Filippo Montemurro, M.D.
Design, implementation and conduction of ‘hypothesis-driven’, precision medicine trials based on the translational discoveries of the FPO-IRCC research laboratories Background: Precision medicine brings a new set of challenges to clinical application. To hasten the adoption of new therapies we need to achieve a deeper molecular understanding of cancers and reliably translate results from representative preclinical models into clinical trials enriched with suitably identified patients.
At Candiolo we have started to confront precision medicine hurdles by creating a clinical platform integrating, under the same virtual roof, the efforts of surgeons, pathologists, radiologists, and medical oncologists from the IRCC clinical network (25 centers around Italy), in order to assemble the timely collection of high quality, clinically annotated biological samples at meaningful time points, to feed research projects and precision medicine trials. Five translational protocols are now feeding the translational Labs of the Institute (PROFILING, AGNOSTOS-Profiling, GEA, FUNNEL and CORNUCOPIA). Together with the translational scientists, we are also building a “cancer knowledge network” to store the resulting molecular and medical data in digital form and to deliver them, in comprehensible ways, to scientists, clinicians, and patients (Projects LAS and PROBUS). Three hypothesis driven clinical trials have been designed and implemented (HERACLES and ARES in colorectal cancer, AGNOSTOS in cancer of unknown origin). HERACLES has been the the Institute first precision trial designed upon the discovery, based on PDX studies, that HER2 amplification in metastatic colorectal cancer (mCRC) associates with resistance to anti-EGFR therapy, and predicts response to the combination of lapatinib and trastuzumab for a dual blockade of the HER2 pathway. Accordingly, we conducted a proof-of-concept trial testing the combination in HER2 amplified mCRC patients failing standard therapies. The trial has proven the efficacy of the combination with 8 long lasting responders out of 23 patients treated, proving HER2 as the first bona fide actionable target in mCRC. Genotype/response correlation has shown that only patients with truly ‘HER2 addicted’ tumors benefit from this therapy. The tumor genomic landscape of non-responders and relapsing cases is under scrutiny to define the determinants of primary and secondary resistance.
Conclusions and perspectives:
In the next year we will focus on addressing the obstacles encountered in HERACLES: unexplained primary drug resistance, inadequacy of current criteria for monitoring tumor response and recurrence, limited knowledge of genomic heterogeneity of mCRC. We will also extend the dynamic research infrastructure which we have created for mCRC to gastric cancer and cancers of unknown origin. Two new resource-dense, hypothesis-driven trials deriving their rationale from the results of the Institute’s translational labs, will be embedded and nurtured by this infrastructure.