Diapositiva 1 - Belnuc26/02/2020 12 Lopci # 2020 Seminar on Immunotherapy Scatter plots with...

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Lopci # 2020 Seminar on Immunotherapy

Cancer immunotherapy treatment response criteria in clinical practice and imaging

hallmarks of treatment toxicity.

EGESTA LOPCI, MD, PhD

Nuclear Medicine department

Humanitas Clinical and Research Hospital

Via Manzoni 56, 20089 Rozzano (MI)

E-mail: [email protected];

[email protected]


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WHAT KIND OF MICROENVIRONMENT SORROUNDS THE TUMOR?


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mailto:[email protected]


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http://cancerworld.net/e-grandround/the-role-of-immunotherapy-in-treating-solid-cancers/

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Ipilimumab, the first immune checkpoint

inhibitor to receive approval, showed a

significant improvement in survival for

patients with malignant melanoma, with the

characteristic tail showing a proportion of

patients derive long term benefit

Source: Adapted from FS Hodi et al. (2010) Improved Survival with Ipilimumab in Patients with Metastatic Melanoma, NEJM 363:711–723. © 2010


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Landmark analysis of OS beginning from 4 wk post-progression to death in patients who were treated and not treated with nivolumab beyond progression.

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Source: http://cancerworld.net/e-grandround/the-role-of-immunotherapy-in-treating-solid-cancers/

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Total tumor burden

Baseline lesion tumor burden

Ipilimumab dosing

time points

Tumor burden of new lesions

Thresholds for response or

progressive disease

Reduction in tumor burden after appearance of new lesions

Response after initial increase in tumor volume

Ch

an

ge f

rom

baselin

e

SP

D (

%)

SP

D (m

m2)

Relative day from randomisation date

–63 –21 21 63 105 147 189 231 273 315 357

50

25

0

–25

–50

–75

–100

–125

2810

2482

1826

1496

1171

515

187

–468

2154

–140

843

Ch

an

ge f

rom

baselin

e

SP

D (

%)

SP

D (m

m2)


–63 –21 21 63 105 147 189 231 273 315 357

150

50

0

–25

–50

–75

–100

–125

25

100

19,373

17,242

12,980

10,849

8718

4456

2325

–1937

15,111

194

6587

Ch

an

ge f

rom

baselin

e

SP

D (

%)

“Stable disease”: Slow, steady decline in tumor volume

SP

D (m

m2)

Ch

an

ge f

rom

baselin

e

SP

D (

%)

Response in baseline lesions


SP

D (m

m2)


50

25

0

–25

–50

–75

–100

–125

153

135

99

82

64

28

10

–26

117

–8

–63 –21 21 63 105147189231273315357399441483525 –63 –21 21 63 105147189231273315357399441483525

50

25

0

–25

–50

–75

–100

–125

2810

2482

1826

1496

1171

515

187

–468

2154

–140

843

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Confirmation of progression via a subsequent scans; Measuring new lesions to include them into the total tumor volume;

Accounting for durable stable disease as benefit; Treating beyond conventional progression if the clinical situation allows.

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~ 4%

33% COMBI

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Adapted from Wang et al. Int Immunopharmacol 2018

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MSKCC

GRCC

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≥10 mutations per megabase


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https://www.taconic.com/taconic-insights/microbiome-and-germ-free/microbiome-impacts-immunotherapy-efficacy.html


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How can metabolic imaging be of

help in immunotherapy?

















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Metabolism

?

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Scatter plots with Spearman’ correlation coefficient (rho) and linear regression tests. A) Correlation of semi-quantitative parameters on FDG-PET (i.e. SUVmax and SUVmean) with human NSCLC stained for CD8-TILs and PD-1-TILs (average values); B) Correlation for CD8-TILs and CD68-TAMs (average values) with respect to PD-1 and PD-L1 (average values).

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Loss of CXCR5+ CD8+ TILs with lung cancer disease progression. (A) SUVmax values among NSCLC patients with pStage I (n = 24), II (n = 15), or III (n = 15); *, P < 0.05; **, P < 0.01; Mann-Whitney t test. (B) Based on the SUVmax values, samples were divided into SUVmax

low and high with the median SUVmax value as cut-off. Frequency of Phenograph cluster 17 (CD69+CXCR5+) is depicted in the SUVmax low (n = 17) and high (n = 16) groups. *, P < 0.05; Mann-Whitney t test. (C) Frequency of Phenograph cluster 17 (CD69+CXCR5+) in tumor samples from patients with NSCLC pStage I (n = 19)

versus II-IVA (n = 34). *, P < 0.05; Mann-Whitney t test. Data were obtained in six independent experiments. *, P < 0.05; **, P < 0.01; Mann-Whitney t test.

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This finding should not be surprising, since the logical consequence of tumors having a high PD-L1 expression is accompanied by the presence of inactive or inefficient immune system response in the surrounding environment, leading to immune tolerance toward malignant cells that would necessarily face no limits to their proliferation and progression. The logical equation might be therefore reported as:

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EORTC 1999

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HR 0.229; p=0.02

EORTC 1999

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PERCIST 2009

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Q J Nucl Med Mol Imaging. 2019 Jun;63(2):150-158.


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This research was originally published in JNM. © SNMMI.

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RECIST iRECIST PERCIST PECRIT

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imPERCIST

PERCIST1

PERCIST

Metabolic response in Immunotherapy

SMD with imPERCIST5

PMD with PERCIST1/5


imPERCIST

PERCIST1

PERCIST

imPERCIST

PERCIST1

PERCIST

*


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PERCIST 2009

PETinterim2 demonstrated

iPDhomogeneous, iDR and PsPD in

42% (8/19), 26% (5/19), and

32% (6/19), respectively


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EORTC 1999

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EORTC 1999

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b

• Metabolic response allows for prediction of outcome in solid tumors under immunotherapy

C

• Clinical benefit remains a major component for the discontinuation of treatment

D

• New criteria are introduced to overcome the occurence of new lesions.

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Why not combining parameters?


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EORTC 1999

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Hierarchical clustering combining circulating, tissue

and metabolic parameters identified clusters of

patients with high metabolic tumor burden or high

expression of plasma PD-L1 levels (Z-score≥2) as

having a poor DFS (p= 0.033).

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Circulating Tumor Cells and Metabolic Parameters in NSCLC Patients Treated with Checkpoint Inhibitors

Castello A, … and Lopci E, Cancers 2020

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Figure 3. Two cases of progression (A–C) and response (D–F) to ICI according to metabolic parameters and CTC evaluation. (A) Maximum Intensity Projection (MIP) with two axial slices of liver and celiac node metastases at baseline. (B) Increase of tumor burden and appearance of further metastatic sites within the liver and in the abdominal nodes at the first restaging. (C) Bar graph representation of MTV (blue bars) between the baseline (49.4 ml) and the first restaging (97.2 ml). Likewise CTC count (red bars) increases from 30 to 60. (C) MIP with two large lesions within the lung and liver at baseline. (D) 18F-FDG PET/CT at 8 weeks, which demonstrates a decrease of overall tumor burden. (F) Bar graph representation of MTV (blue bars) at baseline (256.5 ml) and at 8 weeks (48 ml). Likewise CTC count (red bars) decreases from 30 to 5, *= 97.2 ml; **= 256.5 ml.




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There exists a comprehensible mutual interaction between tissue and circulating predictive factors with tumor metabolism, leading to the depiction of potential different clusters of patients showing diverse responses to immunotherapy. The holistic vision of the patient as an entity, not just as a summary of single compartments (i.e. tumor, blood, immune system, microbiome, etc.), would lead to the tailored therapeutic approaches becoming mandatory in modern oncology.

Cancer management in the era of immunotherapy: “much more than what strikes the eyes”

Lopci E, Haanen J, QJNM 2020 (in press)


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Aide N, De Pontdeville M, Lopci E, EJNMMI 2020


b • IrAE can lead to misinterpretation and drop-offs

C • Clinics play an important role in their recognition

D • Biopsy or confirmation with subsequent scan

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Lopci E, Meignan M. PET Clinics 2019

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Disease progression

BX

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A B C

D E F

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Lopci #101


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3331 Studies found for: immunotherapy | cancer

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132 Studies found for: immunotherapy, PET | cancer

• [11C]-PBR28

• [11C]-PK11195

• [18F]-FHBG

• [18F]-AraG

• [18F]-PD-L1

• [18F]-CFA

• [18F]-FB-IL2

• [68Ga]-NOTA-GZP

• [89Zr]-Ipilimumab

• [89Zr]-Atezulizumab

• [89]Zr-Durvalumab

• [64Cu]-NOTA-Ipilimumab

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Ehlerding E, Cai W, ImmunoPET: The Future of Response Evaluation for Cancer Immunotherapy, Springer: «Atlas of response to Immunotherapy» Lopci E, Fanti S, Editors

ClinicalTrials.gov number

Imaging agent Target Indication

NCT03313323 89

Zr-ipilimumab CTLA-4 Metastatic melanoma

NCT03065764

89

Zr-pembrolizumab

PD-1 Non-small cell lung cancer

NCT03514719 89

Zr-avelumab PD-L1 Non-small cell lung cancer

NCT02453984 89

Zr-atezolizumab PD-L1 Breast, urinary tract, non-small

cell lung cancer

NCT03107663 89

Zr-IAB22M2C CD8 Non-Hodgkins lymphoma,

select solid tumors

NCT02922283 18

F-FB-IL2 IL-2 Metastatic melanoma

NCT02888301 18

F-Clofarabine dCK Any cancers

NCT03409419 18

F-Clofarabine dCK Advanced melanoma

NCT03311672 18

F-AraG dCK/dGK Non-small cell lung cancer

NCT03142204 18

F-AraG dCK/dGK Any cancers

NCT03129061 18

F-AraG dCK/dGK Squamous cell carcinoma of the

head and neck

NCT02323893 18

F-AraG dCK/dGK Healthy volunteers

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https://eproofing.springer.com/books_v2/mainpage.php?token=obeNGBhakMkICAkYfyugRWL9X2ao7I8XGkhKRcPJhpA

https://eproofing.springer.com/books_v2/mainpage.php?token=obeNGBhakMkICAkYfyugRWL9X2ao7I8XGkhKRcPJhpA

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Fondazione AIRC per la Ricerca sul Cancro

Grants & research support from…

Lectures for…

Royalties from …

DISCLOSURES

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EGESTA LOPCI, MD, PhD

Nuclear Medicine department

Humanitas Clinical and Research Hospital

Via Manzoni 56, 20089 Rozzano (MI)

E-mail: [email protected];

[email protected]

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