what is new in immunotherapy, biomarkers and side effects€¦ · pd-l1 scoring on digital images...
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What is new in Immunotherapy, Biomarkers and Side Effects
Prof Dr Christian Rolfo, MD, PhD, MBADirector of Phase I – Early Clinical Trials UnitDirector of Clinical Trial Management Program
Oncology DepartmentAntwerp University Hospital Center for Oncology Research (CORE)Antwerp UniversityBelgium
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.
PDL-1 may vary inside the same tissue section
PDL-1 status
4
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
1. Blueprint phase 2A involving real-life clinical lung cancer samples and 25 pathologists largely affirms the results of Blueprint phase 1
2. 22C3, 28-8 and SP263 are comparable, SP142 detects less, while 73-10 stains more PD-L1 positive tumor cells
3. PD-L1 scoring on digital images and glass slides show comparable reliability
Mutational Tumor Burden
Checkmate 227 patients with hight TMB (>10)
NEJM 3/2018
Liquid Biopsy in IO. The new frontier… CD8+ T cells that express PD-1
Ton N Schumacher & Wouter Scheper, Nature April 2016
Image from Nishino et al, Nature Reviews Clinical Oncology, June 2017
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
Unmeet Medical Need:
Validated Biomarkers in Blood!
Liquid Biopsies in Immunotherapy
Liquid Biopsy in Immunotherapy is challenging!
A complex microenvironment
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
Gandara DR et al. Ann Oncol 2017;28(suppl 5):Abstr 1295O
00 2 4 6 28
Time, months
PFS,
%
8 12 20
Atezolizumab (n=216)Docetaxel (n=209)
bTMB ≥16 bTMB <16100
80
60
40
20
00 2 4 6 24
Time, months
PFS,
%
10 14 18
Atezolizumab (n=77)Docetaxel (n=81)
10 16 24 0.2 1.0 1.5
HR
Favours atezolizumab Favours docetaxel
Population
bTMB ≥16
bTMB <16
BEP
ITT
PFS HR (95%CI)
0.65 (0.47, 0.92)
0.98 (0.80, 1.20)
0.87 (0.73, 1.04)
0.95 (0.82, 1.10)
n (%)
158 (27)
425 (73)
583 (100)
850
208 12 16 2214 18 2622
90
70
50
30
10
100
80
60
40
20
90
70
50
30
10
Interaction p=0.036
BEP, biomarker-evaluable population
211/273 samples from POPLAR and 583/797 samples from OAK were biomarker-evaluable
In patients undergoing therapy with IO a higher amount of mutations was associated with a better PFS and OS
Khagi (Kurzrock) et al. 2017 Clinical Cancer Research
HR 0.52
HR 0.39
Hypermutated Circulating Tumor DNA
Variable All Patients % (N, if applies)
VUS > 3% (N, if applies)
VUS < 3% (N, if applies) P valuec
Disease Control Rate[SD/CR/PR] (% (N))b 24% (16/66) 45% (9/20) 15% (7/46) P = 0.014
Median PFS, monthsb 2.3 (95%CI: 0.7-5.0) 3.84 2.07 P = 0.019
(HR 0.52; 95% CI 0.31-0.87)
Median OS, monthsb 15.3 (95%CI: 6.80-15.68) Not Reached 10.72 P = 0.042
(HR 0.39; 95% CI 0.18-0.83)
CORRELATION OF PD-L1 FROM PLASMA WITH CLINICAL RESPONSE IN PATIENTS WITH LUNG CANCER
Raez L. et al. J Clin Oncol 35, 2017 (suppl; a11550)14
No overlap in relative PD-L1 expression between patients showing response to Nivolumab in (p = 0.0073, Wilcoxon Rank Sums)
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 Change in Overall Survival with I/O in 2nd Line EGFR Mutated Lung Cancer: A Meta-Analysis
Lee (Yang) et al. 2017 Journal of Thoracic Oncology
Key:Checkmate 057 (N=582) NivolumabKeynote 010 (N=1034) PembrozulimabPOPLAR (N=287) Atezolizumab
Lee (Yang) et al. 2017 (Oct 2016) Journal of Thoracic Oncology
EGFR Mutated or ALK Fusions as Negative Predictors of Response to I/O in 2nd+ Line in Lung Cancer
Gainor (Mino-Kenudson) et al. Clin Cancer Res; 22(18); 4585–93. 2016
Response
N=28 N=30
PFS
Low rates of concurrent PD-L1 expression and CD8+ TILs within the tumor microenvironment may underlie these clinical observations.
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)
Conclusions: Which mutations may be best for PD-(L)1 monotherapy?<br />
Presented By Ben Creelan at 2017 ASCO Annual Meeting
Pseudoprogression: a new concept in cancer immunotherapyKwak et
Kwak et al, Radiographics, 2015
Pseudoprogression in NSCLC
Sarfaty et al, Medicine: January 2017 - Volume 96 - Issue 4 - p e5951
Response of a subcutaneous metastatic lesion to nivolumab, by week of treatment.
SPSLIDES/SPEXIB/ONCOBU/563495/04/05/2016
Durvalumab + Osimerinib: TATTON trial(NCT02143466)
European Lung Cancer Conference (ELCC), Geneva, Switzerland, 13 to 16 April, 2016
SPSLIDES/SPEXIB/ONCOBU/563495/04/05/2016
Durvalumab + Osimertinib: adverse events
European Lung Cancer Conference (ELCC), Geneva, Switzerland, 13 to 16 April, 2016
The study has been suspended
Combination with cytokine-analogues : AM0010
Aung Naing, et al Clin Oncol 34, 2016 (suppl; abstr 3018)
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, 91–97 (2018)
Antibiotics prescription decreases progression-free survival (PFS) and overall survival (OS) in patients with advanced cancers treated with PD1/PDL1 immune checkpoint inhibitors
Slide 4
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