1. Advances in Personalized Medicine
and Improving Quality-of-Life:
The Future of Cancer Care
Maurie Markman, M.D.
Senior Vice President for Clinical Affairs
Cancer Treatment Centers of America

2. Goals of Anti-Neoplastic Therapy
• Maximize/improve overall survival (“cure”, if
possible)
• Treat and prevent (if possible) cancer-related
symptoms
• Delay the time to measurable and symptomatic
progression of the disease process
• Maximize overall quality-of-life (including the
impact of the cancer, its therapy, and highly
relevant psychological/emotional factors)
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© 2011 Rising Tide

3. Relevance of Quality-of-Life to
Cancer Survival
• Staren ED, et al, The Breast Journal 2011
• 1,511 breast cancer patients (analytic and non-
analytic) treated at Cancer Treatment Centers of
America (1/01 – 12/08)
• Mean age at presentation 52.5
• Median overall survival 32.8 months
• EORTC-C30 survey instrument
• QOL scores at presentation predictive of
survival, particularly role function, independent
of tumor stage.
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© 2011 Rising Tide

4. Relevance of Quality-of-Life to
Cancer Survival
• Braun D, et al. BMC Cancer 2011
• 1,194 lung cancer patients (analytic and non-
analytic) treated at Cancer Treatment Centers of
America (1/01 to 12/08)
• EORTC-C30
• Every 10-point increase in “physical function”
predicted for a 10% increase in survival
• Every 10-point increase in “global QOL”
associated with 9% increase in survival
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5. Relevance of Quality-of-Life to
Cancer Survival
• Braun D, et al. Health and Quality of Life
Outcomes 2011
• 396 patients stages III-IV colorectal cancer
treated at Cancer Treatment Centers of
America, followed for a minimum of 3 months
• Appetite loss and global health at baseline
strongly correlates with survival
• Improved physical functioning at 3 months
correlates with a superior survival outcome
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© 2011 Rising Tide

6. “Targeted”, “Personalized”, or
(most recently) “Precision” therapy
• Not a new concept
• Hormonal therapy of breast/prostate cancer:
Earliest systemic anti-neoplastic strategy
ER receptor discovered 40 years ago
• HER-2 over-expression in breast cancer
• CML/GIST (profoundly different pathology but
similar molecular abnormalities resulting in
essentially identical highly effective therapy)
• Resulting over-simplification of complex biology
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© 2011 Rising Tide

7. EGFR (Epidermal Growth Factor
Receptor)
• Major research efforts to develop EGFR receptor
inhibitors, known in pre-clinical systems to be
relevant in tumor progression
• Majority of lung cancer patients over-express
EGFR receptor
• 10% of patients with metastatic lung cancer
major response to one EGFR inhibitor
• Phase 3 randomized trials with this agent
(combined with chemotherapy) negative
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© 2011 Rising Tide

8. EGFR Receptor
• Evidence that over-expression of receptor in
lung cancer is not clinically relevant, but the
presence of particular EGRF mutations predict
for clinical activity (approximately 20-25% of
patients - more commonly observed in non-
smokers, Asian population, women)
• Definitive evidence lung cancer patients with a
mutation experience a superior outcome when
treated with EGFR inhibitor alone, rather than
chemotherapy (Lancet Oncology 2012; 13:239)
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9. Other Examples of Effective
“Precision” Therapy
• ALK rearrangement (4-5% of lung cancer)
– Crizotinib - FDA approved 8/2011
• BRAF mutation (50% patients with melanoma)
– Vemurafinib – FDA approved 8/2011
• Hedgehog pathway inhibitor (basal cell
carcinoma – locally advanced/metastatic)
– Vismodegib – FDA approved 1/2012
• PARP inhibitor (5-10% of ovarian cancer
patients with BRCA1 or 2 abnormalities)
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© 2011 Rising Tide

10. Issues for Future “Precision
Medicine” Drug Development
• Small subsets of patients: How does one prove
clinical benefit? Is a phase 3 randomized trial
always required? How does a drug achieve
FDA approval?
• Quality of evidence for clinical utility of
molecular/biological markers (e.g., individual/
institutional financial conflict-of-interest)
• Insurers willingness to pay for anti-neoplastic
therapy based on molecular test results, rather
than on data from phase 3 randomized trials?
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© 2011 Rising Tide

11. But ….
• The future is here
• Within the next year it will be possible to
sequence the entire genome of a tumor and the
corresponding normal genome of an individual
cancer patient for < $3,000 (12-15 years ago
this would have cost $6,000,000,000)
• So, the issue is not whether the data will be
available to patients, but rather how to optimally
convert this massive quantity of raw data into
information of genuine value in individual patient
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© 2011 Rising Tide

12. Declining Cost of
Sequencing a Human Genome
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© 2011 Rising Tide

13. “The STEPS”
• Discovering the “code” in an individual patient–
(“sequencing”) (easy)
• Attempting to break the “code” – (“bio-
informatics) (difficult - extremely difficult)
• Exploring the relevance of the proposed solution
(“clinical validation with a targeted therapeutic”)
(unknown difficulty) –
• Proving the relevance of the solution (“N of 1”
research) (soon-to-be the new paradigm in
clinical cancer therapeutic research)
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© 2011 Rising Tide

14. This future of cancer medicine is very
real and is today ….
• Bergethon K, et al (+ 22 other authors) ROS1
rearrangements define a unique molecular class
of lung cancers. Journal of Clinical Oncology
2012; 30(8):863-870.
• Recently described molecular abnormality
• In vitro studies revealed cancer cells with this
abnormality respond to crizotinib (“FDA
approved ALK rearrangements in lung cancer”)
• 1,073 lung cancer patients screened 1.7% with
abnormality (Less than 1 in 50 patients)
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© 2011 Rising Tide

15. This future of cancer medicine is very
real and is today ….
• (page 867) “The patient is a 31-year old male
never-smoker diagnosed with multifocal
bronchiolalveolar carcinoma in August 2010.
Genetic testing of his tumor demonstrated no
EGFR mutation or ALK rearrangement. He was
treated at an outside institution with first-line
erlotinib with no response. As a result of
progressively worsening symptoms and hypoxia,
he was referred to MGH for additional genetic
testing and was found to be ROS1 positive.”
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© 2011 Rising Tide

16. This future of cancer medicine is very
real and is today ….
• “On August 20, 2011, the patient was started on
crizotinib at the standard dose of 250 mg twice
daily. In less than 1 week, he noted a significant
improvement in symptoms, and by 2 weeks, his
hypoxia had resolved. Restaging scans at 8
weeks demonstrated near complete resolution of
his multifocal lung tumor, which was
subsequently confirmed at 12 weeks. At the
time of this report (6 months), the patient
continues on crizotinib with no evidence of
recurrence.”
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© 2011 Rising Tide

17. This future of cancer medicine is very
real and is today ….
• “This case suggests that patients with ROS-
positive non-small cell lung cancer may be
exquisitely sensitive to therapeutic ROS1
inhibition”
• N of 1
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© 2011 Rising Tide