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

Thanks for your attentionchristian.rolfo@uza.be