NCCN Clinical Practice Guidelines in Oncology: 2024 Updates

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The National Comprehensive Cancer Network® published its first set of Clinical Practice Guidelines in Oncology (NCCN Guidelines®) in 1996, covering eight tumor types. Currently, guidelines are available for more than 60 tumor types, subtypes, and related topics. The NCCN’s 29th Annual Conference featured presentations on updates to the NCCN Guidelines for a number of those malignancies. Key changes have been captured by The ASCO Post.

Multiple Myeloma

“Immunotherapy is where myeloma is going in the next few years, in a big way.” 

Natalie S. Callander, MD

Updates in multiple myeloma were presented by Shaji K. Kumar, MD, the Mark and Judy Mullins Professor of Hematologic Malignancies at the Mayo Clinic Cancer Center, Rochester, Minnesota, and Natalie S. Callander, MD, Professor of Medicine at the University of Wisconsin Carbone Cancer Center, and Director of the UW Carbone Cancer Center Myeloma Clinical Program.

Shaji K. Kumar, MD

Shaji K. Kumar, MD

Natalie S. Callander, MD

Natalie S. Callander, MD

Risk stratification helps determine prognosis, with different outcomes partly defined by the underlying cytogenetic abnormalities determined at diagnosis. These cytogenetic factors have been considered in greater detail in the second revision of the International Staging System, which has been incorporated into the NCCN Guidelines for disease staging and risk stratification of newly diagnosed patients. The section describing factors associated with high risk for disease progression or relapse has also been revised.

Adding to the growing number of immunotherapies are antibody-drug conjugates and bispecific T-cell engagers. In addition to the bispecific antibody teclistimab-cqyv, which became a recommended treatment 18 months ago, the NCCN Guidelines have been updated also to include talquetamab-tgvs and elranatamab-bcmm for patients previously treated with at least four prior lines. The NCCN Panel has also offered new guidance for managing infections, which are common with these therapies.

Several new regimens have been added as primary treatment of transplant candidates, all considered “useful in certain circumstances.” They include:

  • Isatuximab-irfc, lenalidomide, bortezomib, dexamethasone;
  • Daratumumab with or without lenalidomide as maintenance;
  • Ixazomib as maintenance.

A growing number of patients have disease that is refractory to lenalidomide, and this creates a treatment challenge. Preferred new regimens include selinexor, bortezomib, dexamethasone and elotuzumab, pomalidomide, dexamethasone. Other regimens for previously treated patients (one to three prior lines) now include the following:

  • Chimeric antigen receptor (CAR) T-cell therapy with ciltacabtagene autoleucel or idecabtagene vicleucel (preferred);
  • Ixazomib, lenalidomide, dexamethasone (other);
  • Venetoclax and dexamethasone with and without daratumumab or a proteasome inhibitor only for patients with t(11;14; useful in certain circumstances).

Hormone Receptor–Positive, HER2-Negative Breast Cancer

“The thing that changed, certainly in the space of advanced disease, is that rather than thinking of the sequential use of monotherapy, we are using doublets in many different places.”

William J. Gradishar, MD

Treatment approaches for hormone receptor–positive, HER2-negative breast cancer are becoming increasingly individualized, driven by the development of targeted therapies and further description of the tumor landscape, according to William J. Gradishar, MD, the Betsy Branson Professor of Breast Oncology; Professor of Medicine; and Chief, Division of Hematology and Medical Oncology, Feinberg School of Medicine, Northwestern University, Chicago.

William J. Gradishar, MD

William J. Gradishar, MD

Supported by the CAPItello-291 trial, the November 2023 approval of the AKT inhibitor capivasertib plus fulvestrant for previously treated patients with locally advanced or metastatic disease harboring at least one PIK3CA, AKT1, or PTEN alteration represents a breakthrough in personalized disease management. The Targeted Therapies and Associated Biomarker Testing for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease section of the NCCN Guidelines was updated to recommend this doublet as a “preferred” second- or subsequent-line option (category 1), followed by a recent extensive revision.

CDK4/6 inhibitors have shown benefit in the adjuvant, early-stage setting. Treatment with abemaciclib plus endocrine therapy for a 2-year period has been incorporated into NCCN Guidelines for high-risk patients with node-positive disease (category 1), based on data from the monarchE trial; however, the NATALEE trial regimen of ribociclib plus endocrine therapy is still awaiting approval from the U.S. Food and Drug Administration (FDA). “Whether we’ll have a choice between ribociclib and abemaciclib and how we make those decisions will be based on further maturity of the ribociclib data,” Dr. Gradishar explained.

In further exploring the current adjuvant endocrine therapy paradigm, at the conference, Dr. Gradishar introduced questions regarding the role of ovarian function suppression. Although some remain unanswered, the recently revised Principles of Adjuvant Endocrine Therapy section of the NCCN Guidelines may guide relevant clinical decision-making. Other sections have updated recommendations for ovarian function suppression in the context of hormone receptor–positive, HER2-negative disease.

Metastatic Urothelial Cancer

“What a difference 10 years have made in this field, as there are now several significant advancements that have altered the way we treat metastatic urothelial carcinoma.”

Thomas W. Flaig, MD

Thomas W. Flaig, MD

Thomas W. Flaig, MD

Back in 2015, the NCCN Guidelines featured platinum-based therapy as the preferred first-line treatment option for locally advanced or metastatic disease. However, with the incorporation of targeted immunotherapies, the current recommendation is to stratify patients based on their eligibility for cisplatin therapy.

“This demonstrates just how quickly the NCCN can adapt to changes in this regard,” commented Thomas W. Flaig, MD, a medical oncologist practicing at the University of Colorado Cancer Center and Professor of Medicine at the University of Colorado Anschutz Medical Campus, upon presentation of the following key changes to the guidelines:

  • Supported by the EV-302/KEYNOTE-A39 trial, pembrolizumab and enfortumab vedotin-ejfv was added as an option for cisplatin-eligible patients, notably with “preferred” status in this population and in those who are ineligible for such chemotherapy (both promoted from category 2A to 1 after addition).
  • Nivolumab, gemcitabine, and cisplatin followed by maintenance therapy with nivolumab was added as a category 2A, “preferred” regimen for cisplatin-eligible patients, informed by the CheckMate 901 trial, with subsequent changes in its NCCN Category of Preference (other) and Recommendation (category 1) designations.

“What I think is notable here is that all of our ‘preferred’ or recommended regimens [consist of] a combination that includes an immune checkpoint inhibitor,” Dr. Flaig remarked. Of note, some NCCN Category of Preference and Recommendation designations for other first-line systemic therapies have also changed.

With its removal as an “other recommended” second-line systemic therapy option for patients who underwent immune checkpoint inhibition, erdafitinib has been added as a “preferred” agent in both the cisplatin-eligible and cisplatin-ineligible, chemotherapy-naive settings. This pan-FGFR tyrosine kinase inhibitor also attained a category 1 recommendation as a “preferred” subsequent-line regimen. Furthermore, in the aforementioned clinical contexts, erdafitinib is now exclusively recommended for patients harboring susceptible FGFR3 genetic alterations; the NCCN Guidelines previously enabled its use in those with mutations in FGFR2 or FGFR3.

Endometrial Cancer

“We have not been doing so well in managing endometrial cancer, but with advancements in treatment, we are starting to see light.”

Nadeem R. Abu-Rustum, MD

Nadeem R. Abu-Rustum, MD

Nadeem R. Abu-Rustum, MD

The key updates to the NCCN Guidelines for uterine neoplasms regarding endometrial cancer were centered on the addition of immunotherapeutic agents to chemotherapy regimens in the advanced and recurrent disease settings, according to Nadeem R. Abu-Rustum, MD, Chief of the Gynecologic Service at Memorial Sloan Kettering Cancer Center, New York. “It’s wonderful to have a modality that may actually produce a fantastic response in patients with recurrent disease, particularly if they are mismatch repair–deficient (dMMR),” he said.

The following recommendations for two triplet regimens—(1) pembrolizumab, carboplatin, plus paclitaxel, and (2) dostarlimab-gxly, carboplatin, plus paclitaxel—were recently made, based on the results of the NRG-GY018 and RUBY trials, respectively:

  • Category 1, “preferred” primary therapy for stage III or IV disease;
  • Category 1, “preferred” first-line therapy for recurrent disease.

Of note, the NRG-GY018 trial did not include patients with carcinosarcoma disease. The NCCN Panel thus does not recommend the corresponding study regimen for those with such histology.

Here are other recent updates regarding systemic therapy for endometrial cancer:

  • Systemic therapy was added as an option for the primary treatment of suspected locoregional extrauterine disease that is not suitable for surgery.
  • Regarding primary or adjuvant chemoradiation therapy for stage I to IV disease, a section outlining “other” recommended regimens for instances in which cisplatin and carboplatin are unavailable has been added, with capecitabine/mitomycin, gemcitabine, and paclitaxel as options.
  • For the second-line or subsequent treatment of recurrent disease, cisplatin/gemcitabine has been added as an “other recommended” regimen, and fam-trastuzumab deruxtecan-nxki (T-DXd) was deemed “useful in certain circumstances” (for HER2-positive tumors).
  • A new category, “useful in certain circumstances,” recommending both letrozole/ribociclib and letrozole/abemaciclib for estrogen receptor–positive tumors, has been added to the table representing hormonal therapy options for recurrent or metastatic disease.

The NCCN Guidelines continue to reflect the importance of molecularly refining endometrial tumors. Of note, the current version encompasses revisions to the Principles of Molecular Analysis section.

The NCCN Panel has expressed concern about the 2023 revised International Federation of Gynecology and Obstetrics (FIGO) surgical staging system, opting instead to continue adherence to the 2009 system in the current version of the guidelines. Dr. Abu-Rustum stated: “Many gynecologic pathologists are interested in coming up with new standards…, because at this point, the data do not support what FIGO is telling us to do.”

Cutaneous Melanoma

“If you compare [the era before 2011] with right now, we have a lot of different systemic therapy options [for cutaneous melanoma].”

Douglas B. Johnson, MD, MSCI

Douglas B. Johnson, MD, MSCI

Douglas B. Johnson, MD, MSCI

At the conference, Douglas B. Johnson, MD, MSCI, Associate Professor of Medicine in the Department of Medicine at Vanderbilt University Medical Center, Nashville, discussed the consequential updates to the NCCN Guidelines resulting from several influential clinical trials.

Particularly, he noted that the NCCN’s recommendations for neoadjuvant therapy have been revamped. A new section, Principles of Neoadjuvant Therapy, was added. Furthermore, the recommendation “neoadjuvant therapy options,” encompassing pembrolizumab (preferred), nivolumab/ipilimumab (preferred), nivolumab (other), nivolumab and relatlimab-rmbw (other), and dabrafenib/trametinib (useful in certain circumstances: BRAF V600–mutated disease), was added for the following clinical scenarios:

  • Primary treatment of stage III (clinically positive node[s]) resectable nodal disease, also now followed by wide excision of the primary tumor (category 1) plus therapeutic lymph node dissection (TLND);
  • Initial treatment of stage III (clinical satellite/in-transit and local satellite/in-transit recurrence) limited resectable disease, also now followed by complete excision to clear margins;
  • Treatment of resectable nodal recurrence and biopsy-confirmed disease limited to nodal recurrence, also now followed by excision of the recurrence or TLND.

Shifting focus to adjuvant therapy, Dr. Johnson highlighted a key update: the inclusion of nivolumab as a category 1 recommendation for pathologic stage IIB and IIC disease. The NCCN Panel furthermore stratified both single-agent nivolumab and pembrolizumab as “preferred” regimens for cases where microscopic satellites are present in biopsy specimens from the primary lesion or in wide excision specimens with a negative or unknown sentinel lymph node (SLN) status. Dabrafenib/trametinib, a recent addition, also holds this designation for BRAF V600 mutation–positive disease in these clinical contexts.

Most recently, the NCCN Guidelines were updated to include the tumor-infiltrating lymphocyte product lifileucel as a “preferred” second-line or subsequent therapy in the metastatic or unresectable disease setting. The latest version also encompasses changes to the Systemic Therapy Considerations section, namely updated BRAF V600 mutation status–based recommendations for patients who experienced disease progression with systemic therapy.

Basal Cell and Squamous Cell Skin Cancers

“[For both patients with basal cell and squamous cell carcinomas], staging is challenging.”

Jeremy Bordeaux, MD, MPH

Jeremy Bordeaux, MD, MPH

Jeremy Bordeaux, MD, MPH

Despite limited data and the absence of universally accepted staging systems for basal cell and squamous cell carcinomas, the current NCCN Guidelines remain a cornerstone in providing risk-tailored recommendations for the treatment of these non-melanoma neoplasms. Some of the key updates, which are highlighted here, were presented by Jeremy Bordeaux, MD, MPH, Professor in the Department of Dermatology, School of Medicine at Case Western Reserve University, Cleveland.

“Not all basal cell carcinomas are the same,” commented Dr. Bordeaux. Drawing on examples of a less than 1-cm superficial vs deeply infiltrative basal cell carcinoma, he stated: “What these two cancers need is very different.” For these tumors, the NCCN Guidelines provide the following risk category– and disease progression–informed updates:

  • Regarding low-risk disease, the primary treatment options were revised to include the following nonsurgical modalities for tumors clinically and histologically consistent with superficial disease (without dermal extension): topical fluorouracil (useful in certain circumstances); topical imiquimod (preferred); photodynamic therapy (useful in certain circumstances); and cryotherapy.
  • The primary treatment option for nonsurgical candidates with high-risk disease was revised to suggest multidisciplinary consultation and discussion of definitive radiation therapy.
  • A new treatment algorithm was added for advanced disease, with an emphasis on multidisciplinary consultation for clinical decision-making.
  • The Principles of Systemic Therapy section now includes a preference stratification table for advanced disease, outlining the recommended regimens.

The updates to the NCCN Guidelines in squamous cell carcinoma also focus on refining treatment approaches to better address varying risk levels and disease stages. Particularly, the treatment algorithm for patients with high-risk or very high–risk cutaneous disease, now specific for those in whom surgery or radiation therapy has a high likelihood of cure, incorporates the following revisions:

  • Sentinel lymph node biopsy was added as a treatment planning option for cases that are recurrent or with multiple high-risk features, with a new footnote detailing recommendations for action in the event of a positive result.
  • For the primary treatment of nonsurgical candidates, multidisciplinary consultation and discussion of definitive radiation therapy are now recommended.
  • The additional treatment options for patients with positive margins have been revised.

A new treatment algorithm has been added for very high–risk cutaneous squamous cell carcinoma with significant risk of extensive local recurrence or nodal metastasis. Also now included is an algorithm for locally advanced or unresectable cutaneous disease.

Inaugural Guidelines for Neuroblastoma

“Neuroblastoma is a clinically and biologically very heterogeneous disease, and it is very important to think about risk classification when approaching a patient with neuroblastoma.”

Rochelle Bagatell, MD

The inaugural NCCN Guidelines in neuroblastoma were released on February 7, 2024. Rochelle Bagatell, MD, Professor of Pediatrics and Solid Tumor Section Chief, Children’s Hospital of Philadelphia, Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, described this rare cancer at the conference and gave attendees an overview of the recommendations.

Risk classification, focusing on clinical stage, MYCN amplification, age, and other features (eg, based on histology and presence or absence of segmental chromosome aberrations), should inform treatment selection. Here are highlights of the first version of the guidelines pertaining to the management of patients deemed to have high-risk disease:

  • The current treatment approach includes induction, consolidation, and postconsolidation phases.
  • Induction therapy involves multiagent cytoreductive chemotherapy and stem cell harvest, followed by resection of the primary tumor and locoregional disease.
  • The standard consolidation phase involves both high-dose chemotherapy with autologous stem cell rescue and consolidative radiotherapy; per the panel, tandem transplantation is recommended for the majority of patients (category 1). Afterward, in North America, it is common practice to deliver radiotherapy to the primary site and sites of residual metastatic disease detected at the end of induction therapy.
  • There is a category 1 recommendation for anti-GD2–based postconsolidation therapy.
  • The NCCN Panel recommends discussing eflornithine, an ornithine decarboxylase inhibitor, as an option for continuation therapy with high-risk patients and their families.

Although there is considerable focus on high-risk disease, in fact, about half of newly diagnosed children have non–high-risk neuroblastoma, Dr. Bagatell noted. These patients fare well, she added, with the therapeutic objective outlined by the NCCN Guidelines being a cure with minimal toxicity. Observation, surgical resection, and chemotherapy comprise the recommended primary treatment approaches for patients with low- and intermediate-risk disease, depending on the clinical scenario and tumor biology. 

Pancreatic Cancer

“We know chemotherapy remains the mainstay of treatment [for metastatic pancreatic cancers], but, even with our contemporary regimens…, survival still remains poor.”

Andrew H. Ko, MD

Andrew H. Ko, MD

Andrew H. Ko, MD

Following the results of the NAPOLI-1 trial, the FOLFIRINOX (fluorouracil plus leucovorin, irinotecan, and oxaliplatin) regimen was modified to replace irinotecan with nanoliposomal irinotecan, an agent that was originally approved for use in the second-line setting, to form the NAPOLI-3 trial regimen NALIRIFOX. According to Andrew H. Ko, MD, Professor of Clinical Medicine and Associate Chief in the Division of Hematology/Oncology, University of California San Francisco (UCSF), and a member of the UCSF Helen Diller Family Comprehensive Cancer Center, the key update to the NCCN Guidelines in pancreatic cancer is the inclusion and subsequent promotion of this novel combination to “preferred” (from “other recommended”) status and category 1 (from 2A) for the first-line treatment of patients with metastatic disease and a “good” Eastern Cooperative Oncology Group (ECOG) performance status.

NALIRIFOX was also recently promoted from an “other recommended” to “preferred” regimen for the first-line treatment of patients with locally advanced disease and a “good” ECOG performance status. However, for both those with locally advanced and metastatic disease who have an “intermediate” ECOG performance status, the combination is no longer considered “useful in certain circumstances.”

Other updates to the chemotherapeutic landscape include the following additions:

  • FOLFOX (fluorouracil plus leucovorin and oxaliplatin), FOLFIRI (fluorouracil plus leucovorin and irinotecan), and CapeOx (capecitabine plus oxaliplatin) as “preferred” first-line regimens for patients with metastatic disease and an “intermediate” ECOG performance status who are unable to tolerate FOLFIRINOX;
  • Bolus fluorouracil plus leucovorin as an “other recommended” regimen for subsequent therapy in patients with locally advanced or metastatic disease or for therapy in those with recurrent disease, all with a “good” ECOG performance status, who previously received gemcitabine-based therapy.

“Emerging evidence for molecular and genetic subtyping of pancreatic cancer may help guide the selection of some therapies, but it is important to note this only applies to a minority of patients,” Dr. Ko stated. The current NCCN Guidelines advocate for germline testing in all patients diagnosed with pancreatic cancer and in those in whom there is a clinical suspicion for inherited susceptibility. Additionally, for patients with locally advanced or metastatic disease who are candidates for anticancer therapy, the NCCN Panel recommends testing for potential actionable somatic mutations.

The treatment landscape has thus expanded to include targeted agents, which are reflected by additions to the NCCN Guidelines (all considered “useful in certain circumstances”) in patients with the following corresponding biomarkers:

  • NTRK gene fusion: Both entrectinib and larotrectinib are recommended for the first-line treatment of locally advanced disease with a “good” and “intermediate” ECOG performance status; first-line treatment of metastatic disease with a “good” and “intermediate” ECOG performance status; and subsequent therapy for locally advanced or metastatic disease, and therapy for recurrent disease, with an “intermediate” ECOG performance status.
  • Microsatellite instability–high, dMMR, or tumor mutational burden–high: Pembrolizumab is recommended in the aforementioned clinical scenarios, notably with a preexisting indication for the first-line treatment of metastatic disease with a “good” ECOG performance status.
  • BRAF V600 mutation: Dabrafenib plus trametinib is recommended in the aforementioned clinical scenarios.
  • RET gene fusion: Selpercatinib is recommended in the aforementioned clinical scenarios, albeit without indication for subsequent therapy for locally advanced or metastatic disease, nor for therapy for recurrent disease, with an “intermediate” ECOG performance status.
  • HER2 positivity: T-DXd is recommended as a subsequent therapy for locally advanced or metastatic disease, and as therapy for recurrent disease, with a “good” ECOG performance status.

“[It is noteworthy that, although] KRAS G12C mutations comprise only approximately 2% of all patients with pancreatic cancer…, there is now a class of drugs that are direct inhibitors,” Dr. Ko explained during his presentation. He highlighted data supporting the additions of sotorasib and adagrasib as subsequent therapies for locally advanced or metastatic disease and as therapies for recurrent disease (useful in certain circumstances; category 2B for a “poor” ECOG performance status).

Of note, this year, the algorithms for the management of resectable and borderline resectable (no metastases) disease were revised. A new algorithm was added to guide clinical decision-making after neoadjuvant therapy. 

DISCLOSURE: Dr. Kumar has received grant or research support from AbbVie, Amgen, Bristol Myers Squibb, CARsgen Therapeutics, GSK, Janssen, Oricell, Regeneron, Roche Laboratories, sanofi-aventis, and Takeda; has received honoraria from BeiGene; has served as a scientific advisor for AbbVie, Amgen, Bristol Myers Squibb, GSK, Janssen, Regeneron, Roche Laboratories, sanofi-aventis, and Takeda; and has received consulting fees from Moderna and Pfizer. Dr. Callander reported no conflicts of interest. Dr. Gradishar has received honoraria from AstraZeneca and Daiichi Sankyo; and has served as a scientific advisor for AstraZeneca, Daiichi Sankyo, and Eli Lilly. Dr. Flaig has received grant or research support from Agensys, Astellas, AstraZeneca, Bristol Myers Squibb, Genentech, Janssen, Merck, sanofi-aventis, and SeaGen; has equity interest/stock options or intellectual property rights in Aurora Oncology; has served as a scientific advisor for Criterium and Janssen; and has received consulting fees from Criterium. Dr. Abu-Rustum has received grant or research support from GRAIL. Dr. Johnson has received grant or research support from Bristol Myers Squibb and Incyte Corporation; and has served as a scientific advisor for Bristol Myers Squibb, Merck, Mosaic Biosciences, Novartis, Pfizer, Targovax ASA, and Dr. Bordeaux reported no conflicts of interest. Dr. Bagatell reported no conflicts of interest. Dr. Ko has received grant or research support from AbGenomics, Apexigen, Astellas, Biomed Valley Discoveries, Bristol Myers Squibb, Celgene, Genentech, Merck, and Verastem Oncology; and has served as a scientific advisor for Aadi Bioscience, Arcus Biosciences, Eisai, FibroGen, Genentech, GRAIL, Ipsen, and Merus.