Table 2.

Development of HER3-directed monoclonal antibodies.

Monoclonal Antibodies	Study Population	Clinical Trial Phase	Adverse Events	Status Finding	Reference
Lumretuzumab	Advanced or metastatic NSCLC	NCT02204345 phase I + II	Gastrointestinal, hematological, and nervous system toxicities, but generally mild and manageable	Terminated Efficacy of lumretuzumab + carboplatin + paclitaxel is similar to chemotherapy alone	[140]
	Metastatic BC expressing HER3 and HER2	NCT01918254 phase I	Diarrhea and hypokalemia	Completed Lumretuzumab + pertuzumab + paclitaxel was correlated with a serious incidence of diarrhea	[141]
	Metastatic and/or locally advanced malignant HER3 + solid tumors of epithelial cell origin	NCT01482377 phase I	Gastrointestinal and skin toxicities	Completed Moderate clinical activity with toxicity manageable	[142,143]
ISU104	Advanced solid tumors	NCT03552406 phase I Dose escalation study (PART I) Dose-expansion study (PART II)	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	Status unknown ISU104 was well tolerated up to 20 mg/kg/day without DLT and showed a disease control rate of 60% ISU104 monotherapy or with cetuximab was safe with promising clinical outcomes in recurrent or metastatic HNSCC treated with the combination	[144]
CDX-3379	Advanced cancer	NCT02014909 phase I	Diarrhea, fatigue, nausea, and rash	Completed CDX-3379 can be combined safely with cetuximab, erlotinib, vemurafenib, or trastuzumab at 15 to 20 mg/kg	[145]
	HNSCC	NCT02473731, phase I	Diarrhea, fatigue, and acneiform dermatitis, but mild or moderate	Completed CDX-3379 was well tolerated and associated with tumor regression	[146]
	Advanced stage NRAS mutant and BRAF/NRAS wild-type melanoma	NCT03580382 phase I + II		Terminated
	Advanced HNSCC	NCT03254927 phase II		Terminated CDX-3379 in combination with cetuximab is well tolerated with signs of antitumor activity	[147]
	Thyroid cancer	NCT02456701 phase I		Completed Vemurafenib + CDX-3379 is safe and enhances efficacy for RAI uptake	[148]
AV-203	Metastatic or advanced solid tumors	NCT01603979 phase I		Completed 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	[149]
GSK2849330	Advanced HER3 + solid tumors	NCT01966445 phase I	Drug tolerated with no major issues	Completed GSK2849330 has a durable response in an exceptional responder with an advanced CD74–NRG1-rearranged IMA	[150]
	Advanced HER3 + solid tumors	NCT02345174 phase I	Decreased appetite and diarrhea	Completed Despite the restricted number of patients, an exploratory ID50 of 2 mg/kg and ID90 of 18 mg/kg have been reported	[151]
Seribantumab	Advanced NSCLC	NCT00994123 phase I + II	Diarrhea, rash, decreased appetite, fatigue, and nausea	Completed 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 and combination therapy. However, retrospective analyses suggest that detectable NRG mRNA levels identified patients who may benefit from MM-121	[152]
	NSCLC expressing NRG	NCT02387216 phase II	Diarrhea, fatigue, and neutropenia in the combination treatment	Terminated Seribantumab does not improve PFS when added to docetaxel	[153]
	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 Unlike doublet treatment, seribantumab + cetuximab + irinotecan was difficult to tolerate. However, MM121 + cetuximab with and without irinotecan had no activity in the vast majority of patients with prior exposure to EGFR-directed therapy	[154]
	Advanced gynecologic and breast cancers	NCT01209195 phase I		Completed
	ER +, HER2- BC, and TNBC	NCT01421472 phase II		Completed
	Platinum-resistant or refractory recurrent/advanced ovarian cancers	NCT01447706, phase II	Diarrhea, vomiting, stomatitis, and mucosal inflammation	Completed	[155]
	Locally advanced or metastatic ER + and/or PR + and HER2- BC	NCT01151046 phase II	Diarrhea, nausea, fatigue, and arthralgia	Completed The addition of MM-121 to exemestane did not significantly prolong PFS in the unselected population	[156]
	CRC, NSCLC, and HNSCC	NCT02538627 phase I		Terminated
	Advanced solid tumors	NCT00734305 phase I		Completed
	Advanced solid	NCT01447225	Diarrhea, nausea, and fatigue,	Completed MM-121 can be administrated with	[157]
	Tumors	phase I	Anemia, vomiting, hypokalemia, decreased appetite, thrombocytopenia, peripheral edema, neutropenia, and constipation	Gemcitabine, pemetrexed, cabazitaxel, and carboplatin
	Postmenopausal women with metastatic BC	NCT03241810 phase II		Terminated
	Locally advanced or metastatic solid tumors	NCT01436565 phase I		Completed
	NRG1 gene fusion-positive advanced solid tumors	NCT04383210 phase II		Active, not recruiting
	An NRG1 fusion-positive metastatic pancreatic cancer patient	NCT04790695 phase II		Completed
Patritumab	Advanced, refractory solid tumors	NCT01957280 phase I	The most frequently reported treatment-related AEs were gastrointestinal	Completed Well tolerated with no anti-patritumab neutralizing antibodies formation and with normal bioavailability	[158]
	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 Patritumab + erlotinib apparently do not have better results than placebo + erlotinib
	Recurrent or metastatic HNSCC	NCT02633800 phase II	Rash, anemia, neutropenia, hypomagnesemia, and nausea	Terminated Patritumab + cetuximab + platinum was safe but not more efficacious than cetuximab + platinum	[159]
	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 Patritumab improved PFS in the NRG high, but not in the ITT population
	Recurrent or metastatic HNSCC	NCT02350712 phase I	Skin and subcutaneous tissue disorders	Completed Patritumab (18 mg/kg loading dose, 9 mg/kg maintenance dose) with cetuximab, and platinum therapy was tolerated and active in HNSCC	[160]
	Advanced solid tumors	NCT01479023, phase I	Diarrhea, dizziness, fatigue, headache, hypertension, and weight loss	Terminated [64Cu]DOTA-patritumab and unlabeled patritumab are safe and well tolerated	[161]
	Newly diagnosed HER2 + metastatic BC	NCT01512199 phase I + II		Terminated
	Advanced solid tumors	NCT00730470 phase I	Fatigue, diarrhea, nausea, decreased appetite, and dysgeusia	Completed Patritumab treatment was well tolerated and some evidence of disease stabilization was observed	[132]
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 As of 4 October 2013, LJM716 demonstrated clinical activity in combination with trastuzumab in trastuzumab-resistant patients with an acceptable safety profile	[162]
	Metastatic HER2 + BC	NCT02167854 phase I	Diarrhea, hyperglycemia, hypokalemia, mucositis, and transaminitis	Completed The combination treatment of LJM716, BYL719 (PI3K inhibitor) and trastuzumab has antitumor activity in these pretreated HER2 + metastatic BC with PIK3CA mutations	[163]
	Patients with previously treated ESCC	NCT01822613 phase I + II		Completed
	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 LJM716 was well tolerated, with a manageable safety profile	[164]
	Japanese patients with advanced solid tumors	NCT01911936 phase I	Diarrhea, stomatitis, fatigue, pyrexia and paronychia	Completed LJM716 was well tolerated and a degree of tumor shrinkage was reported	[165]
REGN1400	Patients with advanced NSCLC, CRC, or HNSCC who progressed on prior erlotinib or cetuximab	NCT01727869 phase I	Rash, diarrhea, nausea, and hypomagnesemia	Completed REGN1400 as monotherapy or combined with erlotinib or cetuximab was generally tolerated	[166]
Sym013	Patients with advanced epithelial malignancies	NCT02906670 phase I + II		Terminated

NSCLC: non-small cell lung cancer, BC: breast cancer, HNSCC: head and neck squamous cell carcinoma; AEs: adverse events; PFS: progression-free survival; ITT: intention to treat; ESCC: esophageal squamous cell carcinoma; CRC: colorectal cancer.