Unità Operativa di Oncologia Medica Direzione Scientifica Istituto Tumori Giovanni Paolo II Bari.

Transcription

1 Unità Operativa di Oncologia Medica Direzione Scientifica Istituto Tumori Giovanni Paolo II Bari

2 LAPACT mffox + PEGPH20 (SWOG study) COMPASS trial Immune landscape

3 ABSTRACT 204 Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

4 introduction Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

5 Study design Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

6 Patient Disposition Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

7 Patient Disposition Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

8 Efficacy during induction Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

9 Best change from baseline in sum of longest diameters <br />of target lesionsa Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

10 Investigator s choice of therapy IN 45/61 PATIENTS <br />who completed induction Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

11 Time to treatment failure was 8.8 months<br />(protocol-specified target was 6.6 months) Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

12 Progression-free and overall survival Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

13 Conclusions II Presented By Pascal Hammel at 2018 Gastrointestinal Cancers Symposium

14 Slide 11 Presented By Brian Wolpin at 2018 Gastrointestinal Cancers Symposium

15

16

17 Slide 2 Presented By Ramesh Ramanathan at 2018 Gastrointestinal Cancers Symposium

18 Slide 3 Presented By Ramesh Ramanathan at 2018 Gastrointestinal Cancers Symposium

19

20 Slide 5 Presented By Ramesh Ramanathan at 2018 Gastrointestinal Cancers Symposium

21 Slide 6 Presented By Ramesh Ramanathan at 2018 Gastrointestinal Cancers Symposium

22 LAPACT mffox + PEGPH20 (SWOG study) COMPASS trial Immune landscape

23 Genomics-Driven Precision Medicine for Advanced Pancreatic Ductal Carcinoma (PDAC) - Early Results from the COMPASS Trial (NCT ) Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium

24 Slide 2 Despite decades of research and exhaustive Phase III trials, median survival for patients with advanced PDAC remains less than 12 months Presented By Steven Leach at 2018 Gastrointestinal Cancers Symposium

25

26 Thus, better patient stratification is needed to prevent harmful chemotherapy and to develop personalized treatment strategies to improve outcomes Genomic-driven precision medicine may fulfill this urgent unmet need

27 Slide 8 Presented By Steven Leach at 2018 Gastrointestinal Cancers Symposium

28

29 Slide 6 Almost all PDAC harbor a key driver mutation in KRAS, and over half have mutations and/or copy number losses of TP53, SMAD4 and CDKN2A Yet none of these changes are directly druggable Presented By Steven Leach at 2018 Gastrointestinal Cancers Symposium

30 23 patients with germaline PDAC mutation-associated PDAC were treated with Olaparib after gemcitabine therapy; all patients had received prior gemcitabine and > 50% received a prior platinum-containing regimen. The ORR was 22%, PFS was 4,5 months, and OS was 9,8 months

31 To date, clinically meaningful real time whole genome sequencing (WGS) and RNA sequencing (RNA seq) to identify predictive mutational signatures and RNA profiles has not been established To overcome this challenge, COMPASS (Comprehensive Molecular Characterization Of Advanced Pancreatic Ductal Adenocarcinoma for better Treatment Selection) was launched in December 2015 Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium

32 Study Design Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium

33 Patients: Dec Jun Ongoing Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium

34 WGS Performance Characteristics Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium

35 Study Design Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium

36 Results from the Australian Pancreatic Cancer Genome Initiative within the International Cancer Genome Consortium defined four subtypes of PAC: stable, locally rearranged, scattered, and unstable Of particular interest is the unstable phenotype, which was observed in 14% of the 100 patient samples analyzed. Unstable genomes were found to contain more than 200 structural variation events, which often suggests damage to the DNA repair pathways Patients with PAC who have DNA damage repair alterations may be particularly sensitive to platinum-containing chemotherapeutics and/or PARP inhibitors

37 Genomic Results Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium

38 By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes (classical and basal like), including a basal-like subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers.

39 RNA Subtype & Chemotherapy Response Objective response to first line chemotherapy was significantly better in patients with the classical PDAC RNA subtype compared to those with the basal-like subtype

40 Survival by Moffitt RNA Signature The best PFS was observed in those with classical subtype treated with mfolfirinox Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium

41 Conclusions Presented By Kyaw Aung at 2018 Gastrointestinal Cancers Symposium

42 Slide 1 Presented By Steven Leach at 2018 Gastrointestinal Cancers Symposium

43 To define the importance of neoantigens in pancreatic ductal adenocarcinoma, we compared stage-matched cohorts of treatmentnaive, surgically resected, rare longterm survivors (LTSs, median survival 6 years, n = 82) to shortterm survivors with a more typical poor outcome (median survival 0.8 years, n = 68) Presented By Steven Leach at 2018 Gastrointestinal Cancers Symposium

44 Using nine-parameter multiplexed immunohistochemistry and immunofluorescence in tissue microarrays, we found greater densities of CD8+ T cells (3-fold), cytolytic CD8+ cells (12-fold) Presented By Steven Leach at 2018 Gastrointestinal Cancers Symposium

45 Patients with both the highest predicted neoantigen number and either the greatest CD3+CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival Presented By Steven Leach at 2018 Gastrointestinal Cancers Symposium

46 Slide 34 Together, these data suggest that neoantigen immunogenicity and quality, and not purely quantity, correlate with survival Presented By Steven Leach at 2018 Gastrointestinal Cancers Symposium

47 The theory of molecular mimicry postulates that TCRs that can recognize pathogenic antigens can also recognize non-pathogenic antigens, which has been documented in autoimmunity but not in the cancer context

48 Slide 39 Presented By Steven Leach at 2018 Gastrointestinal Cancers Symposium

49 LAPACT mffox + PEGPH20 mttf: 8.8 months (exceeded the protocolspecified target of 6.6 months) Addition of PEGPH20: detrimental COMPASS trial WGS: feasible; predictive Immune landscape Selection of patients for immunotherapy protocols Design of individualized peptide-based vaccines GRAZIE n.silvestris@oncologico.bari.it