Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.
BACKGROUND
We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2-amplified metastatic colorectal cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer.


METHODS
HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33.


RESULTS
Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51-127), eight (30%, 95% CI 14-50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI -3 to 11) achieving a complete response, and seven (26%, 95% CI 9-43) achieving partial responses; 12 (44%, 95% CI 25-63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events.


CONCLUSIONS
The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer.


BACKGROUND
Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche.
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Andrea
A
Sartore-Bianchi
Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy; Dipartimento di Oncologia, Università degli Studi di Torino, Torino, Italy.
Livio
L
Trusolino
Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy.
Cosimo
C
Martino
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Katia
K
Bencardino
Oncologia Medica 1, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
Sara
S
Lonardi
Oncologia Medica 1, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
Francesca
F
Bergamo
Oncologia Medica 1, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
Vittorina
V
Zagonel
Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy; Dipartimento di Oncologia, Università degli Studi di Torino, Torino, Italy.
Francesco
F
Leone
Dipartimento di Oncologia, Università degli Studi di Torino, Torino, Italy.
Ilaria
I
Depetris
Seconda Università degli Studi di Napoli, Napoli, Italy.
Erika
E
Martinelli
Seconda Università degli Studi di Napoli, Napoli, Italy.
Teresa
T
Troiani
Seconda Università degli Studi di Napoli, Napoli, Italy.
Fortunato
F
Ciardiello
Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy.
Patrizia
P
Racca
Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy; Dipartimento di Oncologia, Università degli Studi di Torino, Torino, Italy.
Andrea
A
Bertotti
Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy; Dipartimento di Oncologia, Università degli Studi di Torino, Torino, Italy.
Giulia
G
Siravegna
Istituto Mario Negri IRCCS, Milano, Italy.
Valter
V
Torri
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Alessio
A
Amatu
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Silvia
S
Ghezzi
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Giovanna
G
Marrapese
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Laura
L
Palmeri
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Emanuele
E
Valtorta
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Andrea
A
Cassingena
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Calogero
C
Lauricella
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Angelo
A
Vanzulli
Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy; Dipartimento di Oncologia, Università degli Studi di Torino, Torino, Italy.
Daniele
D
Regge
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy.
Silvio
S
Veronese
Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy; Dipartimento di Oncologia, Università degli Studi di Torino, Torino, Italy.
Paolo M
PM
Comoglio
Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy; Dipartimento di Oncologia, Università degli Studi di Torino, Torino, Italy.
Alberto
A
Bardelli
Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy. Electronic address: silvia.marsoni@ircc.it.
Silvia
S
Marsoni
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy; Dipartimento di Oncologia e Emato-Oncologia Università degli Studi di Milano, Milano, Italy.
Salvatore
S
Siena
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D003062:Codon / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016879:Salvage Therapy; D015996:Survival Rate; D000068878:Trastuzumab / Q000008:administration & dosage
D014408:Biomarkers, Tumor; D003062:Codon; D000077341:Lapatinib; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C117307:KRAS protein, human