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Nuovi farmaci nel tumore del polmone: razionale biologico, tossicit ed efficacia Michele Fiore Radioterapia Oncologica Universit Campus Bio-Medico di Roma - Via lvaro del Portillo, 21 - 00128 Roma Italia www.unicampus.it Shifting

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Università Campus Bio-Medico di Roma - Via Álvaro del Portillo, 21 - 00128 Roma – Italia www.unicampus.it

Nuovi farmaci nel tumore del polmone: razionale biologico, tossicità ed efficacia

Michele Fiore

Radioterapia Oncologica

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UNIVERSITA' CAMPUS BIO-MEDICO DI ROMA www.unicampus.it

Adapted from Pao W et al. Lancet Oncol. 2011

Lung cancer

NSCLC

SCLC

Histological breakdown

Molecular pathology

Present view

Traditional view

Shifting from an empiric to a customized approach

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UNIVERSITA' CAMPUS BIO-MEDICO DI ROMA www.unicampus.it

Target Treatments according to:

  • Tumor histology (squamous vs non-squamous)
  • Epidermal Growth Factor Receptor
  • ALK mutations
  • Immune checkpoints
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Scagliotti GV, J Clin Oncol 2008; 20;26(21):3543-51

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Worse outcomes for Squamous NSCLC compared to Adenocarcinoma

Epidemiological overall survival data: better for adenocarcinoma, worse for squamous tumors

1-year OS / 2-yr OS Period All (N=129.337) ADC (n=53.300) SQ (n=22.944) HR; P value 1990–1993 13.2 / 4.6 15.5 / 5.4 13.5 / 4.3 0.990; p = 0.62 1994–1997 14.1 / 4.9 16.1 / 5.7 14.3 / 4.9 1.007; p = 0.72 1998–2001 17.2 / 6.5 20.4 / 7.9 17.1 / 6.4 0.997; p = 0.85 2002–2005 19.3 / 7.8 23.3 / 9.9 19.9 / 7.2 1.033; p = 0.02

Adapted from Morgensztern DJ et al. J Thorac Oncol. 2009

SEER Database 129.337 patients

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Lung cancer has a high rate of somatic mutations

Mutation frequencies observed in cancers

Adapted from Lawrence MS et al. Nature 2013

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EGFR-mutated NSCLC is a distinct disease

Paz Ares L, J Cell Mol Med 2010;11:2693-2694

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Mok TS, N Eng J Med 2009; 361:947-957

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Mok TS, N Eng J Med 2009; 361:947-957

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Mok TS, N Eng J Med 2009; 361:947-957

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Mitsudomi T, Lancet Oncology 2010; 11(2):121-8

172 chemotherapy-naive patients

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154 patients HR 0.16 (95% CI: 0.10-0.26) p < 0.0001

Lancet Oncol 2011; 12:735-42

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PLoS One. 2014; 9(2):e85245

12 Phase III RCTs 1821 patients with EGFR mutation

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PLoS One. 2014; 9(2):e85245

Erlotinib, gefitinib, afatinib and icotinib shared equivalent efficacy but presented different efficacy- toxicity pattern for EGFR-mutated patients. Erlotinib and afatinib revealed potentially better efficacy but significant higher toxicities compared with gefitinib and icotinib.

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Understanding and overcoming acquired resistance during target therapies

Lovly CM, ASCO 2015

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Mechanisms of resistance to TKi

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Half of patients treated with EGFR TKIs progress due to T790M mutations in EGFR

Chen X, Lung Cancer 2013; 81(2):155-61

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  • Chromosomal translocation

most common ALK abnormality in cancer

  • Rearrangement of genetic info

when parts of one chromosome break off and fuse with another, or flip around (inversion)

  • Results in new gene and

expression of fusion protein

Adapted from Cancer Genome Atlas, National Cancer Institute

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 ALK (anaplastic lymphoma kinase) is a tyrosine kinase target in several different cancers, including NSCLC  In NSCLC, ALK is activated by chromosomal rearrangement, leading to constitutive kinase activation and oncogene addiction

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Crossover on PD

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PROFILE 1007 NCT00932893

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Shaw AT, N Engl J Med 2013; 368: 2385-94 Accrual period: February 2010 − February 2012

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Shaw AT, N Engl J Med 2013; 368: 2385-94

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ORR ratio: 3.4 (95% CI: 2.5 to 4.7); p< 0.0001 HR: 1.02 (95% CI: 0.68 to 1.54); p= 0.54 OS

Shaw AT, N Engl J Med 2013; 368: 2385-94

Median OS: 20.3 vs 22.8 months

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Shaw AT, N Engl J Med 2013; 368: 2385-94

Common AE associated with Crizotinib were visual disorders, gastrointestinal side effects and eleveted liver aminotransferase levels

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Shaw AT, N Engl J Med 2013; 368: 2385-94

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Symptoms: Greater improvement from baseline in cough, dyspnea, fatigue, alopecia, insomnia, and pain with Crizotinib (all p<0.0001) Quality of life: Greater improvement from baseline in global quality of life in patients treated with Crizotinib (p<0.0001)

Shaw AT, N Engl J Med 2013; 368: 2385-94

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Solomon BJ, N Engl J Med 2014; 371:2167-77

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Solomon BJ, N Engl J Med 2014; 371:2167-77

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Solomon BJ, N Engl J Med 2014; 371:2167-77

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Solomon BJ, N Engl J Med 2014; 371:2167-77

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Choi YL et al, Katayama R et al, Doebele RC et al, Sasaki T et al, Gainor JF et al, Kim S et al, Huang D et al, Costa DB et al.

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Crinò L, J Clin Oncol 2016; 34:2866-2873 140 patients enrolled

  • Two or more prior lines of antineoplastic therapy,

including platinum-based chemotherapy;

  • all patients had experienced progression during crizotinib

treatment. Patients who experience progression in the brain during crizotinib treatment may benefit from subsequent treatment with an alternative ALK-targeted therapeutic.

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Checkpoint inhibitors: tumors express “checkpoint” proteins on their cell surface to escape detection from the immune system; targeted inhibition towards these receptors enhances T cell response towards the tumor

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UNIVERSITA' CAMPUS BIO-MEDICO DI ROMA www.unicampus.it Target Antibody Development stage Phase 1 Phase 2 Phase 3 Approved PD-1

Nivolumab (BMS-936558) Nivolumab (+ipilimumab) Pembrolizumab (MK-3475) Pembrolizumab (+chemotherapy)

PD-L1

Durvalumab (MEDI-4736) Atezolizumab (MPDL3280A) Avelumab (MSB0010718C)

CTLA-4

Ipilimumab Tremelimumab (+durvalumab)

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Nivolumab: mechanism of action

Pardoll DM, Nat Rev Cancer 2012; 12(4):252-64

  • PD-1 expression on tumor-infiltrating lymhocytes is associated with decreased cytokine production

and effector function

  • Nivolumab binds PD-1 receptors on T cells and disrupts negative signaling triggered by PD-L1/PD-

L2 to restore T-cell antitumor function

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 Expression of PD-L1 on tumor-infiltrating immune cells or tumor cells may potentially be used as a biomarker to predict anti-tumor response to PD-1 / PD-L1 inhibitors  Several clinical trials are assessing the role of PD-L1 expression on the clinical activity of PD-1 / PD-L1 inhibitors to determine if higher expression correlates definitively with increased clinical activity.

Tumor T cell

PD-1 PD-L1 PD-L2

nivolumab

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Approved for metastatic squamous and non-squamous NSCLC and progression

  • n and after platinum-based chemotherapy

Brahmer J, N Engl J Med 2015; 373:123-135 Borghaei H, N Engl J Med 2015; 373:1627-2639 Borghaei H, J Clin Oncol 2016; 34(suppl):Abstract 9025

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  • Metastatic NSCLC tumors that express PD-L1 and progression on or after

platinum-based chemotherapy

  • Studies performed with 2 or 10 mg/kg (doses similar with regards to toxicity

and efficacy)

Herbst RS, Lancet 2016; 387:1540-1550

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  • There are now many options for patients with lung cancer
  • Recent advances in the understanding of NSCLC biology have revealed a

number of ‘targetable’ alterations that underlie cancer growth and survival in specific patients subgroups.

  • Checkpoint inhibitors have a favorable toxicity profile
  • Multiple combinations with checkpoint inhibitors and chemotherapy are

currently being pursued and the results are eagerly waited.