Copyright ©The Author(s) 2018.
World J Gastrointest Oncol. Jul 15, 2018; 10(7): 159-171
Published online Jul 15, 2018. doi: 10.4251/wjgo.v10.i7.159
Table 1 Summary of selected randomized phase III HER2 trials in HER2-amplified gastro-oesophageal cancer and breast cancer
Study titleSettingnTreatment armsPrimary endpointOSPFSHR and P value
Trastuzumab 1st line metastatic
ToGA[5]1st line metastatic GOC594Trastuzumab + chemotherapy vs chemotherapy aloneOSTrastuzumab + 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 cancer469Trastuzumab + chemotherapy vs chemotherapy alonePFSTrastuzumab + chemotherapy: 25.1 mo Chemotherapy alone: 20.3 moTrastuzumab + chemotherapy: 7.4 mo Chemotherapy alone: 4.6 moP = 0.046
Lapatinib 1st line metastatic
LOGiC[7]1st line metastatic GOC545Lapatinib + CAPOX vs Placebo + CAPOXOSLapatinib + 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 cancer444Lapatinib + paclitaxel vs Placebo + paclitaxelOSLapatinib + 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 GOC261Lapatinib + Paclitaxel vs Paclitaxel aloneOSLapatinib + Paclitaxel: 11.0 mo Paclitaxel alone: 8.9 moLapatinib + Paclitaxel: 5.5 mo Paclitaxel alone: 4.4 moHR = 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 cancer324 included in preliminary analysisLapatinib + capecitabine vs capecitabine alonePFSNot reportedLapatinib + capecitabin: 8.4 mo Capecitabine alone: 4.4 moHR = 0.49; 95%CI: 0.34 to 0.71; P < 0.001
T-DM1 2nd line metastatic
GATSBY[35]2nd line metastatic GOC345T-DM1 vs taxaneOST-DM1: 7.9 mo Taxane: 8.6 moT-DM1: 2.7 mo Taxane: 2.9 moHR = 1.15, 95%CI: 0.87–1.51; P = 0·86
EMILIA[33]2nd line metastatic breast cancer991T-DM1 vs lapatinib + capecitabinePFST-DM1: 30.9 mo Lapatinib + capecitabine: 25.1 moT-DM1: 9.6 mo Lapatinib + capecitabine: 6.4 moHR = 0.65; 95%CI: 0.55 to 0.77; P < 0.001
Table 2 Selected perioperative (neoadjuvant + adjuvant) clinical trials currently underway targeting HER2 in HER2-amplified localised gastro-oesophageal cancer
Official study titleStage and study numberTreatment armsEstimated enrollmentPrimary endpoint
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 000016920Preoperative S-1 + cisplatin + trastuzumab vs S-1 + cisplatin Followed by adjuvant chemotherapy with S-1 for 1 yr130OS
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 NCT01472029Pre-operative 5-FU + leucovorin + docetaxel + oxaliplatin (FLOT) + trastuzumab Post-operative trastuzumab monotherapy53pCR
Trastuzumab plus XELOX for HER2-positive stage III gastric cancer after D2 gastrectomy: prospective observational Study[77]Phase II NCT02250209Trastuzumab + capecitabine + oxaliplatin after D2 gastrectomy403-yr DFS
A phase III trial evaluating the addition of trastuzumab to trimodality treatment of HER2-overexpressing esophageal adenocarcinomaPhase III NCT01196390Radiotherapy + paclitaxel + carboplatin + trastuzumab vs Radiotherapy + paclitaxel + carboplatin591DFS
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 NCT00450203Epirubicin + cisplatin + capecitabine (ECX) + lapatinib vs ECX40 (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 NCT02205047Cisplatin/capecitabine or cisplatin/5-fluorouracil vs cisplatin/capecitabine + trastuzumab or cisplatin/5-fluorouracil + trastuzumab vs cisplatin/capecitabine + trastuzumab +pertuzumab or cisplatin/5-fluorouracil + trastuzumab + pertuzumab220Near 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 NCT025814625-FU + leucovorin + docetaxel + oxaliplatin (FLOT) vs FLOT + trastuzumab + Pertuzumab404pCR OS
Feasibility study of chemoradiation, TRAstuzumab and pertuzumab in resectable HER2+esophageal carcinoma: the TRAP studyPhase I/II NCT02120911Pertuzumab + trastuzumab + standard chemoradiation with carboplatin and paclitaxel.40Safety
Table 3 Selected clinical trials currently underway targeting HER2 in advanced and metastatic HER2-amplified gastro-oesophageal cancer
Official study titleStage and study numberTreatment armsEstimated enrollmentPrimary 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 NCT01359397Docetaxel, oxaliplatin, capecitabine, bevacizumab vs Docetaxel, oxaliplatin, capecitabine, bevacizumab, trastuzumabInformation not availablePFS
A phase II study of afatinib (BIBW 2992) and trastuzumab in patients with advanced HER2-positive trastuzumab-refractory advanced esophagogastric cancerPhase II NCT01522768Afatinib (BIBW 2992) + trastuzumab40ORR
Intraperitoneal trastuzumab
Phase I trial of intraperitoneal ²¹²Pb-TCMC-trastuzumab for HER-2 expressing malignancyPhase I NCT01384253²¹²Pb-TCMC-trastuzumab + trastuzumab36Safety
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 NCT01702558Capecitabine + trastuzumab emtansine (T-DM1) vs T-DM1235Safety ORR
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 NCT02564900Trastuzumab deruxtecan (DS-8201a)198Safety ORR
Safety and clinical activity of lapatinib in patients with HER2-positive refractory advanced cancer: a phase II single arm prospective studyPhase II NCT02342587Lapatinib25ORR
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 cancerPhase I/II NCT01746771HM781-36B(Poziotinib) (Other Names: NOV120101) + paclitaxel + trastuzumab48Safety 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 availablePhase I NCT01148849MGAH22 (margetuximab)67Safety
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 tumorsPhase I NCT02576548MEDI4276120Safety MTD
A phase I study of pyrotinib in combination with docetaxel in patients with HER2 positive advanced gastric cancerPhase I NCT02378389Pyrotinib + docetaxel28Safety
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 therapyPhase I NCT02500199Pyrotinib70Safety MTD
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 amplificationPhase II NCT01953926Neratinib292ORR
HER2-targeted immunotherapy
A phase Ib/II study of pembrolizumab and monoclonal antibody therapy in patients with advanced cancer (PembroMab)[77]Phase I/II NCT02318901Pembrolizumab + trastuzumab vs pembrolizumab + ado-trastuzumab emtansine (T-DM1) vs pembrolizumab + cetuximab90Safety 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 cancerPhase I NCT01526473AVX90112Safety
HER2-peptide vaccination of patients with solid tumorsPhase I NCT02276300Cyclophosphamide sargramostim HER2-Peptid-Vakzine imiquimod12Safety