNSCC | NCT02633800, phase II | Rash, anemia, neutropenia, hypomagnesemia and nausea |
Terminated (Trial was terminated by sponsor due to lack of efficacy). Study results available online Patritumab + cetuximab + platinum was safe but not more efficacious than cetuximab + platinum [105] |
| EGFR treatment naïve subjects with advanced NSCLC who have progressed on at least one prior chemotherapy | NCT01211483, phase I + II | AE grade > 3 included diarrhea and rash |
Completed. Study results available online Patritumab improved PFS in the NRG high, but not in the ITT population [106] |
| Recurrent or metastatic HNSCC | NCT02350712, phase I | Skin and subcutaneous tissue disorders |
Completed. No results posted Patritumab (18 mg/kg loading dose, 9 mg/kg maintenance dose) with cetuximab and platinum therapy was tolerated and active in HNSCC [107] |
| Advanced solid tumors | NCT01479023, phase I | Diarrhea, dizziness, fatigue, headache, hypertension and weight loss |
Terminated (treatment was not working). No results posted This study confirmed that the administration of [64Cu]DOTA-patritumab and unlabeled patritumab is safe and well-tolerated [108] |
| Newly diagnosed HER2 + metastatic BC | NCT01512199, phase I + II | Terminated (Improved, different standard of care caused business decision to terminate). No results posted | |
| Advanced solid tumors | NCT00730470, phase I | Fatigue, diarrhea, nausea, decreased appetite and dysgeusia |
Completed. No results posted Patritumab treatment was well tolerated and was observed some evidence of disease stabilization [109] |
| Elgemtumab (LJM716) | |||
| Platinum-pretreated recurrent/metastatic HNSCC | NCT02143622, phase I + II | Withdrawn | |
| Advanced HER2 + BC or gastric cancer | NCT01602406, phase I | Diarrhea, nausea, fatigue and chills |
Completed. No results posted As of October 4, 2013, LJM716 demonstrated clinical activity in combination with trastuzumab in trastuzumab-resistant patients. The safety profile of the combination was acceptable [110] |
| Metastatic HER2 + BC | NCT02167854, phase I | Diarrhea, hyperglycemia, hypokalemia, mucositis and transaminitis |
Completed. No results posted The combination treatment of LJM716, BYL719 and trastuzumab has antitumor activity in these pre-treated HER2 + metastatic BC with PIK3CA mutations [111] |
| Patients with previously treated ESCC | NCT01822613, phase I + II | Completed. No results posted | |
| HER2 + BC, HER2 + gastric cancer, HNSCC and ESCC | NCT01598077, phase I | Diarrhea, decreased appetite, pyrexia, fatigue, nausea, infusion-related reactions, vomiting, constipation and dyspnea and anemia and hypomagnesemia |
Completed. No results posted LJM716 was well tolerated, with a manageable safety profile [112] |
| Japanese patients with advanced solid tumors | NCT01911936, phase I | Diarrhea, stomatitis, fatigue, pyrexia and paronychia |
Completed. No results posted LJM716 was well tolerated and a degree of tumor shrinkage was reported [113] |
| REGN1400 | |||
| Patients with advanced NSCLC, CRC or HNSCC who progressed on prior erlotinib or cetuximab | NCT01727869, phase I | Rash, diarrhea, nausea and hypomagnesemia |
Completed. No results posted REGN1400 as monotherapy or combined with erlotinib or cetuximab was generally tolerated [114] |
| Sym013 | |||
| Patients with advanced epithelial malignancies | NCT02906670, phase I + II | Terminated (Business reasons). Study results available online | |