Table 2 Bispecific antibodies against HER3 under clinical development
Study population | Clinical Trial, phase | Adverse events | Status, conclusion (references) |
|---|---|---|---|
Zenocutuzumab (Zeno, MCLA-128) | |||
 Solid tumors harboring an NRG1 fusion | NCT02912949, phase I + II | Infusion related reactions, diarrhea, rash and fatigue | Recruiting As of January 2017, MCLA-128 reported a safety profile and antitumor activity in pretreated metastatic BC patients progressing on HER2 therapies [194] |
 A patient with advanced NRG1-fusion positive solid tumor | NCT04100694, NA |  | Available |
 Metastatic BC | NCT03321981, phase II | Neutropenia/neutrophil count decrease, diarrhea, asthenia/fatigue and nausea | Active, not recruiting The combination of MCLA-128 + trastuzumab + vinorelbine is active in pretreated patients with HER2 + metastatic BC. The treatment is safe with manageable AEs mainly related to chemotherapy [195] |
SI-B001 | |||
 Locally advanced or metastatic epithelial tumors | NCT04603287, phase I |  | Active, not recruiting |
 Recurrent and metastatic HNSCC | NCT05054439, phase II |  | Recruiting |
 Recurrent metastatic ESCC | NCT05022654, phase II |  | Recruiting |
 Recurrent and metastatic NSCLC | NCT05020769, phase II + III |  | Recruiting |
 EGFR/ALK wild-type recurrent or metastatic NSCLC | NCT05020457, phase II |  | Recruiting |
 Recurrent and metastatic HNSCC | NCT05044897, phase II |  | Recruiting |
 Unresectable or metastatic digestive system malignancies (colorectal and gastric cancer) | NCT05039944, phase II |  | Recruiting |
MM-111 | |||
 Advanced, refractory HER2 amplified, NRG + BC | NCT01097460, phase I | Fatigue, diarrhea and dyspnoea | Completed. Study results available online |
 Advanced, refractory HER2 amplified, NRG + cancers | NCT00911898, phase I |  | Completed. Study results available online |
 Advanced HER2 + solid tumors | NCT01304784, phase I | Anemia, acute renal failure (assessed as cisplatin-related), chest pain, decreased appetite, diarrhea, febrile neutropenia, hyperuricemia, hypokalemia, hyponatremia, hypophosphatemia, mucosal inflammation, nausea, neutropenia, stomatitis, thrombocytopenia and vomiting | Completed. No results posted Treatment with MM-111 and standard of care HER2-directed regimens was viable [196] |
 HER2 + carcinomas of the distal esophagus, gastroesophageal junction and stomach | NCT01774851, phase II | Diarrhea, anemia, decreased appetite, alopecia, fatigue, nausea, vomiting, asthenia, neutropenia, constipation and cough | Terminated (DSMB recommendation due to lack of efficacy. There were no safety signals). Study results available online MM-111 did not improve PFS or OS when added to paclitaxel + trastuzumab [197] |
Istiratumab (MM-141) | |||
 Advanced solid tumors | NCT01733004, phase I | Vomiting, nausea, fatigue, abdominal pain, increased AP, dyspnea, diarrhea, anemia, increased AST and rash | Completed. No results posted MM-141 was well tolerated as monotherapy and in combination with everolimus or paclitaxel + gemcitabine in patients with relapsed/refractory solid tumors [198] |
 Metastatic pancreatic cancer | NCT02399137, phase II | Neutropenia, alopecia, diarrhea, fatigue, thrombocytopenia, anemia and decreased appetite | Completed. No results posted Istiratumab failed to improve the efficacy of chemotherapy [199] |
 CRC, NSCLC and HNSCC | NCT02538627, phase I |  | Terminated (Sponsor decision). No results posted |
Duligotuzumab (MEHD7945A, RG7597) | |||
 Locally advanced or metastatic solid tumors with mutant KRAS | NCT01986166, phase I | Diarrhea, general disorders, dermatitis acneiform, rash, rash erythematous, rash maculo-papular and nausea | Completed. No results posted The combination of cobimetinib and duligotuzumab was related with increased toxicity and limited efficacy [200] |
 Locally advanced or metastatic epithelial tumors | NCT01207323, phase I | Headache, rash and diarrhea | Completed. No results posted Duligotuzumab was well-tolerated with evidence of tumor pharmacodynamic modulation and anti-tumor activity in HNSCC [201] |
 Recurrent/metastatic HNSCC | NCT01911598, phase I | Neutropenia, hypokalemia, dehydration, anemia and diarrhea in arm A and neutropenia, anemia, febrile neutropenia, leukopenia, thrombocytopenia and hypomagnesemia in arm B | Completed. No results posted Duligotuzumab with cisplatin + 5-fluorouracil (arm A) or carboplatin + paclitaxel (arm B) demonstrated promising activity despite chemotherapy dose reductions and could be maintained with duligotuzumab alone [202] |
 KRAS wild-type metastatic CRC | NCT01652482, phase II | Rash, diarrhea, fatigue and nausea. There were fewer rash events of any grade in the duligotuzumab arm but more diarrhea | Completed. No results posted The combination of FOLFIRI with duligotuzumab generally did no improve clinical outcomes benefit compared with cetuximab combination [203] |
 Recurrent/metastatic HNSCC | NCT01577173, phase II | Rash, infections, diarrhea, fatigue and nausea | Completed. No results posted Duligotuzumab demonstrated similar activity to cetuximab, but not superior [204] |