HER2 inhibition in gastro-oesophageal cancer: A review drawing on lessons learned from breast cancer

Table 1 Summary of selected randomized phase III HER2 trials in HER2-amplified gastro-oesophageal cancer and breast cancer

Study title	Setting	n	Treatment arms	Primary endpoint	OS	PFS	HR and P value
Trastuzumab 1st line metastatic
ToGA[5]	1st line metastatic GOC	594	Trastuzumab + chemotherapy vs chemotherapy alone	OS	Trastuzumab + chemotherapy: 13.8 mo (95%CI: 12-16) Chemotherapy alone: OS 11.1 mo (10-13)	Trastuzumab + chemotherapy: 6.7 mo (95%CI: 6-8) Chemotherapy alone: 5.5 mo (5-6)	HR = 0.74; 95%CI: 0.60-0.91; P = 0.0046)
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2[19]	1st line metastatic breast cancer	469	Trastuzumab + chemotherapy vs chemotherapy alone	PFS	Trastuzumab + chemotherapy: 25.1 mo Chemotherapy alone: 20.3 mo	Trastuzumab + chemotherapy: 7.4 mo Chemotherapy alone: 4.6 mo	P = 0.046
Lapatinib 1st line metastatic
LOGiC[7]	1st line metastatic GOC	545	Lapatinib + CAPOX vs Placebo + CAPOX	OS	Lapatinib + CAPOX: 12.2 mo (95%CI: 10.6-14.2) Placebo + CAPOX: 10.5 mo (9.0-11.3)	Lapatinib + CAPOX: 6 mo (95%CI: 5.6-7.0) Placebo + CAPOX: 5.4 mo (4.4-5.7)	HR = 0.91; 95%CI: 0.73-1.12 P value not significant (exact value not given)
Randomized trial of lapatinib vs placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer[29]	1st line metastatic breast cancer	444	Lapatinib + paclitaxel vs Placebo + paclitaxel	OS	Lapatinib + paclitaxel: 27.8 mo (95%CI: 23.2-32.2 mo) Placebo + paclitaxel: 20.5 mo (17.9-24.3 mo)	Lapatinib + paclitaxel: 9.7 mo (95%CI: 9.2-11.1 mo) Placebo + paclitaxel: 6.5 mo (5.5-7.3 mo)	HR = 0.74; 95%CI: 0.58-0.94; P = 0.0124
Lapatinib 2nd line metastatic
Tytan[8]	2nd line metastatic GOC	261	Lapatinib + Paclitaxel vs Paclitaxel alone	OS	Lapatinib + Paclitaxel: 11.0 mo Paclitaxel alone: 8.9 mo	Lapatinib + Paclitaxel: 5.5 mo Paclitaxel alone: 4.4 mo	HR = 0.84; 95%CI: 0.64-1.11 P = 0.1044
Lapatinib plus capecitabine for HER2-Positive advanced breast Cancer[30]	2nd line metastatic breast cancer	324 included in preliminary analysis	Lapatinib + capecitabine vs capecitabine alone	PFS	Not reported	Lapatinib + capecitabin: 8.4 mo Capecitabine alone: 4.4 mo	HR = 0.49; 95%CI: 0.34 to 0.71; P < 0.001
T-DM1 2nd line metastatic
GATSBY[35]	2nd line metastatic GOC	345	T-DM1 vs taxane	OS	T-DM1: 7.9 mo Taxane: 8.6 mo	T-DM1: 2.7 mo Taxane: 2.9 mo	HR = 1.15, 95%CI: 0.87–1.51; P = 0·86
EMILIA[33]	2nd line metastatic breast cancer	991	T-DM1 vs lapatinib + capecitabine	PFS	T-DM1: 30.9 mo Lapatinib + capecitabine: 25.1 mo	T-DM1: 9.6 mo Lapatinib + capecitabine: 6.4 mo	HR = 0.65; 95%CI: 0.55 to 0.77; P < 0.001

HER2: Human epidermal growth factor receptor 2.

Table 2 Selected perioperative (neoadjuvant + adjuvant) clinical trials currently underway targeting HER2 in HER2-amplified localised gastro-oesophageal cancer

Official study title	Stage and study number	Treatment arms	Estimated enrollment	Primary endpoint
Trastuzumab
A randomized phase II trial of systemic chemotherapy with and without trastuzumab followed by surgery in HER2-positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301 (Trigger Study)[23]	Phase II UMIN 000016920	Preoperative S-1 + cisplatin + trastuzumab vs S-1 + cisplatin Followed by adjuvant chemotherapy with S-1 for 1 yr	130	OS
Multicenter, explorative phase II study of perioperative 5-FU, leucovorin, docetaxel, and oxaliplatin (FLOT) in combination with trastuzumab in patients with HER2-positive, locally advanced, resectable adenocarcinoma of the gastroesophageal junction or stomach (HerFLOT)	Phase II NCT01472029	Pre-operative 5-FU + leucovorin + docetaxel + oxaliplatin (FLOT) + trastuzumab Post-operative trastuzumab monotherapy	53	pCR
Trastuzumab plus XELOX for HER2-positive stage III gastric cancer after D2 gastrectomy: prospective observational Study[77]	Phase II NCT02250209	Trastuzumab + capecitabine + oxaliplatin after D2 gastrectomy	40	3-yr DFS
A phase III trial evaluating the addition of trastuzumab to trimodality treatment of HER2-overexpressing esophageal adenocarcinoma	Phase III NCT01196390	Radiotherapy + paclitaxel + carboplatin + trastuzumab vs Radiotherapy + paclitaxel + carboplatin	591	DFS
Lapatinib
A randomised phase II/III trial of peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma and a feasibility study evaluating lapatinib in HER-2 positive oesophagogastric adenocarcinomas and (in selected centres) MRI and PET/CT sub-studies (STO3 trial)	Phase II/III NCT00450203	Epirubicin + cisplatin + capecitabine (ECX) + lapatinib vs ECX	40 (within lapatinib sub-study)	Safety
Pertuzumab + Trastuzumab
INtegratioN of trastuzumab, with or without pertuzumab, into perioperatiVe chemotherApy of HER-2 positive stomach cancer: the INNOVATION-TRIAL[77]	Phase II NCT02205047	Cisplatin/capecitabine or cisplatin/5-fluorouracil vs cisplatin/capecitabine + trastuzumab or cisplatin/5-fluorouracil + trastuzumab vs cisplatin/capecitabine + trastuzumab +pertuzumab or cisplatin/5-fluorouracil + trastuzumab + pertuzumab	220	Near complete pathological response rate
FLOT vs FLOT/Herceptin/Pertuzumab for perioperative therapy of adenocarcinoma of the stomach and gastroesophageal junction expressing HER-2 A phase II/III trial of the AIO. (PETRARCA study)	Phase II/III NCT02581462	5-FU + leucovorin + docetaxel + oxaliplatin (FLOT) vs FLOT + trastuzumab + Pertuzumab	404	pCR OS
Feasibility study of chemoradiation, TRAstuzumab and pertuzumab in resectable HER2+esophageal carcinoma: the TRAP study	Phase I/II NCT02120911	Pertuzumab + trastuzumab + standard chemoradiation with carboplatin and paclitaxel.	40	Safety

pCR: Pathological complete response; DFS: Disease-free survival.

Table 3 Selected clinical trials currently underway targeting HER2 in advanced and metastatic HER2-amplified gastro-oesophageal cancer

Official study title	Stage and study number	Treatment arms	Estimated enrollment	Primary endpoint
Trastuzumab in combination with targeted therapies
Phase II study of docetaxel, oxaliplatin, capecitabine with bevacizumab and trastuzumab in case of HER2-positivity in patients with locally advanced or metastatic gastric cancer or adenocarcinoma of the gastro-oesophageal junction (B-DOCT study)	Phase II NCT01359397	Docetaxel, oxaliplatin, capecitabine, bevacizumab vs Docetaxel, oxaliplatin, capecitabine, bevacizumab, trastuzumab	Information not available	PFS
A phase II study of afatinib (BIBW 2992) and trastuzumab in patients with advanced HER2-positive trastuzumab-refractory advanced esophagogastric cancer	Phase II NCT01522768	Afatinib (BIBW 2992) + trastuzumab	40	ORR
Intraperitoneal trastuzumab
Phase I trial of intraperitoneal ²¹²Pb-TCMC-trastuzumab for HER-2 expressing malignancy	Phase I NCT01384253	²¹²Pb-TCMC-trastuzumab + trastuzumab	36	Safety
T-DM1
A combination study of kadcyla (trastuzumab emtansine, T-DM1) and capecitabine in patients with HER2-positive metastatic breast cancer and patients with HER2-positive locally advanced/ metastatic gastric cancer (TRAX-HER2 study)[78]	Phase II NCT01702558	Capecitabine + trastuzumab emtansine (T-DM1) vs T-DM1	235	Safety ORR
DS-8201
Phase 1, two-part, multicenter, non-randomized, open-label, multiple dose first-in-human study of DS-8201A, in subjects with advanced solid malignant tumors[36]	Phase II NCT02564900	Trastuzumab deruxtecan (DS-8201a)	198	Safety ORR
Lapatinib
Safety and clinical activity of lapatinib in patients with HER2-positive refractory advanced cancer: a phase II single arm prospective study	Phase II NCT02342587	Lapatinib	25	ORR
New HER2 inhibitors
A phase I-II study to assess the safety, efficacy and pharmacokinetic profile of HM781-36B combined with paclitaxel and trastuzumab in patients with HER-2 positive advanced gastric cancer	Phase I/II NCT01746771	HM781-36B(Poziotinib) (Other Names: NOV120101) + paclitaxel + trastuzumab	48	Safety DLT
A phase 1, dose escalation study of MGAH22 in patients with refractory HER2 positive breast cancer and patients with other HER2 positive carcinomas for whom no standard therapy is available	Phase I NCT01148849	MGAH22 (margetuximab)	67	Safety
A phase I multicenter, open-label, dose-escalation, and dose-expansion study to evaluate the safety, pharmacokinetics, immunogencity, and antitumor activity of MEDI4276 in subjects with select HER2-expressing advanced solid tumors	Phase I NCT02576548	MEDI4276	120	Safety MTD
A phase I study of pyrotinib in combination with docetaxel in patients with HER2 positive advanced gastric cancer	Phase I NCT02378389	Pyrotinib + docetaxel	28	Safety
A two-part phase I, open label, dose escalation study to evaluate the safety, tolerability and pharmacokinetics of pyrotinib in patients whose disease progressed on prior HER2 targeted therapy	Phase I NCT02500199	Pyrotinib	70	Safety MTD
Neratinib
An open-label, multicenter, multinational, phase 2 study exploring the efficacy and safety of neratinib therapy in patients with solid tumors with activating HER2, HER3 or EGFR mutations or with EGFR gene amplification	Phase II NCT01953926	Neratinib	292	ORR
HER2-targeted immunotherapy
A phase Ib/II study of pembrolizumab and monoclonal antibody therapy in patients with advanced cancer (PembroMab)[77]	Phase I/II NCT02318901	Pembrolizumab + trastuzumab vs pembrolizumab + ado-trastuzumab emtansine (T-DM1) vs pembrolizumab + cetuximab	90	Safety and dose-finding
A phase I study to evaluate the antitumor activity and safety of DUKE-002-VRP (HUHER2-ECD + TM), an alphaviral vector encoding the HER2 extracellular domain and transmembrane region, in patient with locally advanced or metastatic human epidermal growth factor receptor 2-positive (HER2+) cancers including breast cancer	Phase I NCT01526473	AVX901	12	Safety
HER2-peptide vaccination of patients with solid tumors	Phase I NCT02276300	Cyclophosphamide sargramostim HER2-Peptid-Vakzine imiquimod	12	Safety

ORR: Overall response rate; HER2: Human epidermal growth factor receptor 2.