Rank #1: Dr. Neelima Denduluri Highlights Key Poster Presentations in Breast Cancer from ASCO's Annual Meeting
Dr. Neelima Denduluri Highlights Key Poster Presentations in Breast Cancer from ASCO's Annual Meeting
Rank #2: Immunotherapy: ASCO 2017
Rank #3: ASCO18 Takeaways: Dr. John Sweetenham
Editor-in-Chief of the ASCO Daily News John Sweetenham, MD, FRCP, FASCO, discusses the practice-changing science presented at the 2018 ASCO Annual Meeting.
Rank #4: Spanish Language Discussion of Developmental Therapeutics, New Drugs, and Phase I Highlights From the ASCO Annual Meeting
Spanish Language Discussion of Developmental Therapeutics, New Drugs and Phase I Highlights From the ASCO Annual Meeting with Dr. Gilberto Lopes and Dr. Christian Rolfo.
Rank #5: Dr. Marco Davila Discusses How CAR T-Cell Therapies in B-Cell Malignancies Show Promise for Other Cancers
Dr. Marco Davila Discusses How CAR T-Cell Therapies in B-Cell Malignancies Show Promise for Other Cancers.
I'm Lauren Davis. And joining me today is Dr. Marco Davila a medical oncologist in the Department of Blood and Marrow Transplantation and Cellular Immunotherapy at Moffitt Cancer Center. His clinical focus is utilizing cell therapies to treat patients with hematologic malignancies. Dr. Davila, welcome to the podcast. Thanks so much for the invitation.
Today we're talking about CAR-T therapies and B-cell malignancies. Your work with targeted therapies in leukemias and lymphomas has grant great promise for patients who, historically, we would not expect to have seen such sustained responses. What do you attribute these response rates to?
Well, this is really a tremendously novel therapy. These patients that have been approved for this therapy have been deemed to be chemotherapy refractory, meaning kind of the standard treatments that you'd give these patients, the patients' malignancies have become well adapted to or are able to evade the treatments. So the immunotherapies that are being applied for these B-cell leukemias and lymphomas really are a complete paradigm shift for medical oncology as well as for the patient's cancers. So these patients' cancers, while they've been well-adapted to chemotherapies, they have not been adapted so well to CAR T-cell therapy.
Can you walk me through the process of obtaining these therapies? What's the general timeline?
Sure, so the first thing we have to do as a medical oncologist is determine that the patient is eligible for the CAR T-cell therapy, if they meet the indications in the label provided by the FDA and the drug manufacturer. So that involves mainly making sure that they have the diagnosis of an aggressive B-cell lymphoma and/or a B-cell acute lymphoblastic leukemia that has relapsed and received at least one prior therapy. So once we deem that the patient is eligible for therapy, we then arrange for the patient's peripheral blood mononuclear cells, and more specifically, T-cells, be isolated from their blood.
So this involves a apheresis procedure, where the patient comes in, usually has the large-bore needle inserted in one arm to collect the blood. It goes through a machine, filters out the cells, and returns the blood through another large-bore [INAUDIBLE] needle in the patient's other arm. So this procedure can last several hours. But afterwards, billions of cells are sent to the manufacturer for isolation of T-cells, and then genetic retargeting to the CD19 antigen present on the patient's B-cells, malignant B-cells.
Amazing-- what other cancers can be targets in the future?
So the initial approvals, as I said, have been for B-cell acute lymphoblastic leukemia and aggressive B-cell lymphoma, but there is very promising late-stage data targeting multiple myeloma, targeting the B-Cell Maturation Antigen, BCMA. And I think many of us expect that myeloma will get an approval for this treatment with BCMA-targeted CAR T-cells sometime in the next year or so. And that's going to really represent another kind of big change to a medical oncology and bone marrow transplantation programs throughout the US.
And that's because two of the major indications for autologous stem cell transplantation, so auto stem cell transplants, are aggressive B-cell lymphomas and myelomas. So many of these patients that standardly would receive an autologous stem cell transplantation may in fact be candidates for CAR T-cell therapy instead. So while myeloma is next in line, I think there's a lot of interest in adopting this technology later to, or hopefully shortly to acute myeloid leukemia as well.
What are some of the obstacles in applying this technology at a cancer center?
Well, I think probably one of the biggest obstacles is that there is a time of production, a time of [? TCQA ?] analysis to make sure that the product that's been made is safe, is not contaminated or anything like that. And sometimes the production time and the [? TCQA ?] time could be short, maybe about two to three weeks. Sometimes this lasts longer than a month.
And as I said earlier, in terms of the indications for this therapy, aggressive B-cell leukemias and lymphomas that are chemotherapy refractory, that these are patients that can't necessarily wait months for a product. So that I think is probably the biggest challenge, to be able to see a patient in the clinic and go, yes, you have very bad aggressive leukemia and lymphoma. And you meet this indication for this therapy. So we're going to collect the cells. And you know, we'll see you sometime in a few weeks or in a few months when the product is ready. That's probably the biggest challenge.
I think, luckily, for some of these products, it seems that their production times have been relatively reasonable, maybe two to three weeks. Other kind of products have really unfortunately taken longer than a month. And those are probably one of the reasons that some of these products are favored by medical oncologists right now, because of disparate in production times. So it kind of has meant that, for some of these patients, we have to kind of keep them in the hospital to give them a bridging therapy, meaning that we try to keep their disease kind of quiet until their cells are ready. So that's probably been the biggest obstacle.
Of course, there is a financial obstacle. There is toxicity obstacles. You know, these CAR T-cell therapies are associated with a unique set of inflammatory or immune-related toxicities and neurologic toxicities, so we've had kind of, as a group of investigators, develop diagnostic and grading schemes and management schemes to manage these toxicities. And I think overall, the last few years, we've seen a lot of progress in this area. And overall, the therapy has become safer than it was maybe 10 years ago when we started developing the first clinical trials for patients with B-cell leukemias and lymphomas. So in terms of growth, how quickly can this adapt from, say, 20 to 30 cancer centers to other hospitals? Well, I mean, I think that's the huge need, is that we need this technology be applied at multiple centers. At the center that I'm located at, we are a major CAR T-cell therapy center for probably the Southeast, and really, in the world. We have patients from other countries that come to my institution to get this therapy because it hasn't yet been improved that their own country. But it means that we're starting to kind of reach our own capacity to be able to provide standard of care, as well to provide know experimental cell therapies, to try to begin pushing the envelope. What's the next disease that we can use to target with these novel T-cell therapies? That means that, for us to be able to do these innovative clinical trials, we need other institutions to be able to kind of shoulder the standard of care. So right now, there is probably about 30 sites that are providing this technology across the US. Probably the vast majority of these cell therapies really are probably given by only 10 centers. So there is a really big need to be able to go from 30, to really, close to 100 centers in the US need to be providing this therapy for patients to be able to be located close to these sites, for providers to be able to kind of start learning about this technology as well. And I think probably the big obstacle for that is just kind of just somewhat of the infrastructure that's required to be able to provide this therapy. So institutions have to be able to have a [? FACT-accredited ?] clinical site, where they are approved to be able to collect cells, to be able ship cells, to be of a process these cells for infusion into patients. They have to be able to have multiple doses of tocilizumab, for example, to be able to manage the toxicities. They have to go through kind of an onboarding and auditing process by the manufacturers of these technologies, because it's given under a REMS program, a Risk Evaluation Mitigation Strategy mandated by the FDA. So there is a lot of hoops that these centers have to be able to go through to provide the therapy. And I think that many of them are, but it's just taking them-- they're the second or third big groups that are going to be getting their approval to be able to provide this therapy. But I think that it's a need for patients. It's a need for the primary centers that are providing this technology right now, is to have collaborators to be able to do this. And as I said earlier, one of I think the biggest pushes that we've had for developing these kind of harmonized toxicity grading schemes, and diagnostics schemes, and management schemes, is to be able to provide this to new CAR T-cell clinicians to be able to say, this is the path you should follow in terms of managing or infusing and managing these therapies. That brings me to my next question. And you just mentioned toxicities. What kind do you expect? And how do you manage them? There is two well-characterized toxicities now associated with CAR T-cells. And there is the third as well that I want to mention that I think now is being a little more appreciated. The first is the Cytokine Release Syndrome, or CRS. And this is essentially a constellation of symptoms that is associated with cardiovascular and pulmonary kind of toxicities. So patients can be hypoxic, tachycardic, hypotensive, any of these number of symptoms. And really, the hallmark of the CRS bill is a high-grade fever that can occur as early as the night of infusion. And what's believed to be the mechanism behind this toxicity is the in-mass activation of CAR T-cells by their antigen. And with these CAR T-cells get activated, they secrete cytokines and then activate other immune cells that then can get activated and secrete other cytokines, and kind of create this rapidly escalating inflammatory kind of syndrome. And so we and the other CAR T-cell investigators across the US and the world have developed diagnostic and grading schemes to be able to classify CRS. And while maybe 10 years ago, the standard of management of CRS was really kind of trying to withhold therapy until-- there was concern that the patient was at high risk of death, over the last few years, we moved an early intervention program, where we really kind of intervene at grade two levels of CRS, whereas maybe 10 years ago, it was grade four CRS. And I think that had a really huge impact at making the technology much safer. The concern was that, by intervening, you may be impacting the efficacy of the CAR T-cells, but luckily, that has not borne true. The second major toxicity is considered to be a neurologic toxicity. So these are, again, another constellation of symptoms that can range from mild kind of confusion, difficulty speaking, to sometimes grand mal seizures and the patients completely obtunded to the point where that they need to be intubated to protect their airway. And this one, while there is, I think, again, a good uniform harmonization of the way we grade these neurologic toxicities, in the way we intervene them, there is still not a great understanding of what's the mechanism behind this toxicity. So our interventions really rely only mostly on steroids. And some of course will get tocilizumab as well. But we're not certain if how well these agents are at actually mitigating some of these toxicities, or not certain how to treat neurologic toxicity also in the setting of a patient with cytokine release syndromes. There is guidelines, but we're not certain in terms of how effective those guidelines are, probably because we don't necessarily have objective markers to follow with neurologic toxicity. So I think that's a huge area of need right now for CAR T-cell research. And the last one that we're starting to learn about, at least, again, based on the FDA-approved therapies, is B-cell aplasia. Since this CD19 antigen that's been targeted on malignant B-cells is also expressed on normal B cells, that means patients' normal B-cells will be killed by this therapy as well. So you can have patients that have six months, nine months after treatment, or sometimes years after treatment that, when you check their peripheral blood or their bone marrow, they actually have no B-cells. And they have very, very low gamma goblin levels, which are the antibodies that are secreted by B-cells, and that these patients can be prone to developing infections. And so I've seen a few patients in my own clinical experience coming back to the hospital six months, a year later with these recurrent infections. Then, lo and behold, it turned out that they have hypogammaglobulinemia. They have B-cell aplasia, that these patients that required longer course of antibiotics, and potentially IVIG to help kind of support them through these periods of infections. And that's something that really has to be kind of-- what I'm working on is trying to make sure that this is communicated well to the primary medical oncologist, because those are the patients that are really going to be following the patient's long term. So most of these CAR T-cell centers evaluate the patient, and treat the patient, and kind of get the patient through that first month or so after CAR T-cell infusion. But it's ultimately the patient's primary medical oncologist that is going to be managing the patient long term, and it's going to be likely then that's going to be managing the complications of B-cell aplasia long term. How about clinical trials? Are there any trials that are looking towards the future to move the field forward? Absolutely, so there are trials, as I said before, targeting AML. There is NKG2D-based CAR technology that already been part of a report that's shown patients with objective responses with this therapy. So we're really excited about that technology. There is also TCR-based gene therapy as well, going on for multiple different solid-tumor malignancies. There are CARs that are being clinically evaluated for glioblastoma multiforme. And there are also CAR-T developed for any number of other malignancies, such as mesothelioma, prostate cancer. So these are all things that are in the clinical pipeline already there. And there is a next iteration of technologies where, really what we're seeing is the clinical application of the technologies that were developed probably 5 or 10 years ago.
But there is a whole new pipeline of exciting innovations or refinements of CAR T-cells, so bringing in a kind of third generation or armored CAR design, where you add in a cytokine secreting element to it, or where you have a molecular switch so that you can finally control the expression of the CAR or the downregulation of the CAR for safety issues. So these are things that I imagine are going to reach the clinic in the next year or two. And there is a lot of excitement for it, because that's going to really add to our CAR toolkit for the future, to be able to make this technology more efficacious, but also more safe.
That's fantastic. Again, my guest today has been Dr. Marco Davila of Moffitt Cancer Center. Thank you so much for being on our podcast.
And to our listeners, thank you for tuning in to the ASCO Daily News Podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple Podcast.
Rank #6: Triple-Negative Breast Cancer: Dr. Heather L. McArthur
Heather L. McArthur, MD, MPH, of Cedars Sinai Medical Center, discusses advances in the treatment landscape for patients with triple-negative breast cancer.
Rank #7: Lung Cancer: ASCO 2017
Rank #8: Key Takeaways from the 2019 Gastrointestinal Cancers Symposium with Dr. Stephen Leong
Key Takeaways from the 2019 Gastrointestinal Cancers Symposium with Dr. Stephen Leong
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to the ASCO Daily News podcast. I'm Lauren Davis, and joining me today is Dr. Stephen Long, associate editor of ASCO Daily News. Dr. Long is associate professor in the division of medical oncology and is a translational researcher in the GI and developmental therapeutics programs at the University of Colorado Cancer Center. Dr. Long, welcome to the podcast. Thanks for having me. It's a pleasure to be here. Dr. Long, you've just returned from the Gastrointestinal Cancers Symposium. How was this year's event compared with previous years? First of all, I love you GI ASCO. I always find it informative. And I love the format of the talks and presentation. This year there was no significant practice changing presentations like in years past. However, there were still some excellent presentations and talks. And what were some of the presentations that stood out to you? There were some reports of a couple of clinical trials that sort of intrigued me. One was KEYNOTE-181. This was a phase III study comparing pembrolizumab monotherapy versus standard chemotherapy in patients with local events and metastatic esophageal cancer in the second line setting. They reported a significant improvement in overall survival in patients with PD-L1 combined positive score of greater than 10. And these patients received 9.3 months overall survival compared to 6.7 months for those who received [INAUDIBLE] choice of chemotherapy, which then consists of paclitaxel, docetaxel, or irinotecan. In addition, pembrolizumab was better tolerated and had a better safety profile. What made it really intriguing was of the total 628 patients that were enrolled in the trial, 64% of them had squamous cell carcinoma of the esophagus, which is unusual, especially in a phase II setting. And even though the study had a statistic overall survival benefit, in the squamous cell carcinoma cohort, there was a non-statistical trend in overall survival of 8.2 months versus 7.1 respectively. Pembrolizumab did boost the objective response rate compared with chemotherapy in the PD-L1 CPS greater than 10 and a response rate of 21.5% versus 6.1%. And then squamous cell carcinoma, it was 16.7% versus 7.4%. That leads to a whole bunch of questions. One, should we improve our PD-L1 scoring by including a CPX score greater than 10 and making our predictions based off that? In addition, should pembrolizumab expand its indications to include squamous cell carcinoma, since presently in the United States, pembrolizumab is only approved for adenocarcinoma. Also, there were the reports of the phase II ROAR study, which was looking at biliary tract cancers with BRAF V600E activating mutations. And these patients received a combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. There were 33 patients. And they had an objective response rate of 42%. All of them with partial responses. And 7 of the 14 patients with responses had the responses lasting more than six months. And adding those with stable disease, they had reported a disease control rate of 88%. They looked at survival data. And the median progression free survival in this cohort was 9.2 months with an overall survival of 11.7 months. And to put this into context, usually second line biliary tract cancers we rarely ever see survival being more than five months. And these PFS and overall survival is very comparable to the first line setting for gemcitabine cisplatin, where the original study showed a PFS of eight months and overall survival of 11.7 months. So this potentially could be another treatment option for people with V600E biliary tract cancers. And then there were the preliminary results of a single phase II study at Memorial Sloan Kettering, which was evaluating pembrolizumab in conjunction with trastuzumab HER2 antibody with CAPOX and those with HER2 positive metastatic esophageal gastric adenocarcinoma. They had 32 patients with the overall response rate of 87%. They reported three CRs and 25 partial responses. And then when you factor in the stable disease, they had 100% disease control rate. And all the patients had some degree of tumor regression. The PFS were 11.4 months with an overall survival having not been met after six months. This is extremely exciting, and this has already led to the development of a global phase III study, which will be known as KEYNOTE-811. That's great. That sounds very promising. Were there any research presentations that you were interested in? Oh, yeah. There was a lot of great preclinical work. One of the most intriguing was in pancreatic cancer, where the Canadians did a study known as COMPASS, where they took advanced pancreatic ductal adenocarcinoma, and these patients underwent whole genome sequencing, as well as RNA sequencing of their tumors, prior to the initiation of first line chemotherapy with either modified FOLFIRINOX or gemcitabine and abraxane. Treatment outcomes were then compared to their molecular characteristics. The data suggests that chemotherapy differs depending on the transcription features of the tumor. So for example, the best survival data came out of those patients with the classical ductal adenocarcinoma subtype that were treated with FOLFIRINOX. And they had a median survival of 7.17 months. And when they were compared to the basal-like subtypes and were treated with FOLFIRINOX, they had a median progression free survival of 2.5 months. Now, patients with the basal-like subtype actually had a better response to gemcitabine and abraxane, which had a PFS of 5.65 months compared to the classical subtype, where they had median progression free survival of 4.93 months. So in summary, those with the basal-like subtype actually had a resistance for FOLFIRINOX. In addition, the researchers also mentioned that GATA6 RNA expression significantly correlates to the PDAC classic and basal-like molecular subtype. So it could actually be used as a marker in determining subtypes. And all this put together means that we could potentially identify patients who have a better chance of responding to FOLFIRINOX versus gem abraxane in the first line setting in pancreatic cancer. And obviously there needs to be more work to validate this, but this actually is quite intriguing. Also, there was data from the amino scoring testing, which was looking at its test in high risk stage 2 colorectal cancer patients. And for those who are not familiar, patients with stage colon cancer have a poor prognostic if they had a T4 disease, had fewer than 12 lymph nodes removed, had a point differentiation subtype, and also had evidence of vascular emboli, lymphovascular invasion, perineural invasion, or actually had a presentation of bowel obstruction or bowel perforation. And these patients are often offered adjuvant chemotherapy following curative resection due to their high risk of recurrence. The amino score test measures the density of CT3 positive T cells, as well as cytotoxic CDH cells within and surrounding the tumor to gauge the strength of the host immune response at a tumor site. So therefore a high amino score indicates a high anti-tumor immunity, which correlates with a low risk for disease recurrence. And these investigators looked at 1,130 patients with stage two colon cancers. And their conclusion for time to recurrence was those with high risk disease with high amino scoring compared to those with low risk disease had a very similar five-year survival of 87.4% versus 89.1% respectively. In contrast, if you have a high risk disease and a low amino scoring, your five-year time to recurrence was only 72.2% in the absence of adjuvant therapy. So this could potentially be used as a prognostic tool for those who are high risk stage two in the future. What about education sessions? Were there any that caught your attention? So my favorite was the neuroendocrine session. Neuroendocrine, as most people know, is a pretty rare disease population. However, there has been significant advances in the past few years with new drugs, new understanding of the biology, new diagnostic procedures, as well as testing. And it was a great panel of leading experts to help us navigate the new landscape of neuroendocrine and understanding how we should be approaching this. So that was my favorite session. Were there any other takeaways that were important during the symposium? There were a few other presentations I thought that were quite interesting. The Japanese presented their Prep-02 or JSAP-05 trial. And this was the first study to ever demonstrate the efficacy of neoadjuvant therapy in resectable pancreatic cancer. And their neoadjuvant chemotherapy regimen was a combination of gemcitabine with an oral drug S1. And they showed that it met its primary endpoint of overall survival of 36.72 months in those patients who received neoadjuvant therapy versus 26.65 months in those who went from upfront surgery. And for the Japanese, which tend to do upfront surgery followed by adjuvant chemotherapy in the past, I think this may be a shift in their paradigm, where this could be the new standard in Japan of using neoadjuvant therapy prior to surgery. Also, there was the oral drug trifluridine and tipiracil, which was studied in a phase III metastatic gastric and GE junction adenocarcinoma for those who have received two previous line of therapies. And they were randomized to the drug versus placebo. And it demonstrated a 2.1 survival benefit over placebo. And their main concern was a lot of these patients end up getting gastrectomies. But being an oral drug, could that affect its efficacy? And it seems like this benefit was also seen in those who had a gastrectomy versus those who didn't as well. So this potentially could be another option for those in the third line setting for gastric cancer. However, the big debate is even though it met its overall survival, is 2.1 months clinically significant? And I guess we'll have to have more data regarding safety and tolerability before we can make that decision. There is also the French GRECCAR-6 trial, which was evaluating the optimal time to surgery following chemoradiation for rectal cancer, where patients who underwent neoadjuvant chemoradiation were randomized to waiting 7 or 11 weeks prior to a mesoresection of the rectal cancer. They demonstrated that they had very similar path CR rates between the two. But more interesting, they found that if you had a good disease response to chemoradiation, there was no difference in disease free survival if you waited 7 weeks versus 11 weeks prior to surgery. However, if you were a bad disease responder, you had a poorer disease free survival if you waited more than seven weeks. However, this was not statistically significant. And then the authors concluded that we shouldn't be waiting more than seven weeks prior to surgery following neoadjuvant chemoradiation for rectal surgery. Thank you so much. Again, today my guest has been Dr. Stephen Long. Thank you for being on our podcast today. And to our listeners, thank you for tuning into the ASCO Daily News podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple podcast.
Rank #9: Key Takeaways from the ASCO-SITC Clinical Immuno-Oncology with Dr. Steven Eric Finkelstein
Key Takeaways from the ASCO-SITC Clinical Immuno-Oncology with Dr. Steven Eric Finkelstein.
Welcome to the "ASCO Daily News podcast." I'm Lauren Davis and joining me today is the "Immuno-oncology Daily News" Associate Editor, Dr. Steven Eric Finkelstein with Florida Cancer Affiliates the US Oncology Network. Dr. Finkelstein, welcome to the podcast. Thank you so much for having me. The Immuno-oncology Symposium just concluded on Sunday. How was this event compared to last year's? Well, this year's event was, again, extremely exciting. This year's event featured research and discussion surrounding themes of patient-centered rational steps to move the field of immuno-oncology towards the future. Now, as many of us know, immuno-oncology has dramatically altered the treatment landscape for many malignancies, and this progress has been extremely rapid over the last decade. As the field has progressed, researchers and clinicians are pushing it towards a better understanding of how immunotherapy can affect patients and the best and most rational combination approaches can improve responses and long-term outcomes. What presentations stood out to you? Another exciting area of research was that the combination of lenvatinib and pembro yielded promising antitumor activity and progression-free survival in patients with metastatic urothelial carcinoma. In abstract 11, a Phase Ib/II study was reported. And as we know, urothelial cancer can account for 90% of all bladder cancers. Pembro monotherapy is currently approved as a first-line therapy in patients who are ineligible to receive cisplatin or platinum-based chemotherapy. It's also approved as a second-line treatment for patients with advanced or metastatic urothelial cancer. Lenvatinib, a multikinase inhibitor, a VEGFR-1 through 3, FGFR-1 through 4, PDGFR-alpha, RET, and KIT is used as a single agent in several malignancies, including thyroid cancer and hepatocellular cancer. Dr. Vogelzang, who presented the results of the study, discussed the Phase II portion of the study, which included 20 patients with histologically confirmed metastatic urothelial carcinoma. The primary outcome in the trial was immune-related resist objective response at 24 weeks. Five patients achieved such a response for an overall response rate at 24 weeks of 25%. Dr. Vogelzang's conclusion was that lenvatinib plus pembro demonstrated promising antitumor activity with manageable adverse events. The response rate warranted further investigation and lenvatinib plus pembro combination will be studied in a Phase III trial in urothelial carcinoma. What other research were you interested in? A Phase Ia/Ib trial was launched in order to evaluate the safety of LY3321367, an anti-T cell immunoglobulin-domain and mucin-domain containing molecule 3, or TIM-3 antibody. Administered alone or in combination to LY3300054, which is an antiprogrammed death ligand, or PD-L1 antibody in patients with advanced, relapsed, or refractory solid tumors. An analysis of the trial that was presented by Harding at the meeting in Abstract 12. This focused on the safety, efficacy, pharmacokinetics, and pharmodynamic results seen with these treatment regimens. The key points are as follows-- treatment-related adverse reactions were mild, i.e. Grade two or less, in both treatment groups except for one patient with a Grade three anemia in Arm B. No dose-limiting toxicities, dose-limiting equivalent toxicities, treatment-related serious adverse events, or death was observed in either treatment arm. Approximately 68% in Arm A and 88% in Arm B of patients were positive for treatment emergent antidrug antibodies related to the LY3321367. Despite antidrug antibodies, there was no effect on pharmacokinetics noted That's great. Were there any education sessions that caught your attention? I think at the 2019 ASCO SITC Clinical Immuno-Oncology Symposium, what really struck me were the keynote addresses. On March 2, the keynote lecture from Dr. Rafi Ahmed of Emory University examined the basic scientific underpinnings of the field and focused deeply on T cell exhaustion and differentiation. In a second keynote address, Dr. Jedd Wolchok, of Memorial Sloan Kettering, took a broader look of the future of immunotherapy. And his main thesis was there was a need for a more rational approach to combination therapies. Indeed, it is apparent that the combination of therapies will be an important role for our future. That's wonderful. Were there any other takeaways that were important during the symposium? ASCO and the Society of Immunotherapy of Cancer, SITC, have really focused on developing recommendations for clinical trial reporting. Indeed, we need trial reporting that addresses the unique efficacy, toxicity, combination, and sequencing aspects of immuno-oncology treatments. As many know, ASCO and SITC had convened a working group that consisted of medical oncologists, immunologists, clinical research, biostatisticians, and representatives from industry and government to develop important recommendations, also known as Trial Reporting in Immuno-oncology, or TRIO recommendations. The recommendations based on expert consensus are important given that existing data to support evidence-based recommendations are limited. The recommendations given by TRIO are intended to improve the reporting of IO clinical trials and thus, provide more complete evidence on the relative benefits and risks of immuno-oncology. Given the rapid expansion of the number of IO clinical trials and ongoing improvements to evidence base using IO treatments and clinical care, it is apparent that these recommendations will likely need regular revision. And the annual meeting of ASCO and SITC will be an important place for TRIO recommendations to continually be updated. Thank you. Again, today, my guest has been Dr. Steven Eric Finkelstein. Thank you so much for being on our podcast today. It's been an absolute pleasure. Thank you so much. And to our listeners, thank you for tuning into the "ASCO Daily News" podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple Podcast.
Rank #10: Immuno-Oncology: Dr. Seth M. Pollack
Seth M. Pollack, MD, of the Fred Hutchinson Cancer Research Center, discusses immunotherapy for sarcoma and how varying microenvironments in sarcoma subtypes impact response to immunotherapy.
Rank #11: Dr. Benjamin Maughan Discusses GU Cancer Symposium Takeaways
Dr. Benjamin Maughan who is the mentee of the GU Daily News Associate Editor, Dr. Neeraj Agarwal, discussed the presentations and research that stood out to him during the recent GU Cancer Symposium. Dr. Maughan is an Assistant Professor in the Division of Medical Oncology at Huntsman Cancer Institute.
Welcome to the ASCO Daily News podcast. I'm Lauren Davis, and joining me today is Dr. Benjamin Maughan, who he was the mentee of the GU Daily News Associate Editor, Dr. Neeraj Agarwal. Dr. Maughan is an assistant professor in the Division of Medical Oncology at Huntsman Cancer Institute. Dr. Maughan, welcome to the podcast.
Well, thank you. It's a pleasure to speak with you, Lauren. So you've just returned from the GU Cancer Symposium. How was this year's event compared with previous years?
It was fantastic. Lauren, I've been going to GU ASCO for a number of years now since I was starting fellowship at Hopkins, and it just keeps getting bigger and bigger. So it's a fabulous meeting. One significant change, I will say, this year compared to the previous year is, as the meeting is getting bigger and there's a lot of research going on in the GU malignancies, we're starting to see more and more practice-changing results and research being presented at GU ASCO.
That's very exciting. What presentations stood out to you? There, actually, were quite a few, as I was alluding to with your previous question. But definitely the practice-changing data really stands out the most. And we saw that both in the field of prostate cancer and kidney cancer. I guess specifically in the prostate cancer, we saw a number of trials that have been published to date exploring in this M0CRPC space, or patients who have castration-resistant prostate cancer but no identifiable metastases on scans since M0CRPC. We've seen a couple of these trials with PROSPER and SPARTAN showing that apalutamide and enzalutamide respectively improved metastasis-free survival in this setting. Now, at GU ASCO 2019, we saw the third big trial presented, which was darolutamide with the ARAMIS trial. This, again, was in an M0CRPC patient population, and they were randomized 2-to-1 to darolutamide or a placebo. Of note, the baseline characteristics were pretty similar to what we've seen with the PROSPER and SPARTAN trial, in that the PSA doubling time was pretty short, meaning these were fairly aggressive patients.
That's an important point because some patients have a very prolonged PSA doubling time, and those patients may not benefit from any of these therapy. Those specific trials have not been done. So it's unclear the value of these therapies in those better prognostication patients. But regardless, in the ARAMIS trial, we saw a significant improvement in the primary endpoint, which was metastasis-free survival. It was 40 months with darolutamide versus 18 months with a placebo, and led to a significant improvement as measured by the hazard ratio and it was statistically significant.
Interestingly, all of the other specific subgroups appeared to benefit-- age, prior [INAUDIBLE] therapy, radiation, or surgery. So now we have a lot of data between all three of these trials showing that novel hormonal therapies with either apalutamide, enzalutamide, or now darolutamide significantly benefited these patients. Now, because these patients have no metastases, we always have to ask our question-- and therefore, they're not having any symptoms from their disease-- we have to be very cognizant of any specific side effects that we may cause or a worsening of their quality of life by introducing therapy this early in their treatment process. And that was really encouraging news with the darolutamide.
The discontinuation rate of darolutamide was the same as the placebo group, 8.9% and 8.7% respectively. Fatigue is a big issue with this patient population because of their ADT therapy, which causes a lot of fatigue. We've seen fatigue with apalutamide and enzalutamide. And there was a slight increased rate of fatigue or asthenia in the darolutamide compared to the placebo, but it was small-- it was around 15% or 16% versus something like 11% with placebo. So it appears that it's very well-tolerated. So that was really encouraging news overall.
The other big news with prostate cancer was in a slightly different space, it was in the metastatic hormone-sensitive prostate cancer population. And this was the ARCHES trial, specifically with enzalutamide versus placebo. So in this trial, patients were randomized one-to-one to either ADT with placebo or ADT with enzalutamide. Now, historically for these patients, the treatment-- we've seen a number of clinical trials looking at ADT plus chemotherapy or ADT plus abiraterone, both showing improvement over ADT plus placebo alone. And so this trial, we've been anticipating for a while.
Again, it showed that patients regardless of high volume or low volume disease, if they had de novo metastatic disease, so they were presenting with metastatic disease at presentation of their diagnosis of prostate cancer or if they had previously been treated for localized disease and then progressed to metastatic disease, all of those patients appeared to benefit with the addition of enzalutamide over placebo. Very importantly, though, a number of these patients, just because of the CHAARTED and the STAMPEDE data that came out before, a number of these patients were allowed to receive docetaxel before enrolling in this trial. Somewhere around 20% of the patients had received prior docetaxel, and those patients also appeared to benefit from the enzalutamide. And that's particularly important because now we're starting to ask the question, since docetaxel and these novel hormonal therapies have non-overlapping toxicities and distinct mechanisms of action, what about trimodality therapy? So again, it's a relatively small subset, only about 20% of the patients, but it's intriguing and interesting to note that they also did benefit. So now in the prostate cancer realm at GU ASCO 2019, we saw further evidence that the M0CRPC population benefits from darolutamide. We saw that in the ARCHES trial, enzalutamide is another therapy that appears to be highly effective in these patients with metastatic hormone-sensitive prostate cancer patients. And so all of that was very encouraging news.
That's very exciting in the research front. What about the education sessions? Were there any that caught your attention?
Yes. So in terms of the educational sessions-- again, that's one of the nice features about some of these disease specific symposia, as opposed to the annual ASCO meeting, is there's a lot of education, as well as just straight research. And so we get lots of debates about controversial topics with a lot of thought leaders in the field, et cetera. So that's another nice part of GU ASCO.
One debate or educational session that I thought was very interesting was this discussion between a radiation oncologist, [? Jason ?] [INAUDIBLE], and a urologic oncologist, Michael Cookson, about what's the ideal first line therapy for patients with muscle-invasive localized bladder cancer. Is it trimodality therapy or is it neoadjuvant chemotherapy followed by cystectomy? This is something that's a growing debate in the field. Now historically, it's always been viewed as the neoadjuvant chemotherapy followed by cystectomy is the ideal treatment for these patients.
First line therapy and the trimodality therapy-- I guess I should specifically mention-- so trimodality therapy is where patients have optimal debulking with the TURBT, followed by concurrent chemotherapy and radiation therapy, followed by surveillance. So they felt that that trimodality therapy is best reserved for those patients that are not cystectomy candidates for a variety of reasons, comorbidities or other such problems.
There's some growing evidence to suggest that perhaps trimodality therapy may be an equally effective way at achieving oncologic outcomes, ie, cures, at the same time, though, preserving the patient's native bladder, and therefore improving their overall quality of life. So this debate was highly instructive and very interesting. I will say, Dr. Cookson was pointing to the National Cancer Database information comparing retrospective data, but comparing the overall survival with radical cystectomy versus trimodality therapy, suggesting that radical cystectomy is more effective in achieving oncologic outcomes with cure.
But Dr. [INAUDIBLE] appropriately pointing out that these are retrospective analysis and there's a lot of patient bias that goes into this, because again, historically, trimodality therapy is reserved for those patients that are not deemed surgical candidates, oftentimes because of comorbidities. So their worst prognosis patients, and you would predict that those patients have inherently a worse overall survival anyway. So it was a very instructive and intriguing debate, and I anticipate perhaps we eventually will see the gold standard of a randomized controlled trial performed, which will answer the debate. But very instructive, very interesting, and a great component of these meetings.
Are there any other takeaways that were important during the symposium?
As I mentioned, prostate cancer isn't the only disease area where there were some interesting and exciting clinical trials that came out that are practice-changing. We also saw a number in kidney cancer. The two highlights in this area were both asking the question, does a tyrosine kinase inhibitor, a molecule targeted therapy in combination with a checkpoint inhibitor improve cure rates over tyrosine kinase inhibitor alone?
Currently, the standard of care for patients with metastatic kidney cancer is either monotherapy with the tyrosine kinase inhibitor or combination checkpoint inhibitor with ipilimumab and nivolumab. So we've seen some data come out recently looking at these molecularly targeted therapies plus checkpoint inhibitors. And so at GU ASCO 2019, we saw updated results on a number of things. One, on the updated results from ipilimumab and nivolumab, demonstrating that the complete response rate is somewhere around 10%, 11%. But then we also saw some updated results of axitinib plus nivolumab versus [INAUDIBLE].
In this trial, about 20% of patients had favorable risk disease, 65% or so had intermediate risk disease, and another 20ish percent or so had poor risk disease, so about what we typically see in clinic. And the response rates were high with the PD-L1-based therapy. The complete response rate was around 4%. The trials that we were really excited to see the results from was the KEYNOTE 426 study, which was axitinib plus pembrolizumab versus monotherapy with sunitinib. So again, this, similar to the others, w
as a first line therapy. Patients were started on a lower dose of axitinib of 5 milligrams, and it could be dose escalated if it was tolerated. And the enrollment across the trial based on the risk categorization of INDC was similar to what we've seen in a lot of these trials. Again, about 30% of favorable, a little less than 60% had intermediate risk diseases, something around 15% had poor risk disease. So very similar to the other targeted therapy plus checkpoint inhibitor trials that had just recently been reported. The results were pretty encouraging. The hazard ratio was 0.69 for death or progression, favoring axitinib plus pembrolizumab. Around 90% of patients were alive at 12 months versus just under 80% for sunitinib. The complete response rate was around 6%. So again, very encouraging data. The one potential issue that we need to look to is safety as we're comparing these strategies versus the current gold standard immunotherapy approach, which is ipilimumab plus nivolumab. So the proportion of patients discontinuing treatment on this axitinib/pembrolizumab trial was 30% versus 14% for [INAUDIBLE]. And that's approximately what we see with the ipilimumab and nivolumab data.
Again, this appeared to be well-tolerated and safe, and it seems to have advantages over ipilimumab and nivolumab in that regard in terms of safety. The big question that everyone's asking is, which strategy is more effective and [INAUDIBLE] a larger proportion of patients that have durable responses? These may be cures. Again, that number is around 11% based on the updated data that was presented at GU ASCO for ipilimumab and nivolumab versus in the 5% range that we're seeing so far with the axitinib-based combinations with either pembrolizumab or atezolizumab. So it's still fairly early with either of these trials. We need to see if with time the complete response rate improves. But overall, really exciting and really encouraging, because these combinations appear to be active, well-tolerated, and are definitely leading to durable responses in patients.
That's great. It sounds very promising. Again, today, my guest has been Dr. Benjamin Maughan. Thank you for being on our podcast today.
Thank you so much. I appreciate the time Lauren.
And to our listeners, thank you for tuning in to the ASCO Daily News podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple Podcast.
Rank #12: Anxiety or Depression in Patients With Cancer: Dr. Barbara L. Andersen and Dr. Marlena M. Ryba
Babara L. Andersen, PhD, of Ohio State University, and Marlena M. Ryba, PhD, of Coastal Carolina University, discuss recognizing, assessing, referring, and monitoring patients with cancer experiencing moderate to severe anxiety or depression symptoms.
Rank #13: Hematologic Cancers: ASCO 2017
Rank #14: Plenary Coverage: ASCO Chief Medical Officer Dr. Richard L. Schilsky Discusses LBA4
Plenary Coverage: ASCO Chief Medical Officer Dr. Richard L. Schilsky Discusses LBA4 with Dr. Hedy Kindler.
Welcome to the ASCO Daily News podcast. I'm Dr. Richard Schilsky, Senior Vice President and Chief Medical Officer of ASCO. I'm pleased to be joined by Dr. Hedy Lee Kindler, Professor of Medicine at the University of Chicago Medicine where she is Associate Vice Chair for Clinical Research in the Department of Medicine as well as Director of the Mesothelioma Program. Dr. Kindler presented abstract LBA4, olaparib as maintenance treatment following first-line platinum-based chemotherapy in patients with a germline BRCA mutation and metastatic pancreatic cancer, Phase III POLO trial during the plenary session. Dr. Kindler, welcome to the podcast.
Thank you for inviting me to share the results of our study.
The five-year survival rate for people with metastatic pancreatic cancer is still less than 5%. So there's a real sense of urgency to develop new treatments. The POLO trial evaluated the efficacy of maintenance treatment with olaparib, a PARP inhibitor in patients with metastatic pancreatic cancer and a germline BRCA1 and/or BRCA2 mutation. What did the study show?
Well, in this study, patients with metastatic pancreatic cancer with germline BRCA1 or 2 mutations who had received at least 16 weeks of a first-line platinum-based chemotherapy were randomized 3 to 2 to olaparib tablets or a placebo. The primary endpoint was progression-free survival by blinded independent central review. This study showed that maintenance olaparib provided a statistically significant and clinically meaningful improvement in progression-free survival. The progression-free survival was 7.4 months with olaparib and 3.8 months for placebo, with a hazard ratio of 0.53 and a p-value of 0.038. Progression-free survival on olaparib was the same irrespective of whether patients had stable disease or a complete or partial response to first-line chemo.
From six months onwards, more than twice the proportion of olaparib arm patients were progression-free compared with the placebo arm. 23% of patients had a response to olaparib. And what is truly remarkable is that the median duration of response to olaparib treatment in these patients with metastatic pancreatic cancer was over two years. The interim survival data at 46% maturity showed no difference between arms. And final survival results will be evaluated at 46% maturity.
Health-related quality of life was preserved with olaparib treatment and showed no difference between arms. And maintenance olaparib was quite well-tolerated with an AE profile similar to that seen in other tumor types.
So those are really quite exciting results. One question I had in looking at the study design is that, as you mentioned, patients in the trial all received four months of standard chemotherapy and were then randomized to continue treatment with placebo or olaparib. The question is, is it standard practice to stop active cancer treatment after four months? Would there be some rationale to adding olaparib to standard chemotherapy rather than using it as maintenance?
Actually, they did not. Patients had at least 16 weeks of first-line platinum-based chemotherapy with no maximum limit to the duration. Actually, about a third of patients received more than six months of chemotherapy. This was up to the treating physician and the patient. And remember, in their cord 11 trial, the median number of cycles was 10. Continuing on folfirinox does increase cumulative toxicity, principally myelosuppression and neuropathy. So it is a very reasonable thing to want to switch to a potentially less toxic treatment.
Understood. Thanks for that clarification.
So you asked about whether one could combine olaparib with standard chemotherapy. Unfortunately, myelosuppression at greater than anticipated rates is the common experience of combinations of olaparib and other PARP inhibitors with chemotherapy. For example, in a phase I trial of olaparib plus gemcitabine, which had a pancreatic cancer expansion cohort, it was not possible to administer gemcitabine above a dose of 600 mg per meter squared or olaparib above a dose of 100 mg bid. So it's quite unlikely that a combination of the highly myelosuppressive, folfirinox, could be administered safely with olaparib. So if I'm understanding you correctly though, there were a proportion of patients in this study who continued chemotherapy beyond four months but also then had olaparib added during that period of time?
They had chemotherapy for four months or greater and then, they stopped chemotherapy and at that point, were randomized to receive either monotherapy with olaparib or placebo. There was no combination of chemotherapy plus olaparib.
Sorry, for not being able to follow this as clearly as you've laid it out. So what was the trigger to discontinue the chemotherapy then leading them to the randomization to olaparib or placebo?
That was investigator and patient choice. Some patients wanted to receive only four months of chemotherapy and switch over, others wanted to continue chemotherapy for longer. Remember, there is no standard of care, particularly at the time that the study was initiated, for maintenance chemotherapy. And so, four to six months of chemotherapy, at the time of the study design, was considered a very reasonable option.
Were all of the patients not progressing at the time of randomization?
Correct. All patients were required to have stable or responding disease at the time of randomization.
OK, so I wanted to ask you about the germline mutations in BRCA1, BRCA2. We commonly think of BRCA mutations as being associated with breast or ovarian cancer and maybe a few other cancer types, but how often is it that a patient with pancreatic cancer will be a carrier of a germline BRCA mutation?
Studies have shown that between 4% and 7% of pancreatic cancer patients harbor a germline BRCA1 or 2 mutation. In view of the results of this study, now, do you feel that all patients with metastatic pancreatic cancer should be tested for a germline BRCA mutation?
Well, given the treatment implications demonstrated in the POLO trial, I think it is incumbent upon oncologists to offer all pancreatic cancer patients the option of germline testing. This is supported by an ASCO provisional clinical opinion from January of 2019, which recommended that patients with pancreatic cancer undergo risk assessment for hereditary syndromes that increase pancreatic cancer risk.
It states that germline genetic testing for cancer susceptibility, including testing for BRCA mutations, may be discussed with individuals diagnosed with pancreas cancer even if family history does not clearly suggest an inheritable cancer-related syndrome. Similarly, the NCCN now recommends germline testing for all patients with pancreas cancer due to data that demonstrates that germline mutations can occur at a similar rate in pancreas patients with or without a family history of any type of cancer.
Thanks. So one final question for you. Given the difficulty that we've had in developing effective new treatments for pancreatic cancer patients, given the lack of effective targeted therapies, this study would seem to open up new possibilities. But as someone who's an expert in the field, what do you see as being on the horizon in pancreatic cancer research?
This is an exciting trial because it's the first phase III randomized study to establish a biomarker-driven approach in the treatment of metastatic pancreas cancer. And while I hope that it will open the door to a new era of personalized care for this disease, I think we've been burned many times before. It's so common, in this disease, to see superimposable KM curves. And so, when one sees a hazard ratio of 0.53, it's genuinely exciting. But I really would not hazard a guess as to where we are going next. It's fraught with too many problems.
Understood. Again, today, my guest has been Dr. Hedy Kindler of the University of Chicago Medicine. Hedy, thank you so much for being on the podcast with me.
Thank you, Rich.
And to our listeners, thank you for tuning into the ASCO Daily News podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple podcast.
Rank #15: Spanish Language Discussion of Lung Cancer Highlights From the ASCO Annual Meeting
Dr. Luis E. Raez and Dr. Gilberto Lopes review review practice changing lung cancer research presented at the ASCO Annual Meeting.