Download Small Cell Lung Cancer

What is Happening in Clinical Trials for
Small Cell Lung Cancer?
Joshua Bauml, MD
Assistant Professor of Medicine
Perelman School of Medicine at the University of
Pennsylvania
Objectives
 What is small cell lung cancer?
 How is small cell lung cancer treated today?
 How might small cell lung cancer be treated in the future
• Research advances
• Current clinical trials
What is Small Cell Lung Cancer?
 Lung cancer is divided into two groups
• Small Cell and Non-Small Cell
 Small cell lung cancer is a biologically distinct cancer from
other types of lung cancer
• Tends to grow very quickly
• Spreads to other parts of the body early
 Represents 15% of all lung cancers
Question
What is the most important risk factor for
the development of small cell lung
cancer?
1. Genetics
2. Smoking
3. Obesity
4. I don’t know
Small Cell Lung Cancer
 In contrast to Non-Small Cell Lung Cancer, nearly all Small Cell
Lung Cancer is associated with smoking
How is Small Cell Lung Cancer treated?
 Staging is divided into two groups
• Limited stage is disease sufficiently “limited” that a radiation oncologist
can treat it with a safe radiation treatment plan or field
• Extensive stage is when the cancer has spread to other organs
 Prognosis is very different between these groups
• Limited stage can be cured
• Extensive stage disease has a much worse outcome
Limited Stage Small Cell Lung Cancer
 Limited stage can be cured
 Treatment with chemotherapy and radiation at the same time
• Cisplatin and etoposide or carboplatin and etoposide
 Most patients will respond quite nicely to chemotherapy
• But, many patients will have their disease relapse or come back
Extensive Stage Small Cell Lung Cancer
 Chemotherapy is the mainstay of therapy
•
•
•
•
•
•
•
Cisplatin
Carboplatin
Etoposide
Topotecan
Irinotecan
Paclitaxel
Nivolumab +/- ipilimumab
 Radiation can sometimes be used if response to chemotherapy
is excellent
 Responses can be impressive, but are often brief and very rarely
long-lasting (years)
Brain involvement
 Over half of patients with Small Cell Lung Cancer will develop
brain metastases
 Chemotherapy has limited effectiveness on brain metastases
 Prophylactic (preventive) radiation to the brain helps patients
with both limited and extensive stage disease live longer
• Brain radiation can have some short and long-term side effects
Clinical Trials are Critical
 Current treatment options are disappointing
 We need to have a better understanding of why this disease has
been so hard to treat
 Performing clinical trials in this disease is a key component of
this effort
 Our group is committed to advancing the treatment of this
disease
What is different about Small Cell?
NonSmall
Cell
Small
Cell
Limited stage
Limited stage
Extensive
stage
Extensive
stage
Targeted therapy?
 Many of the talks you will hear today discuss what are called
“targeted” therapies
 These advances are not currently part of the standard of care in
small cell lung cancer
• Previous efforts have failed to improve outcomes beyond what we can
accomplish with chemotherapy
 We have been unable to find the key “driver” mutations for small
cell
• Cancers have many mutations, the key is finding which ones are the
“drivers” and which are the “passengers”
p53 is a common mutation
 p53 is the most commonly mutated gene in human cancer
 It codes for a tumor suppressor or an “off switch”
• If a gene codes for an oncogene, or “on switch” we can target that
pathway and turn it off
• If the problem is in an “off switch” many pathways are activated, and
targeting is more complicated
 New agents are being identified that activate mutated or “broken
off switch” versions of p53
 These could be interesting in small cell
Is the presence of lots of mutations a clue?
 Small cell lung cancers have a lot of mutations
 The body normally has mechanisms to repair mutations
• Mutations are damage to the DNA
 Healthy cells are constantly checking their DNA strands, and
when errors are seen these cells are eliminated
• When this doesn’t happen, cancer develops
 What if we could just try to target the abnormal gene
proofreading, instead of the mutations?
PARP1: A Proofreading Protein
 PARP1 is a gene encoding a protein that helps to fix broken DNA
strands
 Inhibitors of this protein have few side effects and seem to be
effective in some tumors
• Effectiveness is determined by how dependent a cell is on PARP1
 Small cell lung cancer often has a large amount of PARP1
• This implies that it may be dependent on PARP1 for its well-being
Chemotherapy with or without Veliparib
 We participated in a trial at Penn of chemotherapy with or
without veliparib
• Veliparib is an oral PARP inhibitor
 We are awaiting results of this study
• If a positive result is seen, meaning that the effectiveness of
chemotherapy is improved, this would be a huge advance
• Then the next step would be to test it in limited stage disease to see if
we can increase the number of patients who are cured of their disease
What about a different kind of target?
 In lung cancer, most of our targeted therapies are built around
mutations in the tumor genome
 What if we just looked at the cell and identified things that were
different?
Normal Cell
Normal Cell
Small Cell
Normal Cell
DLL3 is Overexpressed in Small Cell
 DLL3 is a receptor which is overexpressed in small cell
• Also seen in other neuroendocrine tumors
• Expressed at very low levels in normal tissue
 Rovalpituzumab tesirine is an antibody drug conjugate
• Once the antibody binds DLL3, the drug is released
• Cells which do not have DLL3 do not get exposed to chemotherapy
Rovalpituzumab tesirine in Small Cell
 We have a trial open at Penn for rovalpituzumab tesirine in small
cell lung cancer
• Tumors need to stain positive for DLL3
• We can check in advance of needing to put a patient on trial
 This is a new way of treating small cell
• Early data is very exciting
• Seems to be effective regardless of prior therapies