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 NTRK gene fusion and fam-trastuzumab deruxtecan-nxki (Enhertu, T-DXd) for adults with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors.1,2 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.3 For certain cancers, early versions of the 2025 guidelines have already been released as well.4-8

“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.”

In exclusive interviews with OncologyLive, 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,9 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 OncLive.com.

Multiple Myeloma

Shaji Kumar, MD

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.”

Chronic Lymphocytic Leukemia

Matthew Cortese, MD, MPH

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.”

Chronic Myeloid Leukemia

Neil P. Shah, MD, PhD

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.”

B-Cell Lymphomas

Leo I. Gordon, MD

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 TP53 mutations, for example. We have relied upon next-generation sequencing [NGS] as the way to determine if there is a TP53 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] ‘TP53 by IHC is not a proven surrogate for a TP53 mutation or deletion 17[p]’ [to say] that ‘TP53 sequencing is preferred’. However, because NGS may not be available everywhere and all the time, we think that in the frontline setting [TP53 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.”

Breast Cancer

Jairam Krishnamurthy, MD, FACP

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.”

Gastrointestinal Malignancies

Al B. Benson III, MD

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

Regarding Rectal and Colon Cancer:

Venook: "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.”

Benson: "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.”

Venook: "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].”

Alan P. Venook, MD

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

Regarding Biliary Tract Cancer:

Venook: "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.”

Venook: "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.”

Regarding HCC:

Venook: "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.”

Venook: "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.”

Benson: "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.”

Venook: "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.”

Genitourinary Malignancies

Sandy Srinivas, MD

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.”

Ovarian and Cervical Cancers

Stephanie Gaillard, MD, PhD

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

Regarding Ovarian Cancer:

"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.”

Regarding Cervical Cancer:

"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.”

Melanoma/Skin Cancer

Douglas B. Johnson, MD, MSCI

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.”

"Community oncologists should continue to communicate with their surgical oncologists and other surgical specialists who see some of the patients who have lymph node involvement with melanoma. It is important to alert the pathologists as well. Pathologists need to be aware if the patient’s going to receive some sort of response-directed treatment.”

Lung Cancer

Jonathan Wesley Riess, MD, MS

Member of the Non–Small Cell Lung Cancer NCCN Guidelines Panel

Medical director of thoracic oncology and associate professor of medicine in the Division of Hematology and Oncology at UC Davis Comprehensive Cancer Center in Sacramento, California

Regarding NSCLC:

Riess: "The other chemoradiation study was the phase 3 LAURA study [NCT03521154]....looking at osimertinib after completion of chemoradiation for patients with unresectable stage III NSCLC harboring the more common EGFR mutations of exon 19 deletion and L858R. The findings showed an impressive PFS benefit [with osimertinib in patients reaching] [39.1] months vs [5.6] months for chemoradiation alone. That study was also practice changing and [that regimen now has] a category 1 recommendation in the guidelines.”

Daly: "[It is] important to get upfront molecular testing [performed] for all patients, not just for patients with metastatic disease. It is recommended now that all patients should have molecular tumor testing to test for these targetable mutations because it has such a clear difference in how we treat patients. For example, in the unresectable stage III setting whether they would go on to durvalumab or osimertinib.”

Megan E. Daly, MD

Member of the Small Cell Lung Cancer NCCN Guidelines Panel

Professor in the Division of Radiation Oncology at UC Davis Comprehensive Cancer Center in Sacramento, California

Regarding SCLC:

Riess: "The 2 most practice changing [trial] findings [that led to guideline updates] were for consolidation therapy after treatment with chemoradiation. One [trial that affected] the SCLC guidelines was the phase 3 ADRIATIC study [NCT03703297] which [was presented in the] American Society of Clinical Oncology [ASCO] plenary session this year. The results showed a dramatic improvement in progression-free survival [PFS] and overall survival [(OS) with the addition of adjuvant] durvalumab after concurrent chemoradiation [vs placebo] for patients with LS-SCLC. That was practice changing, and [that regimen] is now a category 1 NCCN recommendation, so I’ve adopted that into my practice.”

Daly: "In the SCLC setting, the ADRIATIC [trial data] have had a large impact, which has been great to see [because] these are patients who historically have had relatively poor outcomes. Having something with such a remarkable PFS and OS benefit has been wonderful for our patients with LS-SCLC. It does open some questions, for example, [regarding] prophylactic cranial irradiation [PCI] that are still being answered by ongoing trials like the phase 3 MAVERICK study [NCT04155034], but certainly [I now] let all my patients with LS-SCLC know up front that prior to chemoradiation they’ll likely be receiving durvalumab following completion of chemoradiation.”