Ruolo dei checkpoint inhibitors in oncologia

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I CONGRESSO NAZIONALE DI CARDIO-ONCOLOGIA Negrar, 25-26 gennaio 2019

Ruolo dei Checkpoint Inhibitors in Oncologia

Alessandro Inno

Unità di Oncologia Medica – Unità Clinica di Fase 1 Cancer Care Center

IRCCS Ospedale Sacro Cuore Don Calabria Negrar, Verona

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The Cancer-Immunity Cycle

Chen DS, Mellman I. Immunity 2013;39:1-10

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Immune Checkpoints

Pardoll DM. Nat Rev Cancer 2012;12:252-64

Multiple

Immunomodulatory Ligands and Receptors

Regulate Anti-tumor

Immunity

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T-cell targets for immunoregulatory antibody therapy

Mellmann I. Nature 2011;480:480-9.

Turning up the Activating Blocking the Inhibiting

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Blockade of CTLA-4 and PD-1/PD-L1 Signaling

Ribas A. N Engl J Med 2012;366:2517-2519

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Cancer Immunotherapy

• INTRINSIC THERAPY

• MEMORY

• SPECIFICITY

May work across tumor types

May result in long-lasting response

May have limited side effects

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FDA Approval Timeline of Checkpoint Inhibitors

MSI/MMRd

Zhang J et al. Front Oncol 2018;8:351. https://www.fda.gov/drugs – Retrieved on Mar, 2018

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5-yr Follow-Up of Nivolumab in previously treated advanced NSCLC (CA209-003 study)

Gettinger S et al. J Clin Oncol 2018;36:1675-1684

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5-yr Follow-Up of Nivolumab in previously treated advanced NSCLC (CA209-003 study)

≈ 20% of long-term survivors

(Immunological Memory)

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5-yr Follow-Up of Nivolumab in previously treated advanced NSCLC (CA209-003 study)

… but > 50% of patients die within 1 year

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How to raise the bar in Immuno-Oncology?

• Predictive biomarkers

• Combination Tx

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PD-L1 as a Biomarker in advanced NSCLC

< 1% 1-49% > 50%

Garon EB et al. N Engl J Med 2015; 372:2018-28 Reck M et al. N Engl J Med 2016; 375: 1823-1833. Brahmer JR, WCLC 2017

KEYNOTE-001

KEYNOTE-024

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Towards Personalized Medicine in Immuno-Oncology

Presented by Prof Benjamin Besse at ESMO-Asia 2017

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IO-based Combinations

IO/IO IO/CTx

IO/Target IO/RTx

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IO/CTx combination in NSCLC

Non-Squamous

Squamous

OS data not yet mature

1. Gandhi L et al. N Engl J Med 2018;378:2078-92. 2. Barlesi F, ESMO 2018 3. Paz-Ares L et al. N Engl J Med 2018; 379:2040-51. 4. Jotte RM, ASCO 2018.

KEYNOTE-407^[3]

KEYNOTE-189^[1] IMpower132^[2]

IMpower131^[4]

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IO/IO combination in NSCLC

Hellmann MD, et al. N Engl J Med 2018;378(22):2093-2104

Efficacy of Nivo+Ipi in pts with High TMB (≥10 mutations per megabase) - CheckMate 227

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Toxicity of Checkpoint Inhibitors

Pembrolizumab N = 154

Chemotherapy N = 150 Median (range) treatment duration with initially

assigned therapy, mo

7.9 (0.03–28.8) 3.5 (0.03–30.5)

Treatment-related adverse events, n (%) 118 (76.6) 135 (90.0)

Grade 3–5 48 (31.2) 80 (53.3)

Serious 35 (22.7) 31 (20.7)

Led to discontinuation 21 (13.6) 16 (10.7)

Led to death 2 (1.3) 3 (2.0)

Immune-mediated adverse events,^bn (%) 52 (33.8) 8 (5.3)

Grade 3–5 21 (13.6) 1 (0.7)

Led to death 1 (0.6) 0

aDuring treatment with the initially assigned therapy.

bIrrespective of attribution to treatment by the investigator.

Data cutoff: July 10, 2017.

Adverse Event Summary

^a

of KEYNOTE-024 study

Reck M et al. N Engl J Med 2016; 375: 1823-1833 Brahmer JR, WCLC 2017

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Toxicity of Checkpoint Inhibitors

Pembrolizumab N = 154

Chemotherapy N = 150 Median (range) treatment duration with initially

assigned therapy, mo

7.9 (0.03–28.8) 3.5 (0.03–30.5)

Treatment-related adverse events, n (%) 118 (76.6) 135 (90.0)

Grade 3–5 48 (31.2) 80 (53.3)

Serious 35 (22.7) 31 (20.7)

Led to discontinuation 21 (13.6) 16 (10.7)

Led to death 2 (1.3) 3 (2.0)

Immune-mediated adverse events,^bn (%) 52 (33.8) 8 (5.3)

Grade 3–5 21 (13.6) 1 (0.7)

Led to death 1 (0.6) 0

aDuring treatment with the initially assigned therapy.

bIrrespective of attribution to treatment by the investigator.

Data cutoff: July 10, 2017.

Adverse Event Summary

^a

of KEYNOTE-024 study

Reck M et al. N Engl J Med 2016; 375: 1823-1833 Brahmer JR, WCLC 2017

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Immune-Related Adverse Events

Dysimmune toxicities may potentially

affect all organs

Champiat S et al. Ann Oncol 2016; 27:559-74

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Incidence of irAEs

with anti-CTLA4 and anti-PD1/PDL1 agents

Michot JM et al. Eur J Cancer 2016;54:139-148.

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Toxicity of Combinations

IO/IO combo more toxic

than single agents IO/CTx toxicity similar to CTx alone

G3-5 AEs In KEYNOTE-189:

67.2% with Pembro+CTx vs 65.8% vs Placebo+Ctx

Boutros C et al. Nat Rev Clin Oncol 2016; 13:473-86.

Gandhi L et al. N Engl J Med 2018;378:2078-92.

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In Summary, Checkpoint Inhibitors:

• Have extended survival across several tumor types

• Will be increasingly used to treat cancer, either alone or in combination

• Have a unique toxicity profile (immune-related

toxicity)

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Ruolo dei checkpoint inhibitors in oncologia