2017 ASCO Annual Meeting Research Round Up: Managing Side Effects, Breast Cancer, Chronic Myeloid Leukemia, and Myeloma

September 5, 2017
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The ASCO Annual Meeting is the premier educational and scientific event where physicians, researchers, and other health care professionals gather to discuss the latest in cancer care and treatment. In today’s podcast, Cancer.Net Associate Editors answer this question: “What was the most exciting or practice-changing news you heard at the 2017 ASCO Annual Meeting?”

Transcript: 

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ASCO: 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.

You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer.

The ASCO Annual Meeting is the premier educational and scientific event where physicians, researchers, and other health care professionals gather to discuss the latest in cancer care and treatment. In today’s podcast, Cancer.Net Associate Editors answer this question: “What was the most exciting or practice-changing news you heard at the 2017 ASCO Annual Meeting?”

First, Dr. Charles Loprinzi discusses new results in a study that showed that patients with advanced cancer who electronically reported their symptoms to their health care team not only had a better quality of life, but also lived longer. He also discusses a potential new option for managing fingernail-related side effects common with a particular type of chemotherapy. Dr. Loprinzi is a medical oncologist and the Regis Professor of Breast Cancer Research at the Mayo Clinic. He is also the Cancer.Net Associate Editor for psychosocial oncology.

Dr. Loprinzi: Good day, this is Dr. Charles Loprinzi, a medical oncologist at Mayo Clinic in Rochester, Minnesota, and I'm going to discuss with you an ASCO abstract that was presented at the plenary session at the June 2017 ASCO meeting. This trial was presented by Dr. Ethan Basch who's at the University of North Carolina at Chapel Hill.

Patients on this study were patients who had advanced cancer, a variety of different types of advanced cancers. They were being treated as outpatients. They were at Memorial Sloan Kettering Cancer Center. They were randomly assigned to usual care, or they were assigned to a group that would complete questionnaires on a regular basis while they were outpatients. And these would be reported on tablet computers, and reported to the nurses at the institution, and they also would have this information available when the physician saw the patient.

What they did on this study was recorded in the Journal of Clinical Oncology, in 2016, showing that this actually improved quality of life in the patients who actually reported their information on a regular basis as opposed to patients who got regular care. At this ASCO meeting, however, they looked at survival outcome in this group of patients. Now the patients were followed for 7 years in total. There were over 750 patients who participated in this clinical trial and they noted that the groups who actually filled out the questionnaires lived 5 months longer than the control arm. This went along with increased quality of life in the patients who filled these out. So this was very interesting information. Dr. Basch and his colleagues are looking at doing this in a multi-institutional practice, so that you would include a number of different institutions as opposed to a single institution. This has led to thoughts that it's good for patients to make sure they report their symptoms to their nurses and to their doctors to help with controlling those symptoms and improving quality of life and also improving survival.

All right, I'm going on to the next item. I'm going to talk a little bit about a toxicity that's common with some chemotherapy drugs, but not well-appreciated. And this is a toxicity with fingernail and toenail toxicity. They come from taxane-type therapies, docetaxel, otherwise called Taxotere, or paclitaxel, otherwise called Taxol. The symptoms are most prominent with the docetaxel/Taxotere medication. And what happens with this is over time when patients get their therapy over several months, the fingernails can separate partially or almost completely from the nailbed and sometimes fall off, and this can be a vexing sort of problem. There's some information that if the hands and/or feet are cooled with ice so that less chemotherapy gets to the fingernails or toenails, that that will help prevent the problem. But that's kind of a hassle to give in practice and not everybody gets the problem, and so it's not utilized all that often. And once a patient starts to get the nail toxicity, the ice is not necessarily going to help prevent what already happened, it might help prevent more toxicity.

So at this year's ASCO, there was a couple of abstracts that looked at plant-based products that they would put on the fingernails for 3 times a day in 1 study, and another group got petroleum, like a Vaseline-type jelly instead. There were 60 patients on this study randomly allocated to the 2 different groups, and then they looked at the nail toxicity, both by what the patient said and the doctor said, and they had patients fill out some questionnaires. And there was substantially less nail toxicity in the group that got the plant-based substance. Now, one of the concerns with this sort of information is there's only been one single trial now that looked at this. It was a relatively small trial. We always like to repeat these sorts of things. The other question is can the product be reproduced in subsequent batches? So more study is needed, but in fact, this looks like it is a promising lead here.

Another abstract at the same meeting was this 1 from South Korea looked at another product that also looked promising for helping to prevent the fingernail toxicity. So more information should be coming along with this data in the near future.

ASCO: Thank you Dr. Loprinzi.

Next, Dr. Erica Mayer, the Cancer.Net Associate Editor for breast cancer, discusses new research in each of the 3 major subtypes of breast cancer. Dr. Mayer is a Senior Physician and a breast cancer medical oncologist at the Susan F. Smith Center for Women’s Cancers/Dana-Farber Cancer Institute, as well as an Assistant Professor in Medicine at Harvard Medical School.

Dr. Mayer: Hello, this is Dr. Erica Mayer from Dana-Farber Cancer Institute in Boston. I’d like to share with you some of the highlights in breast cancer advances from the 2017 ASCO Annual Meeting. First, just a reminder that breast cancer is divided into 3 main categories determined by the presence or absence of receptors on the outside of the cancer cell. These categories include hormone receptor-positive, HER-2 positive, and the so-called triple negative, when all 3 receptors are negative. It has been an amazing year for breast cancer research, and we saw presentations of breakthrough trials in each of these 3 major subtypes.

First, I want to talk about a trial called OLYMPIAD. This trial was one of the top 4 studies presented at ASCO this year of all the studies, and focused on a type of targeted pill medicine called olaparib, also known as Lynparza, and which is a PARP inhibitor. This type of medicine has been specifically designed for people who have developed breast cancer related to an inherited BRCA1 or 2 gene mutation, and targets DNA repair. In the OLYMPIAD trial, people with BRCA1 and 2 mutations and metastatic breast cancer were treated with either the PARP inhibitor Olaparib, or a standard chemotherapy. The people who received olaparib not only had improved survival outcomes, but also had less toxicity with their treatment and improved quality of life compared with those who received regular chemotherapy.

Olaparib is already approved for ovarian cancer, and it is expected that based on the results of the OLYMPIAD study, Olaparib will become approved for breast cancer in people who have inherited BRCA1 and 2 gene mutations. This will be the first medication approved in breast cancer for people with these mutations, and is a great breakthrough showing how what we learned a decade ago in the research lab can translate into medicines that help people in clinic. This also means that now more than ever, it may be important for breast cancer patients to pursue genetic testing and learn whether one has a BRCA1 or 2 mutation and could be a candidate for this kind of medication.

Moving on, for hormone receptor-positive breast cancer, we saw a trial called MONARCH 3. This trial was studying a medicine called abemaciclib, a targeted pill medicine which inhibits a cancer cell protein called CDK 4/6. There are 2 other inhibitors of CDK 4/6 which are currently FDA approved. There’s palbociclib also known as Ibrance, and ribociclib, also known as Kisqali. Like the 2 other medications, the MONARCH 3 study of abemaciclib showed that adding this agent to standard hormone therapy for metastatic hormone receptor-positive breast cancer significantly improved people’s survival outcomes, and likely this data will lead to FDA approval of this third medication. The MONARCH 3 study definitely confirms for us the benefit of this class of medications for hormone receptor-positive breast cancer. It is expected the majority of people with metastatic hormone receptor-positive breast cancer will have exposure to this class of drugs at some point in time in their therapy. Additionally, we look forward to the next wave of trials, which are studying new ways to use these kinds of medications, as well as their activity in patients who do not have metastatic breast cancer.

Finally, an important trial was presented in HER-2 positive breast cancer called APHINITY. This trial was studying whether adding pertuzumab, also known as Perjeta, one of the targeted medicines for HER-2 positive breast cancer, to standard therapy after surgery for breast cancer would decrease the rate of cancer recurrence. In this trial, all patients received standard chemotherapy and Herceptin, and half the patients also received pertuzumab. Long-term follow-up of the study overall suggested the vast majority of patients did extremely well, with very few patients experiencing a cancer recurrence. The addition of the pertuzumab did slightly reduce the risk of recurrence for some, particularly in people with cancers that were hormone receptor negative and had gotten into the lymph nodes. Adding pertuzumab to standard therapy after surgery is likely not necessary for all patients with HER-2 positive breast cancer, but it can be considered in this subset of people who got the most benefit as shown in the APHINITY trial.

Well, that’s it for the quick update from ASCO 2017. Overall, we continue on a fast track in breast cancer with many new and exciting therapies being actively studied. Stay tuned for future updates from upcoming breast cancer conferences!

ASCO: Thank you Dr. Mayer.

Next, Dr. Bruno Medeiros discusses a study that looked at a new tyrosine kinase inhibitor to treat chronic myeloid leukemia, or CML. Dr. Medeiros is an Associate Professor of Medicine at Stanford University School of Medicine, the Director of the Stanford Acute Leukemia Clinical Research Program, and Director of the Stanford Hospital Hematology inpatient service. He is also the Cancer.Net Associate Editor for leukemia. 

Dr. Medeiros: Hi, my name is Bruno Medeiros. I'm an Associate Professor at the Stanford University School of Medicine. I'm also the Associate Editor for the leukemia section of the Cancer.Net ASCO website. Today I'm going to discuss with you the results of an exciting, randomized clinical trial that was presented in the oral session of the most recent 2017 ASCO meeting in Chicago. The randomized trial was for patients with chronic phase, chronic myeloid leukemia. And it was named the BFORE Trial, which is an acronym that is commonly used for these studies. The BFORE Trial was, as I mentioned, a large randomized trial, multi-center, multi-national study testing bosutinib, a second-generation tyrosine kinase inhibitor versus imatinib, a first-generation tyrosine kinase inhibitor in patients with chronic phase, chronic myeloid leukemia that were previously untreated. Bosutinib is a medication that is, in addition to being an Abl inhibitor, it is also a Src inhibitor. And it has been tested in this setting previously at a higher dose. The objectives of this trial was to test a lower dose of bosutinib comparing to the standard 400 milligram dose of imatinib.

So briefly, a description of the study. There were over 530 patients that were randomized. As I mentioned, these patients needed to have previously untreated chronic phase CML. They were randomized on a 1:1 fashion to receive bosutinib 400 milligrams daily or imatinib 400 milligrams daily, and the primary endpoint was the response rate as reported on the abstract in the presentation at 12 months.

So briefly, to summarize the results of this study, at 12 months there were a similar percentage of patients in each one of those arms that continue to receive therapy, suggesting that the therapies were equally well-tolerated. In excess of 70% of patients were still receiving each one of those therapies at 12 months. Also noted in the presentation is that patients randomized to bosutinib had a higher response rate compared to those patients randomized to imatinib. The higher response rate included a higher rate of patients achieving a major molecular response, which is defined as a greater than 3 log reduction in the Bcr-Abl transcript level. Also a higher rate of complete cytogenetic response in those patients randomized to bosutinib. In addition, the time to major molecular response in complete cytogenetic response was shorter for those patients receiving bosutinib.

So in summary, patients receiving bosutinib had a higher response rate and a shorter duration to achieve that response. There was a similar rate of transformation to accelerated or blast crisis in each one of those arms. And patients randomized to bosutinib had a slightly higher rate of discontinuation from therapy compared to those patients receiving imatinib, specifically discontinuation secondary to side effects. The most common grade 3 side effects that were prevalent in the bosutinib arm included diarrhea and laboratory abnormalities including increase in the LFTs.

This is a unique study because it validates the utilization of a third second-generation tyrosine kinase inhibitor for patients with previously untreated CML. And the value of this particular randomized trial is that it demonstrates this efficacy without an increase in toxicity to bosutinib compared to imatinib, and previous studies have demonstrated that bosutinib appears to be very well tolerated long term without any evidence of cardiovascular or pulmonary toxicities as commonly seen with other second-generation inhibitors. To that point, the rate of cardiovascular or pulmonary toxicities seen in this study was less than 1% in both arms. So a very valuable study validating the use of a third second-generation inhibitor for patients with previously untreated chronic phase CML. Thank you very much.

ASCO: Thank you, Dr. Medeiros.

Finally, Dr. Paul Richardson discusses 1 study of a new immunotherapy option for people with relapsed, refractory myeloma, and another study that looked at the use of a targeted therapy after stem cell transplant. Dr. Richardson is the Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, and the RJ Corman Professor of Medicine at Harvard Medical School. He is the Cancer.Net Associate Editor of myeloma.

Dr. Richardson: Hello. My name is Dr. Paul Richardson and I am the Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, Massachusetts. And I'm also the RJ Corman Professor of Medicine at Havard Medical School. And it's my privilege to be talking to you today about some highlights from the recent ASCO meeting held in Chicago in June. In this context, I wanted to discuss with you 2 major abstracts but I wanted to start today on an oral presentation given by my colleague, Dr. Joseph McCale. The study of ours, which was a phase IB study of isatuximab in combination with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. Now, by way of background, isatuximab is an anti-CD38 monoclonal antibody which kills tumor cells via multiple mechanisms. And in this context, we report the use of this particular antibody from a variety of dose escalation cohorts in a phase 1B study of isatuximab plus pomalidomide and dexamethasone, which are backbone drugs in the treatment of relapsed refractory multiple myeloma.

Now, as many of you may be aware, the excitement around CD38 monoclonal antibodies has best been best exemplified by the success of daratumumab-based therapy. Isatuximab is very similar to daratumumab in many respects in that it targets CD38. But very importantly, it has certain qualitative differences in the way it works, such that it may offer certain advantages. Specifically, it may trigger the apoptotic pathway, targeting CD38, and at the same time, it may have less complement-mediated activity, which means that it can be given over a shorter infusion time and at the same time may be associated with less in the way of infusional side effects. In this study, we combined isatuximab with pomalidomide and dexamethasone. Patients had to have received at least two or more prior therapies including lenalidomide and a proteasome inhibitor, such as bortezomib or carfilzomib. And patients then went on to receive isatuximab, either a dose of 5, 10, or 20 mg/kg. Now, doses would start initially for weekly for the first 4 doses and then converted to every 2 weeks thereafter. This obviously provides an advantage because in other antibody studies, or another antibodies that is now approved, for example such as daratumumab and milatuzumab, typically these antibodies are given weekly for two months before then being converted to every 2 weeks and monthly. In any event, isatuximab 2 combined with pomalidomide given over 3 weeks and dexamethasone given weekly. In this study, we were able to evaluate patients up to a dose of 10 mg/kg. And we were also able to do an expansion cohort in this group. I should also mention that there was an exploration of the 20 mg/kg group, but in the context of this trial, 10 mg was chosen to take forward based upon the overall picture of side effects and efficacy. And we'll come to that in a bit more detail.

In our presentation at the ASCO meeting, we reported on 26 patients, in whom 8 were assigned to the 5 mg/kg group, 12 to the 10 mg/kg group, and as I mentioned a small number were assigned, 6 in fact, 20 mg/kg. The median age of the patients was 65 with a range of 42 to 80. Patients had received a median of 4 prior therapies including 1 patient who had received 11. And almost all of the patients, 80% were refractory to prior immunomodulatory drug therapy. And all were relapsed and refractory at the time of study entry. The median duration of isatuximab treatment was almost 20 weeks. And in fact, of the study, 26 patients have been analyzed, 16 remain on treatment. Importantly, two patients discontinued treatment because of adverse events at 10 mg/kg. Conversely, however, dose-limiting toxicities were relatively uncommon and included neutropenia as probably the most important side effect that we saw. Encouragingly, maximum tolerated dose was not reached. In the context of other side effects, fatigue was an important one to note as was some diarrhea and some shortness of breath. But again, these proved manageable with dose-reduction and supportive care. Important, as I mentioned, neutropenia was the dominant hematological abnormality. We did see a number of patients experience thrombocytopenia, as one would expect from pomalidomide-based treatment. And I think what was particularly encouraging was infusion associated reactions were very uncommon and occurred in only about 12 patients but with grade 3 in only 1. So thus, the infusional rate of toxicity was very low.

Now, I think what was particularly attractive about this trial was the response rates. What we were able to show in this group of patients is that two thirds achieved at least a partial response. We had a number of patients achieve very good partial response, in fact eight in total. And we even had one patient achieve complete remission, which is very unusual in the relapse refractory population. Importantly, for those patients who achieved a minimal response or better, that was in over 70% of patients, which is very encouraging in itself, particularly in the relapse refractory patient cohort. Responses were rapid in the first 4 weeks or so, and the median duration of response was very impressive at 26 weeks, which is of course equivalent to approximately 6 and a half months. Importantly, when we looked at the pharmacokinetics in this trial, the PK parameters of isatuximub were not affected by co-administration of pomalidomide and dexamethasone, suggesting that this combination is a very safe platform going forward, or rather I should say not perhaps safe because that perhaps can be an overstatement in the absence of a randomized trial, but I might say a very feasible and likely to be safe combination going forward.

Now, in the spirit of a randomized trial, what future directions are now in place? These include a randomized prospective phase III trial which is comparing isatuximab combined with pomalidomide and dexamethasone to pomalidomide and dexamethasone alone. The combination of isatuximab and pomalidomide and dex was manageable and clinically active and [inaudible] refractory myeloma as the study demonstrated. And so the conclusion of our presentation was in fact that the phase III trial of this combination just as I outlined is now not only up and running in a variety of countries and centers, but is very much ongoing with enrollment underway. Final comment about this combination is that very recently the combination of daratumumab and pomalidomide and dexmethasone was FDA approved and I think that's a very good thing for patients. In terms of isatuximab, this may provide a next generation or next step antibody which might prove very helpful for patients in the future with this particular approach.

Now, the next abstract I wanted to discuss with you today was a particular interest. This was led by my colleague Dr. Philip McCarthy and his partner, Sarah Holstein. There was an updated presentation on the CALGB ECOG 10104 alliance study comparing lenalidomide maintenance to placebo after stem cell transplantation for patients with multiple myeloma. And in this particular analysis was an overall survival and progression-free survival evaluation adjusted for treatment crossover. Now, what this helps us understand is whether or not using lenalidomide maintenance later in management is potentially as good as starting from the beginning. And this, in fact, was derived from a prespecified interim analysis in December of 2009 where we were able to demonstrate that lenalidomide significantly improved progression-free survival compared to placebo after transplant. And that allowed us, under the guidance of our steering committee, to convert the majority of patients who had been assigned to placebo, to lenalidomide maintenance. This updated analysis was able to show the considerable clinical benefit derived from lenalidomide maintenance both at the time of crossover and in fact from the beginning. Now, what's important to note is that an updated analysis, which we did in March of 2015, showed a significantly longer overall survival with lenalidomide maintenance. Very important, because this actually led to the FDA approval of lenalidomide maintenance after stem cell transplantation for this indication.

Now, the current analysis that was presented at ASCO, and was of such interest, was one where we examined the effect of lenalidomide versus placebo in overall survival and progression-free survival from randomization, adjusted for crossover effects. Now, we used a particular number of statistical methods to do this, and this was kindly provided to us through the help of a number of study statisticians who were particularly helpful in this regard. And we were able to do an adjustment for crossover using these particular statistical methodoligies as well as using the technique of what's called a landmark analysis where survival was also portioned assuming a residual lenalidomide effect after discontinuation. Very interestingly, what we found was that approximately 80 patients without progressive disease who were on placebo at the time of the initial interim analysis and then crossed over from placebo to lenalidomide. The median time from randomization to the crossover was about a year.

Very interestingly, the relative treatment effect for both overall survival and progression-free survival increased for lenalidomide when adjusting for this crossover. The landmark analysis of the interim analysis of December 2009 showed that, in fact, this treatment effect was not dissimilar to the intent to treat analysis. So adjusting for the potential diluting effects of crossover, we were able to show median overall survival and progression-free survival was markedly improved in favor of lenalidomide maintenance when one made these adjustments for crossover. Why that's so important is because it suggests not only that lenalidomide maintenance is vital to pursue from stem cell transplantation onwards, but also it shows the impact on overall survival which was diluted, as I mentioned, by the crossover effect. And when one takes that out of the mix you can see that in fact the hazard ratios really do improve.

Now, what kind of degree of hazard ratio did we see? Well, very interestingly, from the intent to treat unadjusted, the hazard ratio was 0.56. And just to explain what hazard ratios mean, the smaller the number the better. So anything less than 1 is good, 0.56 is very respectable. But when you did the actual adjusted analyses by using the statistical methods that I mentioned, one of which was the Rank Preserving Structural Failure Time Model or RPSFTM. And the other one was the Iterative Parameter Estimation or IPE. By both models, the hazard ratio improved for survival from 0.56 to 0.48. Very interestingly, we showed the same degree of improvement for progression-free survival as well where the hazard ratio was 0.58 by intent to treat. And this improved using these statistical tools to 0.5 RPSFTM and 0.48 for IPE. Now, that almost sounds a little bit complicated but essentially the conclusion is that lenalidomide maintenance has not only progression-free but overall survival benefit when given after transplant. The hazard ratios generated are quite dramatic. Basically, what we see is a doubling or more of progression-free survival. And in the same context of overall survival benefit, this seems to be very substantial as well. And the hazard ratios when using this technique to eliminate the dilutional effect of crossover on the overall analysis suggests there is even further improvement if one uses lenalidomide maintenance from the get-go.

So given that lenalidomide maintenance has now become a standard of care in maintenance, the question is where are we going? In terms of future directions, 1 of the most important new directions that we're going is to improve on lenalidomide maintenance as a backbone. We've established that the use of lenalidomide maintenance until progression is clearly superior both in terms of progression-free and overall survival benefit by virtue of a published meta-analysis across multiple randomized trials. And now how we can build upon that is with the integration of proteasome inhibitors and monoclonal antibodies. And a variety of studies are now integrating this approach and evaluating them in perspective randomized fashion. And we're very hopeful that augmented maintenance which may incorporate immunomodulatory therapy with lenalidomide as an example as a backbone can be further expanded to include proteasome inhibition, include monoclonal antibody therapy, and so further improve outcome. So please watch this space as maintenance post-transplant, and for that matter also, maintenance post-non-transplant continues to be evaluated as an important area and critical area of clinical research given the striking clinical benefit seen from this approach.

ASCO: Thank you Dr. Richardson.

To learn more about all of the science presented at the 2017 ASCO Annual Meeting, visit www.cancer.net/ascoannualmeeting. If you have questions about whether new research may affect your care, be sure to talk with your doctor.

Cancer.Net is supported by the Conquer Cancer Foundation, which is working to create a world free from the fear of cancer by funding breakthrough research, sharing knowledge with physicians and patients worldwide, and supporting initiatives to ensure that all people have access to high-quality cancer care. Thank you for listening to this Cancer.Net Podcast.

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