Immunoterapia e farmaci innovativi

Transcription

1 Immunoterapia e farmaci innovativi Emilio Bria Oncologia Medica, Dipart. di Medicina, Università di Verona, Az. Osp. Univ. Int., Verona emilio.bria@univr.it Padova, 29 Ottobre 2015

2 Disclosures Advisory Boards/Honoraria/Speakers fee/consultant for: Celgene, Pfizer, MSD, Astra-Zeneca, Helsinn, Eli-Lilly, BMS, Novartis Research Support / Grants from: A.I.R.C. (Associazione Italiana Ricerca sul Cancro) I.A.S.L.C. (International Association for the Study of Lung Cancer) Fondazione Cariverona

3 The Immune System: an Ideal anti-cancer Weapon Modified - Topalian S, ASCO 2015

4 NSCLC: Immuno-mediated Disease [TITLE] Adapted by L.Chow, 2013 ASCO Annual Meeting

5 [TITLE] Adapted by L.Chow, 2013 ASCO Annual Meeting

6 Checkpoint inhibitors AGENT Ipilimumab Tremelimumab Nivolumab Pembrolizumab Atezolizumab TARGET CTLA-4 CTLA-4 PD-1 PD-1 PDL-1 Support a non-specific enhancement of innate immune response Modified - Drake et al, Nat Rev 2013

7 Primary endpoint: irpfs Lynch et al, JCO 2012

8 PFS & OS according to Histology In the PHASED-ipilimumab arm, improvement in irpfs, mwho-pfs and OS versus control appeared greater for squamous histology than for non-squamous Not the same trend in the concurrent-ipilimumab arm Modified by Brahmer, ASCO 2013

9 How do perform our best benchmark? Garassino M, ASCO 2015

10 CheckMate 017 CheckMate 017 (NCT ) - Study Design CheckMate 057

11 Is NIVO more effective in squamous than adenoca? Presented By Marina Garassino at 2015 ASCO Annual Meeting

12 CheckMate 017: Updated OS Data Reckamp K ORAL02.01

13 PD-L1 status according to sampling Slide 17 Herbst R, ASCO 2015

14 The Biomarker Issue: PD-L1 & Histology CheckMate 017 [Squamous] CheckMate 057 [non-squamous] Modified Spigel ASCO 2015; Paz-Ares ASCO 2015

15 CheckMate 017 OS by PD-L1 Expression Presented By David Spigel at 2015 ASCO Annual Meeting

16 CheckMate 057 OS by PD-L1 Expression Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting

17 CheckMate 017 CheckMate 057

18 CheckMate 017: Updated Safety Time to Onset of First Treatment-related Select AE With Nivolumab by Category (Any Grade) Pts still on study, n Pts still on treatment, n Total pts with first event, a n The majority of patients who experienced treatment-related select AEs with nivolumab experienced their first event within the first 3 months of treatment Select AEs: AEs with potential immunologic etiology that require frequent monitoring/intervention. Based on December 2014 DBL. Includes events reported between first dose and 30 days after last dose of study therapy. Within each time interval, patients with 1 event were counted only once in each category but could be classified into more than one category Reckamp K ORAL02.01

19 CA : Safety according to PS Treatment-related Select AEs by ECOG PS Ussain M ORAL02.02

20 Slide 20 Presented By Marina Garassino at 2015 ASCO Annual Meeting

21 Slide 22 Presented By Marina Garassino at 2015 ASCO Annual Meeting

22 Phase Ib GP28328: ATEZO + Chemo [1 st line] ATEZO no unexpected toxicities No pneumonitis or other respiratory AEs of concern ORR 50% ORR 76.5% ORR 56.3% Rizvi N ORAL02.05

23 PD-L1 positivity is a Flexible concept Peters S Discussant

24 PD-L1 status: Methodology Issues Antibodies are Not Identical: >25% Discordant Herbst R, ASCO 2015

25 <1% 1-49% 50% Garon NEJM 2015

26 Pembro: Immune-Related Events & Steroids KEYNOTE-001, Data from 505 pts PFS and OS and Steroids Use to Manage Immune- Mediated AEs Leighl N ORAL31.02

27 Pembro: Phase II Brain Metastases Data from 18 pts Best Brain Metastases Response by mrecist Time to Brain Metastases Response Goldberg SB ORAL31.07

28 Slide 30 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting

29 Non-synonymous mutations per tumor Smart Cancer Multiple mutational drivers Large Mutational load Multi-targeted therapy Resistance common, early Stupid Cancer NON-ONCOGENE ADDICTION Single Dominant Mutation Small Mutational Load Monotherapy is effective Resistance rare, late ONCOGENE ADDICTION

30 Large Mutational Load? Luo Cell 2009

31 Large Mutational Load? Wolchok JD, Chan T, Nature 2014

32 Topalian S, ASCO 2015

33 A high mutational burden increased the likelihood of the development of specific neoepitopes that would confer clinical benefit from CTLA-4 blockade. In the era of immunotherapy, genetic diversity of cancer may, in fact, be a good thing. Snyder A, NEJM 2014 Boussiotis VA, NEJM 2014

34 Slide 32 Modified - Topalian S, ASCO 2015

35 Conclusions Immunotherapy may represent a new treatment opportunity for the treatment of lung cancer in general, and represents an appealing option for tumors with a high mutational load A new standard for Squamous came out Non oncogene-addicted Adenocarcinoma is going to have a new treatment option Intriguing perspectives for SCLC The potential key role of predictive biomarkers is under investigation according to histology NIVO improves OS regardless of PD-L1 in Squamous NIVO improves OS according to PD-L1 in nonsqcc PD-L1 expression may allow to optimize treatment efficacy for non-squamous histology Challenging issues SAFETY: pay attention to immunorelated toxicities ACTIVITY: immunorelated response criteria vs traditional WHO criteria

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