Accelerating Innovation: Oncology Translational Research

so in the eight-year period of time I spent two years as a medical oncology fellow here at UCSF and while I was a second-year fellow I obtained a master’s degree in epidemiology and biostatistics I spent two years at the Uganda Cancer Institute studying kaposi sarcoma doing my own SAS programming and trying to figure out how to do clinical research I spent two years as what my parents call a real doctor as a community oncologist taking care of patients and then I spent two years learning from some of the greats in traditional cancer chemotherapy at bristol-myers squibb about what an IND and an NDA actually meant regulatory science thinking about working with the Food and Drug Administration writing a product label drug safety so again in retrospect and I didn’t realize this when I moved back to San Francisco to work at Genentech I would submit that I had had a fantastic experience getting ready to be an expert in translational science and that wasn’t purposeful that was accidental but they do say that something about a prepared mind so in my talk today I’d like to speak about the future of translational research at UCSF and I tell that story about my journey to genentech in the hopes that it might make you think a little bit about at UCSF what do we need to do to make more individuals prepared to make that kind of a difference and to be experts at an area that is somewhat hard to put your fingers on what does it take to prepare people to be experts in translational research so in order to do this justice I want to take a look back at my experience in product development in oncology and talk about a problem statement that I think we have but let’s start out with the good news so I would submit two things first of all that the finish line not the finish line but the goal in product development should be Food and Drug Administration approval and I know there are people who think getting a product into clinical trials are moving into Phase two or moving into phase 3 can be or should be a goal but my goal has always been FDA approval and commercialization of a product because I think that that allows for a product to get to the greatest number of patients and potentially have the greatest good for society so if you will just accept that that definition is reasonable if that’s your goal then then I would say that the years between 1997 and 2001 was one of the most amazing times in oncology that I’ve seen in my life then I want to talk about the state of cancer research today and a little bit of my thinking about what we could do at UCSF to contribute to someone giving a talk like this a decade from now saying what would make 97 to 2001 pale in comparison to the decade 2010 to 2020 so in my short experience as an oncologist I think these five years in terms of product approvals again that period of time was one of the best ever in oncology Rituxan was approved by the Food and Drug Administration in 1997 Herceptin in 98 and Gleevec in 2001 and for me these are three products that are worth thinking about how do you make products like that become available for patients so when I pushed myself to say what I think was so good about these three products and why they for me to find a period of time that was so special in cancer product development here are some of the attributes that I think made me think they were so good so special first of all a major unmet need so these products each of them came into a treatment area that was not just somewhat met but truly unmet that there wasn’t something that you could tell patients that you had for

them biomarker driven patient selection particularly for Herceptin was unique and and at that time unprecedented and it brought very special challenges but outcomes that were much better than we had expected I think good looks like extending survival it is great to stall a tumor it can help a patient if you can slow a tumor or shrink a tumor and not markedly decrease the patient’s quality of life but extending survival for me is part of what very good looks like and well tolerated when I first started working on Herceptin at Genentech one of the amazing things was having moved from having spent a couple of years working on paclitaxel which many in this audience know doesn’t just make you lose all your hair on your head but your eyebrows and eyelashes and that experience of patients and their describing to me what it was like never left me so having a medicine that could be powerful and has side effects very important side effects but a very different impact on patients quality of life I think is part of what good looks like for me so i know that this audience probably knows quite a bit about Herceptin so i’m going to start on my description of what good looks like with Rituxan the first monoclonal antibody approved in the United States for the treatment of cancer rituxan truly was a new and groundbreaking approach to treatment in that it was able to harness the body’s immune system and one of the most amazing things about developing this antibody approach to lymphoma was something that again taught me a lot one of the aspects of product development that I always enjoyed was product safety and one day when we were developing Rituxan for lymphoma one of the product safety experts at Genentech came to my office and said one of our patients has experienced tumor lysis syndrome we got a report of tumor lysis syndrome in a patient with non-hodgkins lymphoma and a high level of circulating malignant lymphoma cells and the patient had a very classic tumor lysis syndrome rapid breakdown of tumor cells they had had 90,000 circulating malignant lymphocytes and the next morning they had 10,000 and they were in renal failure and requiring dialysis and I asked was the patient on any chemotherapy and the answer was no they received single agent rituximab or Rituxan and I had a discussion with the drug safety expert on whether we thought that this was due to the Rituxan therapy and is certainly seen related and before that moment I personally underestimated the power of treating a cancer with a naked unarmed antibody and how much tumor cell killing could ensue because at the time in the 90s we often described antibody therapy as kinder gentler therapy well there was nothing kind or gentle about causing tumor lysis syndrome so a quite a remarkable experience to see something that was that powerful with a naked antibody and then rituxan was special because of its rapid approval and launch the pivotal trial for Rituxan had 166 patients sorry Deb it was uncontrolled you’ll have to forgive that it was uncontrolled because the standard therapy for non-hodgkins lymphoma at the time was watching wait so that was standard to avoid the complications of not very effective chemotherapy so the total number of patients submitted to FDA was just over 300 and the pivotal trial had 166 patients so before Rituxan was approved aggressive non-hodgkin’s lymphoma was curable with chemotherapy in a percentage of patients but after there was increased survival demonstrated among patients with aggressive lymphoma in a randomized comparative trial by 23% the cure rate significantly increased and one of the most interesting aspects that still under study is this possibility of turning cancer into a chronic disease coming back in and having repeated doses of the antibody to keep the patient in remission and again because of the absence of rapid emergence of resistance

and the tolerability it was possible to even discuss coming in every six months for repeated doses of antibody so in many ways for me thinking about the power of monoclonal antibodies and what’s possible for patients with lymphoma there was before Rituxan and there was after Rituxan it changed many of our concepts of what we would get with this type of therapy now those concepts changed even more dramatically when less than one year later Herceptin was approved for her2-positive metastatic breast cancer and having just heard the tail end of the last talk I don’t need to tell this audience how important personalized medicine is and targeting a specific mutation is but I will tell you that having practiced in the community when I came to work on Herceptin I had had conversations with patients that sounded like you have an overexpression of this pro that we know from the work of Dennis Slamon and others decreases your expected survival from an average of seven years and her2 negative to about three years and her2 positive and I had no remedy for that the outcome of that knowledge was only to make the patient and me more nervous more anxious about their outcomes and their eventual fate and so for me to be able to work on a product that was the answer to the question what do we do now when you know that you have a prognostic marker was really quite dramatic Herceptin was the first product ever launched with a companion diagnostic and it took an enormous amount of scrambling the initial dokko test was late in coming we had a test that could only be used in the lab not available for commercialization not scalable and in a company that had never had a diagnostic approved we needed to work with that aspect of FDA and we did it in a very MacGyver like way in our spare time so the the rapid FDA approval was due to a large unmet need and patient advocate demands and her septum was also and I know this was part of the experience at UCSF with patient advocacy her septum was the first product that I experienced in oncology where patient advocates not only drove much of the program but interacted in ways that initially were incredibly difficult and ended up being extremely important with the company with FDA and with most importantly the patient community in her septons approval so before there was no treatment options specific to her to positive breast cancer and it was a rapid death sentence for most women and after with the adjuvant data about a twenty percent difference in disease-free survival at five years and reduced the risk of the cancer returning by fifty two percent and three years after more than 12,000 patients were studied in adjuvant therapy eighty-five percent of the patients had no tumor recurrence for this most difficult to treat form of breast cancer so again for me the definition of good is completely changed the field and how we thought about treating women with this form of breast cancer now Gleevec is so important it was on the cover of Time magazine and it really was the perfect storm of discovery advocacy and commitment with a fast FDA approval and a phenomenal success rate I had a conversation with someone who was thinking about asking Kareem abdul-jabbar to do some advocacy on behalf of the University of California because we’re all trying to get the state to give us more money and the individual who was talking to me said boy I would love to get cream abdul-jabbar in Sacramento in front of our legislators to talk about how important higher education is in this state but you know he has leukemia now and and I got a smile on my face and I said no no he doesn’t have leukemia he has CML he should be fine and I I think that my definition of good is that that if you heard about someone with CML 15 years ago you would have the impression oh you know this is really serious and rapidly life-threatening in adult leukemia but CML treatment was transformed so before gleevec only thirty percent of patients with CML survived five years after diagnosis and treatments had serious side effects after there’s a complete hematologic response in ninety-eight percent of patients and nearly a ninety percent five-year survival rate in patients this is what we should be doing these are the kinds of outcomes we should strive for in oncology so where are we today I

remember telling someone after her septum was approved we’re going to do this all the time every year we’ll have one of these so you know now that if you want a stock tip or a prediction of the future don’t check with me cancer research today is too slow too expensive too inefficient and too uncertain I went back and looked for a talk I gave about the timetable for bevacizumab Avastin and I tracked it back to the idea which might not be fair but the idea the concept of anti-angiogenesis as first published by Judah Folkman in the new england journal of medicine that was 1971 so 26 years from concept to to treatment and I thought well maybe this is just historical i’m looking back at something that happened in the 70s what about something new like telomerase Liz Blackburn and her co-workers topic that just was awarded a Nobel Prize well the identification of telomerase was Christmas 1984 and I think the clinical trials are in phase two today so when I said okay maybe I’m just looking too far back I don’t think it was looking too far back that’s still what we’re seeing from identification of a potential target to again my benchmark approval so that these products can be available for society it’s too slow cancer drugs are too expensive and the media covers this in cost of cancer drugs to force hard decisions the unbearable cost of living rising drug prices hard to swallow costly cancer drug offers hope but also a dilemma so if we want to change how cancer patients are treated we need to have access patients need to be able to afford and to receive these products but I don’t want to be pessimistic I think there’s glimmers of hope and I picked four areas that are under study now is the examples by pulling several people on where are the next magnificent drugs where the next products that are going to change cancer now I’m not mentioning some that are already approved that are under study that with biomarkers outcomes may change or things may improve in the future but I think products like b-raf inhibition for selected melanomas is exceptionally exciting I think that this this Avenue is both exciting and has the possibility to change therapy for as many as sixty percent of patients with melanoma and eight percent of patients with solid tumors the systemic Hedgehog inhibitor for basal cell carcinoma and medulloblastoma is another targeted therapy that I think is is nearly like insulin and diabetes the role of the hedgehog pathway in basal cell carcinoma is so seminal that it’s mutation leads to gorlin syndrome a genetic abnormality that causes congenital basal cell carcinoma so it’s a fundamental driver of this malignancy and some types of medulloblastoma the alch inhibitor for patients with selected lung cancers a very narrow group of patients only about four to five percent but it again appears to be a potentially perfect remedy for this type of lung cancer and and last but certainly not least the parp inhibitors for selected triple negative breast cancers and potentially ovarian cancers as well I think these are the kinds of products that give me optimism that this approach to cancer therapy and I would submit the speed along with that may in fact be changing so what about the future what can we do at UCSF and what can be our role in thinking about that Platinum era the next decade in product development for cancer so I have some metrics for success should be faster should be cheaper and I think more than either of those should be more predictable it isn’t just a problem that on one of 10 or perhaps even less than that products that go into clinical trials become approved therapies the problem is we don’t know which one in ten will succeed in the trials we need to understand earlier and with greater confidence what the best ideas are so that we can focus our attention on those best ideas here’s one of the reasons why

we need to do a better job this is from a list of products that Pharma put together total cancer drugs in development 861 think about the time effort patient time and energy investigator time and energy and money for to study appropriately 861 potential new therapies in cancer it’s overwhelming it’s also exciting there’s a lot that can be done so with this in mind with so much substrate so much great biology and wanting us to be better than ever before I had four different areas that I’ve listed on this slide of how I think we could get to that platinum era in cancer product development and it starts really with discovery many of the products that I just described have something in common and that is they’re driven primarily by a single pathway there there is uncle gene addiction there is something that we can turn off and make a difference I think we should be incredibly dogged even if it’s a narrow group of patients to uncover those cancers that are driven primarily by a single pathway but I don’t think it ends there most common cancers are complex and there are multiple signals but we need technical breakthroughs to enable development we need to understand how to test more one product at a time and to do so efficiently in a way that gives us clear signals we need better surrogates I think survival is the best outcome measure but if survival is extended I’m not willing to wait beyond our lifetimes to know the answer and more importantly patience shouldn’t wait for us to find the answers we need to understand particularly what products deserve survival trials with better surrogates for activity earlier on very importantly safety and comparative effectiveness there’s no reason in today’s world with electronic medical records and a newer informational technology that we shouldn’t know what happens to every patient we need both outcomes and molecular correlates on every cancer patient think of the amount of information that we know nothing about on patient outcomes and I think we should be dogged in asking those questions there is so much information on safety efficacy potential good and potential harm and we need to know that and then access we need to make sure the right product reaches the right patient at the right time and they can afford it and so this efficiency and understanding when a product is best used in an individual patient is essential that’s a big list but I am optimistic as I mentioned my training at UCSF included a two-year sojourn to East Africa in Uganda Thea ganda Cancer Institute and my expertise was in Kappa si sarcoma and so I had a quite a remarkable experience as did many of my peers in training at a period of time when the age-adjusted death rate of HIV looked like that but I happily also experienced that think of think of what that would look like if that happened in cancer that would really be sweet you wouldn’t have to look real hard to see that so I think what happened in HIV was quite remarkable no one’s declaring victory we still need a vaccine it still needs to be much better but that kind of inflection seemed to me in no small part driven by the availability of a surrogate HIV viral load an outcome measure that was readily available could be measured as early as phase 1 or pre clinically that said this is going to be the right product for this patient and during the course of patient therapy when the virus becomes resistant it was measurable and one could adjust so not only did survival change but the number of product launches also skyrocketed so

that there was a menu of choices and patients could have measurements and swap out and if we had the ability to measure quickly in patients their outcome and adjust as was done with the HIV analogy I think we’re far more likely to see that wonderful plummet in death rates as was experienced with HIV so how does UCSF fit into this I think we have incredible opportunities at UCSF i mentioned relentlessly uncovering the key drivers of cancer I think that’s where UCSF shines this is a place where great science has always been done but I want to come back to translation I think we should push ourselves not only to have the best basic science but to be leaders in novel approaches to translate those drivers into new therapies some of what’s going on in the breast cancer program for me is what good looks like in terms of challenging ourselves what are the trial approaches what is the inner vation in how we test products and patients to make it move more quickly and to become more educated and informed about what happens in patients and their outcomes we should push more translation from the clinic to the lab every patient teaches us something and the best thing about clinical trials is you get to know so much if you’re just paying attention patients teach us all the time we just have to be paying attention looking for it and seeing if a group of patients has a different outcome and asking ourselves why they have a different outcome and let me come back to where I started with my own experience we need as a university to help the world define a set of skills it’s a technical expertise and a career path that allows brilliant trainees to show us the way to be more efficient in translation I don’t know the answer to the questions I’m posing I think they’re very hard questions but I know someone can figure out better ways for us to ask questions about how we best help cancer patients and that career path combined with the kind of basic science we do i think is enabling of something that is far better than anything any of us have seen in our careers so I’m going to end with what I think the goal is and I’ll come back to the conversation I used to have with patients as a clinical oncologist for me the goal is that any patient who hears from their caregiver you have cancer expects to live a meaningful life expects to have the conversation here’s the kind of cancer you have and in fact we have something for that so that’s I think what we should push ourselves to do for as many cancer patients as possible and I think UCSF has an unprecedented opportunity given the skills and talent and young talented trainees that we of at ucsf to contribute so thank you for listening and I hope you have a great symposium you