Ongoing projects and perspectives for collaborations

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2 Ongoing projects and perspectives for collaborations Università di Verona AOUI Verona Expanding molecular profiling and implementing a Precision Medicine approach Global Integrated Care

3 Molecular Tumor Board-based implementation of Precision Oncology AIRG IG 2019 submitted Milella & Scarpa co-pis

4 The ICGC-ARGO italian chapter: Profiling OrphaN Tumors for treatment selection - PONTE

5 Implementing Precision Medicine in clinical practice remains challenging, as clinical trials have failed so far to demonstrate OS advantages in unselected patients' populations. We have therefore elected to profile orphan tumors, defined as rare cancers for which orphan-drug status might apply, including: classical rare cancers, rare histologies of common cancers, malignancies that currently have no defined molecular diagnostic paths, thereby excluding common cancers for which a standard molecular profiling is indicated (see national AIOM-SIAPEC guidelines for reference); however, common cancers testing negative for standard molecular biomarkers (e.g. EGFR/KRAS/ALK/ROS1-negative NSCLC) could be considered for profiling within this project upon Molecular Tumor Board discussion and recommendation. Drug access for driver/matched therapy will be prioritized as follows: clinical trials available at the proponent and/or collaborating Institutions, ad hoc designed clinical trials (including clinical trials designed for recurrent - i.e. encountered in >2% of the retrospective dataset - potentially driver aberrations, see below), off label drug use. We aim at demonstrating a prevalence of potentially actionable drivers in at least 30% of the orphan tumors patient population (as defined above). To this purpose, we plan to retrospectively profile 800 cases (which will also be used to define recurrent drivers, see above) and prospectively profile 1200 cases. Clinical data will be collected for both the retrospective and prospective populations (see below).

6 The FoundationOne Lung-Seq Program L'idea di condividere una strategia di "selezione" nasce dalla considerazione che un approccio di profilazione "broad-based" in popolazioni non selezionate ha già mostrato i suoi limiti (in sostanza l'assenza di un vantaggio in termini di outcome di popolazione) nei confronti di una profilazione ristretta alle 3 o 4 alterazioni con implicazioni FOneterapeutiche profiling che free sono già of uno charge standard. for a predefined A Verona number testeremo of quindi ptscon FoundationOne pazienti "quadrupli negativi". NSCLC in first-line treatment Se siete d'accordo condivideremo la seguente strategia di "selezione» e i dati che ne deriveranno: NSCLC (senza distinzione di istologia) Stadio Standard clinico IIIB molecular (non candidato a trattamento profiling loco-regionale/immuno performed at a mantenimento)/iiic/iv sites EGFR/KRAS/ALK/ROS1 negativi (se possibile), oppure EGFR/ALK/ROS1 negativi (se KRAS non è fattibile d'ambleè)

7 Medical treatment of mrcc: an ever evolving timeline Sunitinib Temsirolimus Bevacizumab (+ IFN-α) Ipilimumab + nivolumab Tivozanib Atezolizumab + bevacizumab Axitinib + avelumab ? Axitinib Sorafenib Pazopanib Axitinib Nivolumab + pembrolizumab Cabozantinib 1L Everolimus 2019? Cabozantinib Lenvatinib (+ everolimus) IFN, interferon.

8 Stato dell arte in I-L: la mia (personale) visione

9 troppo facile? Angio-addict Good Intermediate Immunogenic Poor

10 Ma le classi di rischio sono PROGNOSTICHE... Non PREDITTIVE!!! Immunotherapy era 1 Targeted agents era 2 Median OS of good risk patients 20 months 43.2 months (95% CI: ) Median OS of intermediate risk patients 10 months 22.5 months (95% CI: ) Median OS of poor risk patients 4 months 7.8 months (95% CI: ) 1. Motzer RJ, et al. J Clin Oncol 1993;11: ; 2. Heng DY, et al. Lancet Oncol 2013;14:141-8.

11 troppo facile? Angio-addict Good Intermediate Immunogenic Poor PD-L1 expression Other clinico-pathological features (i.e. sarcomatoid component)???

12 troppo facile? Angio-addict Good Intermediate Immunogenic Poor Other clinico-pathological features (i.e. sarcomatoid component)??? PD-L1 expression Angiogenesis signature T- cell effector signature

13 troppo facile? Angio-addict Good Intermediate Immunogenic Poor Other clinico-pathological features (i.e. sarcomatoid component)??? PD-L1 expression Angiogenesis signature T- cell effector signature

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15 Ongoing projects and perspectives for collaborations Università di Verona AOUI Verona Expanding molecular profiling and implementing a Precision Medicine approach Global Integrated Care

16 Focus On Research and CarE (FORCE) Approccio di Presa in Carico Globale Integrata Evidence-based nel Paziente Oncologico Oncologia Medica, Dipartimento di Medicina, Università di Verona, Azienda Ospedaliera Universitaria Integrata, Verona

17 Un Team che si Prenda Cura della Persona Medico oncologo (dott. Sara Pilotto) - Presa in carico - Coordinatore Dietista Nutrizionista (dott. Ilaria Trestini) - Screening e valutazione nutrizionale - Counseling nutrizionale Psicologa in ambito oncologico (dott. Daniela Tregnago) - Supporto psicologico individuale Chinesiologa (dott. Alice Avancini) - Esercizio fisico adattato

18 con un Approccio Personalizzato

19 con un Approccio SCIENTIFICO Rigoroso ed Evidence-based Garantire al paziente il miglior percorso terapeutico possibile Fornire un modello di cura applicabile in modo trasversale al contesto oncologico, ma anche generalizzabile alla cura in patologie croniche complesse Produrre nuove evidenze scientificamente valide in grado di implementare la conoscenza

20 Muscle derangement and alteration of the nutritional machinery in NSCLC. Trestini I, Gkountakos A, Carbognin L, Avancini A, Lanza M, Molfino A, Friso S, Corbo V, Tortora G, Scarpa A, Milella M, Pilotto S. Identifying factors which contribute to a worsening nutritional status and understanding the role of genetic polymorphisms may facilitate the development of a tailored intervention in order to provide optimal care and improve clinical outcomes in NSCLC pts. Submitted to Critical Reviews in Oncology / Hematology

21 Prevalence of clinical and sub-clinical malnutrition in advanced non-smallcell lung cancer patients and association with outcome. Trestini I, Sperduti I, Sposito M, Kadrija D, Drudi A, Tregnago D, Pio Di Noia V, Gkountakos A, D'Argento E, Carbognin L, Santo A, D'onofrio M, Tortora G, Bria E, Milella M, Pilotto S. Objectives The present study aimed to explore prevalence of malnutrition and its correlation with outcome in A-NSCLC pts. Results NRS was a significant independent predictor for PFS (p = 0.01). Pts with baseline NRS 3 had significantly longer 1-year PFS (58.6% vs 16.7%, p = 0.04) and 2-year OS (90.6% vs 68.3%, p = 0.03) and a better ORR than those with NRS > 3 (66.7% vs 21.4%). In pts treated with immunotherapy, loss in muscle mass (p = 0.01) correlated with worse ORR, PFS and OS, although differences did not reach a statistical significance. Conclusion Malnutrition has a detrimental impact on ORR, PFS and OS in A-NSCLC, including pts treated with immunotherapy. Unpublished data

22 CLINICAL REPORT Protein, malnutrition and wasting disorders VOLUME 72 NUMBER 5 MAY 2018 Prognostic impact of early nutritional support in patients affected by locally advanced and metastatic pancreatic ductal adenocarcinoma undergoing chemotherapy. Trestini I, Carbognin L, Sperduti I, Bonaiuto C, Auriemma A, Melisi D, Salvatore L, Bria E, Tortora G. Trestini I, et al. Eur J Clin Nutr The time between the diagnosis of PDAC and the nutritional support was an independent predictor of OS.

23 Abstract/poster presentati a congressi nazionali ed internazionali:

24 Tailored nutritional intervention as a predictive factor for survival outcomes in patients affected by Head and Neck Cancer undergoing chemotherapy and/or radiotherapy. Trestini I, Carbognin L, Sperduti I, Bonaiuto C, Tondulli L, Pilotto S, Tortora G, Milella M, Bria E. The nutritional intervention was an independent predictor for better OS. Unpublished data

25 Progetti ongoing Il Supporto Psicologico Progetto di umanizzazione delle cure: Assistenza psicologica in ambito oncologico Rilevazione dei sintomi ansiosi, depressivi e del distress emotivo nel pazienti oncologici Promuovere il benessere psicologico nei pazienti oncologici attraverso l applicazione del protocollo relativo alla psicoterapia breve per il benessere psicologico

26 L esercizio fisico S.T.I.P.-ON. (Sostenibile Training In Pazienti Oncologici)

27 Progetti ongoing L esercizio fisico adattato C.H.O.iC.E. (Choose Health: Oncological patients Centered Exercise) Trial randomizzato multicentrico, che valuti l efficacia preliminare, di un programma di esercizio fisico, basato sulle attuali linee guida, ma tenga in considerazione le preferenze delle persone. M.O.T.O (Motives, Obstacles Towards run in Oncology) Analisi qualitativa delle motivazioni e delle barriere nell attività podistica, nel contesto dell iniziaiva «Run for Science». E.D.u.C.A. (Educational materials Development for physical activity in CAncer patients) Validazione di una guida informativa e pratica sull attività fisica nei pazienti con diagnosi oncologica. E.C.H.O. (Exercise in Cancer: the Healthcare professionals Opinion) Identificare l opinione degli operatori sanitari verso la raccomandazione della pratica di esercizio fisico nel contesto oncologico; Identificare le conoscenze, le barriere e le motivazioni riguardo la promozione dell esercizio fisico.

28 Impact of a comprehensive lifestyle intervention on immunological parameters and outcome in non-small-cell lung cancer Hypothesis: A comprehensive lifestyle intervention including: 1) nutritional management 2) physical activity and 3) psychological support may modulate immunological parameters and improve immunotherapy outcome in NSCLC patients.

29 Impact of a comprehensive lifestyle intervention on immunological parameters and outcome in non-small-cell lung cancer RETROSPECTIVE & PROSPECTIVE PHASE Task: aims to build a signature for predicting the outcome of immunotherapy-treated NSCLC patients Task: aims to evaluate the effect of our comprehensive lifestyle approach on the outcome of immunotherapy-treated NSCLC patients Tissue-based Blood-based Nutritional status Muscle wasting Physical activity level Psychological state

30 Impact of a comprehensive lifestyle intervention on immunological parameters and outcome in non-small-cell lung cancer INTERVENTIONAL PRECONDITIONING TRIAL Comprehensive lifestyle approach R 2:1 Immunotherapy Recommendations according to guidelines

31 InNovation Experience Resource OpTimization KnoWledge OppOrtunities LeaRning TeamworK