Showcased during AACR´s 2017 Annual Meeting´s Opening Plenary: The Road to Cancer Cures – Discover, Predict, Prevent and Treat, Sunday 02 April (10:00 – 12:00h), Carlos Caldas, CRUK-Cambridge Institute (UK), presented first outing data during his talk entitled Breast cancer intratumor heterogeneity landscapes: what, when, and where. More specifically, his talk focused on the landscape of lethal metastatic breast cancer and he presented findings from research carried out by VHIO´s Leticia de Mattos-Arruda and colleagues during her tenure at his lab (2015 – 2016), supported by an Advanced Program in Oncology award from the Spanish Association against Cancer (AECC).
This collaborative project, also led by Javier Cortés, Associate Translational Researcher at VHIO and Head of Breast Cancer and Gynecological Tumors at the Ramón y Cajal Hospital (Madrid), was carried out in partnership with other colleagues at VHIO and Vall d´Hebron including our Gene Expression and Cancer Group led by Joan Seoane.
Research centered on the analysis of multi-regional sampling of tumor fragments and liquid biopsies from 10 deceased patients with heavily treated metastatic breast cancers, that were integrated for genomic and transcriptomic research, including the repertoire of tumor-associated epitopes derived from mutations and the immune tumor microenvironment (TME) patterns. The landscape of the T cell receptor repertoire of tumor infiltrating lymphocytes in these lethal breast cancers was characterized. Results evidenced marked-intra tumor and immune TME heterogeneity and suggest that the cancer antigenome correlates with the cancer genome for those breast cancer metastases.
“This research represents an important forward step towards advancing immune-genomics for breast cancer patients, and demonstrates the significance of the cancer anti-genome as the basis of novel personalized cancer immunotherapies,” observed Leticia, who recently returned to VHIO as a Junior Group Leader to lead research focused on cancer heterogeneity.
On the same first full day of the meeting Rodrigo Dienstmann, Principal Investigator of VHIO´s Oncology Data Science (ODysSey) Group, served as the final Discussant in the Clinical Trials Plenary Session: Precision Medicine Clinical Trials, 12:45 – 15:00h. Rodrigo reviewed the final results of the phase II, multicenter proof of concept HERACLES trial in HER2-amplified metastatic colorectal cancer (mCRC) investigating the double HER2 targeting with trastuzumab and lapatinib, a duo of agents previously approved for the treatment of HER2+ breast cancer.
Spurred by promising preclinical results showing that dual HER2 blockade with these two agents successfully inhibited tumor growth in patient-derived xenografts (PDX), Silvia Marsoni, Niguarda Cancer Center (Milan, Italy) and colleagues put this anti-tumor activity to the test in patients with HER2+ mCRC. Preliminary findings from the trial, previously published in The Lancet Oncology*, reported the well tolerated clinical activity of trastuzumab in combination with lapatinib in this patient population refractory to chemotherapy and anti-EGFR antibodies.
Set within the context of both standard and emerging therapies for mCRC, with final results reporting a 30% overall response rate and a 70% control of disease of long lasting response duration, dual anti-HER2 therapy in HER2+ mCRC favorably compares with other current and experimental treatment strategies.
In his evaluation Rodrigo explored the three main reasons for success namely, careful patient population selection, meticulous biomarker-drug co-development, and a combined multi-marker multi-drug approach. Driven by robust preclinical data, he concluded that while the trial validated HER2 as a therapeutic target in mCRC, ongoing research will be required to more precisely establish the best timing of molecular testing and therapeutic application, and predictors of response and resistance. Throughout his discussion, he also supported the multi-molecular approach to developing novel anti-colorectal cancer therapies based on established subtypes of CRC.
“Building on the successes of HERACLES and other multicenter precision medicine clinical trials, we must continue to improve clinical benefit through better matching therapies to the molecular make-up of CRC in individual patients and further explore the efficacy of more potent agents and multi-drug combinations including antibody-drug conjugates,” commented Rodrigo.
During this same AACR Session, an additional multicenter and global study led by David M. Hyman, Memorial Sloan Kettering Cancer Cancer Center – MSKCC (New York, USA), involved the collaboration of VHIO Faculty. Jordi Rodón, Principal Investigator of VHIO´s Early Clinical Drug Development Group, and VHIO´s Cristina Saura who leads our Breast Cancer and Melanoma Group, participated in the phase II multi-histology, open label ´basket´ study: neratinib in HER2 or HER3 mutant solid tumors: SUMMIT.
This trial was designed to explore the clinical activity of tyrosine kinase inhibitor neratinib in patients with advanced solid tumors and HER2/HER3 mutations, identified by gene profiling and both tumor and liquid biopsy. SUMMIT provides the largest amount of data to date on using a pan-HER inhibitor in patients with solid tumors with these mutations; 141 patients were enrolled with 21 unique cancer types.
Findings presented at AACR revealed that responses in HER2 mutants varied across tumor types as well as specific mutation, with promising activity in breast cancer. In view of these findings, the study concludes that mutant HER2 is a driver oncogene in some cancers, and that not all mutations generate the same level of either HER2 hyperactivity and/or oncogene dependence.
“The analyses of co-mutation patterns across the various tumor types and their association with sensitivity and resistance to neratinib should reveal important insights in order to more precisely match this promising therapy, in combination, to the specificities of individual patients,” said VHIO´s Cristina Saura.
Coinciding with this year´s AACR meeting most suitably themed Research Propelling Cancer Prevention and Cures, its prestigious journal Cancer Discovery published results from several pioneering studies including a Phase Ib trial** to assess the efficacy of pairing encorafenib with cetuximab, with or without alpelisib as a therapeutic strategy against metastatic BRAF-mutant metastatic CRC (mCRC). First authored by Robin M. J. M van Geel, The Netherlands Cancer Institute – NKI (Amsterdam), Jan H. M. Schellens, NKI and Utrecht Institute for Pharmaceutical Sciences – UIPS (Utrecht), with the equal contribution of VHIO´s Director, Josep Tabernero, the study sought to establish the clinical activity of treating patients with refractory BRAF-mutant metastatic CRC (mCRC) with duo (encorafenib plus cetuximab) and trio (encorafenib plus cetuximab and alpelisib) combinations of treatments.
Enrolling a total of 54 patients into either the dual or triple-combination, both pairings demonstrated efficacy and acceptable safety profiles, with similar overall response rates: 19% in the dual – and 18% in the triple-combination group.
“Reflecting preclinical evidence that showed concomitant BRAF and EGFR inhibition as an effective strategy to suppress MAPK signaling and suppress tumor growth in this difficult-to-treat patient population, we have now evidenced the efficacy and tolerability of these two novel combinatorial approaches. While further evaluation is duly warranted, these findings promise a new therapeutic avenue in our collective efforts to improve outcomes for these patients,” noted Josep Tabernero.
Celebrating five days of the very best cancer science and medicine from across the globe, AACR´s 2017 Annual meeting drew a record attendance of over 21,900 participants from more than 80 countries – making this year´s meeting the largest in AACR´s 110 year history.
To discover more about AACR, its meetings, conferences and leading publications visit: http://www.aacr.org.
* Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, Zagonel V, Leone F, Depetris I, Martinelli E, Troiani T, Ciardiello F, Racca P, Bertotti A, Siravegna G, Torri V, Amatu A, Ghezzi S, Marrapese G, Palmeri L, Valtorta E, Cassingena A, Lauricella C, Vanzulli A, Regge D, Veronese S, Comoglio PM, Bardelli A, Marsoni S, Siena S. 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. Lancet Oncol. 2016 Jun;17(6):738-46.
** Robin M.J.M. van Geel, Josep Tabernero, Elena Elez, Johanna C Bendell, Anna Spreafico, Martin Schuler, Takayuki Yoshino, Jean-Pierre Delord, Yasuhide Yamada, Martijn Lolkema, Jason E Faris, Ferry A.L.M. Eskens, Sunil Sharma, Rona Yaeger, Heinz-Josef Lenz, Zev A. Wainberg, Emin Avsar, Arkendu Chatterjee, Savina Jaeger, Eugene Tan, Kati Maharry, Tim Demuth and Jan H.M. Schellens. A Phase 1b Dose-Escalation Study of Encorafenib (LGX818) and Cetuximab With or Without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer. Cancer Discov. March 31 2017 DOI:10.1158/2159-8290.CD-16-0795