1. Targeted Cancer Therapies
Primary Care Training Programme
14th 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
Targeted therapies…pre-2004
Cabazitaxel
Eribulin
Pemetrexed
Trabectedin
Trifluridine/Tipiracil
Vinflunine
Imatinib
Trastuzumab

6. What are targeted cancer therapies?
Monoclonal antibodies
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
Aflibercept
Atezolizumab
Bevacizumab
Cetuximab
Denosumab
Ipilimumab
Necitumumab
Nivolumab
Olaratumab
Panitumumab
Pembrolizumab
Pertuzumab
Ramucirumab
Trastuzumab emtansine

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
Median survival 7.9 months

44. KEYNOTE-024 Median OS (months) Pembrolizumab 30.2 Chemotherapy 14.2
94 / 151 (62.2%) of patents in chemotherapy arm went on to receive anti-PD-1 MAb
Survival Rate
1 year
2 year
Pembrolizumab
70.3%
51.5%
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:

48. Figure 2. Spectrum of toxicity of immune checkpoint blockade agents.
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 48

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
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
Aflibercept
Atezolizumab
Bevacizumab
Cetuximab
Denosumab
Ipilimumab
Necitumumab
Nivolumab
Olaratumab
Panitumumab
Pembrolizumab
Pertuzumab
Ramucirumab
Trastuzumab emtansine

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 side-effects
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 Lung Cancer Mutations
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: 36-54
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:
3rd 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