Geoffrey Oxnard, MD, discusses the latest research in targeted therapies and molecular testing to treat lung cancer. This presentation was originally given as part of "Living with Lung Cancer: A Forum for Patients and Caregivers" on Nov. 14, 2015 at Dana-Farber Cancer Institute in Boston, Mass.

1. Lung cancer targeted
therapies and molecular
testing
Geoff Oxnard, MD
Lowe Center for Thoracic Oncology
Dana-Farber Cancer Institute

2. Overview
1. What is a targeted therapy?
2. Picking a targeted therapy
3. Genotyping to find a target
4. Liquid biopsies instead of tumor
biopsies

3. Cytotoxic chemotherapy
• Aim is to induce unique toxicity against
dividing cells
• Inherently also toxic to healthy cells
• Various categories we learn in
pharmacology:
– Anti-metabolites
– Microtubule inhibitors
– Alkylating agents
– Topoisomerase inhibitors

4. Cytotoxic chemotherapy
• More chemo is more toxic but not
necessarily more effective
• Chemotherapies are selected empirically
• Prefer combinations of agents with non-
overlapping toxicities:
Drugs that impair
bone marrow
Drugs that cause
neuropathy
Carboplatin
Docetaxel
Gemcitabine
Cisplatin
Paclitaxel

5. Cytotoxic chemotherapy
• Chemotherapy can be curative!
– Chemosensitive cancers
• Germ cell tumors
• Lymphomas
– Adjuvant therapy after surgery
• NSCLC
• Colorectal cancer
• Breast cancer
– Combined with radiation
• Oropharyngeal cancers

6. What is “targeted therapy”?
Empiric therapy:
• Drugs you give to anyone who will tolerate
and will gain some benefit
Rationally-directed targeted therapy:
• Drugs you give to patients who, in
advance, you know will benefit

7. • Erlotinib is
an oral
EGFR
tyrosine
kinase
inhibitor
Hynes et al, Nature Reviews, 2005
EGFR
EGFR
What is “targeted therapy”?

8. Hynes et al, Nature Reviews, 2005
EGFR
EGFR
TKI
• Erlotinib is
an oral
EGFR
tyrosine
kinase
inhibitor
What is “targeted therapy”?

9. Erlotinib for NSCLC
• BR-21 study randomized patients with previously treated
metastatic lung cancer to either erlotinib (EGFR TKI) or
placebo
Shepherd et al, NEJM, 2005

10. Baseline Day 6
Vince Miller, Memorial Sloan-Kettering Cancer Center
Erlotinib for NSCLC

11. Erlotinib for NSCLC
Erlotinib is either:
1. A drug that helps all lung cancer patients,
but just a little bit
2. A drug that helps few lung cancer patients,
but with a major effect

12. Erlotinib for NSCLC
Erlotinib is either:
1. A drug that helps all lung cancer patients,
but just a little bit
2. A drug that helps few lung cancer patients,
but with a major effect
Which would you prefer?

13. 2009 2012
2004
No known
genotype
1984 - 2003
No known
genotype
Stephanie Cardarella, Dana-Farber Cancer Institute
Cancer genetics

14. We use cancer genetics to pick a targeted
therapy:
Erlotinib
Afatinib
Sunitinib
Crizotinib
Alectinib
Dabrafenib
Osimertinib
CLINICAL TRIALS
Cancer genetics

15. We use cancer genetics to pick a targeted
therapy:
Cancer genetics

16. • What characteristics are we looking for in
a great targeted therapy?
Picking a targeted therapy

17. • What characteristics are we looking for in
a great targeted therapy?
Picking a targeted therapy
Pretreatment
After 6 months

18. • What characteristics are we looking for in
a great targeted therapy?
Picking a targeted therapy

19. • Molecular analysis of tumor DNA allows
identification of therapeutic targets
Tumor genotyping

20. • Molecular analysis of tumor DNA allows
identification of therapeutic targets
• Next-generation sequencing is a single
assay covering >300 genes which can
comprehensively characterize a cancer
Tumor genotyping

21. • New approaches can at times allow
noninvasive analysis of a blood specimen
• We are studying the free floating tumor
DNA circulating in plasma
Liquid biopsy

22. • In patients with EGFR-mutant lung cancer,
we can detect response and resistance
EGFR exon 19 del EGFR T790M
Patient 1 Patient 2
Progression
on CT
Progression
on CT
Liquid biopsy

23. • In patients with EGFR-mutant lung cancer,
we can detect response and resistance
EGFR exon 19 del EGFR T790M
Patient 1 Patient 2
Progression
on CT
Progression
on CT
Liquid biopsy

24. • In patients with EGFR-mutant lung cancer,
we can detect response and resistance
EGFR exon 19 del EGFR T790M
Patient 1 Patient 2
Progression
on CT
Progression
on CT
Liquid biopsy

25. DAY 0:
CT shows marked progression
on erlotinib, plasma drawn
DAY 25:
Report from rebiopsy
genotyping shows EGFR
T790M
DAY 73:
CT
demonstrates
a radiographic
response
DAY 1:
cfDNA genotyping detects
806 copies/ml of EGFR
T790M
DAY 31:
Patient starts
treatment with an
investigational
EGFR inhibitor
Sacher et al, ASCO, 2014

26. • We are working to improve our liquid
biopsy technologies in hopes of facilitating
rapid delivery of targeted therapies to as
many patients as possible
Liquid biopsy

27. Living with lung cancer
• 3 rules to living with lung cancer
1. Don’t lose weight
• Maximize calorie intake, even junk food
2. Don’t act sick
• Even when you feel sick, go do something
(and then go take a nap)
3. Don’t be a tough guy
• If your symptoms aren’t well controlled,
call us and we’ll adjust your medications

28. Living with lung cancer
• Lung cancer changes your life
• This is a serious disease, but we
can’t know an individual patient’s
prognosis until treatment starts
• Try to accept the uncertainty:
– Make priorities for yourself
– Make the most of good days
– Try to turn bad days into good days