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UNIVERSITA’ DEGLI STUDI DI PADOVA

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Cancer immunotherapy:the beginning of the end?

Direttore:Prof. PierFranco Conte

Relatori:Dott.ssa Alice MenichettiDott. Alberto Pavan

09 Giugno 2016Padova

Immune System and Cancer

Cancer immune surveillance hypothesis: a process through which the immune system identifies and eliminates self-cells that have become transformed.

PRECLINICAL-Lymphocyte-deficient mice are highly susceptible to MCA (methylcholanthrene)-induced tumor development

EPIDEMIOLOGICAL-Recipients of a kidney, liver, heart, or lung transplant have an increased risk (incidence ratio of 2,1) for diverse cancers, compared with the general population

BIOLOGICAL-A strong lymphocytic infiltration has been reported to be associated with good clinical outcome in many different tumour types

V Shankaran et al, Nature 2001Vajdic CM et al, JAMA 2006

Tumor-Infiltrating-Lymphocyte

WH Fridman et al, Nature Reviews Cancer 2012Dieci MV et al, Annals of Oncology 2013

- Positive correlation between strong lymphocytic infiltration and outcome in several tumor types (melanoma, breast and ovarian cancer, head and neck carcinoma, oesophageal and colon cancer, bladder and prostatic cancer, lung cancer)

- The presence of TILs in residual disease after a neoadiuvant Chemotherapy is associated with better prognosis in TNBC patients

Cancer-Immunity Cycle

Chen DS et al, Immunity 2013

Cancer Immunoediting

Vesely MD et al, Annu Rev. Immunol 2011

Strategy Pathway Mechanism

Negative Feedback Immune checkpoint(CTLA-4, PD-1)

Reduced T-cell proliferation, cytokine production and survival

Impaired antigen presentation

Defective antigen processing

Mutation or downregulation of tumor antigens or MHC genes, defects in antigen processing

Immunosuppressive tumour

microenvironment

Cytokines (TGF-β, IL-10, VEGF, etc.),

prostaglandinsRegulatory T reg

and MDSC

Reduced T-cell activationFavoured tumour outgrowthAngiogenesis

Apoptosis resistance FasL

Expression of anti-apoptotic molecules, downregulation and mutation of pro-apoptotic molecules

Tumor immune escape mechanisms

DM Pardoll, Nature Reviews Cancer 2012

Immune checkpoints

• Maintain self-tolerance• Modulate the duration and amplitude of

immune responses in peripheral tissues

The blockade of immune checkpoints unleashes the

antitumor immune response

CTLA-4 pathway

CTLA-4:•is expressed on activatedT-cells•counteracts the activity of T-cell co-stimulatory receptor CD28•downregulates early stages T-cell activation

Buchbinder EI et al, Am J Clin Oncol 2015

PD-1 pathway

PD-1•is expressed on activatedT-cells•regulates T-cell activation through binding to PD-L1 and 2•downregulates effector T-cell activation in peripheral tissue•hallmark of “exhausted” T-cells after high levels of stimulation

Pardoll DM, Nature 2012

CTLA-4 and PD-1: a comparison

CTLA-4Cytotoxic-T-Lymphocyte Antigen 4

Expression: T cells (CD8+, CD4+)

Ligand: CD80 and CD86 on APC

Regulates the amplitude of T-cell activation in lymphoid tissues

CTLA-4 blocking antibodies: IPILIMUMAB and TREMELIMUMAB

PD-1 Programmed Cell Death Protein 1

Expression: activated T cells, NK and B cells

Ligand: PDL1 and PDL2 on immune cells and non immune cells (including tumor cells)

Limits T cell activity within peripheral tissues

PD-1 blocking antibodies: NIVOLUMAB and PEMBROLIZUMABPD-L1 blocking antibodies: ATEZOLIZUMAB and DURVALUMAB

Immune Checkpoints Inhibitors

Buchbinder EI et al, Am J Clin Oncol 2015

Immune Checkpoint Inhibitors:

…what else?

Clinical Case #1: V.I.

Physiological History-Male, aged 71-Smoker (30 pack years)-No family history of cancer-Retired; worked as an industrial worker for over 40 years

Medical History-Arterial hypertension

June 2010-Cough, no fever-Right chest parietal pain

1st Treatment:-Empirical antibiotic therapy

Chest Rx:-Suggestive for pleural empyema

August 2010SURGERY:-Right pleural decortication

Histological Examination-Epithelioid Mesothelioma


August-September 2010Multidisciplinary Evaluation:

18/08/10

08/09/10

29/09/10

NEOADIUVANT CTCarboplatin + Pemetrexed q3w

November 2010SURGERY:

-Right pleurectomy with

right lung decortication +

prosthetic emi-diaphragm

January 2011-December 2012-Regular follow-up: negative

Histological Examination-Localization of Mesothelioma


December 2012-CT scan: pleural PD PET-CT

January-May 2012Relapse Treatment Carboplatin + Gemcitabine for 5 cycles

June 2012-June 2013-Follow-up with CT scan: SD

June 2013-CT scan: lung PD

- CT-guided pleural biopsy

July 2014-Enrolled in Medimmune D4880C00003 II phase trial


September 2014-After 2nd administration Diarrhoea G1

1st Treatment:-Support-Loperamide- Persistence, no resolution within 10 days:

• Hospitalization Prednisone 1 mg/kg/die

October 2014-During steroid tapering Diarrhoea G2

• Hospitalization Prednisone 2 mg/kg/die

- No fever, no other symptoms- No microbiological findings on stool sample

- Abdominal Rx: no perforation, dilated bowel

R

2nd-3rd Line for Unresectable

Pleural Mesothelioma

Tremelimumab 10 mg/kg q4w

Placebo

October 2014-Rectal-sigmoidoscopy:

• Mucosal swelling• Fibrin membranes


November 2014-Acute abdominal pain

Rx: perforation

SURGERY:-Hartmann procedure: resection of 15 cm of left colon + sigma, cutaneous colostomy

- Physical deterioration, mental decline Best supportive care

End of November 2014 Death

Clinical Case #2: T.L.

Physiological History-Female, aged 31-No family history of cancer-Office worker

Medical History-In 2004: surgical removal of a compound nevus on the left calf

April 2008-Surgical removal of an ulcerated melanocytic lesion on the left calf

Histological Examination-Melanoma: Breslow 11 mm, Clark V (hypoderma)

- Sentinel Node Biopsy: negative

- Whole body CT scan: negativeSTAGE II C-T4b N0 M0

June 2008-June 2009Adiuvant Treatment High Dose IFN-γ


July 2009-July 2015-Regular follow-up: negative

July 2015-Surgical removal a subcutaneous node, next to the previous lesion

Histological Examination-Localization of Melanoma-B-RAF mut (V600E)

- Whole body CT scan: negative

September 2015-Enrolled in CHECKMate 238 phase III trial

q6w10 mg/kg

d1 d15 d22 d29

IPI P IPI P

q6w3 mg/kg

d1 d15 d22 d29

Nivo Nivo P Nivo

R

Complete Resected

Stage IIIb/c-IV Melanoma


December 2015-After 2nd cycle Diarrhoea G1

1st Treatment:-Support-Loperamide- Recurrence after 1 week:

• Prednisone 1 mg/kg/die

- Recurrence after 3 weeks:• Prednisone 2 mg/kg/die

January 2016-During steroid tapering Diarrhoea G2

• Hospitalization

- No fever, no other symptoms- No microbiological findings on stool sample

- Abdominal Rx: negative


January 2016-Steroid-resistant colitis Infliximab 5 mg/kg

Preliminary testing

QTferon Neg

Chest Rx Neg

HBV test Neg

Cardiological evaluation Neg

- Progressive resolution during hospitalization- No adverse effects from Infliximab

February-April 2016-Slow steroid tapering No recurrent episodes

March & May 2016-Drop out from the trial-Regular follow-up: negative

• Whole body CT scan: NED

Clinical Case #3: C.M.Physiological History-Male, aged 36-Exposed to second-hand smoke (father for over 30 years)-No family history of cancer-Work as a coach driver

Medical History-None

November 2014-Cough, mild dyspnoea

Bronchoscopy with biopsies:

Histological Examination-Squamous Cell Lung Cancer

Whole body CT scan:RSL nodule (11 cm) + right hilar adenopathy

January 2015Multidisciplinary Evaluation:

19/01/15

02/03/15

09/02/15

NEOADIUVANT CTCarboplatin + Gemcitabine q3w

Partial Response

April 2015- PET-CT scan: PD (lung + nodes)

May 2015- Starts Nivolumab 3 mg/kg q3w [compassionate]

Clinical Case #3: C.M.


1stdose

09/06/15

23/06/15

07/07/15

21/07/15

04/08/15

25/08/15

08/09/15

22/09/15

06/10/15

20/10/15

03/11/15

6thdose 11thdose

RevaluationCTscan

RevaluationCTscan

RevaluationCTscan

Clinical and radiological stability

June-November 2015


November 2015-Diarrhoea G2, persistent despite Loperamide

- Increased serum amylase and lipase

- Abdominal US CT scan Cholangio NMR: negative

Treatment-Fasting, PN-Antibiotic e.v.-Methylprednisolone 1 mg/kg/die


11/0

1/16

14/1

2/15

28/1

2/15

12thdose

13thdose

14thdose

December 2015-Resume Trial

Pneumonia G1-No fever, no symptoms-No CRP elevation-No microbiological findings on blood sample

Stable Disease, but…

Methylprednisolone 1 mg/kg/die


End of January 2016 End of February 2016

March-May 2016-Whole body CT scan: Stable Disease

Physiological History-Female, aged 44-Smoker (15 pack years)-No family history of cancer-Office worker

Medical History-None

October 2013-Abdominal pain-Decreased Hb (6,4 g/dL)

Clinical Case #4: P.S.

November 2013-Starts regular follow-up

SURGERY: Left nephrectomy + Lymphadenectomy

Histological Examination-Clear Cell Renal Carcinoma; Fuhrman G3

-Invading peri-renal fat;

STAGE III-T3a N0 M0

March 2015-Whole body CT scan: pulmonary micronodules Close Follow-up


June 2015-Whole body CT scan: increased pulmonary micronodules

July 2015-Enrolled in CHECKMate 214 phase III trial

R

Previously Untreated,

Advanced or Metastatic Renal Cell Carcinoma Sunitinib 50 mg/die for 4 weeks q6w

q3w for 4 cycles

IPI 1 mg/kg

+ Nivo 3 mg/kg

Nivo 3 mg/kg q2wUntil PD or tox

September 2015-Whole body CT scan after 4 cycles: Complete Response


October 2015-Malaise, fatigue-Fever (39,5°C)-No coughing, no dysuria, no other symptoms

Febrile Neutropenia-WBC 730/mL, N 200/mL

Anaemia G3-Hb 7,6 g/dL

Hepatic Toxicity G4-AST 932 U/L ALT 1180 U/L-gGT 366 U/L-Tot Bil 46,8 mmol/L (C. 35)-LDH 1736 U/L


First Measures

- Admitted to sterile room

Diagnostics (1)-Chest Rx-Blood and urinocolture-Oropharyngeal swab-Serology:

• HAV, HBV, HCV• CMV, EBV, HSV, VZV• Parvovirus B19

Empirical Treatment

- Antibiotics:• Piperacilline/Tazobactam• Amikacine

- Antifungal prophylaxis:• Fluconazole

- G-CSF- Methylprednisolone 2

mg/kg/die

NEGATIVE

- Support

Diagnostics (2)


- Blood smear:

- Bone marrow aspiration:

- Peripheral blood IFT:

- Bone marrow biopsy: Punctio Sicca


• Corticosteroid• G-CSF• Ig ev +

Cyclosporine• Ig ev

• Corticosteroid• G-CSF• Ig ev• ATG +

Cyclosporine + Methylprednisolone



22-sep 20-oct 23-oct 29-oct 3-nov 9-nov 12-nov 14-nov 18-nov 26-nov 25-jan 15-feb 16-mar0

2

4

6

8

10

12

14

16

18


Steroid taperingMethylprednisolone 4 mg/kg/die

Ig ev 400 mg/kg/die

Cyclosporine 2,5 mg/kg/die + steroid tapering

Neutrophil count n.v. 1,80-7,80 x10^9/LHepatotoxicity

Resolution


November 2015-Fever (>39°C), cough-Bilateral crackles-CRP 302 mg/L-PCT neg

Diagnostics-Blood and urinocolture-Serology:

• Aspergillus Ag• Beta-D-glucan

-Bronchoscopy + BAL

Positive

Aspergillus Flavus

December 2015-Starts Amphotericin-B-Transferred to Division of Infectious Diseases


22-sep 20-oct 23-oct 29-oct 3-nov 9-nov 12-nov 14-nov 18-nov 26-nov 25-jan 15-feb 16-mar0

2

4

6

8

10

12

14

16

18

Cyclosporine 0,3 mg/kg/die + tapering steroid

STOP Cyclosporine and steroid

February 2016-Whole body CT scan

April 2016-Whole body CT scan:

Complete Remission

Immune-Related Adverse Events (irAEs)

Unrestrained T-cell activation with immune checkpoints inhibitors translates into:

- antitumor responses- autoimmune breakthrough or irAEs

These toxicities require:-careful monitoring-specific management strategies

Reversible if treated promptly and appropriately

Immunosuppression using corticosteroid and other agents

Immune-Related Adverse Events (irAEs)

Anti CTLA-4-10% Hypophysitis and hypothyroidism

Anti PD-1-<10% Hypothyroidism

Anti CTLA-4-50% Rash and pruritus (trunk and extremities)

Anti PD-1-37% skin toxicity of all grades-6,5% dry mouth

Anti CTLA-4-30% Diarrhoea (only 10% G3-4)-5% Colitis G3-4

Anti PD-1-1-2% Diarrhoea G3-4

Anti CTLA-4-2.5% Hepatotoxicity G2-2% Hepatotoxicity G3-4

Anti PD-1-<5% Hepatotoxicity

Less frequent irAEs:•Pneumonitis•Asymptomatic pancreatitis•Hematologic syndromes•Ophthalmologic disorders•Renal insufficiency•Neurologic syndromes

Champiat S. et al, Annals of Oncology 2015Villadolid J. et al, Lung cancer diagnostics and treatments 2015

IrAEs: Kinetics of onset

Ipilimumab

Nivolumab

Villadolid J. et al, Lung cancer diagnostics and treatments 2015

IrAEs Management

Eigentler T.K. Et al, Cancer Treatment Reviews 2016

IrAEs Management

How to stop immunosuppressive drugs?

Gradual corticosteroid tapering in at least 1 month

When to resume or terminate immunotherapy?

Temporary suspension Permanent discontinuation

- IrAEs stabilized < G1- Steroid dose reduced to < 10 mg/d

prednisone

- IrAEs G4- IrAEs G3 and recurring- IrAEs G2 not resolutive in 3 months

Immunotherapy dose reduction not recommended

No clear correlation between dose density and efficacy of immunecheckpoints inhibitors: Dose intensity not influenced by delaying immunotherapy

Immune Checkpoint Inhibitors:

Worth the Toxicity?

Ipilimumab: MDX 010-020 trial 676 subjects with advanced or metastatic pre-treated melanoma were randomized in this double-blind, phase III trial that compared:

- Ipilimumab 3 mg/kg + GP100 melanoma peptide vaccine

- Ipilimumab 3 mg/kg monotherapy

- GP 100 monotherapy

RESULTS

Hazard reduction for death of 32% and 34% respectively in the IPI+GP100 and IPI monotherapy groups compared with GP100 monotherapy group

No difference between the 2 groups receiving Ipilimumab

Hodi F. S. et al, N Engl J Med, 2010

IPI+GP100 vs GP100HR 0.68 (0.55-0.85; p=0.0004)

IPI vs GP100HR 0.66 (0.51-0.87; p=0.0026)

Median OS-IPI+GP100: 9.95 m -IPI: 10.12 m-GP100: 6.44 m

Primary endpoint: OS

Ipilimumab: CA 184-024 trial

Robert C. et al, N Engl J Med, 2011

IPI+DTIC median OS:11.2 m vs 9.1 m (p=0.0009)HR 0,72 (0,59-087)

502 subjects with metastatic untreated melanoma were randomized in this double-blind, phase III trial that compared:- Dacarbazina 850 mg/m2 + Ipilimumab 10 mg/kg (concurrent + maintenance)- Dacarbazina 850 mg/m2 + Placebo


RESULTS

OS was significantly longer with Ipilimumab + Dacarbazine:- 1 yr survival rate 47% (vs 36)- 2 yrs survival rate 28% (vs 18)- 3 yrs survival rate 21% (vs 12)

Nivolumab: CHECKMATE-066


418 subjects with BRAF wild-type unresectable or metastatic untreated melanoma were randomized in this double blind, phase III trial that compared:

- Nivolumab (3 mg/kg, q2w)- Dacarbazine (1000 mg/m2, q3w)



Brahmer J. et al, N Engl J Med, 2015

272 subjects with advanced or metastatic squamous-cell non-small-cell lung cancer (NSCLC), progressed during or after 1st line platinum-based chemotherapy, were randomized in this open label, phase III trial that compared:

- Nivolumab (3 mg/kg, q2w)- Docetaxel (75 mg/m2, q3w)


RESULTS

The risk of death was 41% lower with Nivolumab than with Docetaxel


Motzer R.J. et al, N Engl J Med, 2015

821 subjects with advanced clear-cell renal-cell carcinoma, previously treated with one or two regimens of antiangiogenic therapy, were randomized in this open label, phase III trial that compared:

- Nivolumab (3 mg/kg, q2w)- Everolimus (10 mg/die)


RESULTS

The risk of death was 27% lower with Nivolumab than with Everolimus

Pembrolizumab: Keynote-006834 subjects with advanced melanoma, who received no more than one previous systemic therapy, were randomized in this open label, phase III trial that compared:

- Pembrolizumab (10 mg/kg, q2w)- Pembrolizumab (10 mg/kg, q3w)- Ipilimumab (3 mg/kg, q3w)

Primary endpoint: OS and PFS


RESULTSHazard reduction for death of 37% and 31% respectively in the Pembrolizumab q2w and Pembrolizumab q3w groups compared with Ipilimumab group.

No difference between the 2 groups receiving Pembrolizumab

Future Directions: CHECKMATE-067

Larkin J. et al, N Engl J Med, 2015

945 subjects with unresectable previously untreated stage III or IV melanoma were randomized in this double blind, phase III trial that compared:

- Nivolumab (3 mg/kg, q2w)- Ipilimumab (3 mg/kg, q3w)- Nivolumab (1 mg/kg, q3w) plus Ipilimumab (1 mg/kg q3w)

Primary endpoint: OS and PFS

IrAEs and Effects on Survival

IrAEsG1-2 G3 G4 Total

47 % 31 % 7 % 85 %

Single centre retrospective analysis on 298 patients with melanoma treated with Ipilimumab 3 mg/kg q3w showed:

Most common IrAE: diarrhoea (14%)

Neither the occurrence of IrAEs nor the use of systemic corticosteroids influenced OS

Horvat Troy Z. et al, JCO 2015

IrAEs and Effects on SurvivalMulticentre retrospective analysis on 576 patients with advanced melanoma treated with Nivolumab 3 mg/kg q2w showed:

The use of systemic corticosteroids impacts neither Response Rate nor Median time to Response

Weber J.S. et al, JCO 2015 (suppl; abstr)

Total IrAEs: 49%

G3-4 IrAEs: 10%

Take Home Messages

- Immunologic-checkpoint inhibition targeting CTLA-4 and PD-1 has dramatically improved the care of patients with many advanced malignancies

- Treatment is associated with typically transient IrAEs, that have a completely different underlying mechanism compared to toxicities observed with chemotherapy

- Rapid identification of IrAEs and systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition

- The clinical team have to be educated and aware of these potential toxicities if promptly recognized, they’re almost always reversible

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