Transcription:
ASCO 2019 Key Highlights

Dr. John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast: Conversations About New Developments in Medicine, Cancer Care and Research. I’m your host Dr. John Leonard and today we will be reviewing some of the latest updates from the 2019 American Society of Clinical Oncology or ASCO Annual Meeting. ASCO is the world’s leading organization for physicians and oncology professionals who care for people with cancer. Each year, ASCO’s annual meeting brings together over 40,000 oncology professionals from around the world to discuss state-of-the-art treatment modalities, new therapies and ongoing controversies in the field. And beyond that, there is participation from patient advocates and patient advocacy groups as well really working towards collectively fighting against cancer.

So, my guest today is Dr. Manish Shah who is Director of the Gastrointestinal Oncology Program and Chief of the Solid Tumor Service at Weill Cornell Medicine and New York Presbyterian Hospital. Together, Dr. Shah and I will review some of the most significant research findings from the 2019 ASCO Meeting. Dr. Shah will discuss updates in solid tumor oncology, and I’ll cover updates in the field of hematologic malignancies. So, Manish, it’s great to have you here today. Thanks for joining us.

Manish Shah, MD (Guest): Thanks for having me.

Host: And I really could think of few people better to sit and chat a bit about some of the things that have happened at ASCO.  I want to start with there were some important plenary sessions and for those of you who are not used to scientific meetings; there are posters where work is presented kind of informally where you can come and talk to the authors.

There are oral presentations and then the best or the most high-impact presentations are called the plenary sessions where basically everything else at the meeting comes to a halt and more or less everybody gathers in one room and hears about the most important practice changing things and so a couple of those presentations related to solid tumors. So, I’m going to ask you first about pancreatic cancer. And that’s really an area that has been very challenging to take forward, but there were some important findings presented at the meeting. So, if you could take us through that.

Dr. Shah: Sure. So, this was a very important abstract that was presented at the plenary session. It was a study evaluating olaparib in patients who had a BRCA 1 or 2 mutation in pancreatic cancer. So, as you know pancreatic cancer is a relatively uncommon gastrointestinal cancer. What has really emerged over the last several years is that about one in eight people with pancreatic cancer will have a mutation in their germ line that might be associated with the disease. And a common mutation is a BRCA 1 or 2 mutation which is also known as the breast cancer associated gene.

So, it turns out that there are patients with family histories of pancreatic cancer that also carry the BRCA 1 and 2 gene. Importantly is that in another solid tumor breast cancer and in ovarian cancer, a class of drugs called the PARP inhibitor, P-A-R-P inhibitor, olaparib is one of them, can have effectiveness in tumors that have a BRCA mutation.

So, to distill that down a little bit; BRCA in important in repairing DNA damage and if you inhibit PARP, you actually increase the effects of tumors that have a deficiency in this pathway. So, it’s like a way to target specifically, a mutation that is characteristic of these types of tumors.

So, in pancreatic cancer, the study was kind of a novel study design where patients received a combination chemotherapy regimen for about four months and then if they didn’t progress, they were then randomized to receive either olaparib or placebo. And it was a relatively small study in terms of the number of people that were randomized but it was important because it showed that people who received olaparib had a much better time to progression meaning that their disease was controlled for a much longer time with the drug versus not having the drug. And it actually made a big splash.

I think for us as clinicians and also for a lot of out patients; what we realize is that genomic testing for pancreatic cancer is an important thing. And in fact, it’s now part of the guidelines for both ASCO and NCCN so, if you are a patient with pancreatic cancer, or if you have a relative with pancreatic cancer; getting genomic testing is an important thing because it may impact your care. So, that was one of the key findings of this study.

Perhaps a little bit disappointing though, was that patients who received olaparib versus not, there’s no difference in overall survival in this cohort. And what it suggests is that patients who progressed without receiving olaparib, they then went on to receive more treatment and the disease was controlled for a while. So, I think an important abstract is it shows us that testing is important. There is efficacy of this drug, but we still have work to do to improve survival.

Host: So, where do you think it’s going to go? Will there be combinations. Will there be subsets of patients that might get this? Is everybody going to get this or because there’s not an overall survival benefit; perhaps a little less clear. What’s your kind of vision of where that will go?

Dr. Shah: Yeah, I’m not sure. I think that there will try to be an approval for the drug, but right now it’s not approved in pancreatic cancer. It’s only approved in breast cancer and ovarian cancer. The challenge with this drug, this class of drugs is that it has a lot of toxicity. So, you can’t really combine it with chemotherapy. You have to give it by itself. So, I think that there is – the study did show that there is activity and we have to find the right place to use it where it can impact on survival.

One of the ideas that was heard of mulling around as ASCO was that we should use it in the adjuvant setting where we are trying to treat microscopic disease, it’s a pill, it’s relatively well tolerated by itself and it does show activity in this setting. So, that might be a way where this could go in the future.

Host: Okay. That certainly got a lot of attention I think at the meeting again by definition being at the plenary session and again to touch on your point around BRCA testing; so basically every patient with pancreatic cancer and I presume family members as well should have genetic testing for BRCA not only for pancreatic cancer risk, but other cancers associated with this mutation. Is that kind of the general guidance at this point?

Dr. Shah: Yeah. so, the guidance is actually if patients with pancreatic cancer should get tested and if they do test positive for having the mutation; then the family members can get tested afterwards. If the patients don’t have the mutation, then there probably isn’t a need to test the family members yet. But that is the take home point is that genomic testing should be done for patients with pancreatic cancer. There’s about a one in eight chance that you will find something either a BRCA mutation or other mutation that might impact the care that you get down the line. And so, it’s important not only for yourself, as having pancreatic cancer and how it could affect your care; but it’s also important for your family members because there are screening programs as well to help reduce the risk.

Host: Great. So, we’ll come back to GI cancers a little bit more later. I know that’s your area of focus, but I wanted to next jump to breast cancer. There was an important study focused on a relatively new agent in advanced breast cancer that I think also was at the plenary session if I’m not mistaken. So.

Dr. Shah: Yeah, that’s right Dr. Leonard. So, it was the MONALEESA study. This was a study in women who have hormone receptor positive breast cancer, premenopausal and the study was endocrine therapy with or without a drug called ribociclib. That’s a new drug. It inhibits the CDK4 and 6 pathway which is a cell cycle check point inhibitor.  And this was a study examining using it earlier in the care of patients with breast cancer.

So, the way that we treat breast cancer normally is that we – for patients who have hormone receptor positivity; we try to use antihormonal agents, ER inhibitors, estrogen receptor inhibitors specifically and we save chemotherapy for later. And this was a study looking at combining hormonal therapy with a CDK4 or 6 inhibitor to see if we can have benefit. And in fact, the combination was much better than the hormonal therapy by itself. So, it suggests that treating early with a combination therapy, your best treatment actually improves survival. And that’s quite amazing because in breast cancer, as you know, it tends to be a more of a longer lasting disease than GI cancers and the main endpoint for approval in breast cancer is actually not overall survival but progression free survival. But this study did improve overall survival.

Host: So, this is a drug that I think really this study is changing standards of care in patients going forward because of the overall survival benefit pretty clearly will get this combination going forward, is that what you would expect?

Dr. Shah: Yes. Yeah definitely. So, the drug is approved in breast cancer and the research is trying to figure out when’s the best time to use it. And what we are learning is that if we bring the drug earlier, we can have much more benefit. And that’s actually a key finding.

Host: Great. So, I want to jump into the heme malignancies area and talk about one study in chronic lymphocytic leukemia or CLL which is the most common subtype of leukemia. And we really, historically CLL has been treated with chemotherapy based treatments or chemotherapy plus antibody based treatments a drug called rituximab or more recently a drug called obinutuzumab. So, over the last several years, CLL treatment has really changed and a type of drug called a Bruton’s paracene kinase inhibitor or ibrutinib has been approved first in relapsed and refractory patients and more recently upfront as initial treatment and so ibrutinib has come on to the scene and is really largely I think changed CLL management in many situations where people are getting treated with this pill rather than chemotherapy.

So, one of the downsides of a brutinib is that it as of now is an indefinite treatment. And people take it unless they stop tolerating it or it stops working, they take it indefinitely. So, kind of in parallel to this, another drug called venetoclax which venetoclax is another pill that inhibits a protein called BCL2 which is important in keeping cells alive and making them resistant to treatment. So, venetoclax has also been approved in CLL and used in CLL and it’s been used alone or in combination with again on of these antibody treatments in particular, obinutuzumab a newer version of an antibody that targets something called CD20.

So, the study that was presented in the heme malignancy session at ASCO looked at patients treated with either chlorambucil and older chemotherapy and obinutuzumab, the antibody or venetoclax with the antibody obinutuzumab. So, again, comparing essentially an antibody treatment with an older chemo drug or with the newer venetoclax. And this was done largely in older patients with comorbidities or other medical conditions where the chlorambucil based treatment is commonly used because these patients can’t tolerate more aggressive therapy.

And the net of the study to kind of cut to the chase is that this was a fixed duration of treatment where patients took over the course of a year, the combination. So, you see that you have venetoclax obinutuzumab which is a one year treatment in this study versus in other studies the indefinite ibrutinib and the net was that the venetoclax obinutuzumab over the course of year was very effective, was better than the chlorambucil but more importantly, the majority of the patients had what we call MRD negativity meaning with the most sensitive tests, there was no evidence of CLL. So, this was a highly effective regimen, but it really posed a question can you instead of taking ibrutinib indefinitely can you do a year of obinutuzumab plus venetoclax and have a long remission?

So, this didn’t compare those two approaches head to head and in fact in the future, we expect those comparative trials will be there. But it raises the idea which I think is a potential advantage for CLL patients that you can get a novel drug like ibrutinib and take it indefinitely or now perhaps one could do this combination of antibody treatment plus venetoclax for a year and potentially have a long remission at least as suggested by the fact that the rates of MRD negativity or low levels of the disease were quite good. So, I think it really in the CLL world is going to challenge the idea with these new drugs that we need to do it indefinitely or can we do fixed durational therapy. And that’s becoming a better way because it’s obviously easier for patients, less expensive, less toxic.

Dr. Shah: that sounds really exciting. So, with ibrutinib do you get MRD negative status as well?

Host: Interestingly you don’t do it to a high degree. The patients do well despite not often not being MRD negative. They can stay on the drug and the disease is basically suppressed even though patients are not MRD negative. So, MRD negativity is surrogate. For ibrutinib, people can do very well with despite still having MRD present, on the other hand if you can get people with a fixed duration regimen to be MRD negative; then maybe you can stop it and the patients will do well for a very long time.

So, all this needs to be tested but I think for patients, the idea that you can get a new drug for a shorter time might prove to be nice obviously.

Dr. Shah: That’s really exciting. The obinutuzumab is that a CD20?

Host: It’s a CD20, yes.

Dr. Shah: And very different than rituximab?

Host: It’s a newer anti CD20. It has some different properties to it. In some ways it has a little bit more in the way of side effects, but it has more antibody dependent cellular cytotoxicity and in CLL potentially seems to be a bit better than rituximab, at least in randomized trials.

So, now I want to move to prostate cancer. Again, another common cancer and again, I’m going to ask you about some data with a novel drug enzalutamide. What is that all about and how is that potentially changing things for prostate cancer?

Dr. Shah: Sure. So, enzalutamide is a new androgen receptor inhibitor that’s used and approved in prostate cancer and similar to the ribociclib study where we are getting active agents earlier on. This study in hormone sensitive prostate cancer compared the use of enzalutamide with standard of care versus standard of care alone in hormone sensitive prostate cancer. And it asked again, the question of if you are combining therapies earlier on; are you able to improve efficacy. In this case, the standard of care was docetaxel which is a chemotherapy agent that attacks microtubular agents. This is a large study over 1100 patients are randomized in a one to one way and patients who received the combination the androgen receptor enzalutamide with docetaxel actually did much better in terms of survival.

And it’s very similar to the ribociclib study where you combined hormonal therapy with the CDK4 and 6 inhibitor. The combination of hormonal therapy with cytotoxic therapy seems to add activity.

Host: Great. So, from the standpoint of treating patients again, it sounds like another scenario where patient care may change and the new standard of care may include this agent. Is that correct?

Dr. Shah: Yeah, I would think so. I think that the combination did show a lot of activity and improved survival. So, for both in breast cancer and prostate cancer, I think we are seeing some practice changing studies at the plenary session. But I think it actually, for me, it leads to another abstract that was presented at the plenary session. And this was an examination of the time to treatment and the expansion of Medicaid. And this was a very, very important topic that was discussion in the plenary session and it relates because what it really shows is that if you are able to provide insurance and to a large group of people; you are able to reduce the time to treatment.

And these two studies in breast cancer and prostate cancer, showed us that the earlier you treat with a combination therapy; the better your outcomes are going to be. You are improving survival. So, I think that the Medicaid expansion study, which is not a drug development study, I admit, but it actually is an important study because it showed that in areas where Medicaid was expanded; the time to treatment for minority populations went from a difference of about 5% to less than 0.5% so a ten-fold improvement in time to treatment. And we think that treating earlier makes a difference as these other studies showed.

Host: Yeah, I think that really highlights the idea that we go to ASCO and we hear about all these new treatments and often expensive delivery of care; but as my daughter once told me, she was thinking about careers, if we could only deliver the treatments that we know work very well to the patients that need them more effectively; we probably can impact outcomes for patients in a similar or much greater way than by discovering additional new treatments. And it highlights I think the study you cite, that we really need to focus on getting treatments to the patients and breaking down the barriers and often there are financial and insurance coverage as well that can really make a difference and have the impact to improve outcomes.

Dr. Shah: Absolutely. I think it did show that. I think that healthcare is complicated and if we are able to deliver care at the right time to the right person, we can optimize our benefits.

Host: Great. So, I want to talk about immunotherapy a little bit. And we are going to get to the immune check point inhibitors in a minute or two. But before we get there, I wanted to touch on the concept of CAR T Cells and wand what we call BiTE types of treatment. These are novel was of engaging the immune system to fight the tumor. And the concept of CAR T Cells were presented, I’m not going to go into details because I know that many people have heard about these agents. They are approved in ALL, acute lymphocytic leukemia and lymphoma, but the concept of a CAR T Cell is removing a T cell or a population of T cells from a patient. In the laboratory, engineering them to go after new targets and to be stronger immune effector cells, being reinfused into the patient and then working against the tumor cells. And this is again an approved therapy for certain lymphoid malignancies including large cell lymphoma. These can be effective for some patients where standard treatments are working anymore but also have some side effects to them as a byproduct of the immune system engagement.

And so, we saw a number of studies kind of follow up studies and I think it’s safe to say at this point, that in lymphoid malignancies about a third of patients seem to respond pretty well to this with a durable response, about a third of patients have a transient response and a third of patients don’t respond at all or their tumors don’t respond at all. And so, this is a modality where there’s a lot of work going on in trying to make it work better.

Another area is what’s called the BiTEs, and these are modified antibodies. So, they are not immune cells themselves, but they are engaging the immune cells. And the idea being that these have two arms to them, these modified versions of antibodies that we mentioned earlier. One arm of them or one component can engage the immune system and the other component can engage the tumor cells. And so, there was a drug AMG 420 which was presented in myeloma. This was agent that binds something called CD3 on the patient’s own T cells when it’s infused into the patient. And it binds with something called BCMA which is a target on myeloma cells. So, the idea is that it binds with one arm the immune cell and the other arm the tumor cell, brings them together and activates things and in fact, the AMG 420 in a small study had a meaningful response rate in myeloma patients targeting this BCMA target. And so, again, it’s early in the course of this type of treatment, but we have examples of BiTEs in lymphoid malignancies that are exciting and which we heard a little bit about. And we also have that in solid tumors as well. What’s your take on that at this point?

Dr. Shah: This is a very exciting class of drugs. So, in solid tumors, there are some solid tumors where immunotherapy works modestly well. But many solid tumors where immunotherapy doesn’t work that well and that’s where we really think that these novel bidirectional antibodies, the BiTE therapies might have a lot of activity because you can engage either two components of the immune system at the same time or engage a solid tumor cell as well as a component of the immune system. So, there are BiTEs under investigation in solid tumors as well. One of them AMG212 which is being studied in metastatic castrate resistant prostate cancer and obviously it’s early, but the technology is absolutely amazing, and I think that there’s a lot of hope for that.

I think the even next generation is actually not having just two components but actually including a third or forth component to engage multiple different aspects of the immune system to overcome resistance.

Host: So, the immune check point inhibitors have been very important and made a big difference for certain types of solid tumors, not so much in others but certainly a very exciting area and I know that there were many, many studies on immune check point inhibitors at ASCO and these are now standard of care in certain settings. But any kind of topline comments that you would have as to what people should either take away from ASCO in the big picture for these, as a thematic area, are we learning more about who responds, who doesn’t respond, what to do about it and where you see that going.

Dr. Shah: Yeah, so, this is a enormous area and I’ll try to touch on many of the aspects. So, certainly, in some cancers like melanoma, lung cancer, bladder cancer, the immune check point inhibitors actually work quite well and are actually replacing chemotherapy in many settings. So, for example, in lung cancer, if you overexpress the PDL protein in more than 50% of your cells; you actually can get immune check point inhibitor right initially as your first treatment without having any chemotherapy.

In melanoma, that’s commonly done as well especially if you don’t have a BRAF mutation or similar mutation, an immune check point inhibitor either by itself or a combination is quite useful. What we are learning in other cancers, is that the immune check point inhibitors have modest activity, only maybe 10 or 15% might respond by themselves and we are trying to see if there’s a combination. Combining it with either radiation or chemotherapy can have effectiveness.

In gastric cancer, there was a study examining a combination of chemotherapy with immune check point inhibitor pembrolizumab versus chemotherapy alone and in that study, there was a third arm of pembrolizumab by itself as well. And disappointingly, the combination of the immune check point inhibitor with chemotherapy didn’t improve survival versus chemotherapy alone but interestingly, the immune check point inhibitor by itself without chemotherapy, seemed to be as good as chemotherapy by itself. So, is suggested that there is activity, some patients benefit, and others don’t, and I think that the future is really trying to figure out which patients may benefit the most and identifying them so we can target them with the best treatments.

Host: Great. So, I want to come back in just a second and ask you about kind of the other one or two things that really excite you either about ASCO or the future in solid tumor therapy. I want to finish our heme malignancy discussion with a study that I thought was kind of interesting and potentially paradigm changing. This was a study lead by Jason Weston and MD Anderson, and this was the idea that you could treat a curable lymphoma with chemotherapy first with a novel set of drugs. So, in large cell diffuse large B cell lymphoma, the most common subset of lymphomas we cure roughly 70% of patients with chemotherapy called CHOP plus a drug called rituximab, one of the antibodies we referenced earlier.

So, our CHOP is a curative therapy and we’ve – the paradigm has been over the years to try to add things to our CHOP to cure more patients. And that’s been met with I would say limited success although a lot of enthusiasm and still some things in the fire potentially as being promising. So, once you cure a substantial proportion of people with chemotherapy and you have novel drugs; it raises the idea well can you get to a point where you can get rid of chemotherapy? How can you take away a regimen that cures some patients? Can you give other drugs that might be as good or better than chemotherapy with a different panel of side effects?

And so this study looked at a combination of rituximab, a drug called lenalidomide, an immunomodulatory drug and then ibrutinib which we talked about before. And the Bruton’s tyrosine kinase inhibitor. These are all drugs that have activity in a subset of large cell lymphoma called ABC or Activated B cell subtype also referenced as non-germinal center subtype slightly overlapping and so, the concept here was to treat patients even though they have a curable lymphoma, treat them first with these novel drugs and then after a couple of cycles of treatment then come in with the chemotherapy.

So, it’s kind of a first step to say well, how do the novel drugs do and are they good enough that maybe someday we can get rid of the chemotherapy altogether. And so this was a study that basically treated patients with this subtype of lymphoma with a couple of cycles of this rituximab, lenalidomide and ibrutinib and the interesting part was that the majority of patients roughly 70% of patients responded to this type of treatment. So, it wasn’t a home run, necessarily, but the response rates were so good it at least is a baby step toward potentially moving away from chemotherapy. And in fact, there was at least one patient on the study that declined to go on to the chemotherapy part of treatment and actually did pretty well. At least with a degree of follow up of a year and a half or so.

And so, we are moving toward and trying to move toward getting rid of chemotherapy or chemotherapy pre-regimens which we can do in non-curable lymphomas, some of the chronic lymphomas like follicular lymphoma, but the idea that we could move there in an aggressive curable lymphoma is certainly exciting that at least we are moving in that direction. So, I thought that was kind of a paradigm shifting not that we going to necessarily do that in practice, but at least it informs perhaps our clinical trial design to move in that direction.

So, I wanted to give you the last word. What other areas are area is really something that people ought to pay attention to or got you excited at ASCO that we haven’t touched on?

Dr. Shah: Well that’s wonderful. So, it’s good to hear in solid tumors, we are also trying to move away from chemotherapy and trying to provide therapies like the CDK4 inhibitor earlier on with hormonal therapy or immunotherapy before we give chemotherapy to see if we can provide a treatment that doesn’t require cytotoxic therapy which has more side effects and things like that. Outside of those areas, and novel targeted agents, I think the key thing for solid tumors is going to be identifying patients who benefit from immunotherapy so that we can offer these fantastic drugs to them and also the next generation of immunotherapies, the BiTEs that we talked about earlier and the CAR Ts that are just getting into solid tumors. These are things that are going to be practice changing over the upcoming years, I think.

Host: Well great. This has been a great discussion and I with ASCO being so big it was great for me to hear your expert take on areas that I wasn’t able to see at the meeting and I think it gives our audience a flavor of some of the exciting things that are happening across the spectrum of both blood cancers and solid tumors. So, thank you for joining us Manish.

Dr. Shah: Absolutely. Thanks so much for having me.

Host: Great. So, I want to invite our audience to please download, subscribe, rate and review CancerCast on Apple Podcast, Google Play Music or online at www.weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments and topics you’d like to see us cover more in-depth in the future. That’s it for CancerCast: Conversations About New Developments in Medicine, Cancer Care and Research. I’m Dr. John Leonard. Thanks for tuning in.