The soaring number of cancer survivors since the National Cancer Act of 1971 was enacted into law provides a snapshot of the profound progress made against cancer over the past half-century: 3 million survivors in the 1970s,1 compared to more than 18 million today, and that number is expected to climb to 26 million by 2040.2 Advances in early detection and treatment, as well as improvements in smoking cessation strategies, are driving a reduction in the overall cancer mortality rate in the United States, which has fallen by 33% over the past 3 decades, translating into more than 4.1 million cancer deaths averted.3
Despite this improvement, ongoing challenges to overcoming the disease remain. In the coming year, cancer incidence in the United States is expected to reach a dismal milestone. According to the American Cancer Society, for the first time, the number of new cases of cancer diagnosed in the country is expected to top 2 million—nearly 5,500 a day—largely due to an aging population; increasing diagnoses of several common cancers, including breast, prostate, pancreatic, kidney, colorectal, and bladder; and a rising incidence of cancer among younger adults.4 In addition, the American Cancer Society projects that, in 2024, more than 611,000 individuals will die from cancer, accounting for more than 1,600 cancer-related deaths each day.4
In this continuing series on The Future of Cancer Care, The ASCO Post explores research advances being made in multiple myeloma, genitourinary cancers, colorectal cancer, and young-onset pancreatic cancer. Our panel of experts for this installment includes four clinician/scientists from Dana-Farber Cancer Institute in Boston: Irene M. Ghobrial, MD, Senior Vice President for Experimental Medicine, Director of the Center for Early Detection and Interception of Blood Cancers, Lavine Family Chair for Preventive Cancer Therapies, principal investigator of the PROMISE trial, and Professor of Medicine at Harvard Medical School; Bradley A. McGregor, MD, Director of Clinical Research for the Lank Center of Genitourinary Oncology; Benjamin L. Schlechter, MD, a senior physician in the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute and Instructor of Medicine at Harvard Medical School; and Brian M. Wolpin, MD, MPH, Director of the Gastrointestinal Cancer Center and Robert T. and Judith B. Hale Chair in Pancreatic Cancer at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School.
Subsequent topics in this series will include the impact of climate change on the development and treatment of cancer; barriers to accessing care in low- and middle-income countries; and how ASCO is advancing global health equity by diversifying clinical trial representation, increasing access to resources, and strengthening research capacity.
Converting Multiple Myeloma Into a Preventable Cancer
Irene M. Ghobrial, MD
A Conversation With Irene M. Ghobrial, MD
In 2018, Dr. Ghobrial and her colleagues at Dana-Farber Cancer Institute launched PROMISE (ClinicalTrials.gov identifier NCT03689595), a large, ambitious screening study to identify individuals with premalignant precursor conditions to multiple myeloma, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). The goal of the study is to identify the clinical, genomic, and immune markers of MGUS/SMM, to precisely stratify an individual’s risk for transforming to active myeloma; determine which patients might benefit from early therapeutic intervention; and develop effective targeted therapies to prevent disease.
In this conversation with Dr. Ghobrial, she discusses new models to predict transformation from precursor conditions to active disease, treatment interventions to prevent myeloma, and whether cure in myeloma is possible.
What are you learning about the risk factors for developing multiple myeloma and its precursor conditions?
The PROMISE study is ongoing, but we are gaining an understanding of the potential risk factors of developing MGUS and its potential early precursor monoclonal gammopathy of indeterminate potential (MGIP), a monoclonal gammopathy below the clinical immunofixation electrophoresis detection level (< 0.2 g/L).
We recently published the results from our study of the PANGEA model (predictor of the risk of progression from MGUS or SMM to multiple myeloma), which used data on biomarkers—including monoclonal protein concentration, free light chain ratio, age, creatinine concentration, and bone marrow plasma cell percentage—as well as hemoglobin trajectories, to predict progression from precursor disease to multiple myeloma.
We found that the PANGEA model improved the prediction of progression from smoldering multiple myeloma to active multiple myeloma compared with the Mayo Clinic’s 20/2/20 risk-stratification model, and it also outperformed the rolling model developed by the International Myeloma Working Group.5 If additional studies confirm these results, we are hoping that the PANGEA model will help us to really identify the patients with MGUS or SMM who are truly at risk of developing active disease, and when that is likely to happen—is it in 2 years, 5 years, or later?
Then the most critical part comes into play: what therapy intervention will be most effective in eliminating the disease before it progresses? We have several clinical trials underway to answer that question. Probably the most notable drug so far is the bispecific antibody teclistamab, which we are using to boost patients’ immune systems, and we are seeing impressive results, including very deep remissions, with 100% of the patients achieving measurable residual disease–negative status in the very early results of this study. We are hoping to complete the trial this year and publish the results soon.
We have also initiated a chimeric antigen receptor (CAR) T-cell trial in which we are hoping to show that this therapy can effectively eliminate high-risk smoldering myeloma without the use of chemotherapy.
Is it appropriate to use immunotherapy interventions in patients who don’t have active disease? Do patients experience side effects with these drugs?
When bispecific antibodies are used in heavily pretreated patients with relapsed or refractory myeloma, they can frequently cause infections, which is a significant side effect. Interestingly, because the immune system is still robust in patients with smoldering disease and we give the drug less frequently and for a very short period of time, we don’t see those same side effects. We are continuing to assess the risk/benefit in these patients.
The duration of the current trial is 2 years, but we will change the duration to 1 year and are assessing results at 6-month and 3-month durations to determine whether you can kill the cells with treatment, so we can balance response and toxicity.
B-cell maturation antigen–targeted CAR T-cell therapy has been U.S. Food and Drug Administration (FDA)-approved for multiple myeloma that has relapsed after or is refractory to at least four prior treatments. Still, studies show that many patients only achieve short-term efficacy with this treatment. Would this therapy be more effective in the first- or second-line setting rather than in the fourth-line setting, when the immune system is weakened?
We are just in the infancy of knowing how to use the immune system most effectively. I think bispecific antibodies and CAR T-cell therapy are showing us that we can get durable responses, but these therapies also come with toxicities. The questions we are trying to answer are: when is the best timing for these therapies, and is earlier treatment better, when the immune system is more functional, the tumor burden is lower, and there is less genomic complexity?
This is why we think using these treatments in the first-line setting could be a good option to stop smoldering myeloma from progressing to active disease. We will have a better understanding of when and how to use these therapies with more research. Likely, it will be in the earlier setting, but we have to wait for the data to know for sure.
Is cure possible in myeloma?
For me, cure means we give patients a therapy for a short period—not with indefinite maintenance therapy—and they experience complete remissions without evidence of disease for a very long time. So far, we have not seen that in myeloma. Personally, I think it’s because we are treating patients way too late, after the disease has become active.
Let’s see if we can answer this question with interventional therapy in smoldering myeloma. But we won’t know the answer for another 4 or 5 years.
There’s a lot of controversy among oncologists about whether we should treat smoldering myeloma when patients are asymptomatic, and I understand that hesitation. But we should be careful that our opinions are not a mandate, and we should also listen to our patients. Clinical trials are designed to answer questions that could potentially be very helpful for our patients.
Transforming the Metastatic Setting in Bladder Cancer: Is Cure Possible?
Bradley A. McGregor, MD
A Conversation With Bradley A. McGregor, MD
Results from several clinical trials in genitourinary cancers presented during the European Society for Medical Oncology (ESMO) Congress 2024, including the phase III NIAGARA trial and the phase I DAD (Double Antibody Drug Conjugate) trial, have the potential to transform care for patients with metastatic bladder cancer. Data presented from the NIAGARA trial show that adding the immune checkpoint inhibitor durvalumab to standard treatment for muscle-invasive bladder cancer significantly improved patient survival, reducing the risk of death by 25%.6
Updated efficacy data from the DAD phase I trial of sacituzumab govitecan-hziy plus enfortumab vedotin-ejfv in second-line and later treatment for metastatic urothelial carcinoma found an objective response rate of 70%. Of the 16 responders, 4 had a complete response, and 12 had a partial response. The median duration of response was 10 months, with ongoing responses in six patients.7
In a wide-ranging conversation with Dr. McGregor, lead author of the DAD trial, he discusses the potential for cure in metastatic bladder cancer, advances in metastatic prostate cancer, and the value of multicancer early detection tests in early-stage prostate cancer screening.
Please talk about the advances being made in the treatment of genitourinary cancers, especially in metastatic bladder cancer.
When we look at research in prostate, kidney, and bladder cancers, I think the disease that is most ripe for progress is advanced-stage bladder cancer. We’ve had negative trials in bladder cancer for decades. Then, we got the results from KEYNOTE-045 and KEYNOTE-052, investigating the durability of response to pembrolizumab compared with chemotherapy in patients with metastatic urothelial carcinoma, which showed a nearly 30% objective response rate.8
These results have transformed treatment in the metastatic setting, and there’s hope that we can take them into the perioperative setting in stages II and III, providing patients with more options and, hopefully, curing more patients. I’m also very excited about the updated results from our phase I DAD trial combining sacituzumab govitecan and enfortumab vedotin in metastatic urothelial carcinoma, which showed an objective response rate of 70%, with 9 of 23 patients having an ongoing response after a 14-month median follow-up. With enfortumab vedotin alone, the objective response rate was 40%.7
In the DAD-IO trial (ClinicalTrials.gov identifier NCT04724018), we are combining sacituzumab govitecan and enfortumab vedotin with pembrolizumab in patients with treatment-naive metastatic urothelial carcinoma. We expect to see objective response rates of over 75%.
These data are compelling and offer an idea for how we could think about using rational combinations of antibody-drug conjugates in a variety of other cancers as well. It’s very exciting.
What advances are you seeing in other genitourinary cancers?
There are interesting clinical trial results in the treatment of metastatic prostate cancer, including data from the phase III SPLASH trial assessing Lu-177–PNT2002, a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy, in patients with PSMA positron-emission tomography–positive metastatic castration-resistant prostate cancer following disease progression on an androgen receptor pathway inhibitor, which showed clinical benefit.9 We need more information on when to best use this therapy and how to optimize the dose. There are also continuing questions about how to use PARP inhibitors in prostate cancer, with an updated overall survival analysis from TALAPRO-3 being eagerly anticipated.
We are starting to see baby steps forward in the metastatic setting of prostate cancer, and we hope to translate those results into advances in the perioperative setting. The phase III PROTEUS clinical trial investigating perioperative apalutamide plus androgen-deprivation therapy vs placebo plus androgen-deprivation therapy in patients with localized high-risk or locally advanced prostate cancer has completed accrual, and we look forward to the results.
All of these advances highlight the importance of appropriate screening for prostate cancer. But outside of the prostate-specific antigen test, so far, we don’t have great screening tools. The initial concern with screening was that we were treating all patients, no matter their risk for cancer progression. Now, we understand that an active surveillance approach can be very reasonable in the right patient. In addition, we now have better diagnostic tools, such as magnetic resonance imaging, and a better understanding of the pathophysiology of prostate cancer, so we are able to avoid overtreating patients.
Hopefully, with these advances, prostate cancer will not impact the quality of life or life expectancy of many patients.
How valuable are multicancer early-detection liquid biopsy tests in the screening of early prostate cancer?
Although these tests have the potential to find prostate cancer before symptoms appear, we need more evidence of their accuracy and how best to adopt them in the clinic. Ultimately, we want to be able to identify a cancer early and determine the best interventions—and, hopefully, cure that cancer. How these multicancer early detection tests fit into that equation and what difference they can make in the long term are the critical questions going forward.
Overcoming the Challenges of CAR T-Cell Therapy in Solid Tumor Cancers
Benjamin L. Schlechter, MD
A Conversation With Benjamin L. Schlechter, MD
Although CAR T-cell therapy has emerged over the past decade as a vital immunotherapeutic approach in the management of hematologic malignancies, including leukemias, non-Hodgkin B-cell lymphomas, and multiple myeloma, the value of the treatment in solid tumor cancers has remained inconclusive. Among the barriers to overcome with the use of CAR T-cell therapy in solid tumors is the need to -identify a target that is unique to the specific cancer and that is not present on normal tissue, according to Dr. Schlechter.
During the 2024 ASCO Annual Meeting, Dr. Schlechter presented the results from a phase I study of a novel coupled CAR T-cell therapy called guanylate cyclase-C (GCC)19 CART—which pairs a solid tumor targeting CAR with additional CD19-targeting CARs—for patients with refractory metastatic colorectal cancer. Guanylate cyclase-C has been reported to be expressed in over 80% of colorectal cancers, making it an appealing target for CAR T-cell therapy, said Dr. Schlechter. The results from the study (NCT05319314) show that the therapy has an acceptable safety profile and meaningful clinical activity in colorectal cancer.10
Here, Dr. Schlechter describes the barriers to CAR T-cell therapy in solid tumor cancers, discusses young-onset colorectal cancer, and explains why early detection tests for colorectal cancer shouldn’t be used in young adults.
Why is CAR T-cell therapy, so far, ineffective against solid tumor cancers?
In hematologic cancers, CAR T-cell therapy identifies a target that is unique to the cancer or unique in a way that we can target effectively, and then we can engineer T cells to go after that target. In solid tumors, it’s been hard to identify a target that is unique to the cancer and that is not present on some normal tissue.
GCC19 is a target that is present on nearly all colorectal cancers and on the normal gut mucosa. We hypothesize that GCC might be a good marker because it’s on the luminal side of the colon, not the blood side, and we won’t get too much infiltration of the CAR T cells into that part of the colon. But even if we had a perfect CAR T-cell marker for solid tumors, it doesn’t mean the therapy would be effective, because the cells might not have a target to bind to or will become exhausted and die off quickly. So, we need a second signal to promote expansion of the CAR T cells and promote their survival while they do the job of killing off the cancer cells. GCC19 has two targets—CD19 and GCC—so it overcomes those limitations.
We are presenting data on a dose-escalation phase I study of GCC19 in colorectal cancer during the 2025 ASCO Gastrointestinal Cancers Symposium. We are seeing responses, as well as common CAR T-cell–related adverse events including diarrhea and colitis, due to the presence of GCC on the mucosa. As a proof-of-concept study, this is a good trial to show that it’s possible to target colorectal cancer and overcome some of the limitations of CAR T-cell therapy in solid tumors.
We also need to find cells other than CAR T cells that might be effective against solid tumors. We are investigating T-cell antigen coupler (TAC) technology to modify T cells, allowing them to recognize and treat HER2- and Claudin18.2-positive solid tumors, including breast and gastric cancers. During the 2023 ASCO Annual Meeting, we presented results from our dose-escalation phase I/II trial investigating the safety and efficacy of autologous TAC01-HER2 treatment in heavily pretreated patients with breast, colorectal, gallbladder, gastroesophageal junction, gastric, esophageal, lung, and ovarian cancers. Early results showed a manageable safety profile and promising clinical activity,11 although not to the degree of benefit we wanted, but also not to the degree of toxicity we see with CAR T-cell therapy.
What are you learning about young-onset colorectal cancer, and are there differences in the molecular characteristics of colorectal cancer tumors in younger and older adults?
We have to divide younger adults in this scenario into two age groups: those younger than age 50 and those younger than age 35, whose colorectal cancer is probably biologically more distinct than in patients aged 35 to 50. We know that patients 35 and younger have a worse outcome. They usually have more aggressive colorectal cancer, and most likely they have left-sided colon or rectal cancer. These younger patients are also usually diagnosed at a later stage, because no one expects young people to have colorectal cancer even though it is more common now. Younger adults are more likely to be treated with aggressive combinations of triplet chemotherapy regimens instead of doublet combinations, and the outcomes are similar for those aged 35 to 50 and a bit inferior for patients 35 and younger. So, even though they are getting more chemotherapy combinations, they’re getting the same or less benefit from the treatment.
There are interesting risk factors associated with young-onset colorectal cancer, but we don’t know what they all mean in the development of disease. We know that early-onset colorectal cancer is not genetic. It is usually caused by exposure to environmental factors, such as obesity and a sedentary lifestyle. We also know there is a gradient in the presentation of this cancer. Right-sided colorectal cancers are very uncommon in younger patients, and left-sided cancers are much more common.
In some subsets of younger patients, we do see differences in the molecular characteristics of their tumors compared to colorectal cancer found in older adults. However, a comprehensive molecular characterization of early-onset colorectal cancer is lacking, and more research needs to be done to understand the unique biology of this cancer among these younger patients.
On July 29, 2024, the FDA approved Guardant Health’s Shield blood test for colorectal cancer screening in adults aged 45 and older who are at average risk for the disease. Should younger adults also be screened for colorectal cancer using this or another liquid biopsy or stool-based test?
Blood- and stool-based screening tests shouldn’t be used in younger adults outside of a clinical trial, because they can give individuals a false sense of reassurance if the test is negative for colorectal cancer. Young-onset colorectal cancer may be genetically distinct and present differently from older-onset colorectal cancer, and they may have different circulating tumor DNA (ctDNA) profiles in blood and stool samples. But we have to prove that. Until we can prove that young-onset patients can be successfully screened for colorectal cancer, I wouldn’t use these tests, because their dynamics in younger people are unknown.
The bottom line is that we have to think more about cancer being diagnosed in younger people than we ever did before. The standard test for younger patients should still be colonoscopy—and a higher degree of suspicion for colorectal cancer than we had in the past.
Advances That Could Soon Change the Treatment Landscape in Pancreatic Cancer
Brian M. Wolpin, MD, MPH
A Conversation With Brian M. Wolpin, MD, MPH
Pancreatic cancer is among the most lethal malignancies in the United States, and it is poised to become the second leading cause of cancer-related mortality after lung cancer by 2040 (46,000 vs 63,000 deaths, respectively), surpassing colorectal cancer (34,000 deaths).12 Equally troubling is the alarming rise in pancreatic cancer incidence among young women (aged 15–54 years), particularly pancreatic ductal adenocarcinoma, compared to men.13
In this wide-ranging interview with Dr. Wolpin, he describes the overall trends in pancreatic cancer, including more effective treatment, and the disturbing rise in early-onset disease, especially among younger women.
What progress do you see in pancreatic cancer over the next 5 years?
Over the next 1 to 2 years, we will see some long-awaited advances in this cancer, including mutation- and immune-based therapies that are more targeted approaches to treatment. A host of different KRAS inhibitors are either in the clinic or coming to the clinic in the next year. The issue with the currently approved KRAS inhibitors is that they are inhibitors of the G12C mutation, which accounts for only between 1% and 2% of pancreatic cancers, so these drugs haven’t had a big impact on our treatment arsenal. However, the drugs on their way to the clinic now inhibit many different mutant alleles of RAS, or specific RAS mutations, including the G12D mutation, which is the most common KRAS mutation in pancreatic cancer. So, these drugs are poised to make important changes in how we treat this disease over the next several years.
Another genetic alteration that may be targetable leads to the loss of the methylthioadenosine phosphorylase (MTAP) protein, which can make cancer cells more susceptible to inhibition of protein arginine methyltransferase 5 (PRMT5). Multiple PRMT5 inhibitors are now in the clinic and are selective for MTAP-deleted tumors. About 30% of pancreatic cancers have loss of the MTAP protein, and these drugs will provide, we hope, another foothold into how to target this tumor beyond chemotherapy.
An additional exciting research area is tumor-derived vaccines or cell-based therapies to use the immune system against mutations present in specific tumors, providing a more personalized approach to treat this cancer. Currently, several trials are underway testing this strategy in KRAS- and TP53-mutated tumors, in addition to targeting other personalized mutations specific to an individual tumor. So, there is clearly movement in trying to bring immune-based strategies to patients more broadly.
Are you also seeing advances in screening approaches to catch pancreatic cancer at an earlier, more curable stage?
There has been some very interesting progress in this area as well, especially in patients with familial risk. There are data from large familial registries showing that through regular screening with magnetic resonance imaging and -endoscopic ultrasound, pancreatic cancers are being picked up in earlier stages. So, instead of many patients with familial risk being diagnosed with advanced disease, the majority of these patients are now being diagnosed at earlier-staged disease.
But the group with familial or genetic risk only comprises about 10% to 15% of people diagnosed with pancreatic cancer. We need to figure out how to expand our ability to screen the general population, and there is a lot of work underway on how to do that, including looking at medical record data and using machine learning algorithms to help determine who might be at higher risk for developing the cancer. There is also research in designing new multidetection blood-based screening tests that capture ctDNA fragments or other cellular components that indicate the presence of cancer. But at this point, it’s still unclear how well they will function and how many of these cancers, including pancreatic cancer, they will find early.
Studies show an increase in the incidence of pancreatic cancer among younger adults, especially in women younger than 55.13 What are you learning about the rise in this disease in younger adults, and are the risks greater for young women?
We are seeing a rise in younger-onset pancreatic cancer across a number of data sets and pancreatic cancer registries. In my clinic, I am seeing more patients in their 30s and 40s than I saw 15 or 20 years ago, but we don’t know why this is happening.
Obesity, diabetes, smoking, and lack of physical activity are all associated with the development of pancreatic cancer at younger ages. But that being said, many younger patients presenting with this disease do not have any of those risk factors. There may be dietary or environmental risk factors, but we just don’t know yet for certain. More research needs to be done to determine whether any of these exposures explain the increased numbers of patients we are seeing with younger-onset pancreatic cancer.
Some studies have suggested an increase in early-onset pancreatic cancer in younger women. In my clinic I haven’t necessarily noticed a greater rise in younger women compared with younger men, but this will be an important development to follow over time.
Are there differences in the molecular characteristics of the tumors found in younger patients compared to the tumors in older adults?
Yes, there does seem to be enrichment for inherited mutations in younger individuals. We see a slightly lower rate of KRAS mutations in the tumors in younger patients but a slightly higher rate of inherited mutations in genes such as BRCA1/BRCA2. More research needs to be done to understand whether there are other genetic changes happening or changes at the gene-expression level that may be particularly contributing to younger-onset pancreatic cancer.
DISCLOSURE: Dr. Ghobrial has received honoraria from Bristol Myers Squibb, Takeda, Amgen, Janssen, Vor Biopharma, and AbbVie; has served as a consultant to Bristol Myers Squibb, Novartis, Amgen, Takeda, Celgene, Cellectar, Sanofi, Janssen, Pfizer, Menarini Silicon Biosystems, Oncopeptides, The Binding Site, GlaxoSmithKline, AbbVie, Adaptive, and 10xGenomics; has received reimbursement for travel, accommodations, and expenses from Bristol Myers Squibb, Novartis, Takeda, and Janssen Oncology; is the founder and a board member of Predicta; and her spouse, William Savage, MD, PhD, is Chief Medical Officer at Disc Medicine and holds equity in the company. Dr. McGregor is a consultant for Arcus, Aveo, BMS, Daiichi, Eisai, Exelixis, Genmab, Gilead Sciences, and Pfizer; and his institution receives research funding from Aveo, BMS, Exelixis, Gilead Sciences, and Pfizer. Dr. Schlechter is an advisory board member for Agenus and Janssen Pharmaceuticals. Dr. Wolpin is a consultant and serves on the advisory boards of Agenus, BMS/Mirati, EcoR1 Capital, GRAIL, Harbinger Health, Ipsen, the Lustgarten Foundation, Revolution Medicines, Tango Therapeutics, and Third Rock Ventures; and his institution receives research funding from Amgen, AstraZeneca, BMS/Celgene, BreakThrough Cancer, Eli Lilly, Harbinger Health, Lustgarten Foundation, the National Institutes of Health, the National Cancer Institute, Novartis, Pancreatic Cancer Action Network, Revolution Medicines, Servier/Agios, and Stand Up To Cancer.
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