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Good day to everyone joining us and welcome to today’s Xtalks webinar today’s talk is entitled Cancer as a Chronic disease: The Past the Present and the Future of Cancer Research. My name is Sara and I’ll be your Xtalks host for today. Today’s webinar will run for approximately 60 minutes and this presentation includes a Q&A session with our speakers. This webinar is designed to be interactive and webinars work best when you’re involved so please feel free to submit questions and comments for our speakers throughout the presentation using the questions chat box and we’ll try to attend to your questions during the Q&A session. This chat box is located in the control panel on the right-hand side of your screen. If you require any assistance, please contact me at any time by sending a message using this chat panel. At this time, all participants are in listen-only mode and please note that this event will be recorded and made available for future download.
At this point I’d like to thank George Clinical who helped develop the content for this presentation. George Clinical is a leading independent Clinical research organization in Asia with over 260 staff operating in 13 countries. George Clinical provides the full range of Clinical trial services to pharmaceutical, medical device and biotech sponsors for all trial phases, registration and post marketing trials. George Clinical combines scientific and Clinical leadership with expert operational delivery to create a distinctive world-class service. George Clinical’s parent organization, The George Institute for Global Health, is a leader in chronic disease research with a global network of experts with whom George Clinical engages. George Clinical delivers an operationally supportive, internationally recognized scientific leadership service bringing together an extensive series of investigator networks that allow George Clinical to provide customizable Clinical trial excellence from trial design through all aspects of delivery.
And now I’d like to introduce our speakers for today’s event. Dr. Lee Schwartzberg is a scientific leader at George Clinical, a leading CRO with operations throughout the Asia Pacific and the USA. Professor Schwartzberg is also the Executive Director of the West Cancer Center in Memphis Tennessee. He is professor of medicine and chief of the division of haematology oncology at the University of Tennessee Health Service Science Center. Dr. Schwartzberg was the founding editor in chief of the journal community oncology and currently serves as the editor-in-chief of the practice update oncology website. He serves on the editorial board of both the Journal of supportive oncology and the ASCO post. In addition to serving as a reviewer for many prominent medical journals including the New England Journal of Medicine and the Journal of Clinical Oncology Dr. Schwartzberg is also a member of the board of directors for the National Comprehensive Cancer Network. His major research interests are new therapeutic approaches to breast cancer, targeted therapy, supportive care and patient reported outcomes.
Shawn Hart is the managing director USA and global head of late phase studies for George Clinical. Prior to joining George Clinical, Sean was the executive vice president and managing director of Vector Oncology overseeing the global pharma services team including early phase and observational research. Sean is a recognized industry leader in phase IV Clinical trials, post marketing surveillance programs and patient registries. His experience spans all major therapeutic areas and all phases of research and development. So, without further ado I’d like to pass control over to our first speaker today and Dr. Schwartzberg you may start your presentation whenever you’re ready.
Hello everyone it’s a great pleasure to be here today to do this presentation and speak to you on cancer as a chronic disease and I’m going to focus on the past, the present, and the future of cancer Clinical trials to inform the great advances that have occurred in a cancer therapy over the last couple of decades.
We’ll start from acknowledging that cancer is ubiquitous in our society and in the world. In the United States, in an average lifetime, one out of two men will be diagnosed with cancer and one out of three women will be diagnosed with cancer; so we no longer have to do the exercise of asking has cancer affected anyone in your family or you personally, unfortunately it affects all of us in one way or another through our friends and our families. This year approximately 1.7 million patients will be diagnosed with cancer and unfortunately there will still be 600,000 deaths from cancer. The good news is that there are over 16 million survivors of cancer currently in the United States and we’ll talk about the trends of how the survivorship will increase in a bit.
Here are the cancer statistics as collated by the American Cancer Society for our past year. The most common cancers that we see in the United States are breast cancer for men, I’m sorry, for men are prostate cancer, lung cancer, colorectal cancer and bladder cancer. For women breast cancer, lung cancer, colon cancer and uterine cancer. Deaths are different for men and women together. Lung cancer is the most common cause of death, prostate for men, and breast for women follow that and then followed by colorectal in both followed by pancreas in both and we’re seeing an increase in pancreatic cancer which is one of the most lethal forms of cancer still increasing in both the numbers but particularly the deaths in the United States today.
So let’s stop here and do our first poll question and if you will please answer this question we’d like to get your input. Yeah that’s right we’ve got our first poll question for the audience today and audience members can vote live on this poll question the question is which of these two US states represent the highest and lowest numbers of new cancer cases in 2017 respectively. Got four possible combined answers here so is it California in the District of Columbia, Texas and Wyoming, California and Wyoming or Texas and the District of Columbia. So that question again is which of these two US states represent the highest and lowest numbers of new cancer cases in 2017. And it does look like the majority of audience members have voted on this poll today so let’s go ahead and close the poll and take a look at the results. So, 29% answered California and Wyoming, 34% said Texas and Wyoming, 22% answered California and the District of Columbia and just 15% answered Texas and the District of Columbia. So, the correct answer for this question was answer C. So, according to the American Cancer Society the state with the highest number of new cancer cases this year is California at 176,140 new cases and the lowest is Wyoming at 2,780. So, some interesting results there back over to you Dr. Schwartzberg.
Thank you so those results reflect, for the most part, population differences and the fact that California has a huge population as does Texas, but there are also environmental factors. So, literally one state representing 10% of all the cancers that are found in United States each year.
So, let’s expand our horizon beyond the United States and talk about cancer rates mortality around the world. George Clinical is a global CRO and we’re interested in cancer across the globe here are the most common cancer sites in males by country and I think it’s very interesting that you see very specific geographic differences in the types of cancer. So, for example the most common cancer in men in the Western Hemisphere, in Western Europe and in Australia is prostate cancer. Contrast that to Eastern Europe and Asia, where the vast majority of countries, the largest most common cancer is lung cancer with a couple of exceptions and you can see that in Southeast Asia liver cancer is the most common cancer and these and in Africa, there are a variety of different cancers that you see and in West Asia as well. So, here you’re reflecting differences in environmental factors in genomic factors and others but it’s fairly homogeneous.
In women across the globe we see a different pattern we see that breast cancer is the most common cause in across the globe and every continent actually including in the Americas, in much of Africa, in all of Europe, in much of Asia and in Australia and the southeast Pacific. But you can see that lung cancer in China is even in women the most common cause of cancer and remember the United States lung cancer is the most common reason for death in both men and women so this is a critical problem that we see and because smoking has largely reduced, very substantially in Western nations but is still increasing in East Asia including China and India we’re going to see these patterns change; also I’ll point out that cervical cancer for arguably a preventable cancer with an early detection and screening is still the number one cause in India, in large parts of sub-Saharan Africa and in parts of Latin America as well. So, there is work to do here.
The reason that we see these changes is because the causes of cancer vary worldwide. Here are the eight risk factors, which account for 50% of deaths from cancer and that includes lifestyles for example tobacco use and alcohol use, it includes infections like h pylori and hepatitis and it includes diet and exercise, so those who have low fruit and vegetable intake or physical inactivity; interestingly in western society because of lack of exercise and the availability of foods including things like sugary drinks, overweight and obesity is, of these, the one that is increasing in high-income countries and less so in middle and low-income countries and you can see the breakdown there. Again tobacco use is still a huge problem across the globe
It’s really interesting that although we don’t typically think of cancer caused by infectious disease, it actually is and up to five infections account for 20% of the global cancer incidence so this is not as true in the United States but around the world it is and these include Helicobacter pylori, infection of the stomach Epstein Barr virus, papilloma virus which is the proximate cause of cervical cancer which I showed was the most common cause for cervical cancer and hepatitis B and C which is the etiology for liver cancer which is also in high incidence in many parts. So, in certain parts of the world like Africa, 40% of cancers are caused by infections. So, when you start to think in a population approach to cancer and a global approach to cancer one of the most important things we can do is to work on environmental factors and on lifestyle and cultural factors but that still leaves a large amount of cancer that’s not related to these factors.
And you can see here going back to the US what the incidence is of men and women over time in the US, starting back from 1975 to the most current records and you can see there’s been a slight increase in the number of cases of cancer in both men and women it’s about 10% increase over a 35-year period, I’m not exactly sure what that is due to, the spike in male incidence relates to a sensitive screening test, the PSA test, but you can see that that spike disappeared for the most part over time. I want to call your attention to the lower portion of this graph and look at the inflection point in both male and female mortality which began at the beginning of the 1990s. Since 1990, each year we have seen a reduction in mortality from cancer despite the fact that the incidence of cancer is modestly rising and here are those statistics portrayed as if the number of deaths had remained stable over time in terms of the fraction compared to what has happened actually. The blue line shows you where the number of deaths have been through 2012 and the difference between the red and the blue line is the number of deaths that have been averted. So, because of advancements we have averted almost two million deaths in the last twenty years and that’s a fantastic achievement.
Why does that happen? What contributed to the improvement in mortality rate? We’re not if impacting yet the incidence of cancer but we are now substantially and increasingly impacting the mortality rate from cancer.
There are many reasons for that and they’re listed here and there are others but early detection, the use of screening tools to find cancer early before it can spread has contributed to that for men, the PSA tests although not without its critics and concerns about the use of the test and the same is also true for mammograms where there is clear evidence that mammograms have saved lives by screening populations of average risk for cancer. We have over the last couple of decades improved our local control therapies like surgery and radiation therapy those probably are not having a major impact on mortality but they are having a major impact on morbidity and the way that patients function afterwards so a major impact on survivorship by having less invasive surgery and radiation which causes less late complications. A big portion of the improvement of mortality rate is due to the advent of adjuvant systemic therapy giving treatments chemotherapy or anti-hormonal therapy to appropriate patients who are at risk of having micro metastatic disease and curing micro metastatic disease which indisputably occurs in several different types of cancer including breast cancer and colorectal cancer. We’ve had great improvements in metastatic treatment and we no longer think of all cancers once they are advanced and have spread to other parts of the body i.e. stage four, they are no longer a death sentence in most cases, hence the title of the talk cancer as a chronic disease because patients with advanced cancer are living longer often living good quality of lives without impacting their normal activity and patients who have survived cancer are increasingly living normal lives as well. I would also not discount the fact that you have to have access to good care in order to benefit from all the advances that have been made on the clinical aim and so you must have broad access to care.
Now that has a specific concern around the globe because the impact of socioeconomic status has an impact on the cancer burden and on the outcome from cancer. So, if we look at developed countries versus less developed countries the cancer mortality in more developed countries is projected to decrease another 30% in the next 10 or 15 years just like it’s decreased 30% already in the last 25 years. So, the trend continues unabated and the rate is unabated. On the other hand, patients in less developed countries are projected to have their cancer mortality increased by 70% by 2030 and that relates to not only the fact that access to care is compromised and that the quality of care is compromised but the incident in less developed countries particularly as they start to develop a western lifestyle including Western habits like smoking is likely to increase. So, I think we have to be cognizant of the fact that by 2030, 85% of all cancer deaths are going to be occurring in low to middle-income countries and this gives us both opportunities and concern; opportunities to affect those countries by doing certain types of clinical trials there and coming up with strategies that can be broadly applicable to people who have resources which are somewhat constrained. The other thing is that in low and middle income countries there can be cultural impediments to cancer, lack of awareness about cancer and the value of therapy abandonment of therapy because of cultural values and lack of access to curative therapy delay in accurate diagnosis either because the resources are not there to do screening or because there are cultural barriers so we have to work on those as well.
This slide is from a very influential report that was created a few years ago by the Institute of Medicine which describes nicely our current standard of care for the cancer care continuum; how do we think about cancer today and how do we best take care of cancer particularly in high resource countries like the United States and you can follow the continuum from prevention and risk reduction through screening diagnosis treatment survivorship and end-of-life care. And we now transition Cancer Care from the acute care from the time of diagnosis and all the workup that goes into the diagnosis, treatment planning, delivery of the treatment into a chronic care model where some patients remain on treatment for prolonged periods of time, some people are treated intermittently, some people are treated and then are cured and are followed for late effects and toxicity and some people succumb to their cancer and end-of-life care is critical in in those moments to provide palliation.
If we then go back to the prevalence of cancer you can see that it’s rising dramatically in the United States. People with cancer that are living with it and you see or after it you see that we’re at about 16 million people today with that number to over double in the next 20 years and that’s driven in part by the demographics of the baby boomers and if you look at the particular groups here you’ll see that the older groups particularly the 65 to 74 and 75 to 84 year cohorts will be dramatically expanding over the next 20 years. So, one other threat that we have is not having enough practitioners to take care of people who are cancer survivors or are living with cancer as a chronic disease. So, there are workforce concerns as we go forward and as this number expands dramatically because remember cancer is still predominantly a disease of age and once you enter the prime cancer years, if you will, after the age of 65 the incidence goes up as well.
We’ll have more cancer survivors that are alive 15 years or more in 10 years or more and five years or more and you can see in just the next few years that number will approach 18 million people living with cancer almost 10% of the population by a decade from now.
So, how do we get there? Those are great successes. We’ve reduced mortality in the United States by 30% over the last 25 years, we’ve got 16 million cancer survivors, we’re going to double that number in the next 20 years. Why did that really happen? And I would submit that it really happened because we understand the biology of cancer now in a way that was almost unfathomable a few decades ago. We understand at a very high level that the development of an oncogenic state or a tumour that is malignant is a complex process that involves the accumulation of multiple independent mutations and while it may not be directly linear there are clear accumulations of critical so-called driver mutations that cause the cancer phenotype. Those driver mutations lead to deregulation of the complex cellular machinery including deregulation of a variety of cell signalling pathways when those pathways are central to this growth of cell growth and control of cellular processes it’s why each cell in a tissue remains a cell in the tissue and does not tend to grow unregulated or spread into other parts of the body or to not undergo program cell death characteristics of normal cells but characteristics that are lost in cancerous cells.
So, we can think about cancer based on this diagram which has been very useful for cancer clinicians and biologists and translational scientists in way to formulate how to think about cancer. So, there are a number of processes that occur in cancers that are the hallmarks of cancer and each of these can be teased out and each of these can be targeted so it includes things like evading growth suppressors and avoiding immune destruction and activating metastasis and genomic instability and proliferative signalling and you can see here where on the outside of this diagram the kinds of types of drugs that are being developed to target each of these hallmarks of cancer. The good news is that we can explore each of these processes through a variety of Olmec technologies including genomic technologies and proteomics and metabolomics technologies and currently of the ten that are listed on this slide, most of them have drugs available already and those that are in clinical trials are in late clinical trials and we expect to see drugs in those classes. So, we’re already targeting almost all of the hallmarks of cancer, almost all of the critical pathways that a cancer cell uses to usurp the natural machinery of the cell to form a cancer cell that can invade and be a parasite if you will in their host.
So, the war on cancers two greatest successes arguably to date are the understanding of genomics in general and the important pathways underlying cell growth in particular and the understanding of the immune system in a far deeper fashion and importantly the interaction of the immune system with cancer cells.
So, let’s talk about the genomic aspect first and molecular profiling. We’re moving into an era or one could say we are now in right in the middle of an era of personalized or precision cancer care which is abetted by molecular profiling as the emerging standard and the goal here is to tailor the medical treatment to the individual characteristics of each patient’s disease. We now understand that cancers that can look the same under a light microscope can be vastly different in their characteristics in their potential weak spots and they can be lumped into categories that cannot be imagined by looking at traditional histologic diagnosis by pathology. For example, breast cancer can be divided into four or five categories that all look the same under the microscope. We can use therapeutic interventions to anticipate which patients will benefit based on stratifying them molecularly but based on biomarkers and that spares expense and side effect for those who are not going to respond to a particular targeted therapy if they don’t have the target. This concept has been codified as the right patient getting the right drug at the right time in their course. In order to have success for personalized medicine or precision medicine or precision oncology specifically we need to have accurate diagnostic tests that identify patients who will benefit from targeted therapies and I’m happy to report that we have achieved that now and we have very sophisticated tests that allow us to happen the evolution of these tests have occurred extremely rapidly.
It was 50 years from the first description of the DNA structure by Watson and Crick to the first human genome sequence at a cost of a billion dollars to sequence an entire draft human genome. But since 2000, things have been moving very quickly and that has been driven by new generation sequencing technologies now called next-generation sequencing technologies which use massive parallel sequencing in order to do things that were done very slowly just 15 or 20 years ago. So, in rapid order we developed the first cancer genome sequence within ten years and then increased our knowledge to over 500 known cancer genes and we now have thousands of complete cancer genome sequences the Cancer Genome Atlas which was a major big biology project has published now thousands of sequences and multiple omec processing of cancer patients, so we know for each disease state the rough outline of what the different subtypes are. And we are now moving into an era where cancer genomic sequencing is becoming a routine diagnostic.
Now the reason we were able to do that, again, is because the technology has advanced and the cost of the technology has dropped dramatically as shown on this slide comparing the cost of sequencing a genome to the Moore’s Law of computer semiconductors on a chip and it tracked along very nicely until about a decade ago at which point the cost per genome reduction rapidly improved and we’re now down to about $1,000 in raw costs to sequence an entire genome of a human being from 1 billion dollars. Because of this ever-dropping cost of performing broad sequencing the panel sizes that we’re able to do both commercially and in research efforts has been growing dramatically.
At the same time, we’ve been able to identify actionable Molecular targets and we’ve been successful at developing drugs against those targets which yield clinical benefit for patients. One of the first of those was rituximab now 20 years ago approved as a drug and antibody against cd20 which is a molecule found on the surface of B cells and some other cells it’s actually not a malignant oncogenic driver but it is a convenient marker to treat b-cell diseases and it has become basically foundational to the treatment of both malignant and non-malignant b-cell diseases. Trastuzumab was introduced in 1998 for HER2 positive breast cancer, this is a true target that was over expressed in a certain subset of breast cancer patients you cannot tell them by light microscopy you have to use sophisticated techniques of immunohistochemistry or genomics or fluorescent in situ hybridization to detect that subgroup. In that subgroup, monoclonal antibody trastuzumab which inactivates HER2 and the driver signalling of HER2 to create the cancer phenotype was dramatically successful and it was approved first for metastatic breast cancer and now is part and parcel for the treatment of virtually all patients with HER2 positive disease even in the early stages of breast cancer. I’ve had a profound impact and when we’re talking about curing people and saving lives trastuzumab is one of the medicines that have been important there. Another critical medicine was imatinib which is a small molecule receptor tyrosine kinase inhibitor which inhibits the molecular alteration which underlines the disease chronic myelogenous leukemia. This drug was fantastically successful and took a disease which had a median survival of four years to a disease that is now the essence of cancer is a chronic disease. In my own experience every patient I’ve placed on imatinib became available in 2001 continues on either a imatinib or another tyrosine kinase inhibitor with none of them having progressed to acute leukemia which was the terminal event from CML before imatinib was created and we now have over a hundred targeted cancer drugs approved.
The other flipside of it though is the fact that there were 71 cancer drugs approved from the FDA over a 10-year period and most of those up until the most recent era really had fairly modest benefits so the median benefit in progression-free survival was only 2.5 months and the median overall survival was two months. Now in the oncology world 10 or 15 years ago those were seen as successes and I’m happy to report that we’re setting higher bars now and we’re less complacent about the value of new drugs and the value to the patients who need these drugs. So, while it’s true that a median survival that’s improved by two months in a disease we only live six or seven months is a good percentage; it doesn’t translate into a lot more meaningful life so we have to do better as we have now understood the biology better as we’ve been able to create better drugs targeted drugs and as we’ll talk about briefly in a few minutes immune therapy drugs this paradigm is changing and it’s even seeped into the regulatory culture so I think it’s fair to say that the FDA today considering a drug with a two-month survival benefit is going to be much more discriminating than it would have been 20 years ago or even 10 years ago. So, we are holding ourselves the manufacturers the clinical trialists the clinicians and our patients are asking us to do better and I’m happy to report we are doing better we haven’t gotten all the way yet but we are doing better.
So, this is just an example of the new oncology products that were approved in 2015 if you look at this middle column here you’ll see that most of those were precision therapy drugs in other words they were not necessarily empiric and they actually had a specific target in some cases with a companion diagnostic and those typically give better results than drugs that are tested against unselected populations.
I want to spend a couple of minutes using non-small-cell lung cancer as an example of a dramatic change in the way we think about a particular disease.
So, this is the status of non-small-cell lung cancer in 2002, the co-operative group got together and tested four different regimens all of which were based on a platinum backbone with different other agents to use to see if one drug was better than the other and this was the state-of-the-art in 2002 as you can see from this curve there was really no difference in any of these drugs; and if you look at the median survival here it’s about five to six months, very lethal disease advanced non-small-cell lung cancer in 2002. Only 10% of patients living two years. I’ve already told you that the incidence of lung cancer it’s the number one disease around many countries of the world so this does not go well for patients who are diagnosed globally with non-small-cell lung cancer. But let me go back there and let before we go on to this let’s do a just do a survey question.
Yeah that’s right this is our second and final poll question for the audience today as with the first poll question you can vote live on this question at any time so the poll is: The American Cancer Society estimates deaths from lung cancer in the United States in 2017 will be; got four possible responses here so is it: 257,580; 155,870; 175,350; or 215,580. Again, that question is: The American Cancer Society estimates deaths from lung cancer in the United States in 2017 will be. So, it does look like the majority of our audience members have voted on the poll here today so I’m going to go ahead and share those results with everyone. So 50% half of the audience answered 215,580, 22% said 175,350, 14% 155,870 and another 14% answered 257,580. So, the correct answer for this poll was answer B, so there will be about 155, 870 deaths from lung cancer this year with 84,590 in men and 71,280 in women. So, that concludes our final poll back over to you Dr. Schwartzberg.
Thank you so just a note on the poll question a quarter of deaths in the United States due to lung cancer it’s the most common cause of death in both men and women; although, in women breast cancer is more common. So, this is a serious problem here’s the state of the art of lung cancer in 2017. We no longer look at it as a single disease, in fact almost surprisingly what we’ve realized over the last five years or so is that lung cancer is a collection of very different diseases with very different driver mutations that all potentially can be targetable and as you see in this pie chart we have about ten different groups so far that account for two-thirds of lung cancer, non-small cell lung cancer here of course histologies and you can see that two-thirds of these are potentially targetable now unfortunately KRAS, which is the most common mutation that is seen in lung cancer is not currently druggable, if you will, we don’t have drugs that have been created to target this directly. But the good news is all the others including EGFR ALK, HER2, BRAF etc. are all targetable and we now have a multitude of drugs that target each of those mutations and this doesn’t even consider the number of patients that are PDL1 expressing, which makes lung cancer sensitive to treatment with anti-immune therapy which I’ll talk about in a minute.
So, here are where we’ve come in 15 years from lung cancer. We started with platinum doublets and before platinum doublets the debate raged whether we should give patients chemotherapy at all for lung cancer because they didn’t tolerate it very well and it didn’t have much impact on survival. By 2000 we agreed somewhat reluctantly that platinum doublet visit something although it wasn’t too great and since then we’ve developed drugs like Gefitnib and EGFR inhibitor and anti-angiogenic Bevacizumab and we’ve learned that EGFR mutations are the target of TKIs like Gefitnib and others and so now we have a target, we have therapies the first ALK inhibitor was approved in 2011. It was to my knowledge the fastest development of any drug less than two years from discovery of the drug to approval by the FDA, second and third-generation EGFR drugs are on the market now like Afatinib and in the last couple of years we’ve begun to understand the mechanisms of resistance to EGFR inhibitors including primarily a one specific mutational change in the EGFR gene the T790M and we now have ways of testing for T790M in the blood and we have third generation drugs that target T790M specifically.
So, we have come a long way and the way we made that progress was through clinical trials and I’m going to focus on two types of clinical trials. First the Umbrella trial, which is once you know that the where the mutations are in a single type of cancer you can design a clinical trial to multiply interrogate for different mutations and different drugs in a cost-effective and efficient manner.
So, one of those studies was called the battle schema, this umbrella protocol referring to the fact that it’s a single disease but under the umbrella were looking at different subtypes of the disease that have different molecular characteristics and we can test different drugs based on the characteristics. And many of these studies are also adaptive designs which I don’t have time to go into but use novel biostatistics to assign bins, patients to bin, and to borrow from bins to make the clinical trial design even more efficient
Battle, like most umbrella studies had a very robust biomarker discovery platform including a variety of different technologies to understand the biology in the context of this clinical trial that was also testing drugs. So, it not only looked at the tomb of genetic profiling but it also looked at genomic expression or RNA sequencing and protein expression, blood based markers and germline because we’re increasingly seeing that hereditary genes are being found in what appeared to be sporadic cancers in the past and this area is changing very rapidly as well. When you look at all of the different technologies together that’s the way we’re going to ultimately achieve personalized or precision oncology. So, currently today we’re focused on a genomic profiling which has been very rich in the data that we obtained from it but it’s not the end of the story it’s really the beginning of the story and increasingly as we get more facile and the technology improves so that even in embedded tissues that are that don’t have to be fresh tissues we can interrogate for proteins, we can interrogate for pathways not just individual genomic alterations or individual protein or RNA alterations. All of these technologies are in the very near future if they’re not here today.
So, if we now look at the success story of non-small cell lung cancer this is the list of drugs that have been approved in two years. We went from no new drugs over a decade to literally having over ten new drugs in just two years for one disease; and some of these drugs are very specific to mutations other of them like Pembrolizumab is we’re going to talk about briefly about immune therapies that are broadly applicable.
This testing has now become standard of care. This is the NCCN guidelines they’ve been updated since version two they’ve been updated several times halfway through 2017 but I call your attention to the fact that the guidelines mandate testing in broad molecular profiling. So, we went from in just a few years, from testing individual molecular biomarkers for lung cancer to NCCN basically recommending do a broad panel do next-generation sequencing it’s the most efficient way to get all of those mutations and then make a decision on how you should treat the patient. So, this has become standard of care in the first-line setting of non-small cell lung cancer.
So, in the last few minutes I want to talk about the fact that cancer is not just about the tumor but also the interaction with the micro environment and the recognition of the role of the immune system in controlling cancer.
So, we know our immune systems are very potent so why do people get cancer? Because cancer can look like “self”, we don’t normally react against ourselves and cancers have developed evolutionary characteristics to allow them to be detected as self and not as an invader the way bacteria or viruses are to our immune system; and tumors can also actively defeat the host immune response. So, you can think about cancers in a host, a person, as always being this struggle between the immune system trying to control it and the cancer trying to grow and defeating or neutralizing or turning off the immune system and that’s our current understanding is that this is a dynamic process and cancers can reach an equilibrium with the immune system because of certain factors that the cancers have developed.
So, we understand multiple mechanisms now and the strategy is to liberate the underlying and the cancer immune responses and the first group of drugs that have been developed are called immune checkpoint inhibitors. These weren’t even in the picture in 2008.
And here are the first two classes of immune checkpoint inhibitors: the CTLA-4 inhibitors and the PD-1/PD-L1 checkpoint inhibitors. These are different checkpoints in a very complex immune system, which I won’t go into detail except to say that CTLA-4 works on the priming phase when there are antigen presentation by a dendritic cell to a t-cell to prime that t-cell to eventually become a cancer killing cell and then the effector and that effector phase, which is when you have cytotoxic t-cells that are directly facing a cancer cell and are trying to kill it, the effect in the effector phase the cytotoxic t-cell can be turned off by the development of a ligand called PD-1 interacting with PD-L1 and this interaction causes a break on the immune system the break can be released by developing drugs antibodies against either PD-1 or PD-L1 and both of these have been developed and both of these are on the market, there are at least five drugs that are now approved over the last two to three years which are PD-1s or PD-L1 inhibitors is at least 15 others in active development.
This is how well these drugs work, this is the first of the class Ipilimumab a CTLA-4 drug and metastatic melanoma showing a durable overall survival of a disease that was quite malignant quite vigilant with lethality here with the inactive control arm here with virtually all patients succumbing to their disease by 2 to 3 years we now have a tail of patients with about 20% of patients receiving Ipilimumab, now going on 10 years this shows out to almost five years but we now have 10 year data that suggests that those patients are in unsustained remission for 10 years with a previously fatal disease very dramatic results.
In more common cancers like non-small-cell lung cancer here in the squamous cell cohort, Nivolumab, one of the PD-1 inhibitors versus the standard chemotherapy doubling of the overall survival rate in the second line.
And then more recently the use of Pembrolizumab, another PD-1 versus chemotherapy in the first line setting so these are in patients who typically did not have a molecular alteration the 50% of done have a targetable alteration and you can see here that the 12-month survival is 50% higher for the patients who were treated with Pembrolizumab, which is not only more effective but also less toxic.
So, things are changing very quickly. So, what’s the future of clinical trials? We talked about umbrella trials for molecularly targeted trials; basket trials have become very important and we have a large number of basket trials. Basket trials have built on the concept that if you evaluate patients for genomic alterations you will find actionable mutations in many of them. This is the experience of MD Anderson, single institution, large experience for patients that underwent molecular profiling. About 40% of them had potentially actionable mutations at the time the study was done a few years ago, 11% of them went on to trials that were genotyped or required mutations and a few of them went on to other types of trials as well. So, overall about a quarter of patients went on to trial with the appropriate molecular genomic alterations at that time.
More recently we have a broad NCI sponsored trial called the Match study which has now enrolled about 6,000 patients – of those about 15% at a gene old abnormality matching and available treatment arm and we’re evaluated and right now about 10% of them have actually enrolled on a treatment. So, these numbers are snapshots but it gives you an idea that as we start to move to an era where we’re doing routine molecular profiling, increasing number of patients will be eligible for treatment either on clinical trial or have a particular agent available for them that is approved for their disease or for another disease.
The American Society of Clinical Oncology has rolled out a registry study called taper which provides access for patients to drugs who have been molecularly profiled; and this study is now taking off and will allow for any drug that’s on the market from these companies and others that are engaging in this trial, to allow multiple end of one studies and to aggregate the data to see if the promise of molecular targeted therapy actually impacts patient outcome and we await that.
So, this is from a publication in cell earlier this year and you can see that currently we think that a majority of cancers will have a biomarker that can be detected with a particular drug that will potentially impact that disease. It may be as high as 60% in breast cancer in the future or 80% in thyroid cancer and higher in melanoma; the circles are the ones that we already have targeted agents for. So, we have a lot of work to do, we don’t have them yet in prostate cancer or pancreatic cancer or hepatocellular cancer, liver cancer which I mentioned are big concerns worldwide but they will come
So, in the end we’ll move to this kind of concept where we’re doing omic profiling, we interpret the data, we make a management decision if the patient becomes resistant, we’ll do another biopsy or do a liquid biopsy and we’ll go through an iterative process where next-generation drugs are added to the armamentarium we have and we will increasingly convert cancer into a chronic disease.
I will mention that the immune therapy arena is very very active; there are over 800 trials of combinations of all these particular potential checkpoint inhibitors in various combinations that will likely yield fruit in the future as well.
And not only do we have immune checkpoint inhibitors but we have CAR-T cells, cellular therapy that are coming as well, as well as other immune therapy types of drugs
So, we have challenges moving forward we have unmet needs, technology will help to solve those problems.
I will just mention before I hand it over for a few minutes to Sean to finish that George Clinical is poised to facilitate the next generation of cancer clinical trials because of our deep clinical knowledge, the number of scientists and clinicians that are working with George, the global reach our absenting operational staff, the extensive experience around the world and our relationship with academia as a subsidiary of The George Institute, which is a leading academic enterprise that’s working to decrease the burden of cancer and other chronic diseases around the world.
So now let me turn it over to Sean Hart our managing director for George Clinical.
Wonderful thank you very much for that insightful presentation I just think because of our time constraints here we’re going to head straight into the Q&A session for today’s webinar. So, if any attendees today have any questions for Dr. Schwartzberg, please feel free to submit them through that questions chat box. We have received a few so let’s go ahead and get started with those.
So, the first question: How do you manage the rapidly changing standard of care when doing an RCT needing a sixth standard of care and how does it happen?
So, this is one of the challenges that is ongoing in cancer clinical trial development because as I’ve shown you, I hope, the standard of care is changing dramatically and quickly so this is one of the areas I think that that as companies that are developing drugs are thinking about this that having expertise from CROs and other consultants who are tuned in to what the standard of care is today and trying to figure out where the puck is going to be tomorrow so to speak is really important because the failure in my experience of clinical trials sometimes is not the experimental arm where it’s very novel but if the standard of care arm changes during the course of a study, then the study does not enrol the patients in a timely fashion and can be in danger from that.
Great thanks for that. I think we have time for one more question here:
Can you list some of the upcoming advances we expect to see in the next couple of years?
Yeah so as I alluded to, we are definitely going to see more targeted therapies. We’re moving into an era of liquid biopsy it’s hard to read biopsy patients, we do understand that there’s a problem with tumor heterogeneity with biomarkers and that different clones will emerge under the selective pressure of a targeted therapy when you have a specific target that’s a driver target and we already have several drugs that have been approved to overcome that and it’s based on either having repeat biopsy; so we have to understand the temporal nature of the cancer at any given time through the use of cancerous tissue including liquid biopsies. So, we’re going to see more generations of drugs we’re going to see disease agnostic drugs and those have already been this year has been a bellwether year, we have: Pembrolizumab, which was approved for MSI high or mismatch repair deficiency in any cancer type by the FDA a couple of months ago and we also saw encouraging results for rare mutations where that cut across different diseases with very high response rates. Hence the need to molecularly profile ever broader in order to capture these rare event mutations across different cancer types; so, that’s one on the immune therapy side we will definitely see combinations coming to the fore, we don’t know yet which ones but there are 800 trials ongoing it’s likely that some of those combinations will be able to be combined in full doses that will improve upon already a nice foundational response and benefit rate from the PD-1 PD-L1 drugs already.
Wonderful well thank you very much for those answers. We have now reached the end of the question and answer portion of this webinar. If your question wasn’t attended to during the Q&A session, the team from George Clinical will do their best to follow up with you after the webinar. Thank you everyone for participating in today’s conference.
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