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07/12/2025

JCO at ASH 2025: A New Validated Staging System for AL Amyloidosis: AL-ISS

JCO Editorial Fellow Peter Li and author Dr. Jahanzaib Khwaja discuss the ASH 2025 Simultaneous Publication article, "A New Validated Staging System for AL Amyloidosis With Stage lllC Defining Ultra-Poor Risk: AL International Staging System." TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Peter Li: Welcome to this episode of JCO Article Insights. I am Dr. Peter Li, JCO's Editorial Fellow, and today, I am joined by Dr. Jahanzaib Khwaja on a new validated staging system on AL amyloidosis with stage lllC defining ultra-poor risk, AL International Staging System. This is a simultaneous publication that will be presented at this year's ASH Conference. At the time of this recording, our guest has disclosures that will be linked in the transcript. So, Dr. Khwaja, let's start off first: What would you say is the significance of your study? Dr. Jahanzaib Khwaja: Thank you very much. This is an important study in that, in the current treatment era, we have really improved outcomes of patients with systemic AL amyloidosis. Traditionally, the staging systems that have been employed, which are the Mayo 2012 and the European modification 2016, have been founded in eras where there were historic treatment protocols. So the significance of this new staging system is looking at outcomes of patients in the modern treatment era. That is patients who are treated with daratumumab-based treatments in the first line. And this is kind of the largest study which is externally validating a new prognostic model in the current treatment era with modern outcomes. Dr. Peter Li: Can you tell our listeners what is different about your new staging system? Dr. Jahanzaib Khwaja: The traditional staging systems, the Mayo 2012 and the European modification of 2016, looked at outcomes of patients with systemic AL amyloidosis with historic treatment protocols. And we know that they looked at outcomes according to an NT-proBNP and troponin, and in the Mayo 2012, they looked at it with the addition of the dFLC, which is the difference in the involved and uninvolved free light chain. Over the years, we have seen that outcomes have improved, and over decades, actually, outcomes are much better when we compare them to the previous decade. If we look at current treatment approaches, those traditional staging systems inadequately determine the poorest prognostic risk. So they are unable to tell us those who are going to perform poorly. Our current new validated staging system looks at the traditional NT-proBNP and troponin but uses the addition of the longitudinal strain. This is an echocardiographic parameter, and it is used widely in treatment centers who treat amyloidosis. This really identifies those ultra-high risk patients, and these are the patients who will perform poorly in current treatment protocols. And why is that important? Well, we need a robust staging system in the current treatment era which can stratify patients who will do well but also stratify those patients who do not do well. Because that is important for counseling patients, for risk stratification, for treatment approaches, and in the future, for designing clinical trials. Dr. Peter Li: And that is referring to the longitudinal strain greater than -9% and NT-proBNP greater than 8,500 and then the high-sensitivity troponins greater than 50, which will define the new staging system. Can you talk more about how you picked these cutoffs and also what that alludes to in terms of the outcomes that you have discovered in this age of daratumumab-based therapy? Dr. Jahanzaib Khwaja: Yeah, that is a really excellent question because we have aimed to build upon traditional staging systems. So clinicians have used these traditional models for many, many years, and they have robustly underpinned our stratification of patients and how we counsel patients. So we didn't want to change some of these well-established thresholds, but we wanted to test them in the current treatment era. So the NT-proBNP of 8,500 and the high-sensitivity troponin of 50 were the traditionally used thresholds. And they actually stand the test of time. But we found that longitudinal strain additionally and independently predicts outcome independent of these other biomarkers. It is independent actually as a continuous variable, so you can cut this at a number of different stratification points and find independence. But we wanted to determine and discriminate those with the poorest outcomes. So we validated a longitudinal strain threshold of greater than -9% by deriving this from a dataset of patients with the traditionally highest risk. Those are with European stage lllB. And looked at the optimal threshold with time-dependent ROC analysis. So we did this in our derivation cohort and then validated this externally in our external validation cohort amongst a number of centers in Europe, in the US, and in the UK. And it is important to note because longitudinal strain is an echocardiographic parameter, and traditionally the limitations are considered to be inter-vendor and inter-operator variability and intra-operator variability, and there are challenges with reproducibility of some of these measurements. So that is often cited as a limitation. But we found, when we have externally validated this across different centers using different platforms, actually the threshold of -9% is independently predictive of poorer outcomes independent of the traditional NT-proBNP and troponin thresholds, and it is robustly predictive of poorest outcomes. We know that those with stage lllC have a median overall survival of 4 to 7 months in the modern treatment era. And if we sub-stratify these by patients treated with daratumumab, outcomes have improved, but still, even if we look at daratumumab-treated patients, one-year overall survival is still only around 50 percent. So these are a poor risk group in the modern treatment era. Dr. Peter Li: Which kind of makes sense in a way because this kind of predicts whether they have amyloid-related cardiomyopathy. So I think this all tracks with our listeners. But given the poor outcomes even with daratumumab-based therapies, do you think this new staging system would change practice, if at all? Dr. Jahanzaib Khwaja: Yeah, I think that is a really good point because I think it comes to the question of why we use a staging system. What are its applications? I think one of the key things we think about in the clinic is how do we counsel patients when we first talk to them about their diagnosis. So there is a lot of information, but predominantly people want to know, what is my outlook going to look like? And as I say, in the bortezomib treatment era, 2010 to 2020, we used to say you have stage lllB, you have very poor outcomes, median survival maybe around six months. We have shown here that actually those with lllB have much better outcomes definitely over 12 months, up to 24 months in those with daratumumab-based therapies. So we need to counsel them in a different way. We then also need to say, "Well, who are the ultra-high risk?" So we said those with the longitudinal strain of greater than -9% with the traditional NT-proBNP and troponin cutoffs. And those patients will have poor outcomes. We need to talk about palliation. We need to talk about alternate treatment approaches. And then importantly for the community is about treatment and clinical trial design. So again, traditionally the traditional high-risk group lllB used to be considered an exclusion for all major trials. So these were excluded in the ANDROMEDA study, which led to the approval of daratumumab-based therapy, and multiple other trials. And we show here that actually patients with lllB should not be excluded from these studies because they do have good outcomes. And I think we make the important point that those with lllC, who do have poor outcomes, they need a different treatment approach, and we need to think about stratifying these patients differently. So perhaps the next modality of treatment will be the anti-fibril antibodies or a mode of treatment which can clear antibodies or clear the amyloid fibrils from the organs and reduce the organ toxicity early on. We know that those with lllC have poor outcomes particularly within the first year, and organ dysfunction really predominates here. So a different treatment approach is required, and we need to design trials specifically for these patients which look beyond anti-plasma cell clone therapy but also look at clearing the amyloid fibrils and improving organ function as this is predominantly the cause of death in these patients. Dr. Peter Li: That's an excellent point right there. Do you foresee any limitations to this new staging system, or can you comment on is there potentially a better way to refine this staging criteria in the future? Dr. Jahanzaib Khwaja: Yeah, I think that is a really excellent point to consider, that staging systems always need refining across treatment eras. So we have looked at the bortezomib era, and then we have validated this in the daratumumab-based era. We know that amongst different countries access to treatment varies. We know that there are a number of factors which determine your health-related outcomes. That's access to healthcare, speed of diagnosis, access to tertiary diagnostics, ability to biopsy, and then supportive care. And I think our staging system highlights the importance of organ dysfunction predominantly causing death early on. And I think that as treatments improve this should be refined. So the expectation I think is, as we have better anti-plasma cell directed therapies, and as we hopefully develop anti-fibril antibodies and anti-fibril clearance drugs, that we will need to revalidate new models to effectively prognosticate in this treatment era. And I also think that as we become a bit more sophisticated with our approaches, we know t

07/12/2025

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15 min
09/10/2025

Income Among Adolescents and Young Adults Surviving Cancer

Host Dr. Shannon Westin and guest Dr. Giancarlo Di Guiseppe discuss the JCO article "Long-Term Dynamic Financial Impacts Among Adolescents and Young Adults With Cancer: A Longitudinal Matched-Cohort Study" TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hi everybody and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts that are published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, social media editor of JCO and gynecologic oncologist extraordinaire. I'm so very excited to talk to you today. We're going to speak about "Long-Term Dynamic Financial Impacts Among Adolescents and Young Adults With Cancer: A Longitudinal Matched-Cohort Study." And I'm joined today by Dr. Giancarlo Di Giuseppe. He has a PhD in epidemiology that he actually just defended with this very work you're going to hear about today at the Dalla Lana School of Public Health at the University of Toronto. He is now a research fellow at the Hospital for Sick Children. Welcome, Dr. Di Giuseppe. It's so exciting to have you. Dr. Di Giuseppe: Thank you so much for having me. Dr. Shannon Westin: So we'll get right to it. Let's level set. Can you talk a little bit about the financial impact of cancer on survivors in general? I think this has been a growing area of interest and research, certainly. Dr. Di Giuseppe: Yeah, and I think that's a very important question, and I'm so happy that this research is now becoming more popular in the research world because it really addresses a critical issue that cancer survivors and their families must face. You know, you're diagnosed with cancer, and now you need to take time off work because you're hospitalized for chemotherapy. You're going back and forth to the hospital, and that all requires time away from your employment, and as a result of that, that has a significant financial strain, both on you and your family. And that's during therapy. Now, in survivorship, in the years after you've survived your cancer, you still need to deal with all the late effects associated with your treatment and your disease, and that can be psychological, physical, and that impacts your workability as well. So, it's not just exclusive to individuals undergoing treatment but also in survivorship afterwards. It really gets the financial strait that you face as a cancer survivor because you're time away from work and your lost productivity. Dr. Shannon Westin: Yeah, that makes sense. Then I think it would be great to talk a little bit specifically about the patient population that you studied in this particular manuscript. Can you talk a little bit about the adolescent young adult cohort, you know, why you singled out this particular group of people? Dr. Di Giuseppe: Absolutely. Adolescents and young adults, or AYAs, which I'll now refer to them as - I'm one of them - we're at a unique crossroads of our life and in our developmental stage of life. We are finishing our post-secondary education. We're entering the workforce. We're forming romantic relationships, and we're really achieving financial autonomy. It's because of this unique developmental stage in life where we've become quite susceptible to health shocks such as cancer. Really, does a cancer and the associated negative financial impacts affect our long term trajectory? So, I'm just finishing my PhD. If I was diagnosed with cancer, I would require a year or two away from my studies. I may or may not finish my education that could then impact my employment and then my financial outcomes later on in life. So it's really this unique population who are going through so many transitions and changes in their lives. How does that cancer really impact that life course trajectory? I think it's unique from an adult who might have, you know, large savings where they can bear the brunt of their cancer financial impacts, whereas AYAs may not have that same financial stability, provide a safety net for the financial impact resulting from their disease. Dr. Shannon Westin: You broke my heart a little bit. I realized I'm no longer in that group, so I guess it's time to move on. Okay. So, let's talk a little bit about the overall design of the study. Can you just kind of walk us through how you set everything up? Dr. Di Giuseppe: Yeah, absolutely. So it's a matched cohort study at the population level here in Canada. We have large national administrative databases, and we have this really unique set of data at the national level through Statistics Canada that we can link our cancer registry to tax records. It really provides this unique opportunity to longitudinally follow individuals from their disease forward in time. The main overall design is the matched cohort study. At the time of diagnosis of a cancer case, they're matched to someone from the population on certain characteristics. I follow these individuals from the index date of their cancer case forward in time. The crux of the study itself is a quasi-experimental two-group pre-post study design where I have information before the cancer diagnosis, I have information from their income after their cancer diagnosis, and it's really quantifying how much does that total income change from before the cancer to the after-cancer period. Dr. Shannon Westin: I'm always intrigued about hearing more about financial toxicity in general, certainly very multi-dimensional. Can you speak a little bit about the different ways that you can assess this and measure this and kind of what you chose? Dr. Di Giuseppe: Yeah, so financial toxicity really has two main spheres of measurement. There's a direct and the indirect measurements of financial toxicity. So your direct financial toxicities could be related to actually paying for medical treatment and any sort of financial burden as a direct consequence of your disease. Fortunately here in Canada, we have a universal health care system, so patients don't have to pay directly for most of their treatment. There's also indirect financial toxicities, which are not a direct result of the disease. So in this study here, one of the, or the indirect financial toxicity that I measured was the financial impact to income. That's not the only indirect financial toxicity. There could be out-of-pocket expenses for drugs that may not be covered in the universal health care system here. It could be lost productivity at work. There's really this direct and indirect financial toxicities that together result in a significant financial burden and hardships for cancer patients and survivors. Dr. Shannon Westin: Okay, so you guys did a lot of matching. It was extensive. Can you speak a little bit about the factors you used to match your patients and your controls and kind of why you chose them? Dr. Di Giuseppe: Yeah, absolutely. The matching I think is a really critical aspect of the study, and it really establishes this baseline period of individuals who are cancer-free, who look as similar as possible to the individuals who would eventually develop cancer. So I matched on birth year, sex, marital status, whether or not they had children, if they were born here in Canada or not, as well as a geographic measurement of census division. So it's really in the city or in a rural town. Then I also matched on a 5% buffer of their total income in the year prior to the cancer diagnosis. All this matching was really done in the year before they were diagnosed, and it's to establish this comparator cohort of individuals from the general population who looked as similar as possible to the individuals, or the AYAs, who would develop cancer. It's again to establish this baseline period of a control cohort who looks as similar as possible. So any differences that we might see after the cancer can be attributed to the effects of the AYA who would develop cancer. It's quite powerful, I think, from a study design perspective because it establishes causal inference methods through the study design and through the matching itself. Fortunately, I was able to match on an extensive list of covariates given the large population-based data that I used, particularly the tax records. Tax records contain a whole wealth of information, your marital status, your sex, your income, where you live. So it really provided this rich opportunity to match as closely as possible the AYAs who would develop cancer to someone from the population who wouldn't. Dr. Shannon Westin: Yeah, and I mean I think that's the only way to do this type of research and really make it generalizable and actually, you know, know that you can trust the results that you've got. So I just want to again congratulate you because I think this was just- when I read the design, I was so impressed. So now that we know the design and we understand everything, let's talk a little bit about the characteristics of the actual patient population that you studied. Dr. Di Giuseppe: Yeah, for sure. So average age of diagnosis was in their early 30s, so around 32 years old. The breakdown of the population was mostly females, so I think two-thirds of the cohort were actually females who were diagnosed with cancer. Really, a lot of the cancers were thyroid and the breast cancers. These cancers are more common in women than they are in men. So it's really reflective of the different distribution of cancer in AYAs compared to other populations like in children or in older adults. Dr. Shannon Westin: All right, bottom line. What did your primary analysis demonstrate and how was the income different based on the types of cancer that people might have been diagnosed with? Dr. Di Giuseppe: Yeah, the bottom line is actually quite a disturbing message, I would say, and it's really that cancer causes this long, prolonged financial hardship in survivors. That's, I think, a very important result from the study, and I t

09/10/2025

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16 min
10/03/2023

Penile Cancer: EAU-ASCO Guideline

Dr. Scott Tagawa and Dr. Oscar Brouwer come on the ASCO Guidelines podcast to discuss the new EAU-ASCO Collaborative Guidelines on Penile Cancer. These comprehensive guidelines cover pathological assessment of tumour specimens, diagnosis and staging, local treatment of penile carcinoma, radical inguinal lymph node dissection, prophylactic pelvic lymph node dissection, surgical management, neoadjuvant and adjuvant chemotherapy, radiotherapy, systemic and palliative therapies for advanced penile cancer, follow-up, and quality of life. They highlight key recommendations, and describe the importance of a patient-focused and multidisciplinary approach to management of penile cancer. Find more information about the guidelines at www.asco.org/genitourinary-cancer-guidelines The full text of the guideline is available at https://uroweb.org/guidelines/penile-cancer Conflict of interest disclosures: Guideline Working Group Dr. Scott Tagawa Dr. Oscar Brouwer TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Oscar Brouwer from the Netherlands Cancer Institute in Amsterdam, and Dr. Scott Tagawa from Weill Cornell Medical College in New York, co-chairs on the 'ASCO-EAU Collaborative Guidelines on Penile Cancer'. Thank you for being here, Dr. Brouwer and Dr. Tagawa. Dr. Scott Tagawa: Thanks very much. Dr. Oscar Brouwer: Yeah, thanks for having us. Brittany Harvey: Before we discuss this guideline, I'd just like to note that the guideline was led by the European Association of Urology, and the conflict of interest disclosures of the Guideline Working Group are publicly accessible through the European Association of Urology website linked in the show notes. Additionally, Dr. Brouwer's and Dr. Tagawa's individual disclosures are provided in the show notes of this episode. So, to jump into the content of this guideline, first, Dr. Tagawa, could you give us a general overview of the purpose and the scope of this collaborative EAU-ASCO Guideline? Dr. Scott Tagawa: So, I think the key word there is collaborative. This was truly a collaborative effort, and I say that in a number of ways. So, the two key organizations, the EAU and ASCO, came together with a Memorandum of Understanding and got together from the very beginning in terms of developing the scope and then throughout the methodology for the guidelines. And then, on a practical basis, I'd say even more importantly, a collaboration between multiple physicians of different disciplines from across the world. Whether we're talking about surgeons, radiation oncologists, medical oncologists, pathologists, we had panel members from all over the world as well as patient representatives from all over the world. And patient representatives really played a key role in the development of this guideline. By way of background, penile cancer in most places is considered a rare disease. For example, in the United States, we expect around 2000 cases per year. In the genitourinary world, the next rare cancer is going to be testis cancer, which is going to be four or five times higher than that per year and nowhere near prostate cancer, for instance. So, just kind of put that into perspective. But, importantly, a disease that is a worldwide issue in a number of different ways. That includes the kind of general stigma of being diagnosed with that, the physical and emotional consequences of the diagnosis, as well as treatment. And then, because in part of its rarity, the lack of prospective randomized trials to really guide clinicians and that, I would say, that total package underscores the importance of coming together with a guideline. Brittany Harvey: Great. Thank you for providing that background and perspective. So then, next, Dr. Brouwer, I'd like to review the key recommendations of this comprehensive guideline. Starting with what are the key recommendations regarding diagnosis and staging of penile cancer? Dr. Oscar Brouwer: First of all, I guess just to underline what my colleague, Dr. Tagawa, just said, it's a worldwide guideline, international, multi-continental. I think that's quite a special thing. But it also poses a few challenges, of course, because cultural differences and treatments may differ, opinions as well, distances that patients have to travel, lots of factors there, and also economy, et cetera, et cetera. So, to find a consensus there has been one of the challenges. I think we did a good job there to really make it accessible to all patients and physicians, of course, in the world. When talking about diagnosis, I think comparing our new guidelines to old guidelines really emphasizes the new 2022 WHO classification in which distinction between HPV-positive and HPV-negative disease is highlighted. We increasingly have some knowledge on the difference between the HPV-related and the non-HPV-related penile cancers. I'd say it's about 50-50, the distinction. So, 50% is HPV-related, and 50% not HPV-related. But what we know from other cancers, for instance, that HPV-positive disease is associated with better prognosis than HPV-negative. This distinction is not so clear in penile cancer yet. And one of the reasons is just the lack of data, a lack of perspective for large studies, so to say. So, what we're really highlighting and underlining in the new guideline is the importance of doing HPV testing in all patients that have penile cancer, and that tissue is taken from. We chose to go for the cheapest and easiest but reliable methods to do so. So, immunohistochemistry of p16, to be exact. This is one of the important, I think, recommendations, or maybe even more than a recommendation; obligations we set to all physicians treating penile cancer. So, just in terms of diagnosis and in terms of staging, we all know that lymph node status is the most important factor determining survival. So, finding those lymph nodes, if they are involved with cancer, yes or no. So, if they are metastatic, yes or no, is of crucial importance. This has always been the case, but I think it cannot be emphasized enough. And in this new guideline, we again emphasize the importance of doing surgical lymph node staging in high-risk patients. And what's a little bit new is that we are more or less going to the direction of preferring central node biopsy as the best method to do so. You could also, of course, remove all the lymph nodes, what we call radical lymph node dissection. It's still possible inside our new recommendations, depending on availability of all the techniques or availability of expert centers in proximity. But I think we can all see that in terms of complication rates, central node biopsy is probably superior. So this is also one of the new things in terms of staging. Brittany Harvey: Absolutely. Thank you for those highlights of diagnosis and staging in the guideline. So, following those recommendations, Dr. Tagawa, and I know this is a large section, but what does the expert panel recommend for disease management of penile cancer? Dr. Scott Tagawa: A single-sentence summary would say a multi-disciplinary approach in an expert center when possible. Re-emphasizing one of the statements that Dr. Brouwer made about sentinel lymph nodes; it appears to be better, but clearly is not available everywhere. And if I just make this US-centric for a minute, just within this country, where there are centers that are able to do it and have that expertise, there are centers that are not so far away that may not be able to do that. So regional differences within a single country that's what happens. So, anyway, multi-disciplinary input, I think, is important for many diseases, including penile cancer. A little bit of a segue, but one part of this guideline of which most of us are proud is that, front and center really, the introductory paragraph of the guidelines, where it really states that we need to really have this disease and the management patient-focused and that includes addressing some of the emotional aspects of the disease. Those are included in the management. But to kind of go through very quickly on a very high level, in the early stages management is mostly in the hands of the urologist. But sometimes there's dermatologists and others, so when there is superficial disease, we talk about superficial therapy and I'm just going to leave it at that, many of them don't have level 1 evidence, but there is, for instance, topical chemotherapy that can be helpful. And then, as the disease becomes more invasive, so does the treatment. So there's sections on organ or penile sparing that is a reasonable option that needs to be done in a good multi-disciplinary system. That is a good and sometimes a preferred option when there is adequate staging for earlier stage disease. And then the more invasive the disease becomes is when the management needs to become more multi-disciplinary both in terms of workup as well as treatment. Where there is a consideration for, in certain situations, particularly in very locally advanced where it becomes unresectable at least in some eyes, where we say, "Okay, we're actually going to recommend starting off with chemotherapy," the intent is for surgery with an alternative of chemotherapy and radiation. And currently, there are no head-to-head trials, but those are both reasonable approaches for the most locally advanced disease setting. Taking a step back, if someone starts off with a little bit less locally advanced, so we'd say the alias, gross resectable, we would at least discuss in a multi-disciplinary setting what are the risk benefits of then post-operative therapy, whether that is radiation or chemotherapy,

10/03/2023

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18 min
02/06/2025

JCO at ASCO Annual Meeting: Neoadjuvant Osimertinib for Resectable EGFR-Mutated NSCLC

JCO Editorial Fellow Dr. Ece Cali Daylan and JCO Associate Editor Dr. Thomas Stinchcombe discuss the ASCO 2025 Simultaneous Publication paper "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small-Cell Lung Cancer." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series, where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, JCO Editorial Fellow, and I am joined by JCO Associate Editor, Dr. Tom Stinchcombe. In this episode, we will discuss the Journal of Clinical Oncology article and abstract presentation "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer." NeoADAURA is a randomized global phase III study investigating the efficacy of neoadjuvant osimertinib-containing regimens in patients with resectable EGFR-mutated stage II to IIIB non–small-cell lung cancer. 358 patients were randomized 1:1:1 to receive osimertinib plus chemotherapy, osimertinib monotherapy, or placebo plus chemotherapy in the neoadjuvant setting. The primary endpoint was major pathological response. Osimertinib plus chemotherapy and osimertinib alone demonstrated MPR rates of 26% and 25%, respectively, compared to 2% in the chemotherapy plus placebo arm with a p-value of less than 0.001. Tom, can you please explain to our listeners how you interpret this data? Dr. Thomas Stinchcombe: Great question. Yeah, I think to give a little context, obviously, chemotherapy and immunotherapies preoperatively is becoming the standard of care. However, patients with EGFR-mutant lung cancer generally have not responded to immunotherapy, and many of the trials excluded patients with known EGFR mutation. There have been smaller phase II trials that had looked at EGFR TKIs preoperatively, but none of these were definitive. So I think that this trial is a big trial, and I think some of the strengths are that it has osimertinib alone and chemotherapy with osimertinib arms as compared to the standard of chemotherapy. I think it's going to be really interesting at the meeting to see how this is discussed by the discussant and also what the reaction is to its public presentation. And I think that's largely because there's an alternative paradigm now, surgical resection adjuvant osimertinib, that's available to patients. So I think this will be interesting to see what the reaction is to the induction therapy. For patients with known N2 disease, I've generally given some form of induction therapy prior to surgical resection. So I think that's the subgroup of patients that I'm most likely to employ this approach with based on the results. Dr. Ece Cali: So, in this trial, more than 90% of the patients on the osimertinib-containing regimens underwent curative-intent surgery. So, this speaks to the feasibility of the approach, and the higher MPR rate with osimertinib-containing regimens is encouraging. Event-free survival data is currently immature. You have already touched upon some of the strengths of the trial, but what are the weaknesses and the strengths of this trial? Dr. Thomas Stinchcombe: So, I mean, I think there are some weaknesses. A major pathological response was chosen as an endpoint, and there could be an argument that path CR is more of a prognostic marker. However, the rates of path CR are relatively low, so it would have been very hard to design a trial such as that. And then I think the trial started off as a preoperative trial but effectively became a perioperative trial with preoperative EGFR-TKI, postoperative osimertinib. And so I think it's going to be very hard to determine what the contribution of the components are. And then you've hit on another part that I think is very important when we interpret the data that the maturity on the event-free survival is only 15%, and most people are still on therapy. So the event-free survival, which is an important endpoint, is very immature right now. Dr. Ece Cali: And this trial was designed to compare the neoadjuvant approaches, hence the comparator arm here is neoadjuvant chemotherapy followed by surgery. So, considering the ADAURA trial results with upfront surgery followed by osimertinib as adjuvant, so how do you see this trial's impact on the current clinical practice? Dr. Thomas Stinchcombe: Well, very good question, I think one that we're still struggling with as we kind of look at this data. I think, for me, stage II patients will most likely go to surgery and then get adjuvant osimertinib, and then maybe the N2 patients will get an osimertinib-containing regimen as an induction therapy. I think one of the questions is does it really matter when you get the osimertinib as long as you get it at some point? And I think that's going to be the critical interpretation of some of the data at this point. Dr. Ece Cali: And how do you think this trial shapes the future research for patients with resectable EGFR-mutated lung cancer? Dr. Thomas Stinchcombe: Well, I mean, I think it shows that chemotherapy was really modestly active with an MPR rate of 2%, no pathological responses. And then I think you're going to have to look at an osimertinib plus another targeted therapy component. I think, you know, when I looked at the osimertinib versus the chemo-osimertinib arm, I also was sort of surprised that the MPR rate and the path CR rate were very, very similar. So I think that the question is would a double targeted therapy approach or some other approach matter? And I think it also sets a safety standard. And you touched on this in your comments, that there was not a disparity in terms of the rate of going to surgery or R0/R1 resections. So patients were not having progressive disease events or toxicities that prevented surgery. So I think it does give us good safety data. Dr. Ece Cali: Tom, thank you so much for sharing your insights on the JCO article, "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting, and please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

02/06/2025

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7 min
24/02/2025

JCO Article Insights: Long-Term Outcome of Neoadjuvant Chemotherapy for Rectal Cancer

In this JCO Article Insights episode, Peter Li summarizes "Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years," by Dr. Jianwei Zhang et al. published on December 13, 2024. TRANSCRIPT Peter Li: Hello and welcome to the JCO Article Insights. I'm your host Peter Li and today we will be discussing the Journal of Clinical Oncology article, "Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years," by Dr. Jianwei Zhang et al. For a reminder to the audience, the FOWARC study is a Chinese-based study that looked into the treatment of locally advanced rectal cancers with neoadjuvant chemotherapy based regimens with or without radiation. This study was first published back in 2019 where the three-year data showed no difference in three-year disease-free survival over survival between the three study arms. As a reminder of what those arms were, there were one historical control and two interventional arms. The control arm used 5-FU with radiation therapy with five cycles of 5-fluorouracil with radiation during cycles two to four followed by surgery and then seven cycles adjuvantly. Their first interventional arm was the same as the control arm with the addition of oxaliplatin on day 1of each cycle. And lastly, the third arm was FOLFOX only for four to six cycles followed by surgery and then six to eight cycles adjuvantly completing about a total of 12 weeks of chemotherapy. They recruited about 495 patients with 165 patients randomized to each arm. They were relatively well balanced by age, clinical staging and distance from the anal verge. Median age was about mid-50s with a slight male predominance and patients were primarily stage 3 with 20% to 30% being stage 2. About 30% had clinical T4 disease and about 25% had clinical N2 disease. Median follow up time was 122.5 months or 10 years and their follow up endpoints were disease-free survival, overall survival and local recurrence, and they also performed subgroup analyses based on post surgical pathological staging. Survival was analyzed using Kaplan-Meier method with a significant threshold of p being less than 0.05. About 451 patients actually underwent surgery, which is about 91% of patients. The main reason for not going through surgery was due to refusal but one was due to toxicity and two were due to disease progression in the control arm. Follow up loss rate was about 10% in each group. Now looking at their primary endpoints in their initial study, local recurrence was about 8.8% in the control arm versus 7.9% in the FOLFOX radiation group versus 9.2% in the FOLFOX only group. Distant metastasis was about 30% in each arm and the sites of metastases were primarily in the lung and liver. Now, following up with 10 years, there were only three new events in the chemoradiation group with local recurrence happening at 10.8% in the control arm versus 8% in the FOLFOX RT group versus 9.6% in the chemo only group. These findings were not statistically significant. In their subgroup analysis by pathological staging, they found that pathological CR or complete response had a lower rate of local recurrence compared to those with increasing pathological staging coming in at 3% versus 4.3% versus 11.6% versus 15.8% in pCR versus Stage 1, 2, 3 respectively. And they found no difference in each stage with each interventional arm. Looking at long term survival their 10-year disease free survival showed 52.5% in the 5-FU radiation group versus 62.6% in the FOLFOX RT group versus 60.5% in the chemotherapy only group with no statistically significant difference between three groups. By pathological staging, they found improved 10-year disease survival in those who achieved pathological complete response versus those who did not with 84.3% in the pCR group versus 78.7% versus 56.8% versus 27.7% in the stage 1 versus 2 versus 3 group. And again they found no statistical significance difference between each arm. Now looking at the 10-year overall survival rates between the three arms, in the control arm the 10-year overall survival was 65.9% versus 72.3% in the FOLFOX RT group versus 73.4% in the chemo only group. By pathological stage, again, they showed a statistically significant difference in those who achieved pCR versus those who had pathological stage 1 to 3 disease with overall survival being 92.4% in those who achieved pCR versus 84.9% versus 68.6% versus 48.8% in stage 1, 2, 3 respectively. Now in the discussion, authors mentioned that with a median follow up of 10 years, FOLFOX alone had similar disease-free survival, local recurrence and distant metastasis and overall survival compared to those who received neoadjuvant chemoradiation, justifying the omission of radiation without compromising results or outcomes for each patient. There were no differences in subgroup analysis for disease free survival local recurrence or overall survival based on pathological staging. There were only three new events compared to the last follow up, with local recurrence happening only in the chemo radiation groups. Local recurrence rates at 10 years was about 10%. Compared to other clinical trials such as CAO, ARO or AIO-94, the rate of local recurrence was similar to those historical trials. The authors also compared their findings to the PROSPECT study which looks at the use of total neoadjuvant chemo radiation versus chemotherapy alone, which boasted only about a 2% local recurrence rate. But as a reminder, high risk locally advanced rectal cancers were excluded, mainly those with T4 or N2 disease, which may explain the difference in terms of local recurrence in the PROSPECT versus this study. Another finding is that pathological complete responses are also an important prognostic marker with lower 10-year local recurrence rate, disease-free survival and overall survival with worse outcomes with increased pathological staging. Distant metastasis rates were still at 30%, with the most common site being lung then liver then lymph nodes consistent with other historical studies. Chemotherapy seemed to be better at reducing liver mets than lung metastasis per their findings. In their post hoc analysis of their own study, chemo radiation was also associated with higher incidence of low anterior resection syndrome and persistent ostomy compared to chemotherapy alone, meaning that they had better quality of life with the chemotherapy only approach. In conclusion, a chemotherapy only approach can be safe and a feasible treatment for locally advanced rectal cancer without compromising outcomes. Omission of radiation may reduce the risk of overtreatment and improve quality of life for some of these patients. However, this does not necessarily exclude the role of radiation as it may still play a role in a response escalation approach for those who do not respond to chemotherapy alone. This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts. 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. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

24/02/2025

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9 min
31/05/2025

JCO at ASCO Annual Meeting: Lenvatinib Plus Pembrolizumab and Chemotherapy in Gastric Cancer

JCO Editorial Fellow Dr. Peter Li and JCO Associate Editor Dr. Andrew Ko discuss the ASCO 25 Simultaneous Publication paper "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Peter Li: Hello, everyone, and welcome to our 2025 ASCO Annual Meeting Series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Peter Li, JCO Editorial Fellow, and I'm joined by Dr. Andrew Ko, JCO Associate Editor, to discuss the Journal of Clinical Oncology article and abstract presentation "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Now, let's start off with the relevance of this article. Andrew, can you please explain this to our listeners? Dr. Andrew Ko: Sure. Thanks, Peter. So, this was a very large international study evaluating the combination of lenvatinib and pembrolizumab. And just for context, that combination has been approved for use in other solid tumor types. It's FDA approved for renal cell carcinoma, for example, and endometrial carcinoma. But this study was looking specifically at this combination together with a chemotherapy backbone - so either FOLFOX or CAPOX - and comparing that to what at the time was a standard of care, which was just standard chemotherapy by itself. So, this very large study was intending to look at this particular novel combination. And we can get into some of the nuances of this study because the way that the experimental, the combination arm, was designed was perhaps a little bit more on the unusual side and led to maybe some imbalance in terms of how we think about the respective arms. Dr. Peter Li: Okay. We can definitely talk more about that as we go on. So, what are some of the key results of this study, and how do you think this will impact practice in the future? Dr. Andrew Ko: That's a good question. Technically, it was not a positive study. Well, it was positive in the sense that the co-primary endpoints - which included both progression-free survival and overall survival - so, progression-free survival, it did technically meet its endpoint, both in terms of the overall population and the preplanned subgroup analysis of patients who had a PD-L1 CPS of greater than or equal to 1. So, there was a PFS benefit with the experimental combination - the lenvatinib, pembrolizumab, plus chemotherapy - compared to chemotherapy alone. I will say the benefit was on the more modest side. So, if you even look at the medians, it was not a marked difference. If you look at the hazard ratios, they did meet statistical significance. On the other hand, this did not translate into a benefit for overall survival. So, when you ask, "Well, is this going to inform practice?" I'd have to say no. It highlights, I think, that JCO does want to publish articles that aren't necessarily going to be practice-changing, but that I think offer a lot of insights into trial design and important aspects of investigating novel treatments, even if they don't end up moving the needle in routine clinical practice. Dr. Peter Li: I totally agree with you. I mean, it was significant in terms of progression-free survival, but again, not clinically significant. And then overall survival, the interventional arm actually appeared to do slightly worse overall. Can you make some comments on the strengths and the weaknesses of this study, and where do you see us going from here? Dr. Andrew Ko: So, I think a couple of things worth highlighting in this study, very well designed, more than 800 patients in total. So, first of all, as I mentioned at the beginning, the combination was a little bit unique in terms of patients enrolled to the experimental arm got the combination of lenvatinib, pembrolizumab, together with chemotherapy for a very finite duration. So, that period of chemotherapy they received was only three months. And per protocol, patients then just segued to, quote unquote "maintenance treatment" with just the lenvatinib and pembrolizumab combination. Whereas patients on the control arm, meaning chemotherapy alone, would continue chemotherapy basically in perpetuity until their disease progressed or intolerable toxicity. So, there really was an imbalance in terms of, if you think that chemotherapy or continuing chemotherapy beyond that initial three-month period of time may be significant, that could have had some impact on the robustness or the efficacy of the experimental arm. There were some other aspects in terms of perhaps some differences in the rates of post-progression treatment, in other words, patients going on to receive second-line treatment. I think the other very relevant aspect, Peter, in this study was that the control arm - and no fault of the investigators - but the control arm at the time the study was ongoing just consisted of chemotherapy, FOLFOX CAPOX, by itself, without an immune checkpoint inhibitor, right? And we clearly know, based on results of several large phase III studies, and it's now in standard clinical practice, that we routinely use chemotherapy plus an immune checkpoint inhibitor. Certainly for patients with CPS PD-1/PD-L1 scores that are, well, you could argue greater than 1, or perhaps greater than 5 or 10. But the point being that the control arm of the study probably doesn't reflect what is currently used in clinical practice. And that's just always a challenge in clinical trial design, right? That when a study is designed and when it rolls out, you're always at risk in a rapidly changing and moving field that the standard of care may evolve during the lifetime of that particular trial, which is what I think you see in LEAP-015. Dr. Peter Li: Totally understand. And the survival we see from this study is also roughly similar to the combination of immuno-chemotherapy that is the standard of care today, which is, the authors mentioned, 12 to 14 months. Thank you so much, Andrew, for your input and for speaking about the JCO article "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

31/05/2025

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7 min
30/12/2024

JCO Article Insights: Adoption of Capivasertib in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer – Efficacy, Toxicity and Treatment Sequencing

In this JCO Article Insights episode, Giselle de Souza Carvalho provides a summary on "Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies" by Bhardwarj, et al and "US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations" by Dilawari et al published in the Journal of Clinical Oncology. TRANSCRIPT Giselle Carvalho: Hello and welcome to JCO Article Insights episode for the December issue of the Journal of Clinical Oncology. I'm your host Giselle Carvalho, Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers and one of the ASCO Editorial Fellows at JCO this year. Today, I will be discussing two articles. The first one is "Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies," and the second one is the "US FDA Approval Summary on Capivasertib with Fulvestrant for HR-positive HER2-negative Locally Advanced or Metastatic Breast Cancer with PIK3CA/AKT1/PTEN Alteration." As we know, 65% to 70% of all breast cancers are HR-positive HER2-negative and this is also the most common subtype of metastatic breast cancer. The current standard of care for frontline therapy of patients with luminal metastatic disease is a CDK4/6 inhibitor in combination with endocrine therapy. However, as new endocrine and targeted therapies gain approval, choosing the best systemic therapy upon disease progression after frontline therapy is a topic of ongoing debate. Nearly 40 to 50% of HR-positive breast cancers have actionable genomic alterations and molecular testing should be a routine recommendation for patients with metastatic HR-positive HER2-negative disease. This can be performed repeating tissue biopsy at the time of progression or from archival tissue. Treatment options after progression on CDK4/6 inhibitors include alpelisib in combination with fulvestrant in patients with PIK3CA mutant tumors as seen in the SOLAR-1 trial, or capivasertib with fulvestrant in patients with a tumor mutation in (PI3K)–AKT–PTEN pathway as seen in the CAPItello-291 study, which will be discussed further. In approximately 30% of patients, progression on frontline endocrine plus CDK4/6 inhibitor treatment is caused by endocrine resistance, frequently involving activating mutations in ESR1. For those tumors, elacestrant, an oral SERD is an option as demonstrated in the EMERALD trial. For patients with a BRCA mutation, PARP inhibitors represent another option. If no mutations are detected, everolimus, an mTOR inhibitor, can be used based on the BOLERO-2 results. The phase 2 MAINTAIN and PACE trials, along with the phase 3 postMONARCH trial support changing the endocrine therapy backbone with or without switching the CDK4/6 inhibitor. In less resourced areas, fulvestrant monotherapy is still an option to delay cytotoxic chemotherapy, though its efficacy is limited when used as a single agent. Finally, after progression on at least one line of chemotherapy, antibody drug conjugates including sacituzumab govitecan or trastuzumab deruxtecan may be an option. Now focusing on the PI3K AKT PTEN signaling pathway, activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN occur in approximately half of luminal breast cancers. In June 2023, the CAPItello-291 trial was published and treatment with fulvestrant plus capivasertib, a PTEN AKT inhibitor, demonstrated a 3.6 month PFS benefit compared to fulvestrant alone, regardless of the presence of AKT pathway alterations. However, for those with tumors without AKT pathway alteration, an exploratory analysis showed that although there was a numerical improvement in PFS, it did not meet statistical significance, indicating that the biomarker positive population primarily drove the positive results noted in the overall population. Therefore, capivasertib plus fulvestrant was approved by the US FDA in November 2023 exclusively for patients with PI3K/AKT1/PTEN tumor alterations after progression on an aromatized inhibitor with or without a CDK4/6 inhibitor. The approved schedule of capivasertib is slightly different from that of other agents used in breast cancer. It is 400 milligrams taken orally twice a day for four days per week every week in a 28-day cycle in combination with fulvestrant. Diarrhea, rash and hyperglycemia were the most commonly reported grade three or four adverse events in the interventional group. I would like to highlight that even though the CAPItello trial excluded patients with glycosylated hemoglobin levels higher than 8% or those diagnosed with diabetes who required insulin, hyperglycemia occurred in 19% of biomarker positive patients treated with capivasertib, with nearly 2% of this population experiencing grade 3 or 4 hyperglycemia and some patients experiencing life threatening outcomes such as diabetic ketoacidosis. By way of comparison, hyperglycemia of any grade was three times higher with alpelisib therapy in the SOLAR-1 trial, occurring in 64% of the patients and grade three or higher hyperglycemia was seen in 37% of the patients. Diarrhea was the most common treatment related adverse event experienced by 77% of the biomarker positive population. Prompt use of the antidiarrheal drugs when needed, such as loperamide must be encouraged as untreated diarrhea can lead to dehydration and renal injury. Cutaneous rash occurred in 56% of the biomarker positive population in the interventional group and 15% experienced a grade 3 or 4 rash. Nearly half of the patients with cutaneous adverse reactions required treatment and this was the leading reason for dose reduction of capivasertib. In the biomarker positive population, the improvement in medium PFS were 4.3 months by investigator assessment. Overall survival data from the CAPItello-291 trial is still immature, but quality of life data was recently published in September this year and was assessed by the 30 item QLQ C30 questionnaire and the QLQ BR23, the breast module. According to Oliveira et al, global health status and quality of life were maintained for a longer period with capivasertib fulvestrant than with placebo fulvestrant except for symptoms of diarrhea which were significantly worse in the capivasertib group. The median time of deterioration of global health status and quality of life was twice as long in the capivasertib group being almost 25 months versus 12 months in the placebo fulvestrant group. These data reinforced the use of capivasertib in combination with fulvestrant for the treatment of HR-positive HER2-negative advanced breast cancer patients with PIK3CA/AKT1/PTEN tumor alterations who have progressed after an aromatase inhibitor-based therapy with or without a CDK4/6 inhibitor. Thank you for listening to JCO Article Insights. This is Giselle Carvalho. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. See you next time. 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. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

30/12/2024

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9 min
30/05/2025

Day 1: Top Takeaways From ASCO25

In the first episode of a special daily series during the 2025 ASCO Annual Meeting, Dr. John Sweetenham discusses the results of 2 studies on the treatment of advanced colorectal cancer plus an additional study exploring the association of Medicaid expansion with cancer survival outcomes. Transcript Dr. John Sweetenham: Hello, and welcome to our special coverage of the 2025 ASCO Annual Meeting on the ASCO Daily News Podcast. I'm your host, Dr. John Sweetenham, and I'll be bringing you brief analysis on selected abstracts from each day of the Meeting. My disclosures are available in the transcript of this episode. Today, I'll be reviewing three abstracts, the first two of which address the treatment of advanced colorectal cancer. Today's first study is Abstract 3501. These data were presented by Dr. Heinz-Josef Lenz from the USC Norris Comprehensive Cancer Center and report on the expanded analysis of the CheckMate-8HW trial. This was a phase 3, international, multicenter trial in patients with MSI-high/MMR-deficient metastatic colorectal cancer, who were randomized between nivolumab (nivo) alone, nivolumab plus ipilumomab (ipi) or investigators' choice of chemotherapy (FOLFOX or FOLFIRI) with or without bevacizumab or cetuximab. The study showed that nivo plus ipi demonstrated superior progression-free survival compared with chemotherapy in the first-line setting and superior progression-free survival compared with nivo alone across all lines of therapy. These results led to the approval of nivo + ipi in the first-line setting in patients with MSI-H/dMMR mCRC in the U.S., the EU, and many other countries. In today's presentation, Dr. Lenz reported on the expanded analyses of nivo plus ipi versus nivo across all lines of therapy and longer follow-up results for nivo and ipi versus chemo in the first-line setting. With longer follow up (the median is now at 47 months) nivo and ipi continued to show progression-free survival benefit compared with chemotherapy with a median PFS of 54.1 months versus 5.9 months, for a hazard ratio of 0.21. Additionally, the analysis of the effects on PFS2, defined as the time from randomization to progression after subsequent systemic therapy, start of second subsequent systemic therapy, or death, showed that compared with chemotherapy, first-line nivo and ipi was associated with a 72% reduction in the risk of death or disease progression, despite the fact that 71% of those who progressed following chemotherapy crossed over to receive subsequent immunotherapy. The study also showed that across all lines, nivo and ipi demonstrated superior progression-free survival compared with nivo alone, the median not reached versus 39.3 months, for a hazard ratio of 0.62. No new toxicity signals emerged after further analysis. Most treatment-related adverse events with possible immune etiology were observed within the first six months of therapy. The results for PFS2 are particularly significant. Up to now, there has been some reluctance to use nivo and ipi as first-line therapy, partly because of its toxicity profile and based on the rationale that it would be active after other frontline therapies. The observation in this study that the beneficial effects of nivo and ipi are maintained downstream is compelling. The results suggest that delaying the use of this combination to the second line or later may compromise subsequent PFS and supports the use of nivo and ipi as a standard-of-care frontline option for MSI-H/dMMR metastatic colorectal cancer. Moving on, the next study I'm featuring today is Abstract 3503, presented by Dr. Jeanne Tie from the Peter MacCallum Cancer Centre and the Walter and Eliza Hall Medical Institute of Medical Research from Melbourne, Australia. This study reported the impact of circulating tumor DNA (ctDNA)-guided adjuvant chemotherapy escalation in stage III colon cancer, focused on the primary analysis of the ctDNA-positive cohort from the randomized DYNAMIC-III trial. As background, about 30% of patients with stage III colon cancer will recur following standard-of-care adjuvant therapy with oxaliplatin-based regimens. And current data show that for those patients with high-risk disease, 6 months of chemotherapy is associated with a lower recurrence rate than 3 months. Circulating tumor DNA following initial surgery has been shown to be a strong independent prognostic factor for these patients, but questions remain about how ctDNA can be used for adaptation of treatment. Questions regarding treatment adaptation were addressed in the DYNAMIC-III trials – specifically, does treatment escalation benefit those who are ctDNA positive following surgery, and can therapy be de-escalated for those who are ctDNA negative. The first of these 2 questions – treatment escalation in the positive group – is the subject of this report. One thousand and two patients were randomized in this study, between ctDNA-informed therapy (502) or standard management (500). Of those patients included in the intent to treat cohorts, 129 were ctDNA positive in the ctDNA-informed arm compared with 130 in the standard management arm. Various pre-planned treatment escalation protocols were used, depending on the choice of first-line therapy. With a median follow up of 42.2 months, there was no difference in 3-year relapse free survival between the ctDNA informed group (48%) and the standard management group (52%). There was, however, a highly significant difference in relapse-free survival for patients who cleared ctDNA by the end of treatment compared with those who didn't. The authors concluded that the recurrence risk for this group remains high, at about 50%, after adjuvant therapy and that it increases with higher ctDNA burden, but treatment escalation didn't appear to reduce the recurrence risk. Clearance of ctDNA was associated with a favorable outcome, suggesting that as more effective treatments are developed in the future for this group, ctDNA will likely prove to have major utility. Changing gears now, my final selection for today is Abstract 11006, presented by Dr. Elizabeth Shafer from the American Cancer Society. This study explored the association of Medicaid expansion with 5-year survival after a cancer diagnosis. Dr. Schafer began her presentation by providing some historical perspective on the impact of the Affordable Care Act on reducing the number of uninsured adults aged less than 65 years in the United States. She then reviewed some recent data on the impact of Medicaid expansion on cancer care, including improved screening rates, improved access to cancer surgery, and an increase in earlier cancer diagnosis. The current study builds on earlier data from the American Cancer Society which showed improved 2-year overall survival for patients with newly diagnosed cancer following Medicaid expansion. The new study reported by Dr. Schafer examined 5-year cause-specific survival in individuals with cancer since Medicaid expansion, analyzed according to cancer type and various demographic and social factors. Using data from more than 813,000 individuals from 26 states that expanded Medicaid compared with more than 610,000 from 12 states that did not, the authors reported that similar improvements in 5-year cause-specific survival were observed in the expansion and the non-expansion states, but when analyzed by other factors, differences in outcome emerged. For example, although similar improvements in survival between expansion and non-expansion states were seen in urban communities, there was a significant improvement of 2.55 percentage points in survival for individuals in rural communities in expansion states compared with those in non-expansion states. Similar trends were observed in high poverty areas, where improvements in survival were superior in expansion versus non-expansion states. When examined by cancer type, the authors observed greater improvements in 5-year survival for those with pancreatic, lung, and colorectal cancer, possibly due to improvements in screening and early access to treatment. The authors concluded that those residing in rural and high-poverty areas experienced the most improvement in cause-specific cancer survival following Medicaid expansion. In summary, it's encouraging to see an improving trend in cancer mortality overall, independent of Medicaid expansion, but it's also important to remember that this is yet another study which confirms how implementation of the ACA has improved cancer outcomes and begun to address some of the disparities in cancer care. Join me again tomorrow to hear more top takeaways from ASCO25. And if you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts. Disclaimer: 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. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today's speaker: Dr. John Sweetenham Follow ASCO on social media: @ASCO on Twitter @ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. John Sweetenham: No relationships to disclose

30/05/2025

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10 min
28/08/2024

JCO PO Article Insights: Publication Trends in JCO Precision Oncology

In this JCO Precision Oncology Article Insights episode, Miki Horiguchi summarizes an editorial: "Expanding the Reach of Personalized Medicine in Cancer Care: Current Progress and Future Directions of JCO Precision Oncology" by Dr. Yushu Shi et al. published on May 30, 2024. TRANSCRIPT Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Miki Horiguchi, an ASCO Journals Editorial Fellow. Today, I will be providing a summary of the article titled "Expanding the Reach of Personalized Medicine in Cancer Care: Current Progress and Future Directions of JCO Precision Oncology". This is an editorial by Dr. Yushu Shi and colleagues that investigated trends in publication, peer review, and global influence of JCO precision oncology. Before getting into the editorial, I would like to briefly introduce to precision oncology and the JCO Precision Oncology journal as a leading platform for research in this field. Precision oncology is a personalized medicine approach that leverages advances in genomics and molecular profiling of tumors, biomarker-driven decisions, and targeted therapies to enhance clinical care for patients with various cancer types. Since there are many aspects to consider, such as biologic, clinical, and statistical aspects, advances in precision oncology also come with numerous challenges. These include identifying targetable mutations and addressing tumor heterogeneity and drug resistance. Other challenges are developing new study designs and statistical analysis methods to evaluate new approaches, as well as developing methods to manage large and complex datasets. Since the American Society of Clinical Oncology introduced the journal JCO Precision Oncology (or JCO PO) in 2016, it has played an important role as a dedicated platform for publishing high-quality research and promoting discussions on those challenges. JCO PO is a peer-reviewed, online-only, article-based journal publishing articles across multiple categories. These include original reports, case reports, review articles, commentaries, correspondence, editorials, special articles, and molecular tumor board case discussions. The journal's contribution to the advancement of the field is reflected in the journals' impact factor, which was 4.6 in 2022 and 5.3 in 2023. In the editorial, Dr. Shi and colleagues first investigated the publication trends from 2017 to 2022, highlighting cancer types, article types, the number of citations, and topics of papers published in JCO PO that have had broad impact. The papers accepted at JCO PO covered a broad range of research topics, including genomics-driven tumor treatments, molecularly selected targeted therapy, translational oncology, cancer biomarkers, gene expression and profiling, biostatistics and clinical trial methodology, epidemiology, and cancer prevention and control. The most common cancer types are thoracic, GI, and breast cancers. Original reports were more likely to be cited than case reports. The average number of annual citations for original reports was 4.33, while it was 1.39 for case reports. The authors listed the 10 most cited papers published in JCO PO in a table. The most cited paper was an original report titled "Landscape of Microsatellite Instability Across 39 Cancer Types" by Bonneville and colleagues. The paper has been cited more than 600 times since it was published in 2017. Next, the authors conducted an analysis to see trends in peer-review. When manuscripts are submitted to JCO PO, they go through a rigorous peer-review process. Reviewers evaluate them based on five key metrics: importance of the study, originality, quality of writing, relevance to clinical practice, and scientific strength. Each metric is rated on a scale from 1 to 5, with higher scores indicating better performance. Dr. Shi and colleagues compared the rating scores between accepted and rejected manuscripts of original reports and case reports. They found that the median score of accepted manuscripts was above 3.5 for all metrics. The findings highlight that no single metric determines acceptance, underscoring the importance of excelling in all five areas when developing manuscripts. Finally, the authors looked at trends in global influence in JCO PO. Counting the country where the corresponding author's institution is located, Dr. Shi and colleagues found that JCO PO has accepted manuscripts from 36 countries, indicating a steady increase in its global reach. The United States accounts for about 71% of the total contributors. The other top contributors include France, Canada, Italy, Australia, the Netherlands, Germany, Japan, the United Kingdom and China. Notably, global collaborations among authors have significantly increased, with the proportion of papers from multiple countries more than doubling from 12.5% in 2016 to 26.5% in 2022. These facts reflect JCO PO's ongoing commitment to engaging with the international precision oncology community and encouraging global research submissions. At the end of the editorial, the authors provided some guidance for future authors. Across original reports and case reports, successful submissions to JCO PO typically have a translational focus. They provided a mechanistic understanding of tumor biology and utilized cancer genomics to inform clinical decision making. The authors also highlighted several underrepresented but growing areas of interest at JCO PO. These include pediatric oncology, sarcomas, ethics, trial methodology, informatics, computational approaches, and statistical methods related to precision oncology. Furthermore, the increasing significance of germline genetics, pharmacogenetics, molecular diagnostics, and molecular epidemiology in precision oncology has been recognized and valued by JCO PO. JCO PO also has special series issues. The special series feature timely research topics, such as Equity in Precision Medicine, Statistical Methods for Precision Oncology, and Next Generation Sequencing. Through these special series, JCO PO continues to lead the advancement of the application of precision oncology across a diverse patient population. The authors also provided points to consider when submitting case reports. For successful case report submissions, especially n-of-1 reports that showcase novel findings with potential clinical impact, it is crucial to include robust data to support the clinical observations, investigate underlying mechanisms, and ensure proper protection of patients' identity and autonomy. An n-of-1 report alone is often insufficient for publication. Successful case reports typically extend beyond a single patient, examining the phenomenon in multiple patients and providing mechanistic validation, either in vitro or through preclinical models. Thank you for listening to JCO Precision Oncology Article Insights and please tune in for the next topic. Don't forget to give us a rating or review and be sure to subscribe, so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

28/08/2024

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11 min
03/06/2024

EAZ171: Predictors of TIPN in Black Women with Breast Cancer

Dr. Shannon Westin and her guest, Dr. Bryan Schneider discuss the article "ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer" recently published in the JCO and presented at the 2024 ASCO Annual Meeting. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncology Extraordinaire and also the Social Media Editor of the Journal of Clinical Oncology. And it is my great pleasure to present some really incredible work today that is going to be a dual publication in the Journal Clinical Oncology and a presentation at the American Society of Clinical Oncology Annual Meeting on Monday, June 3. And this is the "ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer." And I am joined today by the senior author on the presentation and the primary author on the manuscript, Dr. Bryan Schneider. He is the Vera Bradley Professor of Oncology, the Professor of Medicine and Medical Molecular Genetics at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis. Welcome, Dr. Schneider. Dr. Bryan Schneider: Dr. Westin, thank you for having me on today. Shannon Westin: We're so excited and we're really excited to really summarize this incredible work that's being presented today. So, first, let's just levelset. Can you speak a little bit about peripheral neuropathy and the most common causes in patients with cancer? Dr. Bryan Schneider: Yeah, I mean, I think for those of us who treat patients using the taxanes, we recognize probably one of the most important and common side effects that we deal with is peripheral neuropathy, and one that can, I think, impact both quality of life, but also impacts the ability to maintain dose intensity. When we think about risk factors for neuropathy, historically, I think obesity has been reported as a potential risk factor, as has diabetes and other conditions which put people at risk for neuropathy. Shannon Westin: And prior to your work that you'll discuss with us today, what do we know about the incidence of peripheral neuropathy in patients that identify as black? Dr. Bryan Schneider: Yeah. So, interestingly, I think we've recognized that patients who self identify as black have disparate outcomes in terms of inferior survival and more aggressive subtypes of breast cancer, like triple negative breast cancer. But I think the idea of toxicity being a disparate factor as well is probably a more recent one. Interestingly, as we set out to identify biomarkers to predict outcomes in the large adjuvant trial E5103, we weren't really setting out to look at this by race. We were using at that time, genome-wide approaches to identify biomarkers for toxicity and also efficacy. But what was interesting as we did that one of the most important predictors, as we looked across a number of important toxicities, was ancestry. And really the science spoke to us, it was very clear that patients of African ancestry had higher rates of bev-induced hypertension, anthracycline-induced cardiomyopathies and also peripheral neuropathy. Shannon Westin: That's so interesting. We have so much overlap in gynecologic oncology and breast cancer. And I don't know that I've ever seen work like this. And now it's making me very intrigued and making me want to move forward to that. Can you talk a little bit more about this ECOG-ACRIN E5103, like briefly about the study and what it demonstrated specifically? Dr. Bryan Schneider: Yeah. So E5103 was an adjuvant breast cancer trial that really set out to look at the impact of bevacizumab in the curative setting. This was a 5000 patient trial that randomized patients the standard backbone of chemotherapy. So everyone received four cycles of doxorubicin and cyclophosphamide, followed by weekly paclitaxel, and then with or without the addition of bevacizumab. So the parent clinical trial showed, as we know now, bevacizumab didn't add benefit, but certainly this was a fertile ground for us to use genomic markers to try to identify a number of other important factors and predictors. Shannon Westin: And what did you find genomically in that study that led to kind of where we are now? Dr. Bryan Schneider: Initially, what we found is that ancestry was a major predictor of neuropathy. And in that trial we saw essentially a doubling of the risk of grade 2 and above and a doubling of the risk of grade 3 and above neuropathy. When we then looked comprehensively across the genome for common variants that might put patients at risk for neuropathy, we had enough patients in the black population to identify some markers that seemed to differentially predict the risk of neuropathy in the patients of African ancestry. So there we found a variant in the gene FCAMR, which appeared to be protected from neuropathy, and FCAMR is known to have an immune modulatory effect. But importantly, we also found that rare variants, so we did this using an exome wide approach in a gene called SPF2, predicted an increased risk of neuropathy. Now, interestingly, that gene SPF2 is also thought to contribute to a hereditary form of neuropathy, Charcot-Marie-Tooth. Here, what we found, obviously, is that if you inherit two of these variants, you probably have a hereditary neuropathy, but if you inherit one, you may not have neuropathy at baseline, but if exposed to a neurotoxin, much more predisposed to that event. Shannon Westin: That is so intriguing and makes so much physiologic sense. So, can you talk a little bit about how that led to the development of the current study, the objectives design, that type of thing? Dr. Bryan Schneider: Yeah. I think, overarching question and concern is, and we see this with all clinical trials in the United States, is that we're seeing disparate outcomes in a population that are largely underrepresented in our clinical trials. And so one of the first things we wanted to do was really focus on the population that was being disparately affected. So EAZ171 was set out to accrue patients, and in fact, only accrue patients who were self described as a Bck race or African American. So the goal of this trial then was to see if, number one, we could further predict which patients were going to get neuropathy based on our germline genotyping, and then also to better personalize the type of taxane based, again on genomics, but also on the risk of dose reductions, risk of neuropathy, impact on financial toxicity, quality of life, and a number of other, what we felt to be, important clinical variables. Shannon Westin: So let's get into the details. What did you find regarding the incidence of neuropathy in the study, and how was it impacted by the type of chemotherapy the patient received? Dr. Bryan Schneider: Yeah. So the starting point, the primary objective of that study, was to try to validate a high and low risk composite score for neuropathy. And the trial was negative, meaning our genotypes did not predict significantly differences based on the germline genotyping. Now, interestingly, the genotyping did numerically separate, meaning those in the high risk category had about a 12% higher risk of neuropathy, but this did not meet statistical significance. Another major or key secondary endpoint, though, was to look at the type of taxane and its impact in this population. And indeed, what we found is that patients who received paclitaxel had a markedly and statistically significantly higher risk of both grade 2 and above and grade 3 and above peripheral neuropathy. And in addition, we saw more dose reductions, both because of TIPN and all causes in the paclitaxel arm. Shannon Westin: So why do you think you were unable to validate the genomic predictors in the current study? Dr. Bryan Schneider: This is an incredibly important question. So, number one, I mean, we were happy to see the directionality of our preliminary data be correct. But I do think that neuropathy is a very complicated toxicity, and it's probably a multigenic effect, and it probably is also impacted a lot by a variety of clinical factors. So some of the future work we'll be doing is looking at polygenic risk scores and other known genes that may be impactful, and also melding that with a number of really important clinical variables, because I still think we have the potential to predict this ahead of time. Shannon Westin: I know that this was such a patient driven topic, really focused on the patient experience and how to improve not only survival outcomes, but also toxicities and quality of life. Can you speak a little bit about the role of patients in the design of this trial, and maybe with helping it be as successful as it was with accrual? Dr. Bryan Schneider: Yeah. This has truly been one of the most exciting projects I've ever embarked on, and largely because of the incredible team atmosphere and contributions by so many people. Real thanks to the late Worta McCaskill-Stevens and also the late Edith Mitchell, who were two really fundamental disparities experts who really helped motor this trial to where it was. And also our patient advocates and the community at large really were part of the design and part of this from the very beginning, all the way through the publication, I think, have made it a clinically relevant study, and one that I think we're all very proud of. Shannon Westin: Is paclitaxel typically, what is the go-to? Or are more people using, let's say, docetaxel? Dr. Bryan Schneider: I think it depends a little bit on the disease setting and type. And again, is a function of historical clinical trials

03/06/2024

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15 min

ASCO Podcasts by the American Society of Clinical Oncology, cover a range of educational and scientific content, offering enriching insight into the world of cancer care. Hear innovative interviews with the authors, researchers, and clinicians who are defining today’s standard of care and tomorrow’s breakthroughs. You can find all ASCO podcasts and limited series at ascopubs.org/podcasts