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Across 20 different cancers, tumor-agnostic approvals wove their way into several NCCN guideline updates published throughout 2024; this included the additions of repotrectinib (Augtyro) for patients 12 years or older with solid tumors that have an 

 gene fusion and fam-trastuzumab deruxtecan-nxki (Enhertu, T-DXd) for adults with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors.

 Aside from this, differences were vast and non–small cell lung cancer (NSCLC) was a malignancy that saw the most revisions as it stands with version 11.2024 of the guidelines published.

 For certain cancers, early versions of the 2025 guidelines have already been released as well.

“NCCN guidelines are integral to every practice, not just for providers [as] there are a variety of new drugs that are being approved, but also for our office staff,” said Sandy Srinivas, MD, vice chair of the prostate cancer NCCN guidelines. “Having the approval and having it in the guidelines is integral for our office staff who are working on obtaining prior authorization.”

, 12 clinicians, all of whom are chairs, vice chairs, or members of NCCN guideline panels, provided insights on the biggest changes published in 2024 and how these advancements affect practice.

Jairam Krishnamurthy, MD, FACP, a member of the breast cancer NCCN guidelines panel, noted, “For any HER2-positive cancer, T-DXd could be applicable, which provides another line of treatment for many other cancers where there are not as many treatment options. In breast cancer, we are using it for patients with HER2-positive metastatic disease in the second line [settings] and beyond. We are also using the drug in the HER2-low space. This clearly shows that T-DXd use has only been increasing over the years, and it is likely to increase further with this agnostic indication.”

To parse through pan-tumor approvals, additions and withdrawals of agents, changes in categories of recommendations, and more, we have gathered the top takeaways in updates to the NCCN guidelines and paired them with insights from those who created and amended the guidelines. Notably, Castleman disease has left the B-cell lymphomas guidelines and now has its own guideline,

 and new guidelines are coming soon for appendix cancer, according to Alan P. Venook, MD, vice chair of the colon cancer and rectal cancer NCCN guidelines, and member of the hepatocellular carcinoma (HCC) and biliary tract cancers NCCN guidelines.

“I can’t emphasize enough how these are living documents and how rapidly they can change,” Venook said. “Our goal is to stay on top of it and stay ahead.”

Click on the powerpoint/slide deck to view the NCCN guideline changes in dozens of tumor types, and to read full-length interviews with leading experts covering updates in specific malignancies, visit 

Chair of the Multiple Myeloma NCCN Guidelines Panel Research chair in the Division of Hematology, consultant in the Division of Hematology, and professor of medicine at Mayo Clinic in Rochester, Minnesota

"One of the important changes has been the introduction of quadruplet regimens for newly diagnosed myeloma. Several phase 3 trials have come out supporting the use of quadruplet regimens in transplant-eligible as well as ineligible patient populations. We made some changes in the recommendations for newly diagnosed myeloma [making] the quadruplet regimens a standard of care.”

"We also expanded upon the use of 2-drug maintenance [therapy regimens] in certain settings; increasingly, we have tried to give a bit more direction toward the use of specific therapies, on one hand based on evidence from phase 3 trials, but also giving some directions in terms of specific patient characteristics [regarding] using the specific regimens. We also did a major update for the treatment of [patients with] relapsed/refractory disease, wherein the major change has been the introduction of immunotherapy over the past year; even though some of the agents were already there, we restructured the approach to relapsed myeloma [management], incorporating some of the recent changes in the indications for CAR T-cell therapy.”

"A main update is the different diagnostic perspective. The emphasis on the use of PET/CT [at] baseline is a strong recommendation. It’s important from the point of view of diagnosis and has prognostic value because if you find extramedullary disease, that can modify the outcomes of patients with myeloma. We made some clarifications in terms of the necessary testing.”

"When you have a newly diagnosed patient with myeloma, doing imaging to make sure you make an accurate diagnosis of myeloma vs one of the precursive conditions is important, and [this imaging can] also [rule] out concurrent amyloidosis in some of these patients if the clinical presentation makes you suspect that.”

"We’re working on additional guidance in terms of some of the difficult-to-treat [conditions] like central nervous system myeloma and so forth, and some of those recommendations will also make their way to the guidelines.”

Member of the Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia NCCN Guidelines Panel

Assistant professor of oncology in the Department of Medicine-Lymphoma and the Department of Cancer Genetics and Genomics at Roswell Park Comprehensive Cancer Center in Buffalo, New York

"First and foremost, it’s important to know that chemotherapy has fallen from favor. [Additionally], even if we have our best patients, so to speak, it’s important to check for [mutations]. A lot of patients are not being sequenced looking for some of these high-risk mutations that I’ve seen. The fall of chemotherapy [in recent years] off the preferred list is the number one [takeaway] given that most of our randomized trial data suggest that chemotherapy has less efficacy and more toxicity potential, especially in patients who are immunocompromised with CLL. Chemotherapy is falling from the top to a lesser preferred backup option now.”

"There were a couple of modest revisions over the past year and a bigger revision from a couple of years ago. But the overall theme is that targeted therapies, particularly the second-generation covalent BTK inhibitors like acalabrutinib and zanubrutinib, are now preferred over ibrutinib.… [Additionally], there are new treatments available for relapsed/refractory CLL and SLL, namely pirtobrutinib and CAR T-cell therapy with liso-cel with some others we expect in the near future as well.”

"We’re working on Richter transformation guidelines as well so stay tuned for that; that’s still in the revision stage. We’re taking feedback and requests for help and clarification very seriously with my colleagues on [the] NCCN [panel] and are hoping to fully answer some of these important questions.”

Chair of the Chronic Myeloid Leukemia NCCN Guidelines Panel

The Edward S. Ageno Distinguished Professorship in Hematology/Oncology at UCSF and a professor in the Department of Medicine at UCSF in San Francisco, California

"First and foremost, there is an updated indication of asciminib for newly diagnosed patients with [Philadelphia chromosome–positive] chronic phase CML. In late October 2024, the FDA approved asciminib as a frontline option, so it is now included as an option along with the other 4 approved TKIs. This is immediately affecting practice. Additionally, other changes that have occurred are related to the treatment milestone guidelines.”

"There have been some rare cases where [challenges occur implementing the guidelines into practice]; for instance, up until recently, asciminib was only approved in the third-line and beyond settings based upon its superiority to bosutinib [Bosulif] in a randomized phase 3 study [NCT03106779]. You would think that a patient would not have to take bosutinib if they previously received 2 TKIs and had resistance or intolerance. Nonetheless, there have been cases where asciminib was denied because a patient had not yet taken bosutinib despite the fact that the patient had received 2 prior TKIs, and this of course makes no sense.”

"If we have several therapies that are considered to be equivalent—and that currently is the case looking at second-generation drugs and asciminib for newly diagnosed chronic phase CML—it would be reasonable to recommend [alternatives] in the setting of therapeutic equivalents based on cost differences alone. If they are especially substantial [cost differences], we might consider preferring a cheap generic option to the expensive brand name alternatives. [This is] not necessarily based on the patient’s out-of-pocket costs, but the societal cost that we all pay for.”

Vice chair of the B-Cell Lymphomas NCCN Guidelines Panel

The Abby and John Friend Professor of Oncology Research and a professor of medicine (hematology and oncology) at Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, Illinois

"In follicular lymphoma, one of the more important things is the addition of T-cell engager therapy as third-line [and subsequent therapy options], and that includes both bispecific antibodies, specifically epcoritamab, which was added as a category 2A [preferred recommendation], and CAR T-cell therapy, specifically liso-cel, [which was also included as] a category 2A [preferred recommendation].”

"In MCL, there have been a number of things, [including] the way we think about 

mutations, for example. We have relied upon next-generation sequencing [NGS] as the way to determine if there is a 

mutation, which turns out to be a fairly significant prognostic factor in MCL. One of the questions is whether immunohistochemistry [IHC] on the pathology specimen is a reasonable surrogate for NGS. We’ve revised one of the footnotes in the MANT-1 section of the MCL guidelines [from]

mutation or deletion 17[p]’ [to say] that

sequencing is preferred’. However, because NGS may not be available everywhere and all the time, we think that in the frontline setting

testing by] IHC can be used as a surrogate, but ultimately should be confirmed with sequencing. [This] addresses how we measure that important prognostic factor. Because it’s so important, we’ve now allowed IHC to determine [its status]. Of course, the other question is, how much expression of P53 do you need by IHC to be the equivalent of the mutation by NGS? Anywhere from 30% to 50%, certainly greater than 50%, suggests it’s probably going to be mutated if you order NGS.”

Member of the Breast Cancer NCCN Guidelines Panel

Associate professor in the Division of Oncology and Hematology and codirector of the breast cancer program at the University of Nebraska Medical Center in Omaha

"The most recent updates [included] the addition of ribociclib to the guidelines [in addition to] adjuvant endocrine therapy for those with HR-positive, HER2-negative disease based on data from the phase 3 NATALEE trial [NCT03701334]. Guidelines haven’t been updated [to a heavy extent in 2024] but inavolisib [Itovebi] was approved [recently], so it is also likely to show up on the guidelines. I don’t know if it is happening or not, or when it will happen, but one would expect that to be on the guidelines since the FDA has approved it.”

"The update for adjuvant ribociclib clarifies which indication that [agent] should be used [for], and mentions abemaciclib and which indication that should be used [for]. It’s not a one-size-fits-all [approach]. As in all cases, the risk and benefit of any approach need to be weighed very well. We must always keep in mind that the benefit should always outweigh the risk and keep the quality of life of patients in mind.”

"Convincing patients to take 2 years of abemaciclib is quite hard because these drugs have adverse effects [AEs], and we have to remember that these patients have already undergone surgery, chemotherapy, radiation, and are also committed to [receiving] at least 5 years of endocrine therapy in most cases. We were asking them to do 2 years of abemaciclib as well, and now if we have to talk to them about 3 [years of] ribociclib on top of all of that, that’s going to be the major challenge in terms of convincing and counseling patients and managing their AEs.”

Chair of the Biliary Tract Cancers, Colon Cancer, Rectal Cancer, and Hepatocellular Carcinoma NCCN Guidelines Panels

Professor of medicine in the Division of Hematology and Oncology at Northwestern University Feinberg School of Medicine and director for cooperative groups at the Robert H. Lurie Comprehensive Cancer Center in Chicago, Illinois

"In colorectal cancer we’re creating a new guideline for appendix cancer. It’s a lot of effort to create a new guideline, but we’re just now putting the finishing touches on it. It’ll be posted most likely [in the beginning of 2025], and that’s very important because appendix cancer is a unique disease with special findings—it’s perhaps the one disease that’s amenable to heated intraperitoneal chemotherapy, to tumor debulking. That’s a huge change in the guidelines for colorectal cancer. Historically, colorectal, anal, and appendix [cancers] were all lumped together, as well as small bowel. A few years ago, we created a small bowel guideline and now we’re creating an appendix guideline.”

"It’s important nowadays to grasp that the treatment of [patients with] colon cancer and rectal cancer is evolving and becoming increasingly complex. The use of NGS and marker-driven therapy is becoming more dominant and it’s critical to have an NGS profile particularly for patients with metastatic disease [to] make your treatment decision. It’s important to evaluate patients using a multidisciplinary review, and this is especially critical now in rectal cancer where patients need to have an in-depth, multidisciplinary review. That includes, for example, rectal imaging with MRI; having the radiologist’s and pathologist’s input is essential. Nowadays, we must know the MSI status for every patient with colon and rectal cancers and we’re now including POLE/POLD1 [mutations in decision-making as well]. Having radiation, surgical, and medical oncology [personnel] involved in the multidisciplinary review and the recommendation process requires a very experienced team.”

"One of the challenges is: What do you do when you know that there’s a change coming in the guidelines, but it’s not public yet, and the patient presents to you when you know the change might be applicable to them? That’s an ethical challenge. Let’s say it’s not for public consumption, but if I know [something] and need my colleagues to understand why I’m making a decision or in a tumor board [scenario], [the question of] how you deal with proprietary information [comes into play].”

Vice chair of the Colon Cancer and Rectal Cancer NCCN Guidelines Panels and Member of the Hepatocellular Carcinoma and Biliary Tract Cancers NCCN Guidelines Panels

The Madden Family Distinguished Professorship in Medical Oncology and Translational Research at UCSF, the Shorenstein Associate Director for Program Development at the Helen Diller Family Comprehensive Cancer Center, and a professor in the Department of Medicine at UCSF in San Francisco, California

"In biliary tract cancer, it’s a little different. First of all, for years we had no tissue banks because it’s very hard to collect tissue in these patients. Once we did [collect tissue], we figured out there are a couple of mutations that can be targeted. That’s very exciting and one thing that’s changed over the years. Over the past couple of years, we’ve added IDH1 inhibitors as well as FGFR fusion inhibitors. There are a couple of targeted therapies that work in biliary cancer. That’s the good, exciting news.”

"The other thing that the guidelines are doing is trying to separate out more clearly gallbladder cancer from bile duct cancer from intrahepatic vs extrahepatic bile duct cancer. Historically, we’ve lumped them together and we now know that they should be separated.”

"The changes have mostly been in hepatocellular carcinoma, and the evolution of different combinations of biologics and immunotherapies have made their way to the top of the heap. There are a series of studies that have been done in HCC, [and] we just met about them. HCC in particular is evolving so rapidly.”

"What we don’t know is [if] one of these different checkpoint inhibitors, these immunotherapies, is any different from the other. We have a bunch of [similar] studies, and I’m not sure that these are huge advances. What it amounts to in HCC is we have a number of agents that are approved or in the NCCN guidelines for first-line management. Distinguishing one from the other is impossible and it is likely that these [agents] will never be compared head-to-head because they are [manufactured by] different companies that have the indication from different study designs and it’s not clear that they want to put their drugs up against each other.”

"Another change was in terms of tumor testing. Currently, the panel does not believe that routinely for HCC, there [is] any necessity to test for MSI, TMB, or PD-L1 [status]. That’s because these immunotherapeutic agents appear to offer benefit regardless of selection on the basis of MSI, PD-L1, or tumor mutation burden. I don’t think at this time we should encourage that testing, nor is it useful when we’re making treatment decisions.”

"The interesting finding in HCC is we’ve gone from years where there were no changes in the guidelines, we had virtually nothing, to now a very robust set of recommendations that include numbers of drugs that are recommended. The missing piece for the HCC field globally is still that all these studies are highly selective for patients with reasonably good liver function, and so I’m not clear that these changes are dramatic in terms of offering options for many patients, and it is a [situation where there are similar available] drugs for some patients.”

Vice chair of the Prostate Cancer NCCN Guidelines Panel

Medical oncologist, professor of medicine, and clinical research group leader for the Urologic Cancer Program at Stanford Medicine in Palo Alto, California

"This was a busy year for the kidney cancer [research] groups. I was happy to see that nivolumab plus ipilimumab got updated in the favorable-risk category [recommendation and moved from other recommended regimens to preferred regimens]. Up until now for those with favorable-risk [disease], it’s been the immuno-oncology [and] TKI combinations that have made it to category 1 but the phase 3 CheckMate 214 study [NCT02231749] with 8-year follow-up data [showed that] patients with favorable-risk disease seem to be deriving a benefit, especially those who respond having a durable response. [Therefore], it was great to see [the recommendation in] clear cell RCC.”

"A big change in kidney cancer was [the addition of the] category 1 recommendation for adjuvant pembrolizumab for patients with high-risk kidney cancer post nephrectomy. This is based on data from the phase 3 KEYNOTE-564 study [NCT03142334], which demonstrated an improvement in disease-free survival [with pembrolizumab vs placebo]. But more recently, we also saw that there was a benefit in overall survival, so pembrolizumab made it to the guidelines as a category 1 recommendation in the adjuvant setting.”

"The biggest challenge that I believe all of us face is the rapidity and the pace at which drugs are being approved. One of the biggest challenges that we and many practices have is that the authorization parties have a hard time also keeping up with the guidelines, so our office staff and others who advocate for patients end up spending a lot of time trying to provide evidence to third-party payers about the updated guidelines.”

“[Looking to the future to] a few trials in the prostate space: Within the field of radioligand theranostics, we have lutetium-177–PSMA-617 [Pluvicto] which is currently approved for patients in the very refractory space. These are patients who have had prior taxanes [and] prior novel hormonal therapy. We await the results [as] there have been 2 large [phase 3] trials: PSMAfore [NCT04689828] and SPLASH [NCT04647526]. These are trials that were done in the pre-docetaxel, prechemotherapy space. Both trials have met their primary end point. We are looking forward to having a regulatory approval so that our patients can get this drug prechemotherapy.”

Member of the Cervical Cancer NCCN Guidelines Panel

Director of gynecologic cancer trials, codirector of the Development Therapeutics/Phase I Clinical Trials Program, and associate professor of oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland

"The biggest change that we’ve seen in the past couple of years, and in particular this year, has been [with] the era of antibody-drug conjugates [ADCs]. We’re seeing some great responses to these therapies, longer durations of benefit, and multiple different drugs are available. There’s mirvetuximab soravtansine for ovarian cancer, tisotumab vedotin-tftv [Tivdak] for cervical cancer, and T-DXd for any cancer that has high expression of HER2. Those have come to the fore and made it into the NCCN guidelines.”

"One of the things that is challenging with some of the ADCs is the requirement for a particular molecular profile to be eligible for the treatment. For example, to be eligible for mirvetuximab soravtansine the tumor tissue has to test positive on the companion diagnostic test for FOLR1 and for T-DXd it needs to have an elevated level of HER2 expression by IHC. Because testing for these markers is new and not yet integrated into standard pathology evaluations, we’re often having to go back to the tumor tissue and request additional assessments. Then the question is, should we test the original tumor or obtain a new biopsy? Also, the length of time it may take to test the tissue can be a problem when trying to make quick treatment decisions for patients.”

"One of the recent exciting updates to the [footnotes of the] cervical cancer guidelines has been the addition of pembrolizumab with chemoradiation for patients with stage III to IVA disease based on FIGO 2014 staging. However, since the staging system used for the phase 3 KEYNOTE-A18 study [NCT04221945] was FIGO 2014 and it’s not the staging system that’s currently in use by pathologists, making that conversion to determine whether a patient is eligible to receive pembrolizumab in combination with chemotherapy can be a challenge.”

"Another thing that was included in the [cervical cancer] NCCN guidelines this year was the addition of other recommended regimens for chemoradiation if the preferred chemotherapy is not available. With the shortages in chemotherapy recently, particularly cisplatin and carboplatin, we needed to think about alternatives when those were in short supply. [That was an] important change that went into the NCCN guidelines.”

Vice chair of the Melanoma NCCN Guidelines Panel

Assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee

"The major NCCN update from the past year, which [will also] continue to next year, has been the recommendation of neoadjuvant therapy as a preferred option. For patients with stage III or IV resectable disease, the previous standard of care was surgery followed by adjuvant therapy with anti–PD-1 [agents], but more recently, that’s changed given several practice changing studies that favor neoadjuvant therapy. There are 2 options, really even more than that, but 2 major options, based on randomized [trial] data…. Another major update is the addition of TIL therapy [with] lifileucel being the specific product.”

"In the neoadjuvant setting, it’s important for community oncologists to work with their surgical oncologists and make sure they’re aware of the new guideline changes. In the past, our surgeons would oftentimes do a fantastic surgery and then refer to us. That was the workflow where we wouldn’t see the patient until after surgery, and that was appropriate at that time, but it’s changed. If a patient has a palpable lymph node, an in-transit lesion, or even isolated stage IV [disease], in most cases they shouldn’t go to surgery first. They should see us for a few doses of neoadjuvant therapy and then undergo surgery.”

Articles

In 2024, significant updates were made to the NCCN guidelines across various cancers, including tumor-agnostic approvals and specific changes in treatment protocols for cancers like NSCLC, breast cancer, and multiple myeloma. The guidelines now incorporate new drugs and treatment strategies, reflecting advancements in targeted therapies and immunotherapies. These updates emphasize the importance of molecular profiling and multidisciplinary approaches in cancer treatment. The rapid evolution of guidelines poses challenges for clinical practice, particularly in obtaining prior authorizations and integrating new therapies into standard care.

Experts detail how recent NCCN guideline changes in dozens of tumor types are affecting their practices, and we gather all the NCCN updates in a slideshow.

Critical Recent NCCN Guideline Updates Affect Dozens of Malignancies 

Since it's implementation in 1992, the aim of the 340B Drug Pricing Program has been to offer low-income and underserved patient populations with cancer and other diseases expanded access to affordable medications by selling drugs at discounted prices to eligible centers.

 However, a lack of clarity among these centers has contributed to the program not operating at the peak of its potential in recent years, according to Aaron Ambrad, MD.

“We believe there is a lot of money sitting on the table [in terms of] 340B
reform, with some estimates up to [approximately] $84 billion in potential savings,” Ambrad, a radiation oncologist at Ironwood Cancer & Research Centers in Scottsdale, Arizona, and a member of the Community Oncology Alliance (COA) board of directors, said in an interview with OncologyLive.  The American Hospital Association relies on the 340B program significantly; [however], we believe there are a lot of abuses [of the program]. They say that it’s a good program and it is doing what it’s intended to do. We believe it’s doing a lot more than it was intended to do, which is padding the pockets of these hospitals.”

Participation in the 340B program has experienced significant growth since its inception. There were approximately 1000 covered entities in 1992; in 2021 this figure was over 50,000; 60% were hospitals and 40% were federal grantee clinics.1 More than 40% of US hospitals now participate in the 340B program. The discounted prices offered by the program are equivalent to the average manufacturer price minus the average Medicaid rebate for a unit of that drug during the previous quarter, conferring a discount of approximately 20% to 50% for participating hospitals. 

Beyond the rapid growth of the program, research has shown that the patient populations served by 340B program member hospitals have also shifted over time. Findings from a retrospective study published in 

 showed that before 2004 participating hospitals were larger (439 beds vs 338 beds), more often public (51.4% vs 11.0%), academic (67.9% vs 18.2%), located in counties with lower income levels (18.0% vs 15.0%), and serving higher levels of uninsured patients (14.0% vs 12.0%) compared with hospitals who joined the program after 2004.

Increased participation in the program has led to increased profits for centers. Findings from a cross-sectional descriptive study of 340B revenue from Medicare spanning 2013 to 2016 demonstrated that hospitals received approximately $2.1 billion in revenue from Medicare in 2013 and $3.7 billion in 2016.

 The 2016 median per-hospital profits from the 340B program were estimated to be $0.8 million (IQR, $0.1 million-$2.8 million). Data from another study estimated that the 340B program generated more than $40 billion in total profits for covered entities, contract pharmacies, and potentially patients via reduced drug prices.

Ambrad says the deviation from the program’s intended purpose by participating centers is largely due to a lack of transparency regarding profits and the rapid consolidation of smaller clinics by larger health care systems.

“Our biggest contention is that [health care center] consolidation is what happened with 340B. Over the past 10 years, [340B] hospitals started buying up rural programs, and there is a whole transparency issue of whether this is being policed and whether the oversight is there [to ensure] they are using 340B in the way it was intended,” Ambrad explained.

From 2016 through 2022, research showed that among 52 unique hospitals that were sold and 49 unique hospitals that bought another hospital, 81.6% of buying hospitals were 340B-covered entities.

 This consolidation shifts care delivery from community-based practices to hospital outpatient sites, potentially increasing the cost of care for patients. Importantly, similar consolidation has also been reported in terms of non-340B hospitals and oncology practices, so its precise association with the program has yet to be clearly defined.

This consolidation of smaller centers into larger hospital systems and the funneling of care into hospitals have led to unintended downstream effects, according to Ambrad. Hospitals represent the most expensive part of the health care system and often provide no additional services for the average patient that can’t be performed by a community practice, he said. In addition, there are often fees charged in the hospital setting that do not accompany care in the community setting, he said.

“The discount [that hospitals] get with the 340B program is supposed to only apply to indigent care. An 11.75% [share of patients receiving indigent care] is required, which amounts to approximately 27% of your patients being on Medicaid or uninsured,” Ambrad said. “We believe that they’re funneling this benefit to all the hospitals. One hospital buys all [of a] drug for the whole system at a discount, which is totally unfair, with discounts up to 50% [leading to] huge markups. There needs to be reform and more oversight transparency. There apparently are no rules as to what they can do with this money that they’re saving; they’re supposed to give it back to the patient, but that apparently is not the case.”

Findings from a 2022 COA study showed that self-reported pricing
data from 340B hospitals revealed that top oncology drugs were priced
at a median of 4.9 times higher compared with their 340B acquisition costs, with the lowest median markup being 3.2 times for tisagenlecleucel (Kymriah) and the highest being 11.3 times for fulvestrant (Faslodex).

 The median markup between biosimilars and their reference products was approximately 5.5 times higher.

Ambrad and other investigators are hoping that legislative action can be taken to increase the transparency of member institutions of the 340B program. In May 2024, US Representatives Earl L. “Buddy” Carter (R, Georgia); Larry Bucshon, MD, (R, Indiana); and Diana Harshbarger (R, Tennessee) introduced the 340B Affording Care for Communities and Ensuring a Strong Safety-Net Act (340B ACCESS Act).7 The bill aims to establish oversight and transparency concerning the 340B program and provide practical and achievable solutions to ensure the program works as intended. The bill calls for the establishment of patient affordability requirements, codifying of patient definition, recognition of contract pharmacies, imposing of hospital eligibility, establishment of child site eligibility, and restriction of pharmacy benefit managers and for-profit entities.

“There has been a lot of bipartisan movement, [and we are] getting the ear [of legislators] to listen to exactly what we believe the main issues [with the 340B program] are,” Ambrad said. “We’re trying to get the senators to understand [our problems with the program], but lobbying

is always a big issue. There are real-world effects on a community practice such as ours, and [these issues] start to destroy the independent, physician-run practice.

Knox RP, Wang J, Feldman WB, Kesselheim AS, Sarpatwari A. Outcomes of the 340B drug pricing program: a scoping review. JAMA Health Forum. 2023;4(11):e233716. doi:10.1001/ jamahealthforum.2023.3716

Nikpay S, Buntin M, Conti RM. Diversity of participants in the 340B drug pricing program for US hospitals. JAMA Intern Med. 2018;178(8):1124-1127. doi:10.1001/jamainternmed.2018.2015

Conti RM, Nikpay SS, Buntin MB. Revenues and profits from Medicare patients in hospitals participating in the 340B drug discount program, 2013-2016. JAMA Netw Open. 2019;2(10):e1914141. doi:10.1001/jamanetworkopen.2019.14141

Masia N. 340B drug pricing program: analysis reveals $40 billion in profits in 2019. AIR 340B Alliance for Integrity & Reform. Accessed November 4, 2024. bit.ly/4fXSNLw

Characteristics of hospitals undergoing mergers and acquisitions. Avalere. February 13, 2023. Accessed November 4, 2024. bit.ly/3ZAUEA9

Examining 340B hospital price transparency, drug profits, and incentives. Community Oncology Alliance. September 2022. Accessed November 4, 2024. bit.ly/3CXcPay

Carter, Buschon, and Harshbarger introduce legislation to ensure access and transparency in 340B drug pricing program. News release. Buddy Carter. May 28, 2024. Accessed November 1, 2024. bit.ly/4ikpnZB

Oncology Live®

Transparency and Consolidation Issues Hamper 340B Program in Cancer Care

Waldenström Macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by the malignant accumulation of IgM-producing lymphoplasmacytic cells in the bone marrow and other organs.

 Recurrent somatic mutations in MYD88 and CXCR4 are observed in approximately 90% and 40% of patients with cancer, respectively, and give the malignant cells a survival advantage through apoptosis escape mechanisms.

The genomic profile impacts the clinical presentation of patients with WM. For example, patients with CXCR4-mutated disease typically present with high serum IgM levels, symptomatic hyperviscosity, and acquired von Willebrand disease.

 In contrast, patients with MYD88 wild-type disease have a higher risk of an aggressive transformation and experience inferior survival outcomes.

One-third of patients are diagnosed with WM in an asymptomatic phase, also known as smoldering or inactive WM. These patients have an overall survival similar to age-, sex-, and race-matched individuals of the general population.6 The asymptomatic WM risk scoring system uses the percentage of bone marrow involvement, serum IgM, albumin, and beta-2-microglobulin levels to identify patients at high, intermediate, and low risk of needing therapy.

 As WM is currently incurable using standard therapies, and the available therapies can induce adverse effects, therapy should be reserved for patients with symptomatic WM whose activities of daily living are impacted by the disease.


Approximately 80% of patients with asymptomatic WM will require therapy within 10 years of diagnosis.

 Criteria for treating WM include symptomatic anemia; constitutional symptoms such as fevers, drenching night sweats, or unintentional weight loss; symptomatic hyperviscosity; progressive neuropathy; and symptomatic lymphadenopathy or organomegaly. Other rare indications to treat include symptomatic cryoglobulinemia, cold agglutinin syndrome, systemic light chain amyloidosis, and the rare Bing-Neel syndrome, in which WM cells invade the central nervous system.

Several treatment options exist for patients with symptomatic WM, but no large, randomized studies have compared the commonly used regimens. Therefore, treatment selection is highly personalized and should consider the patient’s clinical presentation, comorbidities, concurrent medications, genomic profile, treatment objective, and personal preferences.

 The modified staging system for WM is an externally validated multi-institutional prognostic model to estimate the survival of patients with active, symptomatic WM and uses age, serum beta-2-microglobulin, lactate dehydrogenase, and albumin to classify patients into low-, low-intermediate, intermediate, and high-risk disease.


Rituximab (Rituxan)-containing regimens, also known as chemoimmunotherapy, are commonly used with a long track record and evidence of durable responses.

Beyond deep and durable responses, advantages of chemoimmunotherapy include a fixed duration, potentially allowing patients to be off therapy for years. However, chemoimmunotherapy can induce cytopenias, a higher risk of infections, and the development of myeloid neoplasms.

Over the past decade, Bruton tyrosine kinase (BTK) inhibitors have become a standard treatment option. Ibrutinib was highly effective in WM and induced deep and durable responses.

 The combination of ibrutinib (Imbruvica) and rituximab induced deeper and more durable responses than rituximab plus placebo in the phase 3 INNOVATE study (NCT02165397).

 Zanubrutinib was as effective as ibrutinib but was associated with lower rates of diarrhea, rash, and atrial fibrillation in the phase 3 ASPEN study (NCT03053440).

These findings supported the FDA approval of ibrutinib in 2015, ibrutinib and rituximab in 2018, and zanubrutinib in 2021 for the treatment of patients with WM. The advantages of BTK inhibitors include the ease of oral administration and the absence of risk of myeloid neoplasms. On the other hand, BTK inhibitors are associated with unique adverse events, such as an increased risk of bleeding, hypertension, and arrhythmia. The duration of therapy is indefinite and should continue until disease progression or unacceptable toxicity.

Beyond chemoimmunotherapy and BTK inhibitors, BCL2 antagonists such as venetoclax and noncovalent BTK inhibitors such as pirtobrutinib are safe and effective options.

 The National Comprehensive Cancer Network guidelines endorse both agents to treat patients with WM with previously treated disease. Tumor lysis monitoring is essential when ramping up the dose of venetoclax (

Clinical trial participation is essential to develop safer and more effective agents to treat WM. Any patient with WM should consider clinical trial participation at any stage of the disease.

In the frontline setting, a series of randomized European trials are comparing chemoimmunotherapy regimens, such as cyclophosphamide, dexamethasone, and rituximab vs ibrutinib plus rituximab in the phase 2/3 RAINBOW trial (NCT04061512) or vs venetoclax plus rituximab in the phase 2 VIWA-1 study (NCT05099471). Single-arm studies are evaluating BTK inhibitors in combination to provide fixed-duration therapy, including acalabrutinib (Calquence), bendamustine (Bendeka), and rituximab in the phase 2 BRAWM trial (NCT04624906); zanubrutinib (Brukinsa), bendamustine, and rituximab in the phase 2 ZEBRA trial (NCT06561347); and zanubrutinib and sonrotoclax in another phase 2 trial (NCT05952037).

In the relapsed setting, the phase 2 CLOVER-WaM study (NCT02952508) evaluating the radioconjugate iopofosine I-131 has completed accrual of patients, and results are expected soon. A number of other agents are under active clinical development and assessment in trials, including the following: pirtobrutinib plus venetoclax in a phase 2 study (NCT05734495), the second-generation BCL2 inhibitor sonrotoclax as monotherapy and in combination with zanubrutinib in a phase 2 study (NCT05952037), and the BTK degrader BGB-16673 in a phase 1/2 study (NCT05006716). Others include NX-5498 in a phase 1a/1b trial (NCT05131022), NX-2127 in another phase 1a/1b trial (NCT04830137), the anti-CD19 antibody-drug conjugate loncastuximab tesirine in a phase 2 study (NCT05190705), and the anti-CD20 bispecific antibody epcoritamab (Epkinly) in another phase 2 trial (NCT06510491). Additionally, chimeric antigen receptor T-cell therapy will soon enter clinical trials for patients with WM.

Clinical trials for special WM populations include a phase 2 study (NCT05065554) evaluating the combination of acalabrutinib and rituximab for patients with IgM monoclonal gammopathy of undetermined significance or WM with predominantly demyelinating neuropathy. Given WM’s rarity, clinical trials are essential to advance the field, and multi-institutional collaboration is crucial.


In Europe, the European Consortium for Waldenström’s Macroglobulinemia (ECWM), under the direction of Christian Buske, MD, was formed to improve the understanding of the biology of WM and develop therapies to enable patients with WM to live a life without compromise, with the final goal of achieving a cure. Dana-Farber Cancer Institute, in Boston, Massachusetts, under the direction of Jorge Castillo, MD, and in partnership with the International Waldenström’s Macroglobulinemia Foundation, created a US-based think tank to advance clinical research in WM, known as the WM-NET.

The WM-NET comprises more than 20 academic institutions in the US and will help design and support scientifically driven multi-institutional clinical trials in the US (

Other projects include the development of an academic prospective database aimed at answering questions that are unlikely to be answered by clinical trials and establishing a biorepository for blood and marrow samples from clinical trial participants to enhance WM-specific research efforts further (

). A cross talk between the ECWM and the WM-NET is being planned.

Swerdlow SH, Cook JR, Sohani AR, et al. Lymphoplasmacytic lymphoma. In: 

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

. Swerdlow SH, Campo, E, Harris NL, et al, eds. IARC Publications; 2017:232-235.

Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. 

. 2012;367(9):826-833. doi:10.1056/NEJMoa1200710

Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. 

. 2014;123(11):1637-1646. doi:10.1182/blood-2013-09-525808

Castillo JJ, Xu L, Gustine JN, et al. CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib. 

. 2019;187(3):356-363. doi:10.1111/bjh.16088

Treon SP, Gustine J, Xu L, et al. MYD88 wild-type Waldenstrom macroglobulinaemia: differential diagnosis, risk of histological transformation, and overall survival. 

. 2018;180(3):374-380. doi:10.1111/bjh.15049

Zanwar S, Abeykoon JP, Ansell SM, et al. Disease outcomes and biomarkers of progression in smouldering Waldenström macroglobulinaemia. 

. 2021;195(2):210-216. doi:10.1111/bjh.17691

Bustoros M, Sklavenitis-Pistofidis R, Kapoor P, et al. Progression risk stratification of asymptomatic Waldenström macroglobulinemia. 

. 2019;37(16):1403-1411. doi:10.1200/JCO.19.00394

8.Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and criteria to initiate therapy in Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. 

. 2003;30(2):116-120. doi:10.1053/sonc.2003.50038

Castillo JJ, Advani RH, Branagan AR, et al. Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia. 

. 2020;7(11):e827-e837. doi:10.1016/S2352-3026(20)30224-6

Zanwar S, Le-Rademacher J, Durot E, et al. Simplified risk stratification model for patients with Waldenström macroglobulinemia. 

. 2024;42(21):2527-2536. doi:10.1200/JCO.23.02066

Kastritis E, Gavriatopoulou M, Kyrtsonis MC, et al. Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenström macroglobulinemia: final analysis of a phase 2 study. 

. 2015;126(11):1392-1394. doi:10.1182/blood-2015-05-647420

Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. 

. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2

Treon SP, Ioakimidis L, Soumerai JD, et al. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. 

. 2009;27(23):3830-3835. doi:10.1200/JCO.2008.20.4677

Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström’s macroglobulinemia. 

. 2014;124(4):503-510. doi:10.1182/blood-2014-03-566273

Castillo JJ, Meid K, Flynn CA, et al. Ixazomib, dexamethasone, and rituximab in treatment-naive patients with Waldenström macroglobulinemia: long-term follow-up. 

. 2020;4(16):3952-3959. doi:10.1182/bloodadvances.2020001963

Castillo JJ, Meid K, Gustine JN, et al. Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia. 

. 2022;36(2):532-539. doi:10.1038/s41375-021-01417-9

Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström’s macroglobulinemia. 

. 2015;372(15):1430-1440. doi:10.1056/NEJMoa1501548

Buske C, Tedeschi A, Trotman J, et al. Ibrutinib plus rituximab versus placebo plus rituximab for Waldenström’s macroglobulinemia: final analysis from the randomized phase III iNNOVATE study. 

. 2022;40(1):52-62. doi:10.1200/JCO.21.00838

Dimopoulos MA, Opat S, D’Sa S, et al. Zanubrutinib versus ibrutinib in symptomatic Waldenström macroglobulinemia: final analysis from the randomized phase III ASPEN study. 

. 2023;41(33):5099-5106. doi:10.1200/JCO.22.02830

Castillo JJ, Allan JN, Siddiqi T, et al. Venetoclax in previously treated Waldenström macroglobulinemia. 

. 2022;40(1):63-71. doi:10.1200/JCO.21.01194

Palomba ML, Patel MR, Eyre TA, et al. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in relapsed / refractory Waldenström Macroglobulinemia: results from the phase 1/2 BRUIN study

. 2022;140(suppl 1):557-560. doi:10.1182/blood-2022-159123

Waldenström Macroglobulinemia (WM) is a rare non-Hodgkin lymphoma subtype characterized by IgM-producing lymphoplasmacytic cells. Key mutations in MYD88 and CXCR4 influence clinical presentation and treatment response. Asymptomatic WM patients have survival rates similar to the general population, but 80% require treatment within 10 years. Treatment options include chemoimmunotherapy and BTK inhibitors, with personalized regimens based on patient profiles. Clinical trials are crucial for advancing WM treatment, with ongoing studies exploring various drug combinations and novel therapies. Collaborative efforts aim to enhance understanding and develop curative strategies.

Understanding Waldenström Macroglobulinemia, and genomic profiles influencing clinical presentation and treatment strategies.

New Advances in Waldenström Macroglobulinemia

A few allosteric inhibitors have arrived that have been developed to reduce toxicities with mutation-specific targeting and build upon the efficacy seen with orthosteric inhibitors such as alpelisib (Piqray) and the recently approved inavolisib (Itovebi) in breast cancer.

 Among the select allosteric kinase inhibitors that currently hold indications from the FDA, 2 in the oncology space are trametinib (Mekinist)—which targets MEK1 and MEK2—for patients with melanoma, and asciminib (Scemblix)—a BCR-ABL1 inhibitor—for patients with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase.

Many allosteric agents are under evaluation in early-phase trials, which, if proved effective in phase 2 and 3 trials, could fill an unmet need for patients with breast cancer who are experiencing adverse effects (AEs) during treatment with alpelisib, according to investigators. Data from the phase 3 SOLAR-1 trial (NCT02437318), which led to the agent’s approval in combination with fulvestrant (Faslodex) for postmenopausal patients with hormone receptor–positive, HER2-negative, 

-mutated, advanced or metastatic breast cancer, showed that 21% of patients permanently discontinued alpelisib and 4.6% discontinued the combination due to AEs.

“The power of allosteric inhibition of the PIK3CA enzyme or gene is [that] it allows for a more focused, selective targeting of the mutant type of 

 and therefore [offers] a better safety and tolerability profile,” Felipe Batalini, MD, a medical oncologist and assistant professor of oncology at Mayo Clinic College of Medicine in Phoenix, Arizona, said in an interview with 

Alberto Montero, MD, MBA, CPHQ, added that “The field has moved toward a more mutation-specific inhibitor. I believe that is going to open the ability to target this hugely important pathway in cancer and enhance the therapeutic index; [this approach could] block the pathway but have less toxicity at the same time.” Montero is clinical director of the Breast Cancer Medical Oncology Program and the Diana Hyland Chair for Breast Cancer at University Hospitals Seidman Cancer Center in Cleveland, Ohio. He is also an associate professor of medicine at Case Western Reserve University School of Medicine in Cleveland.

Targeting PIK3CA With Allosteric Inhibitors

 encodes for the p110 subunit of the PI3K enzyme, and specifically PI3Kα. 

 is the most commonly mutated oncogene across [breast] cancer and can be mutated in as [much] as 40% of breast cancers for the estrogen receptor–positive subtype,” Batalini said. “The issue is that although there are drugs approved—specifically the PI3Kα inhibitor alpelisib in breast cancer—there’s significant toxicity that limits its usefulness in clinic because it also targets the wild-type [enzyme].”

On-target toxicity resulting from treatment with PI3K inhibitors has led to treatment discontinuation in large proportions of patients when hyperglycemia, rash, or gastrointestinal toxicities develop. Research findings published in 

 noted that a modest shift in the potency of orthosteric PI3K inhibitors driven by secondary 

 mutations could have a significant effect on clinical efficacy. Allosteric inhibitors have generated excitement as they may be able to overcome resistance driven by acquired 

 alterations and resistance alterations within the catalytic pocket. The effect on insulin signaling can also be minimized with the selective inhibition of the mutant vs wild-type PI3Kα isoform, thus reducing the frequency of hyperglycemia and enabling higher target engagement and a wider therapeutic index.

“The target itself is [not] new, but the way we are targeting PIK3CA using an allosteric inhibitor is unique because [we’re not] targeting the catalytic domain with small molecule inhibitors, which is the typical way of targeting the ATP binding site, [where] it’s harder to be specific,” Batalini said. “We often see these AEs because this targeting of the catalytic domain may not be very selective to the mutant [enzyme]. Using the whole protein surface and identifying a pocket that is much more specific to the mutant 

STX-478 Shows Promise in Multiple Solid Tumors Including Breast

Initial findings from a first-in-human phase 1/2 study (NCT05768139) were presented at the 2024 European Society for Medical Oncology Congress on the allosteric, central nervous system–penetrant, mutant-selective PI3Kα inhibitor STX-478. The mutant-selective design of the oral agent allows it to selectively target mutant PI3Kα, thus minimizing wild-type toxicities. When investigators gave the agent to efficacy-evaluable patients with advanced solid tumors and 

 helical and kinase domain mutations who received prior standard-of-care therapy (n = 43), the overall response rate (ORR) was 21%. Investigators noted the monotherapy response rate is favorable compared with the monotherapy ORR of 4% to 6% observed with currently approved PI3K pathway inhibitors. Additionally, patients experienced a disease control rate (DCR) of 67%.

“One of the advantages of STX-478 is it has a very long half-life [of approximately 60 hours],” Montero said. “It’s given once daily, and [data from] the pharmacokinetic studies support that. One of the advantages is that you can get continuous blockade of the pathway because of its long half-life, [and] it doesn’t have toxicities that we’ve seen with the other, [similar drugs].”

When examining responses by tumor type, the ORR was 23% among those with hormone receptor–positive breast cancer (n = 22) and 44% among those with gynecologic tumors (n = 9); respective DCRs were 68% and 67% (

 Montero noted that the high ORR seen in the gynecologic cohort could be due to the small number of patients enrolled as well as good patient selection, as the trial excluded patients with downstream mutations, where he said one would not expect to see a response to blocking PI3K.

 is a common mutation, [STX-478] showed initial activity although the numbers are small. That by itself is a huge advance, and the company is looking to add more patients [to that cohort] and look at the drug either as a single agent [or in combinations] because my understanding listening to other gynecologic oncologists is that if that held up that would be clinically meaningful, just the activity that we’ve seen as a single agent. But then coming up with rational combinations [is key] because there are a limited number of therapeutic options for uterine cancer,” he added.

Additionally, STX-478 was given at 6 dose levels in the trial, escalating from 20 mg to 160 mg. The maximum tolerated dose was reached at 100 mg; 2 dose-limiting toxicities of grade 3 myalgia and paresthesia occurred in patients who received the agent at 160 mg and resolved rapidly after dose interruption. Notably, no patients discontinued treatment due to an AE and no grade 3 or higher PI3Kα wild-type toxicities were observed.

“[STX-478] was very well tolerated compared with what we are familiar with for PI3Kα inhibitors,” Montero said. “The 2 important points are [that STX-478 has a] long half-life and it crosses the blood-brain barrier. In the phase 1 trial there weren’t very many patients who had brain metastases. As the trial continues and more patients are enrolled, [we’re] eagerly looking to see [if there’s activity in that population], but at this point we don’t have enough clinical data.”

Furthermore, enrollment in the trial is ongoing in the combination expansion cohort with fulvestrant with or without CDK4/6 inhibitors in patients with hormone receptor–positive, HER2-negative breast cancer. End points of the study include determining the recommended phase 2 dose (RP2D), assessing safety, and examining antitumor activity as well as patient-reported outcomes.

“There’s also a plan to combine it with aromatase inhibitor therapy and CDK4/6 inhibitors. The idea is there’s cross talk between the estrogen pathway and the PI3K pathway, so it’s rational to combine all of them together,” Montero said. “Moving forward with a drug that can be combined with endocrine therapy [that does] not [have] as much potential for toxicity is a big advantage…. I’m enthusiastic for this drug and drugs like [it] that can specifically target a mutated protein and spare the toxicities [of] off-target effects the native, nonmutated protein.”

Allosteric inhibitors are emerging as promising alternatives to orthosteric inhibitors in targeting PIK3CA mutations in breast cancer, offering improved safety and efficacy. These inhibitors, such as STX-478 and RLY-2608, selectively target mutant PI3Kα, minimizing wild-type toxicities and potentially overcoming resistance. Early-phase trials show encouraging results, with STX-478 demonstrating a favorable response rate and disease control in solid tumors. RLY-2608 also shows promise, with significant progression-free survival in breast cancer patients. These developments highlight the potential of allosteric inhibitors in enhancing therapeutic outcomes.

Felipe Batalini, MD, and Alberto Montero, MD, MBA, CPHQ, detail how allosteric inhibitors targeting PIK3CA such as STX-478 may reduce toxicities seen with orthosteric inhibitors.

Vol. 25 No. 16 | Oncology Live®

Critical Recent NCCN Guideline Updates Affect Dozens of Malignancies

Transparency and Consolidation Issues Hamper 340B Program in Cancer Care

New Advances in Waldenström Macroglobulinemia

Allosteric Inhibitors Targeting PIK3CA May Reduce Treatment Toxicities in Breast Cancer

Novel Therapies and Combinations Augment Melanoma Treatment Arsenal

Combination Regimens Make Their Mark in Frontline HCC

The Ongoing Debate: Progression-Free vs Overall Survival as the Primary Study Outcome in Therapeutic Cancer Trials