What is new in Immunotherapy, Biomarkers and Side Effects

Transcription

1 What is new in Immunotherapy, Biomarkers and Side Effects Prof Dr Christian Rolfo, MD, PhD, MBA Director of Phase I Early Clinical Trials Unit Director of Clinical Trial Management Program Oncology Department Antwerp University Hospital Center for Oncology Research (CORE) Antwerp University Belgium

2 Disclosures Novartis:International Speaker Bureau for Lung Cancer Mylan: Scientific advisor for Lung Cancer Products Biocept: Reserch grant for Liquid Biopsy in NSCLC Boeringher Italy spearker bureau MSD speaker bureau OncoDNA: Research collaboration exosomes project Guardant Health Speaker Bureau and Clinical Research Project.

3 PDL-1 may vary inside the same tissue section

4 PDL-1 status 4

5 The IASLC Blue Print Study 39 NSCLC tumor stained with four PD-L1 assays Independent review by three expert pathologists Similar PD-L1 expression for three assays

6 1. Blueprint phase 2A involving real-life clinical lung cancer samples and 25 pathologists largely affirms the results of Blueprint phase C3, 28-8 and SP263 are comparable, SP142 detects less, while stains more PD-L1 positive tumor cells 3. PD-L1 scoring on digital images and glass slides show comparable reliability

7 Mutational Tumor Burden

8

9 Checkmate 227 patients with hight TMB (>10) NEJM 3/2018

10 Liquid Biopsy in IO. The new frontier CD8+ T cells that express PD-1 Ton N Schumacher & Wouter Scheper, Nature April 2016

11 Liquid Biopsies in Immunotherapy Unmeet Medical Need: Validated Biomarkers in Blood! Potential Utility of Liquid Biopsy in Immunotherapy Diagnostic Prognostic Predictive of Response Monitoring Mechanisms if Resistance Current tools: Calculation of circulating TMB Detection of bpdl1 Alellic Fraction Variation Dynamic Liquid Biopsy in Immunotherapy is challenging! A complex microenvironment Image from Nishino et al, Nature Reviews Clinical Oncology, June 2017

12 1295O: Blood-based biomarkers for cancer immunotherapy: Tumor mutational burden in blood (btmb) is associated with improved atezolizumab (atezo) efficacy in 2L+ NSCLC (POPLAR and OAK) Gandara DR, et al Key results Atezolizumab PFS benefit in btmb subgroups: OAK 211/273 samples from POPLAR and 583/797 samples from OAK were biomarker-evaluable btmb 16 btmb < Atezolizumab (n=77) Docetaxel (n=81) Atezolizumab (n=216) Docetaxel (n=209) PFS, % PFS, % Population btmb 16 btmb <16 PFS HR (95%CI) 0.65 (0.47, 0.92) 0.98 (0.80, 1.20) n (%) 158 (27) 425 (73) BEP 0.87 (0.73, 1.04) 583 (100) ITT 0.95 (0.82, 1.10) HR Time, months Time, months Interaction p=0.036 Favours atezolizumab Favours docetaxel BEP, biomarker-evaluable population Gandara DR et al. Ann Oncol 2017;28(suppl 5):Abstr 1295O

13 Hypermutated Circulating Tumor DNA HR 0.39 HR 0.52 In patients undergoing therapy with IO a higher amount of mutations was associated with a better PFS and OS Variable All Patients % (N, if applies) VUS > 3 % (N, if applies) VUS < 3 % (N, if applies) P value c Disease Control Rate [SD/CR/PR] (% (N)) b 24% (16/66) 45% (9/20) 15% (7/46) P = Median PFS, months b 2.3 (95%CI: ) Median OS, months b 15.3 (95%CI: ) Not Reached P = (HR 0.52; 95% CI ) P = (HR 0.39; 95% CI ) Khagi (Kurzrock) et al Clinical Cancer Research

14 CORRELATION OF PD-L1 FROM PLASMA WITH CLINICAL RESPONSE IN PATIENTS WITH LUNG CANCER In two patients with stabilized disease (SD) treated with Nivolumab, PD-L1 became undetectable upon treatment. An increase in PD-L1 ctrna was predictive of resistance to therapy approx. 1.5 months before progression was seen on CT scans. No overlap in relative PD-L1 expression between patients showing response to Nivolumab in (p = , Wilcoxon Rank Sums) Raez L. et al. J Clin Oncol 35, 2017 (suppl; a11550) 14

15 No Change in Overall Survival with I/O in 2 nd Line EGFR Mutated Lung Cancer: A Meta-Analysis Lee (Yang) et al Journal of Thoracic Oncology Key: Checkmate 057 (N=582) Nivolumab Keynote 010 (N=1034) Pembrozulimab POPLAR (N=287) Atezolizumab Lee (Yang) et al (Oct 2016) Journal of Thoracic Oncology

16 EGFR Mutated or ALK Fusions as Negative Predictors of Response to I/O in 2 nd + Line in Lung Cancer Response PFS Gainor (Mino-Kenudson) et al. Clin Cancer Res; 22(18); Low rates of concurrent PD-L1 expression and CD8 + TILs within the tumor microenvironment may underlie these clinical observations. N=28 N=30

17 Poor Response to Immunotherapy in NSCLC Patients with MET Exon14 Skipping Mutations ORR 6.7% 95% CI (0-32%) Adequate Genotyping Identifies Patients Unlikely to Benefit from Immunotherapy Note: PD defined as > 20% growth or appearance of new lesions Sabari et al, J Clin Oncol 35, 2017 (suppl; abstr 8512)

18 Conclusions: Which mutations may be best for PD-(L)1 monotherapy?<br /> Presented By Ben Creelan at 2017 ASCO Annual Meeting

19 Pseudoprogression: a new concept in cancer immunotherapy Kwak et Kwak et al, Radiographics, 2015

20 Pseudoprogression in NSCLC Response of a subcutaneous metastatic lesion to nivolumab, by week of treatment. Sarfaty et al, Medicine: January Volume 96 - Issue 4 - p e5951

21 Durvalumab + Osimerinib: TATTON trial (NCT ) SPSLIDES/SPEXIB/ONCOBU/563495/04/05/2016 European Lung Cancer Conference (ELCC), Geneva, Switzerland, 13 to 16 April, 2016

22 Durvalumab + Osimertinib: adverse events The study has been suspended SPSLIDES/SPEXIB/ONCOBU/563495/04/05/2016 European Lung Cancer Conference (ELCC), Geneva, Switzerland, 13 to 16 April, 2016

23 Combination with cytokine-analogues : AM0010 Aung Naing, et al Clin Oncol 34, 2016 (suppl; abstr 3018)

24 Gut microbiome influences efficacy ofpd-1 based immunotherapy against epithelial tumors Culturomics-based analyses of fecal samples in 16 R and 16 NR NSCLCpatients before therapy, each commensalcolony having been identified by mass spectrometry. Routy et al.,science359, (2018)

25 Antibiotics prescription decreases progression-free survival (PFS) and overall survival (OS) in patients with advanced cancers treated with PD1/PDL1 immune checkpoint inhibitors

26 Slide 4

27

28

29

30

31 Thanks for your attention

32