Eisner, Florian

Goletz, Steffen

Pichler, Martin

Samonigg, Hellmut

Stoeger, Herbert

English

PubMed

OPUS Augsburg

A glyco-engineered anti-HER2monoclonal antibody(TrasGEX) induces a long-lasting remission in a patientwith HER2 overexpressingmetastatic colorectal cancerafter failure of all availabletreatment optionsColorectal cancer (CRC) is one of the mostcommon forms of malignancies and thesecond leading cause of cancer-relateddeath in Western countries.1 Althoughchemotherapy in combination with novelantiangiogenic or antiepidermal growthfactor receptor (EGFR)-directed agents hassignificantly improved the survival time ofpatients with metastatic CRC (mCRC),patients with metastatic disease still face avery poor 5-year survival rate less than10%.2 3 The human EGFR 2 (HER2) hasproven as an effective drug target in breastand gastric cancers. In CRC, data about thetherapeutic utility of anti-HER2 agents aresparse, and had been only reported fortreatment-naïve or second-line-treatedpatients.4 There is only one clinical phaseII study reporting the use of the first-generation HER2/neu-directed trastuzu-mab in combination with irinotecan infirst-line or second-line setting. Althoughsome activity of this drug combination hasbeen observed, the study was terminatedearly due to insufficient patient recruit-ment.5 In this patient case, we reportabout the successful use of a novelglyco-engineered anti-HER2 monoclonalantibody (TrasGEX) with 10-fold toFigure 1 Representative picture of HER2/neu immunohistochemistry of colorectal cancer tissue.(A) A strong brown (+3) reaction in the tumour tissue indicates HER2/neu overexpression. Incontrast, the surrounding normal colon mucosa (*) stains negatively (×100). (B) Highermagnification (×200) showing the homogenous, membranous staining pattern of the tumour cell.1044 J Clin Pathol December 2015 Vol 68 No 12PostScript  on April 3, 2023 at UB Augsburg. Protected by copyright.http://jcp.bmj.com/J Clin Pathol: first published as 10.1136/jclinpath-2015-202996 on 18 September 2015. Downloaded from 140-fold enhanced antibody dependentcellular cytotoxicity (ADCC) activity in afemale patient with HER2/neu overexpres-sing mCRC and FcγRIII status F/V afterfailure of all other available treatmentoptions.A 61-year-old female Caucasian patientwas newly diagnosed with CRC inDecember 2002, and consequentlyunderwent a left hemicolectomy atthe Department of Surgery, MedicalUniversity of Graz. A stage II pathologicalT4N0 CRC was found according to the2002 tumour, node, metastases classifica-tion system. One month later, a single livermetastasis was diagnosed by CT, and pre-operative chemotherapy comprising eightcycles of FOLFOX4 was initiated. Fivemonths later, a partial remission of the livermetastasis was achieved, and a resection ofthe liver metastasis (segment VI) was per-formed in July 2003. After a 30-monthdisease-free period and routine clinicalfollow-up, a CT scan of the abdomendetected enlarged retroperitoneal lymphnodes. Based on an individual patient deci-sion and treatment approach, the patientunderwent lymph node resection and post-operative chemotherapy with seven cyclesof FOLFOX4 regimen. Oxaliplatin had tobe dose-reduced after two cycles due to aprolonged grade III leucopenia. Another9 months later, the disease recurred with asolitary liver metastasis in segment VI andone single metastasis in the right suprarenalgland. The patient again underwent liverresection and subtotal right adrenalectomyin April 2007. Three months after surgery,solitary retroperitoneal lymph node metas-tases were detected and consecutivelyresected. After a 4-month disease-freeperiod, a recurrence of metastasis in theliver was radiologically detected. Palliativechemotherapy with FOLFIRI/bevacizumabwas administered for eight cycles, resultingin partial remission of the liver metastasis.Unfortunately, half an year after a break ofthe therapy, the patient experienced adisease progression with spread to multiplemetastases in both lungs and solitary livermetastasis. Rechallenge of FOLFIRI/bevaci-zumab (80% dose reduction of irinotecandue to prolonged haematotoxicity) resultedagain in partial remission after 12 cycles. InFebruary 2011, the disease progressedagain, and after determining KRAS exon 2mutational status (a KRAS wild-type wasdiagnosed by pyrosequencing) in thetumour tissue, a palliative therapy contain-ing irinotecan (150 mg/m²) plus panitumu-mab (6 mg/kg) was administered every2 weeks for five cycles. Despite the use ofthis combination therapy and the adminis-tration of another two palliative therapyapproaches with FOLFOX/bevacizumab (4cycles) as well as UFT (tegafur 2-1-1 day 1–28, leucovorin 2-2-2 day 1–28 for 4months), no objective response or clinicalbenefit could be reached. A further molecu-lar characterisation of the tumour tissuedetected no mutations in KRAS/NRASexons 3 and 4, as well as no BRAF V600Emutation. Facing the disease progressionand the use of all currently available drugs,the patient consented to participate in thephase I TrasGEX clinical trial(ClinicalTrials.gov numberNCT01409343). After consenting, aHER2/neu immunohistochemical expres-sion in the tumour tissue was evaluated inMarch 2012 (Dako HercepTest). Around95% of tumour cells showed a strong com-plete membranous staining pattern (3+),leading to the enrolment of the patient intothe TrasGEX dose escalation protocol(figure 1A, B).TrasGEX is a humanised IgG1anti-HER2 antibody, and belongs to agroup of antibodies, which areglyco-engineered by the GlycoExpress plat-form with a fully human glycosylation andoptimised key sugar determinants, includ-ing fucose, galactose, sialylation andbranching. Major optimisation forTrasGEX is an enhanced ADCC antitumouractivity in combination with other variabledomain-mediated antitumour activities.ADCC is mediated via the FcγRIIIa recep-tor on immune effector cells. Two allotypesof this receptor differing in amino acid pos-ition 158 (V158F) are known, which havedifferent affinities to human IgG1, depend-ing on the glycosylation of the glycans inthe IgG1 Fc tail. This difference in receptoraffinity results in a reduced natural killercell activation for F-containing allotypes forantibodies generated in Chinese hamsterovary (CHO) or other rodent productionsystems and, therefore, in a reduced ADCCactivity.Figure 2 (A and B) Baseline imaging before therapy with TrasGEX has been initiated. (A)Multiple lung metastatic lesions with one target lesion of 2 cm in diameter (red lines) and (B) aliver metastasis with 11 cm in the largest diameter. (C and D) Three cycles later, the patient has adecrease of size in lung (C) and liver metastases (D). (E and F) Imaging 21 months (30 cycles)after initiation of TrasGEX. The target lung lesion diminished (E) and the target liver lesionmeasures 4.5 cm (F).J Clin Pathol December 2015 Vol 68 No 12 1045PostScript on April 3, 2023 at UB Augsburg. Protected by copyright.http://jcp.bmj.com/J Clin Pathol: first published as 10.1136/jclinpath-2015-202996 on 18 September 2015. Downloaded from Patients with FcγRIIIa allotype (V/V)treated with trastuzumab (Herceptin) orcetuximab (Erbitux) have a better clinicaloutcome than those with F/F or F/V.6–8According to the study protocol, thepatient received 480 mg of TrasGEX intra-venously over 4 h and every consecutivecycle on day 21 with an infusion time of90 min. Three cycles later, the patient hada decrease of size in lung and liver metasta-ses (sum of the longest diameters, targetlesions in the liver and right lowerlung lobe reduced from 19.7 to 11.1 cm(figure 2A, C), target lesion in the rightliver lobe from 10 to 5.7 cm) (figure 2B,D), so, continuation of the targetedtherapy according to the study protocolwas performed. Until now, 21 months (30cycles) after initiation of TrasGEX, thepatient still has a partial remission of thedisease (target liver lesion 4.5 cm), andpresents in excellent clinical condition(figure 2E, F). Remarkably, over the wholestudy period, no side effects including car-diotoxicity (the left ventricular ejectionfraction determined by echocardiographyremained unchanged throughout the21 months) occurred.Florian Eisner,1 Martin Pichler,1 Steffen Goletz,2Herbert Stoeger,1 Hellmut Samonigg11Division of Oncology, Department of InternalMedicine, Medical University of Graz, Graz, Austria2GLYCOTOPE GmbH, Berlin, GermanyCorrespondence to Dr Florian Eisner, Department ofInternal Medicine, Medical University of Graz,Auenbruggerplatz 15, A-8036 Graz, Austria;florian.eisner@medunigraz.atAcknowledgements Special thanks to all thecontributors of the TrasGEX phase I clinical trial.Competing interests None declared.Patient consent Obtained.Provenance and peer review Not commissioned;externally peer reviewed.Open Access This is an Open Access articledistributed in accordance with the Creative CommonsAttribution Non Commercial (CC BY-NC 4.0) license,which permits others to distribute, remix, adapt, buildupon this work non-commercially, and license theirderivative works on different terms, provided theoriginal work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/To cite Eisner F, Pichler M, Goletz S, et al. J ClinPathol 2015;68:1044–1046.Received 1 April 2015Revised 22 July 2015Accepted 31 July 2015Published Online First 18 September 2015J Clin Pathol 2015;68:1044–1046.doi:10.1136/jclinpath-2015-202996REFERENCES1 Siegel R, Naishadham D, Jemal A. Cancer statistics.CA Cancer J Clin 2013;63:11–30.2 Venook AP. Epidermal growth factor receptor-targetedtreatment for advanced colorectal carcinoma. Cancer2005;103:2435–46.3 Damin DC, Lazzaron AR. Evolving treatment strategiesfor colorectal cancer: a critical review of currenttherapeutic options. World J Gastroenterol2014;20:877–87.4 Moorcraft SY, Smyth EC, Cunningham D. The role ofpersonalized medicine in metastatic colorectal cancer:an evolving landscape. Therap Adv Gastroenterol2013;6:381–95.5 Ramanathan RK, Hwang JJ, Zamboni WC, et al. Lowoverexpression of HER-2/neu in advanced colorectalcancer limits the usefulness of trastuzumab (Herceptin)and irinotecan as therapy. A phase II trial. CancerInvest 2004;22:858–65.6 Bibeau F, Lopez-Crapez E, Di Fiore F, et al. Impact ofFcgammaRIIa-FcgammaRIIIa polymorphisms and KRASmutations on the clinical outcome of patients withmetastatic colorectal cancer treated with cetuximabplus irinotecan. J Clin Oncol 2009;27:1122–9.7 Lejeune J, Thibault G, Ternant D, et al. Evidence forlinkage disequilibrium between Fcgamma RIIIa-V158Fand Fcgamma RIIa-H131R polymorphisms in whitepatients, and for an Fcgamma RIIIa-restricted influenceon the response to therapeutic antibodies. J ClinOncol 2008;26:5489–91.8 Musolino A, Naldi N, Bortesi B, et al. ImmunoglobulinG fragment C receptor polymorphisms and clinicalefficacy of trastuzumab-based therapy in patients withHER-2/neu-positive metastatic breast cancer. J ClinOncol 2008;26:1789–96.Open accessScan to access morefree content1046 J Clin Pathol December 2015 Vol 68 No 12PostScript on April 3, 2023 at UB Augsburg. Protected by copyright.http://jcp.bmj.com/J Clin Pathol: first published as 10.1136/jclinpath-2015-202996 on 18 September 2015. Downloaded from 

A glyco-engineered anti-HER2 monoclonal antibody (TrasGEX) induces a long-lasting remission in a patient with HER2 overexpressing metastatic colorectal cancer after failure of all available treatment options

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A glyco-engineered anti-HER2 monoclonal antibody (TrasGEX) induces a long-lasting remission in a patient with HER2 overexpressing metastatic colorectal cancer after failure of all available treatment options

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