Standards of Care and Future Prosepectives in Lung Cancer ... · 1. Challenges and controversies in...

Spotlight:Case-based management issues in immuno-oncology

Rolf Stahel

Chair, Comprehensive Cancer Center Zürich

1 |

Berlin, March 23, 2019

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1. Challenges and controversies in response evaluation

1. Pseudoprogression and GI toxicity

2. Hyperprogression

3. Durable clinical benefit, durable response

4. Major pathological response

5. Molecular response (ctDNA)

6. Abscopal effect and GI toxicity

7. Correlation between toxicity and response

8. Steroids and antibiotics

9. Special situations

2 |

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Case: 72-y/o women with lung adenocarcinoma3 |

Before nivolumab After 6 cycles nivolumab

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Guidelines for the evaluation of immune therapy activity in solid tumors:

Immune-related response criteria: Patterns of response to ipilimumab in

advanced melanoma

4 |

Wolchok, CCR 2009



advanced melanoma

3 |

Wolchok, CCR 2009

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advanced melanoma: Tumor Burden = SPDindex lesions+ SPDnew,

measurable lesions

5 |

Wolchok, CCR 2009

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Comparison of RECIST to immune-related response criteria in

patients with NSCLC treated with immune-checkpoint inhibitors

• Responses of 41 patients were

analyzed:

• Response rate:

• 29.2% assessed by RECIST v1.1

• 34.1% by irRC

• PD: 4.9% defined by RECIST but not

by irRC. The patients eventually

experienced tumor regression,

suggesting delayed

pseudoprogression.

6 |

Kim, Cancer Chemother Pharmacol, 2017

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Pseudoprogression in previously treated patients with NSCLC who

received nivolumab monotherapy

• Retrospective cohort study in

15 centers

• Pseudoprogression:

PD at first evaluation by RECIST1.1

followed by objective response in

second evaluation

• 542 patients

• 20% typical response

• 53% progression

• 3% (14 pts) pseudoprogression

7 |

Fujimoto, JTO 2018

Tumor size in 14 pts with pseudoprogression

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Pseudo progression in previously treated patients with NSCLC who

received nivolumab monotherapy

8 |

Fujimoto, JTO 2018

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Comparison of RECIST1.1 and iRECIST9 |

ETOP | Name Project | Title Presentation | Zurich, July 27, 2009 Seymour, Lancet Oncol 2017

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What happens after immune unconfirmed progressive disease (IUPD)10 |

Borcoman, Ann Oncol 2019

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→ Biopsy of

mediastinal nodes:

Immune cells

→ Biopsy of the colon:

Colitis Grade 2

Curioni-Fonrecedro, Ann Oncol 2017

Before nivolumab After 6 cycles nivolumab

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Management of immune-related GI toxicity12 |

Haanen, Ann Oncol 2017

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Management of immune-related GI toxicity13 |


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Before nivolumab After 6 cycles nivolumab After 12 cycles nivolumab

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Hyperprogressive disease: recognizing a novel pattern to improve

patient management

15 |

Champiat, Nat Rev Clin Oncl 2018

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Hyperprogressive disease in patients with advanced NSCLC treated

with PD-1/PD-L1 inhibitors or with single-agent chemotherapy

• 406 pts treated with ICB in second line:

• 13.8% Hyperprogression*

• 4.7% Pseudoprogression

• 59 pts treated with chemotherapy in second line

• 5% Hyperprogression

• 0% Pseudoprogression

* associated with >2 metastatic sites

16 |

Ferrara JAMA Oncol 2018

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Hyperprogressive disease in patients with advanced NDCLC treated

with PD-1/PD-L1 inhibitors or with single-agent chemotherapy

17 |

Ferrara JAMA Oncol 2018

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Durable clinical benefit, durable response

No firm definition!

18 |

Brahmer, AACR 2017

Felip, ASCO 2018

Rizvi, Science 2015Do not d

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Neoadjuvant PD-1 blockade in resectable lung cancer with two

infusions of nivolumab 2 weeks apart: Major pathological response

19 |

Forde, ESMO 2016 and NEJM 2018

Pre-

nivo

Post-

nivo

63yo M, ex-smoker, adeno, PD-L1 2%+,

<10% viable tumor at resection

Pre-

nivo

% pathological regression:

MPR

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Pathological response after neoadjuvant chemotherapy in

resectable NSCLC: proposal for the use of major pathological

response as a surrogate endpoint

20 |

Hellmann, Lancet Oncol 2014

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Molecular response in ctDNA: Dynamics of tumor and immune

responses during immune checkpoint blockade in NSCLC

21 |

Pt 1 Pt 2

Anagnostou, CR 2019

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47-y/o man with stage IIIB lung adenocarcinoma

• July 2014 Stage IIIB lung

adenocarcinoma (cT1pN3CM0)

• August – September 2014 3 cycles

chemotherapy with cisplatin, docetaxel

and cetuximab (SAKK 16/08)

• September – October 2014

Radiotherapy of primary tumor and

mediastinal nodes

• November 2014 resection of RUL and

mediastinal lymphadenectomy:

pT0pN0,M0

22 |

July 2014 October 2014Do n

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• January – June 2015 3

cycles of carboplatin and

pemetexed followed by

pemetrexed maintenance

• June 2015 Progress in

retroperitoneal and

mediastinal nodes;

Initiation of treatment with

nivolumab

23 |

January 2015 March 2015

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47-y/0 man with stage III lung adenocarcinoma24 |

June 2015 October 2015 January 2016 August 2017

Britschgi, Rad Oncol 2018

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• May 2016 admission

by ER because of

vomiting and

abdominal pain

25 |

May 2016Do not d

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• May 2016 admission

by ER because of

vomiting and

abdominal pain

• May-July 2016

treatment with

methyprednisolone IV,

followed by

prednisone PO,

initially 100 mg, than

slowly reduced

26 |

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Case 1: 64-y/o man with squamous cell lung carcinoma

• June 2015:

• Squamous cell carcinoma right upper

lobe with lymph node and bone metastases

• Pathology: strong positivity of PD-L1

27 |

PD-L1 stainingDo not d

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Case 1: 64-y/o man squamous cell lung carcinoma

• July – September 2015: Chemotherapy with cisplatin/gemcitabine 3 cycles

• October 2015: Palliative resection of right upper lobe

28 |

June 2015 September 2015 November 2015Do n

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Case 1: 64-y/o man squamous cell lung carcinoma

• November 2015: Symptomatic and radiological progression in bone

• December 2015: Radiotherapy to thoracic and sacral lesion, two applications

of nivolumab

29 |

November 2015

January 2016:

Dyspnea on exertion

PiO2 67%

CRP 115

WBC 11 G/l

Hospitalization in intensive care: O2, Methylprednisolon

250 mg IV, followed by Prednison in slowly decreasing

amounts, piperacillin and bactrim

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Case 1: 64-y/o man squamous cell lung carcinoma30 |

November 2015 February 2016 March 2017Do n

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Pneumonitis in

patients treated with

anti–PD-1/PD-L1

therapy

31 |

Naidoo, JCO 2017

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Management of immune-related pulmonary toxicity32 |

ETOP | Name Project | Title Presentation | Zurich, July 27, 2009Haanen, Ann Oncol 2017

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Management of immune-related pulmonary toxicity33 |

ETOP | Name Project | Title Presentation | Zurich, July 27, 2009Haanen, Ann Oncol 2017

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Time of onset of immune-related adverse events34 |


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Pneumonitis in patients treated with anti–PD-1/PD-L1 therapy

• Of 915 patients who received

anti–PD-1/PD-L1 mAbs, pneumonitis

developed in 43 (5%; 95% CI, 3% to 6%)

• Time to onset of pneumonitis ranged

from 9 days to 19.2 months.

• The incidence of pneumonitis was higher

with combination immunotherapy versus

monotherapy (19 of 199 [10%] v 24 of

716 [3%]; P < .01

35 |

Naidoo, JCO 2017

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Pneumonitis in patients treated with anti–PD-1/PD-L1 therapy36 |

Naidoo, JCO 2017

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Comparison of the toxicity profile of PD-1 versus PD-L1

inhibitors in NSCLC: A systematic analysis of the literature

37 |

Pillai, Cancer 2018

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55-y/o man with metastatic adenocarcinoma of the lung

• March 2017 adenocarcinoma with singular brain and multiple bone

metastases, no oncogenic driver mutation, PD-L1 negative

• April 2017 SBRT of brain metastases and palliative radiotherapy to painful

sacral metastasis

• May 18 and June 1, 2017 immunotherapy with ipilimumab and nivolumab as

part of a clinical trial

• June 6 presentation at ER with muscle pain and double vision:

38 |

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55-y/o man with metastatic adenocarcinoma of the lung39 |

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Cardiovascular toxicities associated with immune checkpoint

inhibitors: an observational, retrospective, pharmacovigilance study

42 |

Salem, Lancet Oncol, 2018

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Cardiovascular toxicities associated with immune checkpoint

inhibitors: an observational, retrospective, pharmacovigilance study

43 |

Salem, Lancet Oncol, 2018

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Impact of immune-related adverse events on survival in patients

with advanced NSCLC treated with nivolumab

44 |

Riciuti, WCLC 2018

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Impact of immune-related adverse events on survival in patients

with advanced NSCLC treated with nivolumab

45 |

Riciuti, WCLC 2018

Univariate HazardRatio (95% CI)

P valueMultivariate

Hazard Ratio* (95% CI)

P value

PFS

Any 0.41 (0.3-0.57) P < 0.0001 0.48 (0.34-0.67) P < 0.0001

Lung irAEs 0.54 (0.31-0.92) P = 0.024 0.56 (0.33-0.96) P = 0.038

Gastrointestinal irAEs 0.45 (0.26-0.77) P = 0.004 0.52 (0.3-0.9) P = 0.021

Endocrine irAEs 0.5 (0.34-0.72) P < 0.0001 0.59 (0.4-0.89) P = 0.011

Skin irAEs 0.51 (0.32-0.83) P = 0.007 0.57 (0.35-0.95) P= 0.031

Hepatobiliary irAEs 0.68 (0.4-1.16) P = 0.16 0.72 (0.41-1.24) P = 0.23

OS

Any 0.33 (0.23-0.47) P < 0.0001 0.38 (0.26-0.56) P < 0.0001

Lung irAEs 0.41 (0.21-0.78) P = 0.007 0.46 (0.24-0.89) P = 0.022

Gastrointestinal irAEs 0.38 (0.2-0.73) P = 0.004 0.5 (0.26-0.98) P = 0.045

Endocrine irAEs 0.49 (0.34-0.72) P < 0.0001 0.45 (0.28-0.72) P = 0.001

Skin irAEs 0.6 (0.36-1.02) P = 0.06 0.8 (0.46-1.39) P = 0.43

Hepatobiliary irAEs 0.84 (0.48-1.47) P = 0.55 0.94 (0.53-1.66) P = 0.83

ORR: 51.4% vs. 20%, P < 0.01

DCR: 84.3% vs. 34%, P < 0.00112-weeks landmark 12-weeks landmark

6-weeks landmark 6-weeks landmark

A B

C D

P < 0.0001

HR: 0.48 (95%CI: 0.34-0.69)

P < 0.0001

HR: 0.4 (95%CI: 0.26-0.59)

P = 0.089

HR: 0.69 (95%CI: 0.45-1.05)

P = 0.021

HR: 0.55 (95%CI: 0.33-0.92)

no-irAEs (n: 67) 7.5 (4.2-10.7)irAEs (n: 78) 21..4 (15.5-27.3)

mOS, months (95%CI)

no-irAEs (n:52) 3.2 (2.8-3.7)irAEs (n: 71) 8.0 (5.2-10.9)

mPFS, months (95%CI)

no-irAEs (n: 144) 9.1 (6.1-2.3)irAEs (n: 32) 17.8 (11.4-24.5)

mOS, months (95%CI)

no-irAEs (n:144) 2.8 (2.1-3.5)irAEs (n: 32) 5.0 (1.5-8.4)

mPFS, months (95%CI)

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Outcomes of long-term responders to anti-PD-1 and antiPD-L1

when being rechallenged with the same agent at progression

• 13 patients were treated

for colorectal MSI–high

genotype (n = 5), urothelial

carcinoma

(n = 3),melanoma (n = 2),

NSCLC (n = 2) and TNB

(n = 1) for a median of

12 months (range 10.6–12)

46 |

Bernard-Tessier, EJC 2018

2 PR, 6 SD

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Impact of baseline steroids on efficacy of PD-1 and PD-L1 blockade

in patients with NSCLC

47 |

MSKCC IGR MSKCC IGR

Arbour, JCO 2018

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Negative association of antibiotics on clinical activity of immune

checkpoint inhibitors in patients with advanced renal cell and NSCLC

48 |

Derosa, Ann Oncol 2018

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Profiling preexisting antibodies in patients treated with anti-PD-1

therapy for advanced NSCLC

• 137 patients analyzed for preexisting rheumatoid factors, antinuclear

antibody, anti-thyreoglobulin, and anti-thyroid peroxidase

49 |

Toi, JAMA Oncol 2018

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Safety and efficacy of PD-1 inhibitors among HIV-positive patients

with NSCLC

50 |

Ostios-Garcia, JTO 2017

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Safety and efficacy of PD-1 inhibitors among HIV-positive patients

with NSCLC

• Partial responses to immune checkpoint inhibitors were observed in three of

seven cases. Among four patients with a programmed death ligand-1 tumor

proportion score >5 0%, three partial responses were observed. All patients

received antiretroviral therapy while on anti–PD-1 treatment. None of the

patients experienced grade 3 or 4immune-related adverse events or immune

reconstitutioninflammatory syndrome, and none required PD-1 inhibitor dose

interruption or discontinuation due to toxicity

51 |

Ostios-Garcia, JTO 2017

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Safety and efficacy of anti-PD-1 therapy for metastatic melanoma

and non-small-cell lung cancer in patients with viral hepatitis: a

case series

• Our results indicate that patients with metastatic melanoma and NSCLC can

be treated safely with PD-1 inhibitors in the context of HBV/HCV infection.

However, we recommend that those with active viral hepatitis be monitored

closely in consultation with a hepatologist and treated with antiviral therapy if

• indicated.

52 |

Kothapalli, Melanoma Res 2018

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Mechanisms of resistance to checkpoint inhibitors53 |

Syn, Lancet Oncol 2017

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Key elements in biomarker development for immune-

checkpoint inhibitor therapy

54 |

Nishino, Nat Rev Clin Oncol 2017

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KN-001: 4-year overall survival55 |

Felip, ASCO 2018

48.1% 24.8%

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Tumor burden determined by comprehensive genomic

profiling

56 |

Chalmers, Genomic Med 2017

Comparison of comprehensive

genomic assay targeting 315 genes

with whole exome sequencing of 29

tumors

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MSI-high – KEYNOTE-158/16257 |

Colorectal tumors

None-colorectal tumors

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IFN-γ–related mRNA profile predicts clinical response

to PD-1 blockade

58 |

62 patients with melanomaA) Head and neck cancer (N=43),

B) gastric cancer (N=33) Ayers, JCI 2017

Baseline samples from pembrolizuma treated patients:

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IFN-γ–related mRNA profile predicts clinical response to PD-1

blockade

59 |

Fehrenbacher, Lancet Oncol 2016

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New strategies under evaluation60 |

IMMUNE

STATUS

1. No effective antitumorimmunity

«Cold» tumor

2. Suboptimal or exhaustedantitumor immunity

Example: PD-L+ tumor

3. Antitumor immunitysuppressed by TME

Example: CD73+ tumor

GOAL: Highly activeantitumor immunity

THERAPEUTIC

AIMPrime new response Potentiate existing response

Reverse tumor

immunosuppressionEliminate tumor

CLINICAL

PIPELINE

• Adoptive T cell therapy• CAR T-Cells• Oncolytic viruses• CD40• TLR7/8• Targeted IL2v• Targeting shared antigens• Targeting neoantigens• Personalized vaccines

• PD(L)-1• CTLA-4• PD(L)-1 + OX40• PD(L)-1 + GITR• PD(L)-1 + CD137• PD(L)-1 + CSF 1-R• PD(L)-1 + Lag3• PD(L)-1 + TIM3• PD(L)-1 + TIGIT• PD(L)-1 + T-cell bispecifics• PD(L)-1 + Radiation or chemo• NKG2A

• Adenosine metabolism pathway (A2A2), CD73

• PD(L)-1 + Anti-angiogenics• PD(L)-1 + anti-CFS 1-R• CXCR2• STAT3• Myeloid derived suppressor

cell inhibition/differentiation• Tryptophan metabolism

pathway (IDO)• Treg depletion• TGFß interaction

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2. April

2019

Dokumentname / Autor / Abteilung61

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Efficacy of relatlimab), a monoclonal antibody that targets

LAG-3, in combination with nivolumab in patients with melanoma who

progressed during prior Anti–PD-1/PD-L1

62 |

Pink: PD-L1 ≥ 1% Blue: PD-L1 < 1% Gray: PD-L1 unknown

100

80

60

40

20

0

-20

-40

-60

-100

-80

100

80

60

40

20

0

-20

-40

-60

-100

-80

100

80

60

40

20

0

-20

-40

-60

-100

-80

45% with tumor

reduction

24% with tumor

reduction

13% with tumor

reduction

Be

st

pe

rce

nt

ch

an

ge

in s

um

of

targ

et

les

ion

dia

me

ters

fro

m b

as

eli

ne

a,b

LAG-3 ≥ 1%n = 29

LAG-3 < 1%n = 17

LAG-3

Unknownn = 8

Ascierto, ESMO 2017

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Randomized phase II study of pembrolizumab after stereotactic

body radiotherapy (SBRT) versus pembrolizumab alone in patients

with advanced non-small cell lung cancer: The PEMBRO-RT study

63 |

Theelen, ASCO 2018

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VEGF and target for immune modulation64 |

High levels of VEGF associates with

liver metastases

EGFR signal activation increases

VEGF production

Seo, Cancer 2000:Hung, et al. Oncol Lett 2016: Chen & Hurwitz, Cancer J 2018;

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Impower 150: OAS analyses of a randomized phase III study of

carboplatin and paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC:

Patients with EGFR/ALK+ tumors

65 |

Socinski, ASCO 2018

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Intrinsic Mechanisms of Resistance to Immunotherapy 66 |

Sharma, Cell 2017

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Extrinsic Mechanisms of Resistance to Immunotherapy 67 |

Sharma, Cell 2017

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Impact of oncogenic

pathways on evasion of

antitumor immune

responses

68 |

Spranger and Gajewski, Nat Rev Cancer 2018

• Oncogenic WNT–β‐catenin

signalling reduces T cell

recruitment

• Gain of MYC function inhibits

T cell activation and

infiltration

• Loss of LKB1 function

decreases T cell infiltration

• Loss of PTEN reduces

efficient T cell priming

• Loss of p53 function

decreases T cell infiltration Do n

ot duplic

ate o

r dist

ribute

with

out

permiss

ion from

auth

or and E

SO

Standards of Care and Future Prosepectives in Lung Cancer ... · 1. Challenges and controversies in...

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Transcript of Standards of Care and Future Prosepectives in Lung Cancer ... · 1. Challenges and controversies in...