1. Recent Advances in Systemic Therapy of Lung Cancer
Lung cancer has been in the news in the past year. Patients reading the news and seeing the ads. Drugs that are finally moving the needle.
Amin Kay MD FRCPC
Windsor Regional Cancer Center

2. Disclosure
CME Support from
Boehringer Ingelheim
AstraZeneca
Amgen

3. Canadian Cancer Statistics 2014

4. Squamous Cell Carcinoma
Small Cell
Lung Cancer
Adenocarcinoma
Non-Small Cell
Squamous Cell Carcinoma
Large Cell Carcinoma
STAGE 4

5. Systemic Therapies in Lung Cancer
Chemotherapy
Targeted Therapies

6. For decades people had this idea
For decades people had this idea. But was unclear which immune pathway to target successfully.
The links are what the immune cells using to recognize the cancer cell and then kill it.

7. PD1 – PDL1 Pathway
One of these links between the T-cells and Tumor cells is a brake that prevents this attack. It is a naturally-built regulatory step, that tumor cells take advantage of by over-expressing PDL1.

8. Nivolumab Anti-PD1 Antibody Improves survival Borghaei NEJM 2015
Opdivo
Improves survival by 3 months
But that’s not what we are most excited about
Borghaei NEJM 2015

9. Nivolumab
Those who respond have a lasting reponse.
Borgahei NEJM 2015

10. Side effects of PD1 / PDL1 Drugs
Overall well-tolerated
Autoimmune inflammation of any organ
Managed with steroids and holding the drug

11. Targeted Therapies
Subset of patients

12. EGFR Pathway Key pathway of tumorogenesis.
EGFR mutation turns it on constitutively.
EGFR TKIs bind to intracellular domain of EGFR.
Ou. Crit Rev Oncol Hematol 2012;83:407-21

13. Prevalence of Mutations in Lung Adenocarcinoma
Other: MET amplifications 2%; HER2 1%; MEK1 0.4%; NRAS 0.2%
Kris et al. J Clin Oncology 2011;29:CRA7506

14. Driver Mutation most likely in:
UP TO
Non-Smoker
Female
Asian
Squamous: Only 1%, so don’t bother checking.

15. EGFR mutations in NSCLC
Sequist et al. Presented at the 2012 Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL; Sept 6-8
Pao et al. PNAS 2004;101:

16. EGFR TKI’s GEFITINIB ERLOTINIB AFATINIB Once daily pills
Can anyone name a first line EGFR inhibitor used in lung cancer?
GEFITINIB
ERLOTINIB
AFATINIB
Once daily pills
Response ~ 1 year
Survival:
~2 years vs 1 year

17. EGFR mutation testing: ASCO Guideline
“…patients with NSCLC who are being considered for first-line therapy with an EGFR TKI… should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy.”
PCR
Keedy et al. J Clin Oncol 2011;29:2121-7

18. GEFITINIB

19. CT scans before and after erlotinib therapy.
Pan M et al. (2007) CNS response after erlotinib therapy in a patient with metastatic NSCLC with an EGFR mutation Nat Clin Pract Oncol 4: 603–607 doi: /ncponc0931

20. ERLOTINIB

21. AFATINIB Irreversible More targets (EGFR subtypes) More potent
More toxic
OS the same in all because of cross-over

22. Head-to-head trial
AFATINIB
GEFITINIB
LUX-LUNG 7

23. Acquired Drug Resistance Mechanisms
Resistance develops within ~10 months

24. 2nd line in T790M mutation
OSIMERTINIB
Janne NEJM 2015

25. 2nd line in T790M mutation
ROCILETINIB
Sequist NEJM 2015

26. Side effects of EGFR Inhibitors
Helpful for you to know about if your patient is on these drugs.

27. Rash
EGF plays an important role in maintaining skin (EGFR expressed in basal layer of epidermis), so rash with TKI is not surprising.
Possible with TKI: dry skin, pruritis (moisturize, antihistamine)
Most common is acne-like rash (in appearance and location: usually face, chest).
Rash 37-78%
Rash may be triggered by sun exposure
May get secondarily infected

28. Correlation between rash severity and response
Management of Rash
Moisturizer
Minimize sun, Sunscreen
Hydrocortisone 2.5% BID
Clindamycin 1% BID
Minocycline 100mg BID
If severe: hold TKI, resume at lower dose
Correlation between rash severity and response
Early intervention is key to avoid serious complications.
Avoid OTC acne meds, as can dry out further
Almost all pts have dry skin, so should use alcohol-free emolient cream.
Continue mino/doxy for 4-6 wks
Hirsh. Curr Oncol 2011;18:126-38

29. Paronychia Inflammation/Infection of nail folds
Avoid trauma, wear gloves when working with hands
Emollient lotion
Topical antibiotics (eg. Clinda 1%)
Topical Steroid (Clobetasol)
Vinegar Soak
If severe:
Oral Doxycycline
Silver nitrate
Removal of nail Plate
Veinagar soak: 1:1 water and white vinegar mixture for 15min
Melosky & Hirsh, Frontiers in Oncology, 2014

30. Hair Alterations Thinning Change in colour (Re-pigmentation) thickness
Curling
Fragility
Eyebrows and lashes too

31. Mucositis Soft non-irritating foods Soft Toothbrush
Normal saline or Sodium Bicarb (baking soda) rinse
Miles Solution (steroid, lidocaine, nystatin)
Assess for thrush and herpes

32. Diarrhea GI tract epithelial cells express EGFR Secretory diarrhea
Incidence 27-87% in various trials

33. Diarrhea
Assess for other causes (laxatives, antibiotics, Stool Cx / C.diff, …)
Assess volume status, electrolytes
Diet Modification:
BRAT diet
Avoid milk products, fatty/spicy foods
Keep hydrated
Loperamide
Avoid milk products (lactase activity decreases with epithelial damage)
BRAT: (bananas, rice, applesauce, toast)
Loperamide: 4 mg (2 tablets) immediately after symptoms begin and then 2 mg (1 tablet) after each loose stool to a maximum of 20 mg daily until 12 hours have passed with no episodes of diarrhea
Restarting at lower doses:
Lower the afatinib dose by 10 mg at a time to a minimum dose of 20 mg.
Lower the erlotinib dose by 50 mg at a time to a minimum dose of 50 mg (no sufficient data on efficacy are available in the literature).
Resume gefitinib only at the original dose (the dose of gefitinib cannot be lowered and no data on its efficacy with a modified schedule are available)

34. Severe Diarrhea (Grade 3,4)
Admit to Hospital
IV Hydration, Electrolyte repletion
Continue Imodium
Consider Octreotide
Rule out other causes (eg. C.diff, Imaging, Scope)
Hold drug
Restart at lower dose when improves to grade 1.
Watch out for flare when holding TKI.

35. Prevalence of Mutations in Lung Adenocarcinoma
Other: MET amplifications 2%; HER2 1%; MEK1 0.4%; NRAS 0.2%
Kris et al. J Clin Oncology 2011;29:CRA7506

36. EML4-ALK Rearrangement
FISH

37. CRIZOTINIB

38. Pneumonitis Bradycardia Visual effects:
Visual persistence (trailer), halos
Self-limited, no intervention required
Well tolerated (Grade 3,4 toxicity is very rare)
Pneumonitis
Bradycardia

39. 2nd line ALK inhibitors CERITINIB ALECTINIB
More potent, better CNS response.