Targeted Cancer Therapies

Transcription

1 Targeted Cancer Therapies Primary Care Training Programme 14 th February 2018 Sin Chong Lau Consultant in Medical Oncology

2 Financial Disclosure Honoraria: Amgen, Pfizer, Roche, Sanofi, Servier Meetings: Amgen, Boehringer-Ingelheim, Merck Serono, Lilly, Novartis, Roche, Servier Further information available at:

3 Learning Objectives What are targeted cancer therapies? How do targeted cancer therapies work? What are their side effects? What are the limitations of targeted therapies? Give an example of each type of targeted therapy.

4 What are targeted cancer therapies? Cytotoxic chemotherapy interferes with cell processes essential for cell division that are present in all cells. Rapidly dividing cells are affected the most. e.g. DNA synthesis and mitosis Targeted therapies act on specific molecular targets that are predominantly active in cancer cells. (Hormone therapies for breast and prostate cancer meet this definition but will not be discussed in this presentation)

5 What are targeted cancer therapies? Cytotoxic drugs since 2004 Cabazitaxel Eribulin Pemetrexed Trabectedin Trifluridine/Tipiracil Vinflunine Targeted therapies pre-2004 Imatinib Trastuzumab

6 What are targeted cancer therapies? Monoclonal antibodies Aflibercept Atezolizumab Bevacizumab Cetuximab Denosumab Ipilimumab Necitumumab Nivolumab Olaratumab Panitumumab Pembrolizumab Pertuzumab Ramucirumab Trastuzumab emtansine Small molecules Afatinib Alectinib Axitinib Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Erlotininb Everolimus Gefitinib Lapatinib Lenvantinib Nintedanib Olaparib Osimertinib Palbociclib Pazopanib Regorafenib Ribociclib Sorafenib Sunitinib Temsirolimus Trametinib Vandetinib Vemurafenib Vismodegib

7 How do targeted therapies work? Source: Cell 2011; 144:

8 Lung Cancer & Gefitinib Source: N Engl J Med 2004; 350 :

9 ISEL Source: Lancet 2005; 366:

10 Lung Cancer & Gefitinib

11 Lung Cancer & Gefitinib Source: N Engl J Med 2004; 350 :

12 Driver Mutation An example of a driver mutation causing oncogene addiction

13 IPASS Source: N Engl J Med 2009; 361 :

14 IPASS Source: N Engl J Med 2009; 361 :

15 IPASS Source: N Engl J Med 2009; 361 :

16 IPASS Source: N Engl J Med 2009; 361 :

17 EGFR Toxicity Source: The Oncologist 2011 ; 16:

18 EGFR TKI Resistance Source: PNAS 2008; 105 (6):

19 Overcoming T790M Resistance Source: N Engl J Med 2015;

20 AURA3 Source: N Engl J Med 2017;

21 AURA3 Source: N Engl J Med 2017;

22 Liquid Biopsy Source: J Clin Oncol 2016; 34:

23 Summary (Ideal) Targeted therapy More effective than cytotoxic chemotherapy Less toxic than cytotoxic chemotherapy Predictive biomarker assay Less invasive liquid biopsy

24 Angiogenesis Inhibitors Source: Cell 2011; 144:

25 Angiogenesis Inhibitors Mabs: Bevazicumab, Ramucirumab & Aflibercept Usually in combination with chemotherapy Nibs: Axitinib, Cabozantinib, Nintedanib, Pazopanib, Regorafenib, Sorafenib, Sunitinib Usually as single agent Inhibit interaction between Vascular Endothelial Growth Factor (VEGF) and its receptor

26 NO PFS Source: J Clin Oncol 2008; 26:

27 NO OS Source: J Clin Oncol 2008; 26:

28 NO16966 Source: J Clin Oncol 2008; 26:

29 Renal Cell Carcinoma Source: N Engl J Med 2007;

30 Renal Cell Carcinoma Source: J Clin Oncol 2009; 27:

31 RCC & VEGF Source: Discov Med 2010; 10:

32 Summary Antibody treatment in combination chemotherapy shows modest OS benefit with some increase in vascular-associated toxicity Small molecule treatment effective as single agent in selected cancers with additional toxicity Currently no predictive biomarker assay

33 PARP Inhibitors Source: Cell 2011; 144:

34 Synthetic Lethality Source: N Engl J Med 2009; 361:

35 Study 19 - Olaparib Maintenance Source: N Engl J Med 2012; 366:

36 Olaparib Toxicity Source: N Engl J Med 2012; 366:

37 SOLO-2

38 Summary Proof of concept of synthetic lethality Proven efficacy as maintenance treatment Main toxicities are nausea, fatigue, vomiting, and anaemia Predictive biomarker

39 Immunotherapy Source: Cell 2011; 144:

40 Immune Checkpoints Source: JAMA 2014; 314:

41 Anti-PD-1 Immunotherapy

42 KEYNOTE-024 Source: N Engl J Med 2016; 375:

43 State Of The Art (2007) Platinum-doublet

44 KEYNOTE-024 Median OS (months) Pembrolizumab 30.2 Chemotherapy 14.2 Survival Rate 1 year 94 / 151 (62.2%) of patents in 2 year chemotherapy arm went on to receive Pembrolizumab 70.3% 51.5% anti-pd-1 MAb Chemotherapy 54.8% 34.5% Source: N Engl J Med 2016; 375:

45 KEYNOTE-024 Source: N Engl J Med 2016; 375:

46 KEYNOTE-024 Source: N Engl J Med 2016; 375:

47

48 From: Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper Ann Oncol. 2015;27(4): doi: /annonc/mdv623 Ann Oncol The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oup.com.

49 Financial Toxicity Gefitinib 2168 / month Erlotinib 1632 / month Afatinib 2023 / month Crizotinib 4689 / month Ceritinib 4923 / month Nintedanib 2151 / month Ramucirumab 3500 / 70 kg pt / 3 week cycle Nivolumab 2304 / 70 kg pt / 2 week cycle

50 What are targeted cancer therapies? Monoclonal antibodies Aflibercept Atezolizumab Bevacizumab Cetuximab Denosumab Ipilimumab Necitumumab Nivolumab Olaratumab Panitumumab Pembrolizumab Pertuzumab Ramucirumab Trastuzumab emtansine Small molecules Afatinib Alectinib Axitinib Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Erlotininb Everolimus Gefitinib Lapatinib Lenvantinib Nintedanib Olaparib Osimertinib Palbociclib Pazopanib Regorafenib Ribociclib Sorafenib Sunitinib Temsirolimus Trametinib Vandetinib Vemurafenib Vismodegib

51 Conclusions Targeted therapies can be very effective cancer treatments Patient selection, with predictive biomarkers, can: Select patients more likely to benefit Prevent patients being exposed to unnecessary sideeffects Targeted therapy side-effects can often be predicted by their mechanism of action & usually less severe than with chemotherapy Their high costs inevitably limit their availability within the NHS

52 References Hallmarks of Cancer Hanahan D & Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011; 144: Lung Cancer Mutations Chan BA & Hughes BGM. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res 2015; 4: EGFR signalling and Gefitinib mechanism of action IPASS Mok TS, Wu YL, Thongpasert S et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009; 361: Also see EURTAC, OPTIMAL, LUX-Lung 3 & LUX-Lung 6 EGFR TKI Drug Resistance Yun CH, Mengwasser KE, Toms Av et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. PNAS 2008; 105(6): Takezawa K, Pirazzoli V, Arcila ME et al. Cancer Discovery 2012; 2: rd Generation EGFR TKI Mok TS, Wu YL, Ahn MJ et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 2017; 376: TIGER-X, TIGER-2, AURA extension & AURA-2 studies ongoing

53 References Checkpoint inhibitors Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373: Borghaei H, Paz-Ares L, Spigel DR et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373: Reck M, Rodriguez-Abreu D, Robinson AG et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small- Cell Lung Cancer. N Engl J Med 2016; 375: Haanen JBAG, Carbonnel F, Robert C et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diargnosis, treatment and follow-up. Annals of Oncology 2017; 28 (Supplement 4): iv119 iv142