What is Happening in Clinical Trials for Small Cell Lung Cancer?

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1 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

2 Financial Disclosures Research/Grant Support: Merck, Clovis, Carevive Systems, Novartis, Bayer Consultative Services: Clovis, BMS, Astra Zeneca, Celgene, Boehringer Ingleheim, Merck, Guardant Health, Genentech

3 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

4 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

5 Small Cell Lung Cancer In contrast to Non-Small Cell Lung Cancer, nearly all Small Cell Lung Cancer is associated with smoking

6 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

7 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

8 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)

9 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

10 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

11 What is different about Small Cell? Non- Small Cell Small Cell Limited stage Extensive stage Limited stage Extensive stage

12 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

13 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

14 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?

15 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

16 Chemotherapy with or without Veliparib We participated in a trial at Penn of chemotherapy with or without veliparib Veliparib is an oral PARP inhibitor Some patients may benefit from this combination Future studies are needed to identify the ideal candidates

17 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

18 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

19 Rovalpituzumab tesirine in Small Cell We recently completed a trial at Penn for rovalpituzumab tesirine in small cell lung cancer Tumors need to stain positive for DLL3 This is a new way of treating small cell Early data is very exciting Seems to be effective regardless of prior therapies

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