2021 Research Round Up: Gynecologic Cancers, Melanoma, and Cancer in Adults 65+

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In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today’s episode, 3 Cancer.Net Associate Editors discuss new research in cervical cancer, melanoma, and cancer in adults 65 and over, presented at the 2021 ASCO Annual Meeting, held virtually June 4th through 8th.

This episode has been adapted from the recording of a live Cancer.Net webinar, held August 9th, and led by Dr. Merry Jennifer Markham, Dr. Ryan Sullivan, and Dr. William Dale.

Dr. Markham is Chief of the Division of Hematology and Oncology and a clinical professor in the Department of Medicine at the University of Florida. She is also the Cancer.Net Associate Editor for Gynecologic Cancers. 

Dr. Sullivan is board certified in medical oncology and an attending physician in the Division of Hematology/Oncology at Massachusetts General Hospital. He is also the Cancer.Net Associate Editor for Melanoma and Skin Cancer. 

Dr. Dale is a clinical professor, the Arthur M. Coppola Family Chair in Supportive Care Medicine, and director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center. He is also the Cancer.Net Associate Editor for Geriatric Oncology. 

Full disclosures for Dr. Markham, Dr. Sullivan, and Dr. Dale are available at Cancer.Net.

Greg Guthrie: Good afternoon, everyone. I'm Greg Guthrie, and I'm a member of the Cancer.Net content team. And I'll be your host for today's Research Round Up webinar. This webinar will focus on gynecologic cancers, melanoma, and cancer in adults age 65 and older. Cancer.Net is the patient information website of the American Society of Clinical Oncology, also known as ASCO.

Our participants will be answering questions at the end of this webinar during the Q&A session. Please note that the participants cannot answer questions about anyone's personal medical situation. If you have specific questions about your cancer care, please contact a member of your health care team. Today we'll be addressing research from the 2021 ASCO Annual Meeting, which was held virtually in June, and our participants are members of the Cancer.Net Editorial Board. Now, they are Dr. Merry Jennifer Markham of the University of Florida Health. Dr. Markham is the Cancer.Net Associate Editor for gynecologic cancers. Dr. Ryan J. Sullivan of Massachusetts General Hospital Cancer Center, Harvard Medical School. Dr. Sullivan is the Cancer.Net Associate Editor for melanoma and skin cancer. Dr. William Dale of City of Hope Comprehensive Cancer Center. Dr. Dale is the Cancer.Net Associate Editor for geriatric oncology. And thank you, everyone, for joining us today. So starting us off today is Dr. Markham with highlights in gynecologic cancers.

Dr. Markham: Thank you so much, Greg. It's great to be here talking about a couple of studies that were presented at ASCO. Just to point out that I don't have any conflicts of interest for either of the 2 studies that I'll be presenting today. This first slide is a study that looked at a database to answer a question. And really, the primary question the study was trying to answer was whether HPV screening or cancer screening or HPV vaccination has made any difference in the United States over the last 15 years for HPV-associated cancers. And so the primary population that the results of this study really impact are any people, all people at risk for HPV-associated cancers, and these include oropharyngeal squamous cell carcinoma cancers. So head and neck cancers, anal and rectal squamous cell carcinomas, vulvar, vaginal, and cervical squamous cell carcinomas, and penile as well. So this study evaluated data from 2001 to 2017 in a database, the U.S. Cancer Statistics Database, and specifically tried to answer these questions. And the findings were rather complex, broken down by men and women, and so I'll walk you through.

In women, the overall incidence of HPV-related cancers was 13.68 per 100,000. And so of those cases, 52% were cervical cancer. What the authors found is that over the last 16 years, the incidence of cervical cancer decreased at an annual percent change of 1.03%. So a decrease annually by a little over a percent. And the incidence of cervical cancer in 2017 was 7.12 per 100,000. Over that same timeframe, the incidence rates of other HPV-associated cancers in women increased significantly. So rather than decrease, they went in the opposite direction. And specifically oropharyngeal, head and neck cancer, increased by 0.77% annually, anal and rectal cancer increased by 2.75% annually, and vulvar squamous cell carcinoma increased by 1.27% annually. Specifically in women over age 80, the incidence of anal and rectal cancer approached that of cervical cancer. The incidence of cervical cancer in that age population was 6.95 per 100,000, which was a decrease of 2.9% annually. Anal and rectal cancer incidence in women over 80 was 6.36 per 100,000 or 1.23% increase annually. So the authors did a projection model and found that the incidence in women of anal and rectal cancer was expected to surpass that of cervical cancer by the year 2025 for every age group over age 55.

Now if we switch to men, the incidence of all HPV-related cancers was 11 per 100,000 in the year 2017 and 81% were head and neck cancers. Over the last 16 years, there was an increase in HPV-related cancers in men 2.36% per year, with the highest increase in head and neck cancers, 2.71%, and in anal and rectal squamous cell carcinomas, 1.71% annual increase. Those who were at highest risk of head and neck cancer, the squamous cell carcinoma that I'm referring to, were older men. They were ages 65 to 69 with an incidence rate of 36.5 per 100,000 and an annual increase of 4.24%. White men actually had the highest incidence. So white men ages 65 to 69 had the highest incidence of head and neck squamous cell carcinoma at 41.6 per 100,000.

So it's a lot of numbers, a lot of data. Boiled down, what this really means is that cervical cancer has been decreasing. All other HPV-related cancers have been increasing. Now, the decrease in cervical cancer incidence is likely a combination of factors. Primarily, we have regular screening for cervical cancer, and we have HPV vaccination. Now, the risk for other HPV-related cancers, such as head and neck and anal and rectal squamous cell carcinoma, does remain high and is increasing, unfortunately. These are not cancers with routine screening. And so the authors concluded, and I think this makes sense, that screening and vaccination efforts, specifically HPV vaccination efforts, might help to impact those rising cancer numbers and help to decrease those rising incidence rates. So that is study 1. Greg, are we ready to go to the next one?

Greg Guthrie: Yeah, we are.

Dr. Markham: So this is the OUTBACK study. This is adjuvant chemotherapy following chemoradiation. That's primary treatment for locally advanced cervical cancer compared to chemoradiation alone. This was a phase III randomized study. We refer to it as the OUTBACK study, which was its official name. And this study sort of hits at the opposite end of that HPV cancer-related spectrum. So we're out of the prevention and in sort of incidence arena now in a realm of treatment. So this study impacts women who had locally advanced cervical cancer and specifically those who were able to be treated for cancer with chemoradiation. And just to clarify, chemoradiation, when that term is used together usually means chemotherapy and radiation given at the same time. And the chemotherapy is usually designed to make the radiation work better. So standard practice, the standard treatment that oncologists give for locally advanced cervical cancer is chemotherapy with a medicine called cisplatin and radiation, and this together is again chemoradiation.

So the question the authors wanted to ask in this study was whether adding chemotherapy at the end of chemoradiation helped to improve survival outcomes. So the study compared 2 groups, 1 group of women - and this was randomized - received chemoradiation alone. And that's absolutely standard of care practice. The other group, the experimental group, received chemoradiation, which was standard, but an additional 4 cycles of chemotherapy with a platinum and a taxane chemotherapy agent. The primary endpoint was overall survival. The study took a little bit of time to accrue. It recruited from 2011 to 2017, and ultimately 919 women with locally advanced cervical cancer were eligible and were analyzed in this dataset. Of those, 456 were assigned to chemoradiation, and 463 were assigned to chemoradiation followed by the additional 4 cycles of chemotherapy. What the study found is that overall survival at 5 years was similar in both groups. So 71% for the standard treatment arm and 72% for the arm that received the 4 additional cycles of chemotherapy. In addition, the progression-free survival was similar at the 5-year mark. So 61% compared to 63%. I think important to note is that this is a negative study. So the 4 additional cycles did not make a difference for these women. However, 81% of the women who were assigned to the chemoradiation and the chemotherapy had grade 3 to 5 adverse events within a year of being randomized, compared to only 62% of women who received the chemoradiation alone. So more women who received that experimental arm had more toxicity, more adverse events.

As we like to do in any randomized study, the authors did evaluate both groups of women to make sure there were no differences, and there were no statistical differences inherent between those 2 groups, and patterns of their cancer recurrence were similar in both groups. So what does this mean for our patients? For women with locally advanced cervical cancer, what we know now based on this study is that the standard treatment really does remain chemotherapy with radiation concurrent, so given simultaneously, and that we actually don't get any improvement in survival by adding additional chemotherapy. We do get extra side effects and extra toxicity. But women do not have better outcomes with this regimen. And that's it for these 2 studies, Greg.

Greg Guthrie: Thanks, Dr. Markham. I was wondering if you could really quickly give a sense of scope for how much do grade 3 through grade 5 adverse events affect somebody's well-being, quality of life.

Dr. Markham: Yes, absolutely. So typically, a side effect on a clinical trial are graded from 1 to 5. 5 is the absolute worst. That typically is death from a treatment. Grade 1 is very mild side effects such that you as a patient, if you're being treated with that, that treatment course may not really have much in the way of side effects or symptoms. But once we get to grade 3 and 4, there is some consequence. So, for example, for someone with anemia, they might actually require hospitalization or a blood transfusion. So it's definitely not a mild side effect. These are what we would consider significant or severe.

Greg Guthrie: Thanks, Dr. Markham. Now we'll move on to Dr. Sullivan with highlights in melanoma.

Dr. Sullivan: Greg, thanks so much for the introduction. It's a pleasure to be here today, and I'd like to thank Cancer.Net for the opportunity to provide highlights in melanoma from the Annual Meeting at ASCO. So I thought what I would do is show a few pictures and then describe what these pictures mean. So, the first study that I'm going to talk about is actually not a new trial. This is probably the fifth or sixth time this trial has been presented at ASCO. It's the CheckMate 067 study, which is a trial. And if you look at the upper right, this is a randomized trial. So patients were randomized to receive in gray ipilimumab, which at the time of this study launch was the standard of care for patients with newly diagnosed, advanced or metastatic melanoma. Patients could have been randomized to nivolumab, which had been shown to be effective in the second line after ipilimumab and was being compared in the front line with ipilimumab. And then the third arm and that-- was sorry, that's in green. And then the third arm in orange is the combination of nivolumab and ipilimumab.

As I said, this trial has been presented many times, but this follow-up presentation was with 6 and a half years of following how patients did on the study. And I don't generally like to show survival curves, certainly not overall survival curves, but I want to show them in this scenario, because what we're seeing, if you look at the lower left, this is progression-free survival. These are patients who started therapy and then their disease hasn't-- when the curve sort of flattens out, that means that whatever that number is, that's probably the number of patients at least with 6 and a half years follow-up, who are likely to remain progression-free over time. We know with ipilimumab, which is the gray line, and it shows 7% of patients who started therapy remain without growth of their disease. We know that those patients, if you're alive and without evidence of disease progression at 5 years, you're probably alive and without disease progression at 10 years. And that may be true for the combination of nivolumab and ipilimumab and nivolumab, which are the green and orange lines. And what's important about that is this is probably the potential cure rate of these therapies. As you can see, the numbers at 60 months and the numbers at 78 months don't look a lot different. And I would anticipate that about 30% of patients treated with nivolumab, which is a PD-1 blocking drug, and more than that, maybe 33 or 34% of patients treated with the combination of nivolumab and ipilimumab, are cured of their melanoma, which was metastatic at the time of starting treatment. And that is really amazing, particularly because this is a disease before these drugs came around that generally led to the death of greater than 90% and closer to 95% of patients who developed it. And that leads me to the second curve, which is the lower right, which shows that at 6 and a half years of follow-up, almost half of the patients treated with ipilimumab and nivolumab are alive and again, compared to probably less than 5% in historical dataset. So this is without a doubt, the most remarkable data when thinking about how patients do with melanoma that's ever been shown, and that's why I wanted to show these pictures.

This sort of picture shows actually the number of patients who are alive and treatment-free. So one of the important concepts of oncology, and I think if patients are polled, generally speaking, they would like a therapy that works, they would like a therapy that's tolerable. And ideally, if that therapy makes your disease go away, they'd like a therapy they can stop. And so on the left where it says nivo-plus-ipi and “n equals 145,” what it's saying is that 77% of patients who are alive in and were randomized to that regimen are treatment-free, meaning they never needed another therapy. For the nivolumab, that's 69% of the patients. And for ipilimumab, that's 43% of the patients. And so I think the other point that I wanted to make is that not only does this therapy lead to really remarkable outcomes, but it also leads to one of the key metrics that we want, which are control of disease and not needing to be on therapy.

So to summarize, this study was patients previously untreated with unresectable stage 3 or stage 4 melanoma. It's a 6 and a half year update. And it's a randomized trial of nearly 1,000 patients. This, again, is the longest follow-up data of any anti-PD-1 therapy, with or without an anti CTLA4 antibody like ipilimumab. A durable progression-free survival was seen in about a third of patients with a combination, about 30% of patients with single agent nivolumab, and less than 10% with single agent ipilimumab. And the durable overall survival is close to 50% with the combination, over 40% with single agent nivolumab, and just over 20% for ipilimumab. And then again, importantly, patients alive at this data cutoff, almost 80% with the combination remained off of therapy and never required subsequent therapy.

And then one other important point that was presented by the authors was that in patients who had complete or partial responses, about 80% of those who were treated with a combination, those complete or partial responses were maintained over this time. That was compared to almost 90% of the complete response to the nivolumab, but only a little more than 60% of the partial response with nivolumab were durable. And this is a question that as an oncologist caring for melanoma patients, I'm asked all the time by my patients who have a nice response to therapy, "How long's it going to last, Doc?" And the answer is, in the majority of patients, it seems to last at least 6 and a half years. And again, having additional follow-up data is really important to be able to answer these key questions. So what does this mean for patients? Say the data suggests that a significant minority of patients treated with either the combination of ipilimumab plus nivolumab or single agent nivolumab have durable benefit. I'm not sure if I said it, but it's important that I do say it, that I have been a paid and an unpaid consultant with Bristol Myers Squibb, who is the sponsor of this trial, since 2017.

That goes for this presentation as well. So another really critical presentation that was made at ASCO this year was the so-called RELATIVITY-047 study. So this, again, was a randomized trial. This randomized over 700 patients to either the combination of relatlimab plus nivolumab or to nivolumab by itself. Relatlimab is an anti-LAG-3 antibody. Nivolumab is in the anti-PD-1 monoclonal antibody. Anti-PD-1 antibodies have become the standard of care for a number of different cancers, either in combination or by itself. And they block a key way that the cancer's preventing the immune system from attacking it. Relatlimab is another drug in targeting another one of these important molecules that cancers can use to help prevent immune destruction. And so the idea here is that blocking 2 of these key proteins that the cancer cells may be using to help prevent their destruction by the immune system might be better than just blocking 1.

So this is the progression-free survival. So, again, the number, the percentage of patients over time whose disease hasn't grown since starting the therapy. And what was shown is that the combination was better than just nivolumab by itself at preventing growth of disease. And to say it another way, of preventing disease progression.

And this is busy, and it's not meant to be kind of seen, but essentially that where you see all of those little teal bubbles next to a dotted line, they're all to the left of that dotted line. And that generally means that the combination was better in a lot of different subgroups of patients based on sex, based on age, based on how functional the patients were when they went in, based on BRAF mutation status.

And importantly, they look to see whether or not this was true also for patients who had PD-L1 expression, which is an important, potentially predictive factor of nivolumab treatment, as well as LAG-3 expression, which again was the target of one of the drugs. And the hint here is that there seems to be benefit no matter whether the tumor expresses PD-L1 or not, and whether the tumor expresses LAG-3 or not.

So to summarize, this is another study looking at patients previously untreated, unresectable stage 3 or 4 melanoma, randomized 700 patients, over 700 patients to either a combination of a LAG-3 inhibitor, relatlimab, and a PD-1 inhibitor and nivolumab versus nivolumab by itself. The trial met its primary endpoint. The combination was well-tolerated, although there was some increased toxicity with the combination compared to the single agent. But it doesn't appear that the toxicity is significantly dose limiting, and the majority of patients were able to continue therapy and similarly to those who were treated with nivolumab. And then this subset analysis, it consistently favored the combination. So what does this mean for patients? Well, the data suggests that the combination of relatlimab and nivolumab may be a new standard of care in patients with advanced melanoma. However, there are caveats, including it's contingent on this combination being approved by regulatory authorities. And also important to note that there's no data yet to determine whether this combination would replace or be better than the combination of the ipilimumab and nivolumab, the combination that I talked about in that first presentation that I'm summarizing as part of the CheckMate 067 study. So we really don't know whether this will be replacing frontline therapy for all patients who have unresectable stage 3 or 4 melanoma or just a subset. But it does seem that this data is potentially revolutionary in terms of how we manage this disease.

And finally, I'm going to talk about a clinical trial of a product called lifileucel. This is a trial sponsored by a company called IOVANCE, and I served on a scientific advisory board for the company over a year ago. This is a trial that was looking at the benefit of something called TIL therapy. So TIL stands for tumor infiltrating lymphocytes. So in tumors, we often can identify immune cells that may just be hanging around and watching what's going on or actually may be there with bad intentions, meaning they got there because they can recognize the tumor and are trying to destroy it. And long ago, in the 1990s, a group at the National Cancer Institute began to develop ways of removing these tumor infiltrating lymphocytes, testing whether or not the lymphocytes could recognize a tumor and then would give them back to patients. The cells themselves are unmodified other than they come out, they're grown, expanded, and then given back to patients. The way this works is that a patient will have a tumor removed. So call it the harvest. The lymphocytes or TILs will be removed. They'll be expanded. They'll be tested to see if the TILs actually recognize the cancer. And then a patient will be hospitalized, given chemotherapy to basically prepare their body to receive the TILs. The TILs will be given. And then patients will receive something called interleukin-2, which is a growth factor for the T cells. And then patients remain in the hospital until their blood counts recover from the chemotherapy. And then that's it. That's the only therapy that's given as part of TIL therapy.

So this study was looking at cohort 2, which was patients who had previously been treated for melanoma with a PD-1 blocking drug and then received TILs because the PD-1 blocking drug wasn't working and they needed another therapy. In the bottom left is a curve called a waterfall plot. Down is good. The down can go to 100%, which means that all the tumors that were measurable went away. And in the majority of patients' tumors got smaller. And about 35 to 37% of patients actually had what we call partial response or a complete response. And those responses to the right is shown that they tended to be ongoing and that with a median follow-up of over 30 months, the majority of responders remained in response. So 1 concern is do these responses last, and the answer is they seem to.

So to summarize, this was a trial for patients who had unresectable stage 3 or stage 4 melanoma who were previously treated with an anti-PD-1 antibody. This was an update of a clinical trial for lifileucel. Sixty-six (66) patients were enrolled. The majority had received both ipilimumab and an anti-PD-1 antibody. This it says upfront toxicity. That's why patients are in the hospital. But once patients leave the hospital, there tends to be very few long-term toxicities. Over 35% of patients had a response, and the majority of those responses were maintained with nearly 3 years of follow-up. One additional thing that was presented is that patients who actually had the poorest prognosis factors going in, meaning their disease grew right away when they got immunotherapy before or they had what's called an elevated LDH, those patients actually seem to have the best responses, the best outcomes. So what does this mean? Well, lifileucel's been shown to be effective in a subset of patients with PD-1 resistant disease, the anti-PD-1 resistant disease. And this data suggests that patients with primary refractory disease, anti-PD-1 may benefit the most. And it remains to be seen whether or not this becomes a standard therapy. But if it does, this data supports its use in this setting. I'll stop there. Thanks, Greg.

Greg Guthrie: All right. Thank you, Dr. Sullivan. And now we'll turn to Dr. Dale, who's going to discuss highlights in geriatric oncology research.

Dr. Dale: Well, thank you so much, Greg. And thanks to my fellow panelists, to ASCO, and Cancer.Net for the chance to present this exciting new work in cancer and aging or cancer with older adults. I'm going to present 3 studies, 2 of which are related to each other in that they're both about cognitive loss with the treatment of cancers, and a second one about the pre-existing deficits, which also partners with the others. So I think a really nice, natural follow-up to my colleagues who talked about the risks of balancing toxicities and treatment effects, which is often highlighted for older adults.

So the first study by Schiaffino, et al. is identifying pre-existing dementia in older adults diagnosed with cancer through a national claims database. I'll mention up front that I am a mentor for Dr. Schiaffino, but not of this particular work, which was done independently with another group of providers and mentors. So this study was done in older adults with cancer who were found to have pre-existing dementia of the Alzheimer's type or a related kind of dementia. So the advance of this case is to take a large database, not a clinical trial database, and through the development of a unique algorithm, actually, 2 of them, identify people who have perhaps unknown pre-existing dementia or cognitive impairment. These are all patients over 65 years old in Medicare, combined with a national cancer database called SEER, which is Surveillance, Epidemiology, and End Results study, for about a 10-year period. And it was conducted in people with 6 different kinds of common cancers. And what did we find that was new in this study? It's surprisingly common using this algorithm adapted from clinical diagnostics for people to have pre-existing cognitive impairment concerning for Alzheimer's or another dementia. This is often thought to be quite low, probably because most people with cognitive impairment do not end up enrolled in clinical trials. But if you look at a real-world database like this, 15 to 30% were found to have evidence of pre-existing cognitive losses. So they assessed the prevalence of this pre-existing disease through this algorithm across the cancer types, and it was even more common among certain racial and ethnic subgroups, basically non-white subgroups compared to white subgroups. Again, white individuals are more commonly enrolled to significant degrees in clinical trials.

So what does this mean for patients and caregivers if up to 1 in 3 older adults facing cancer treatment have pre-existing dementia, evidence of Alzheimer's, or related dementia? They need to be identified and screened for in advance of being treated for their cancer. Why is this important? Patients with cognitive impairment are at an increased risk for both overtreatment and undertreatment for their cancers. Those with pre-existing cognitive loss are at very high risk for a number of different toxicities and at high risk for mortality when being treated with chemotherapy and other kinds of cancer treatments. And if it's not identified in advance, they could be placed at higher risk and may want to reconsider the therapy choices. If someone is identified with dementia or cognitive impairment, one thing they're at especially high risk for, as we'll see in the next study, is chemotherapy-related, additional cognitive impairment during treatment, which can lead to a number of complications such as delirium and other problems. On the flip side, patients with dementia are often, as we saw with trials, not offered the most aggressive therapies, even when they're not at risk and offered the appropriate support. And so they're at risk of being undertreated based on perhaps an early kind of dementia that would be perfectly appropriate to be treated. So caregivers and family members may need to advocate on behalf of their older relatives or parents or grandparents to get appropriate treatment. So it's important to ask your oncologists and your primary care doctors about the risks when deciding what treatments and in some cases to undergo appropriate screening and testing for cognitive impairment prior to starting treatment.

So the next study is another study of cognitive impairment moving in the direction that the field of cancer and aging is moving, which is identifying effective interventions rather than simply identifying risk factors. So this is a phase II study of 2 combined interventions, exercise and low-dose ibuprofen for cancer-related cognitive impairment, essentially chemobrain, during chemotherapy for patients with cancer led by Dr. Janelsins and their team at the University of Rochester. Who does this study affect? Patients with cancer receiving chemotherapy who are facing cognitive difficulties with the initiation of chemotherapy and testing for 7 different domains of cognition, including memory, attention, concentration, and executive function, among a few others. This was 86 participants reporting cognitive difficulties during chemotherapy. The majority were breast cancer patients, and the vast majority were women. I do note that patients' average age was 54, younger than our usual cutoff of 65, but highlighting the fact that cognitive difficulties can be identified at any age with chemotherapy. I mentioned the 7 cognitive tests. Patients were then randomized into 3 different groups versus placebo for 6 weeks: an exercise alone arm, which included a walking program and a resistance band training program which has been validated in other contexts for cancer patients; daily ibuprofen, 200 milligrams given twice a day by itself; or a combination of exercise and low-dose ibuprofen together. And what did they find, particularly for the issue of attention? So this is the ability to maintain attention on a cognitive task. Exercise alone was the most valuable intervention. People were able to maintain their attention for a significant amount of time, over 20 seconds. Ibuprofen alone also improved significantly compared to placebo at about 10 or 11 seconds. Interestingly, the 2 together had a non-significant improvement in attention of about 8 seconds and raises some questions about why the 2 together would work less well than either alone, perhaps suggesting they use similar mechanisms. Self-reported cognitive function was also found in both of the exercise groups to be improved. So this was the subjective experience of chemobrain was seen to improve in those randomized to the exercise arms.

So what does this mean for patients with cancer receiving chemotherapy? These simple, validated, home-based exercises improved attention and the self-reported or subjective sense of cognitive performance. These are things that could easily be done in the home during chemotherapy and may well improve the situation for those who are experiencing chemobrain. Low-dose ibuprofen, just 200 milligrams, that's 1 over-the-counter pill twice a day, improves the same attention, although not quite as much as exercise. Again, the caveats are noted that these were younger patients. The benefits may be even greater for older patients who are more likely to have cognitive impairment, as we saw, and that it was primarily breast cancer patients and primarily women. There are still questions remaining about why the combination was less effective than either intervention alone.

And the last study I want to talk about is about other kinds of pre-existing conditions for older adults, focusing on those not with earlier stage disease, but with poor prognosis patients. So this was patients over 65 with poor prognosis cancers defined as a median survival expectation of less than 1 year and combined 2 large databases. To understand this, the Health and Retirement Survey, a large nationally representative study, combined with claims information or people's experience utilizing the health care system or on Medicare, and identified over 2,000 older adults with cancer, and just assessed the frequency of these pre-existing conditions, all of which are detected with a geriatric assessment, which is our standard way of assessing older patients with cancer and as part of the ASCO guidelines that were published a couple of years ago. 26% of the patients had lung cancer, 14% had GI cancer, and 60% had other kinds of cancers. What was found? Patients with poor prognosis have high rates of these pre-existing geriatric conditions. Of greatest concern, perhaps, is daily activities difficulties with well over 60% having difficulty climbing stairs, which are in the homes of many people, nearly 50% had trouble standing up from a chair, and a quarter had trouble walking 1 block. This is important as we anticipate giving people chemotherapy to know that the functional losses should be accounted for in advance, if at all possible, and to be prepared for people who may have lived in a house with stairs for many years or who have a low-slung chair that's difficult to get out of, that will become even more of a problem in the future. About a third of people over the year had a significant fall, 12% of which resulted in injuries, again, suggesting that changes in the home or a falls assessment be done or physical therapy to strengthen prior to treatments. And as we noted, just the last couple studies with cognitive impairment, nearly 1 in 10 had trouble managing their finances and another 6% had difficulties with their medications, highlighting additional challenges that come with older adults when they start on chemotherapies and helping anticipate problems that could be addressed or adjusted for. Of note, as people get older, these problems become even more pronounced. In those who are 85 and older who had cancer, over half had falls and even more presented cognitive problems with a fully one-fourth difficulty managing money, 12% difficulty taking their medications. Often, they're on a number of additional medications, just highlighting the challenges for simply getting through their days and anticipating that in the decision-making for starting on therapy or providing the appropriate support prior to starting on therapy. So I don't have conflicts of interest with this study or the prior study of any kind. And that's my last slide.

Oh, I'm sorry, I have 1 more. Let me do the “what this means for patients and families.”  Advanced cancer is often accompanied by these geriatric conditions that affect health, functional status, cognitive status, falls, and social support is another common one along with the establishing appropriate goals of care. These conditions are detectable with the geriatric assessment. Here I've linked to the ASCO guidelines that came out in 2018. It's now becoming more of a standard of care for older patients. I will point out with the geriatric assessment, it does not require time in clinic to be conducted. It can be done in advance of clinic, and it can be done with nursing support or other staff doing it. Oftentimes online questionnaires can be answered so that these issues can be identified even prior to coming to the clinic or being seen in a video call. Interventions can improve many of these outcomes. We heard earlier from Dr. Markham about chemotherapy toxicities. Geriatric assessment interventions have been shown to decrease toxicities. Polypharmacies, so the reduction in the number of medications that are required that may not be appropriate any longer. Completion of advanced directives goes up with the use of geriatric assessment interventions, and the decision-making choices that need to be made for cancer therapies, whether it's chemotherapy or immunotherapy or others, are enhanced and happen more often with the geriatric assessment being done and help to mitigate the long-term outcomes, especially toxicities and geriatric issues that come up for older adults. I think with my last slide, my timing is just about perfect, Greg, so thanks.

Greg Guthrie: It is perfect, Dr. Dale. So thanks very much for that. And now we can move on to our Q&A session. And we can see what questions we have. Ah, so our first question is for Dr. Sullivan, and it is, is relatlimab a checkpoint inhibitor or is LAG-3 not a checkpoint?

Dr. Sullivan: Excellent question. LAG-3 is an immune checkpoint. Immune checkpoints are molecules that-- I guess the way to step back is to say that to have an active immune response, there needs to be a few things to happen. Typically what the immune response we're talking about against cancer is T-cell immune response. And so the T-cells need to be able to recognize something like a piece of tumor protein that's expressed on the outside of the tumor, like a flag. And then once they've sort of, there's this teaching process or priming process and then that process is involved. So there's a lot of these so-called checkpoints. Some of these checkpoints actually activate the immune system better, and some of these actually block the immune system from working well. And it's this delicate balance. It's almost like our immune systems have to be in the Goldilocks zone so it's not too hot, not too cold, but just right. And so a lot of these drugs, these checkpoint inhibitors, are blocking drugs to either activate cells or once the cells are activated and get into the immune microenvironment of the tumor, then they have to navigate these other potential checkpoints. And so PD-1 and PD-L1 are checkpoints on the immune system that are targeted by drugs like nivolumab, pembrolizumab, atezolizumab. And another checkpoint is LAG-3. So LAG-3 is expressed on what we call exhausted immune cells or T-cells. And so blocking LAG-3 can actually overcome that exhaustion and make those immune cells work better. So LAG-3 is a checkpoint and relatlimab is a checkpoint inhibitor. And that was a long way of saying it.

Greg Guthrie: One of the things that's really interesting about that study is that relatlimab is used in combination, and is that to reach that kind of Goldilocks situation that you were saying?

Dr. Sullivan: It's like the Goldilocks zone. Yeah, not too hot, not too cold.

Greg Guthrie: Just right.

Dr. Sullivan: Well, relatlimab and nivolumab are trying to make the immune system hotter. And so that's a good thing when we're talking about anticancer immunity. The downside, and to Dr. Markham's and Dr. Dale's points about toxicity, the downside of having the immune system too hot is that it can lead to side effects, and those side effects are generally inflammatory. So we worry the more checkpoints we inhibit, that the more side effects we'll see. So the combination in that first study of ipilimumab and nivolumab, when we use that combination, we get a lot of side effects that can be very challenging to get patients through that treatment, which is why we're looking for other combinations that will be more effective than just nivolumab or pembrolizumab by itself, but also will lead to substantial and better antitumor outcomes.

Greg Guthrie: Great. All right. We have another question, this one for Dr. Dale. How often do doctors evaluate patients for ADRD, or if they do not, will they still go ahead and provide chemotherapy?

Dr. Dale: Always risky for me to say what doctors do. I feel like I'm talking about my oncology colleagues like the anthropologist in Mars, I sometimes say where I'm just the geriatrician observing. So I don't know what people do for sure. We do know is that it's still not common for geriatric assessments that include cognitive screening tests to be done in oncology practices for a number of reasons. Resources is a particular challenge. So we already have very busy oncologists, particularly community oncologists, but all of them. And to fit in a cognitive screening test can be a real challenge. And so we have to come up with a different systematic way. Having said that, do they go ahead and treat? I think in most cases when people with dementia are identified, they are less likely to be treated for the concerns people have for cognition. But the way it's identified through family report in patients is known to be inconsistent and not as good as formal testing. So what I would say is we're getting better at creating screening tests that take very little time to do some cognitive assessment. And those who are screened as positive can then be sent for appropriate follow-up with a geriatrician or to a neurologist, whatever is appropriate. But those who are not can then move ahead with chemotherapy and not be excluded. So we're getting there, but there's more work to be done.

Greg Guthrie: Okay, great. And not a follow-up question, but another question for you, Dr. Dale. It seems like we've gotten a couple of questions about ibuprofen. So what is the mechanism by which ibuprofen is thought to improve or affect cognitive function in older adults with cancer?

Dr. Dale: Great. And I'm not an expert in the cognitive impairment directly, more in the health services sense, but my understanding is older adults are especially affected by inflammatory responses. So being frail, for example, is associated with inflammatory markers in our system such as CRPE and other inflammatory markers. And it's thought that ibuprofen as an anti-inflammatory reduces that. And those same markers are associated with this chemobrain cognitive impairment in several different studies. These are still association, so we can't say they're causal relationships. But the hypothesis is if we give ibuprofen and lower the inflammatory profile, that will allow cognition to improve and attention by extension. There is another theory I'll put out there. This is my personal one that I'm a little more sympathetic to, which is the inflammatory response from cancer and cancer treatments is fatigue. And fatigue is by far the most common side effect as Dr. Markham can tell us on the toxicity profile. It's very prevalent. For older adults, being fatigued affects cognition just like it does physical functioning. And it's very difficult to concentrate when you're so tired. And to the extent that we can reduce that inflammatory response and reduce the sense of fatigue, the more people could concentrate. Again, none of this is proven. This is still all at the hypothesis testing stage.

Greg Guthrie: Great. Our next question is for Dr. Markham. Is there any indication from the research that either vaccine, this HPV vaccine, or screening alone made the difference in the lowered incidence rate for cervical cancer? Or was it a combination of vaccination and screening?

Dr. Markham: So I don't think we know the answer to that really, and I have not seen it in studies. We have data that screening is helpful and we have data that the HPV vaccine is helpful.  So I suspect that it's the combination, but I don't know how much of each is contributing. I do think that like many things with cancer, it does take a multiple-pronged approach whether to treat it or to diagnose it. So to me, it makes sense that it's some combination of the 2.

Greg Guthrie: So a quick follow-up. For a lot of the squamous cell carcinomas that are included in that HPV study, they conclude by saying that there aren't a lot of screening protocols in place for these types of cancer. Do you think that we have the knowledge to do screening for those cancers and we just don't? Or will further research be needed to find ways to detect and prevent?

Dr. Markham: So I think like many of these things, we do need more research. The challenge with screening research is that we have to prove, our scientists have to prove that you can screen a lot of people safely and not in a costly   manner and actually reduce the incidence of cancer or some other outcome. And those studies are actually really hard to do, and they take a long time. I think the data that has come out on prostate cancer screening and on breast cancer screening with mammograms and at what age do we start and so on and so forth, I think is just a testament to how complicated the screening studies can be. So do we have the ability to screen? I think yes. I know that some dentists, for example, and head and neck doctors, head and neck specialists like ENT physicians, are able to just visually take a look in the mouth, for example, to screen for any abnormalities that look like cancer. Do we as a country or a health system have the ability to do that on a large scale [not] in a costly manner? I don't know the answer to that. And that's where we really do need more research. And same with anal and vulvar cancers, etc.

Greg Guthrie: That's great. Thanks, Dr. Markham. So I think we're going to move on to our final question, and that's for you, Dr. Sullivan, is how similar is TIL therapy to CAR T-cell therapy?

Dr. Sullivan: That's a great question. Both are T cells that are taken from a patient and given back to the same patient. But a CAR T-cell is made by removing a bunch of white blood cells from the blood and then those white blood cells, those T cells, are modified so that they are able to recognize the cancer. And when they do, the immune cell turns it on and they can actually expand. It's really like a living and modifying kind of in real time drug. And so there are a few of those CAR T cells that are approved by the FDA to treat a number of different diseases that express what we call an antigen that the CAR T recognizes. T-I-L therapy, or TIL therapy, are T cells that are removed from the tumor itself. They are not modified in the way, at least, that the standard NIH protocol, which is the protocol that we presented today and was presented at ASCO, which essentially is take the cells from the tumor, expand them, grow them, make sure they recognize the tumor, and then give them back. And so the difference is-- their similarities is they're both T cells and the T cells theoretically can recognize the cancer. The differences are that CAR T cells are taken from the blood and modified, and TILs are taken from tumors and are not modified.

Greg Guthrie: Great. That's very clear, Dr. Sullivan. Thank you, and thank you to all of our panelists for joining us today and sharing this great research and, of course, your expertise. It's been a real pleasure. And to all of you who attended this Research Round Up webinar, thank you to all of you for joining us today. You can find more coverage of the research from the ASCO Annual Meeting and other scientific meetings at the Cancer.Net blog. That's Cancer.Net/blog. If you're interested in more Cancer.Net content, please sign up for our monthly Inside Cancer.Net newsletter or follow us on social media. We're on Facebook, Twitter, and YouTube. And our handle is always @CancerDotNet with dot spelled out. Thank you for everybody for attending, and have a good day. Thanks.

ASCO: Thank you, Dr. Markham, Dr. Sullivan, and Dr. Dale. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

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