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

Disclosure CME Support from Boehringer Ingelheim AstraZeneca Amgen

Canadian Cancer Statistics 2014

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

Systemic Therapies in Lung Cancer Chemotherapy Targeted Therapies

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.

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.

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

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

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

Targeted Therapies Subset of patients

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

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

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

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;101:13306-11

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

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

GEFITINIB

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:10.1038/ncponc0931

ERLOTINIB

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

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

Acquired Drug Resistance Mechanisms Resistance develops within ~10 months

2nd line in T790M mutation OSIMERTINIB Janne NEJM 2015

2nd line in T790M mutation ROCILETINIB Sequist NEJM 2015

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

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

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

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 http://www.oncolink.org/experts/article.cfm?id=250 Melosky & Hirsh, Frontiers in Oncology, 2014

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

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

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

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)

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.

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

EML4-ALK Rearrangement FISH

CRIZOTINIB

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

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