Experts Unpack the Most Notable NCCN Guideline Changes Heading Into 2026

Updates to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, which have shaped clinical practice, continued to roll out across various cancer types throughout 2025. These updates encompass a wide range of cancer types, affecting treatment selection and sequencing, supportive care, and surgical considerations.

“[The] NCCN has become one of the most important guideline platforms in the world,” Jaffer A. Ajani, MD, chair of the NCCN Clinical Practice Guidelines in Oncology Panel for Gastric Cancers, said in a statement to OncLive®. “Currently, 33 comprehensive cancer centers participate. [The] NCCN not only generates guidelines for cancer treatment but also supportive care. [The NCCN also] produces patient-directed documentation [and] modifies guidelines almost instantly. [In 2026], you will see guidelines will become easier to read and understand.”

Ajani is also a professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

In October 2025, the NCCN also introduced the NCCN Guidelines Navigator for breast cancer treatment and genetic risk assessment during Breast Cancer Awareness Month.1 The resource features content from the NCCN guidelines and uses seamless movement, advanced search and filter capabilities, color-coded navigation links, and other digital enhancements to make the guidelines more accessible. The navigator has since been made available for more than 12 other cancer types.

In exclusive interviews with OncLive, 5 chairs, vice chairs, or members of NCCN guideline panels provided insights on the most notable guideline updates and their effects on clinical practice in lung, colorectal, ovarian, bladder, and esophageal/gastric cancers. We also outlined key updates made to the latest versions of the guidelines in other disease areas as of December 2025.

Lung Cancer

The Most Notable NCCN Revisions in Non–Small Cell Lung Cancer (NSCLC; version 1.2026)2:

• Datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) was added as a preferred second-line regimen for patients with EGFR-mutated NSCLC following disease progression on frontline therapy with osimertinib (Tagrisso) plus chemotherapy.
  • Dato-DXd was added as a preferred third-line therapy following all other preferred first-line regimens.
  • Dato-DXd is also listed as a subsequent therapy option for the treatment of patients with NSCLC harboring EGFR exon 19 deletions or L858R mutations, EGFR S768, L861Q, and/or G79X mutations, as well as EGFR exon 20 insertion mutations.
• Osimertinib/carboplatin or cisplatin/pemetrexed, as well as amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze), were moved from the other recommended category to category 1 as a preferred regimen for the frontline treatment of patients with EGFR-mutated NSCLC whose mutations were discovered prior to first-line systemic therapy.
  • Lazertinib was also designated as "useful in certain circumstances" in this setting.
• Amivantamab plus lazertinib was added to the useful in certain circumstances category as a subsequent therapy if not previously given for patients with NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations with multiple lesions following disease progression on osimertinib.

“[This year], the staging system referred to within the NCCN Guidelines for NSCLC was updated to align with American Joint Committee on Cancer, ninth edition,” Tejas Patil, MD, member of the NCCN Clinical Practice Guidelines in Oncology Panel for NSCLC, said in a statement to OncLive. “The emergence of novel targeted therapies for NSCLC reiterates the importance of biomarker testing, particularly in patients with advanced/metastatic NSCLC, to help clinicians identify the most appropriate treatment options for patients.”

Patil is also an assistant professor of medicine (medical oncology) at the University of Colorado Anschutz in Aurora.

The Most Notable NCCN Revisions in Small Cell Lung Cancer (version 2.2026)3:

• Carboplatin plus etoposide and atezolizumab (Tecentriq) followed by maintenance lurbinectedin (Zepzelca) and atezolizumab was added as a primary treatment option for patients with extensive-stage disease.
  • Consider adding lurbinectedin to maintenance atezolizumab in patients who have achieved at least stable disease following 4 cycles of induction chemoimmunotherapy, have an ECOG performance status of 0 or 1, and have no history of brain metastases.

Gastrointestinal Malignancies

The Most Notable NCCN Revisions in Colon Cancer (version 5.2025)4:

• For patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) disease, consider adjuvant systemic therapy for low-risk stage III disease.
• FOLFOX (folinic acid, 5-fluorouracil [5-FU], and oxaliplatin) and CAPOX (capecitabine and oxaliplatin), both in combination with atezolizumab, have been added as preferred category 2A recommendations for the adjuvant treatment of patients with low- and high-risk stage III dMMR/MSI-H disease.
• Capecitabine and 5-FU changed from a category 2A to a category 2B recommendation for patients with low- and high-risk stage III dMMR/MSI-H disease.
• FOLFOX plus encorafenib (Braftovi) and cetuximab (Erbitux) or panitumumab (Vectibix) was added as systemic therapy for patients with advanced or metastatic disease.

“[During 2025], adjuvant therapy regimens from the [phase 3] ATOMIC trial [NCT02912559]—FOLFOX or CAPOX in combination with atezolizumab—were added in stage III dMMR/MSI-H colon cancer. This change represents the addition of checkpoint inhibitor therapies at earlier points of the patient journey.” Al B. Benson, III, MD, chair of the NCCN Clinical Practice Guidelines in Oncology Panel for Colon Cancer, said in a statement to OncLive. “[There was also a] recommendation for FOLFOX plus encorafenib/cetuximab or panitumumab as first-line therapy for BRAF V600E–mutated metastatic colorectal cancer, based on [data from the phase 3] BREAKWATER trial [NCT04607421] showing better outcomes with this regimen in a population that typically has poor prognosis.”

Benson is also the associate director for cooperative groups at the Robert H. Lurie Comprehensive Cancer Center and a professor of medicine in the Division of Hematology AND Oncology at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

The Most Notable NCCN Revisions in Rectal Cancer (version 4.2025)5:

Chemotherapy with FOLFIRINOX (folinic acid, 5-FU, irinotecan, and oxaliplatin) was added as a neoadjuvant option for patients with mismatch repair–proficient/microsatellite-stable resectable disease with liver-only and/or lung-only metastases.

The Most Notable NCCN Revisions in Hepatocellular Carcinoma (version 2.2025)6:

• Nivolumab (Opdivo) plus ipilimumab (Yervoy) was added as a category 2A recommendation to other recommended regimens for frontline systemic therapy.
• Lenvatinib (Lenvima) and sorafenib (Nexavar) were removed from subsequent-line systemic therapies.
• Nivolumab plus ipilimumab and pembrolizumab (Keytruda) were removed from other recommended subsequent therapies after disease progression.
• Repotrectinib (Augtyro) was removed as a category 2B recommendation from useful in certain circumstances for patients with NTRK gene fusion–positive tumors.
• Entrectinib (Rozlytrek), larotrectinib (Vitrakvi), and repotrectinib were added as category 2A recommendations to the useful in certain circumstances section for patients with NTRK gene fusion–positive tumors.

The Most Notable NCCN Revisions in Gastric Cancers (version 3.2025)7:

• Universal PD-L1 testing is recommended in all newly diagnosed patients.
• FLOT plus durvalumab (Imfinzi) was added as a category 1 preferred regimen for perioperative systemic therapy for patients with a PD-L1 combined positive score or tumor area proportion score of at least 1.
• Fluoropyrimidine, oxaliplatin, and tislelizumab-jsgr (Tevimbra) was added as a category 1 recommendation for the first-line treatment of patients with disease negative for HER2 overexpression.
• Entrectinib, larotrectinib, or repotrectinib were added as category 2B first-line systemic therapy options for patients with NTRK gene fusion–positive tumors.

“[During 2025, we also added] staging sophistications and biomarker amendments,” Ajani said. “[We also saw the] inclusion of new therapies, such as more refined versions of endoscopic therapy guidelines, genetics screening recommendations, and pathologic assessments. [The updates] emphasize the lack of benefit from checkpoint inhibition if the tumor is PD-L1 negative.”

Multiple Myeloma

The Most Notable NCCN Revisions in Multiple Myeloma (version 4.2026)8:

• Belantamab mafodotin-blmf (Blenrep) plus bortezomib (Velcade) and dexamethasone was added as a category 1 recommendation to other recommended regimens after 2 prior therapies, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD).
• Linvoseltamab-gcpt (Lynozyfic) was added as an option for patients with pretreated disease after 4 lines of therapy, including an anti-CD38 monoclonal antibody, a PI, and an IMiD.
• Isatuximab-irfc (Sarclisa) plus bortezomib, lenalidomide (Revlimid), and dexamethasone was added as a category 1 preferred regimen for patients with primary disease who are candidates for hematopoietic stem cell transplant (HSCT).
• Daratumumab (Darzalex) and isatuximab, both in combination with carfilzomib (Kyprolis), lenalidomide, and dexamethasone, were removed from other recommended regimens for patients with primary disease who are candidates for HSCT.
• Maintenance daratumumab was added as useful in certain circumstances for patients with primary disease who are candidates for HSCT.
• Daratumumab plus bortezomib, lenalidomide, and dexamethasone was added as a category 1 preferred regimen for primary therapy in patients younger than 80 years for whom HSCT is deferred or not indicated.
  • Isatuximab plus lenalidomide and dexamethasone was added as a category 1 recommendation to other recommended regimens.
  • Bortezomib plus lenalidomide and dexamethasone was added as a category 1 recommendation to other recommended regimens.
  • Ixazomib plus lenalidomide and dexamethasone was added to useful in certain circumstances.

Bladder Cancers

The Most Notable NCCN Revisions in Bladder Cancer (version 2.2025)9:

The gemcitabine intravesical system was added as an option for select patients with Bacillus Calmette Guérin–unresponsive or -intolerant disease.

“There have been a lot of advances in the world of bladder cancer. The field is changing really quickly—all for the better,” Elizabeth R. Plimack, MD, MS, FASCO, a member of the NCCN Clinical Practice Guidelines in Oncology Panel for Bladder Cancer, said in a statement to OncLive. “In metastatic disease, we added enfortumab vedotin-ejfv [Padcev] and pembrolizumab to the guidelines. The results of this regimen are so far superior to what we had before, which was platinum-based chemotherapy in this space, that everyone is recommended to have this in the first-line setting. With that, then the guidelines changed in the second-line space to move platinum-based chemotherapy there, as well as genomic testing for targeted approaches, such as fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] for HER2-expressing tumors [and] erdafitinib [Balversa] for FGFR3-altered tumors.”

Plimack is also the deputy director of Fox Chase Cancer Center and a professor in the Department of Hematology/Oncology at Temple Health in Philadelphia, Pennsylvania.

Chronic Lymphocytic Leukemia

The Most Notable NCCN Revisions in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (version 1.2026)10:

• Venetoclax (Venclexta) plus atezolizumab and obinutuzumab (Gazyva) was added as a category 2A recommendation for patients with a Richter transformation.
• Epcoritamab-bysp (Epkinly) and glofitamab-gxbm (Columvi) were added as category 2A recommendations for patients with Richter transformation.
• Axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) were added as category 2A recommendations for patients with Richter transformation.

AML

The Most Notable NCCN Revisions in Chronic Acute Myeloid Leukemia (AML; version 3.2026)11:

• Ziftomenib (Komzifti) was added as a category 2A recommendation for the treatment of patients with relapsed or refractory AML harboring an NPM1 mutation.
• CLIA (cladribine, idarubicin, and cytarabine) plus venetoclax was added as a category 2B regimen for intensive induction–eligible patients.
• FLAG-IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin) plus venetoclax was added as a category 2B regimen for intensive induction–eligible patients.
• Azacitidine or decitabine plus venetoclax was added as a sixth regimen after follow-up and reinduction following cytarabine-based induction.
• Olutasidenib (Rezlidhia) was added as a category 2B therapy for patients who are not eligible for a preferred regimen or for ivosidenib (Tibsovo).
• Revumenib (Revuforj) was added as a targeted therapy for patients with relapsed/refractory disease.

B-Cell Lymphomas

The Most Notable NCCN Revisions in B-Cell Lymphomas (version 3.2025)12:

• Tafasitamab-crix (Monjuvi) plus lenalidomide and rituximab (Rituxan) was added as a category 2A preferred regimen for the second-line treatment of patients who have received at least 1 prior systemic regimen, including an anti-CD20 monoclonal antibody.
• Loncastuximab tesirine-lpyl (Zynlonta) plus rituximab was added as a category 2B regimen for third- and subsequent-line therapy.
• Acalabrutinib (Calquence) plus bendamustine and rituximab was added as a category 2A frontline preferred regimen for less aggressive induction therapy.
• Epcoritamab plus gemcitabine and oxaliplatin was added as a preferred regimen for patients with relapsed/refractory disease who are not candidates for chimeric antigen receptor T-cell therapy.
• Glofitamab was added as a category 2B second- and subsequent-line therapy.

Breast Cancer

The Most Notable NCCN Revisions in Breast Cancer (version 5.2025)13:

• Imlunestrant (Inluriyo) was added as a category 2A, other recommended regimen for first- or subsequent-line therapy for recurrent unresectable or stage IV hormone receptor (HR)-positive, HER2-negative disease harboring an ESR1 mutation.
• Abemaciclib (Verzenio) plus fulvestrant (Faslodex) and trastuzumab (Herceptin) was added as a category 2B recommendation for patients with HR-positive, HER2-positive recurrent unresectable or stage IV disease.
• Neratinib (Nerlynx) with or without trastuzumab or fulvestrant was added as a category 2A, useful in certain circumstances recommendation for patients with stage IV (M1) disease harboring HER2 activating mutations.
• Erdafitinib (Balversa) was added as a category 2A, useful in certain circumstances recommendation for patients with stage IV (M1) disease harboring an FGFR1, FGFR2, or FGFR3 fusion or mutation.

Ovarian Cancer

The Most Notable NCCN Revisions in Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer (version 3.2025)14:

• Maintenance olaparib (Lynparza) was added as a category 2B treatment for patients with BRCA1/2 wild-type, homologous recombination–deficient disease who did not receive bevacizumab (Avastin) during primary therapy.
• Avutometinib plus defactinib (Avmapki Fakzynja) was added to useful in certain circumstances for patients with KRAS-mutated, low-grade serous carcinoma.

“[In 2025], indications for PARP inhibitors as first-line maintenance options for advanced ovarian cancer were updated [based] on emerging data on outcomes from longer-term follow-up and new FDA indications. New regimens were added for platinum-sensitive and -resistant recurrent ovarian cancer, including mirvetuximab soravtansine-gynx [Elahere] for platinum-sensitive disease, T-DXd, avutometinib/defactinib, and FOLFIRI with or without bevacizumab,” Lainie P. Martin, MD, a member of the NCCN Clinical Practice Guidelines in Oncology Panel for Ovarian Cancer, said in a statement to OncLive. “These updates reflect a growing emphasis on the behavior of different types of ovarian cancer. A number of these updates include a more specific treatment option based on the growing understanding of the molecular features of these cancers and the efficacy of targeted therapeutics acting on these features in this era of precision medicine."

Martin is also the leader of the Gynecology/Oncology Program, an associate professor of medicine (hematology-oncology), and an associate professor of obstetrics and gynecology at Penn Medicine in Philadelphia, Pennsylvania.

References

1. NCCN Guidelines Navigator for breast cancer genetic testing and treatment debuts during Breast Cancer Awareness Month. News release. National Comprehensive Cancer Network. October 6, 2025. Accessed November 24, 2025. https://www.nccn.org/home/news/newsdetails?NewsId=5239
2. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 1.2026. Accessed November 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
3. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 2.2026. Accessed November 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf
4. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 5.2025. Accessed November 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
5. NCCN. Clinical Practice Guidelines in Oncology. Rectal cancer, version 4.2025. Accessed November 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
6. NCCN. Clinical Practice Guidelines in Oncology. Hepatocellular carcinoma, version 2.2025. Accessed November 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/hcc.pdf
7. NCCN. Clinical Practice Guidelines in Oncology. Gastric cancer, version 3.2025. Accessed November 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
8. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 4.2026. Accessed November 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
9. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 2.2025. Accessed November 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
10. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2026. Accessed November 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
11. NCCN. Clinical Practice Guidelines in Oncology. AML, version 3.2026. Accessed November 26, 2025. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf
12. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 3.2025. Accessed November 26, 2025. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
13. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 5.2025. Accessed November 26, 2025. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
14. NCCN. Clinical Practice Guidelines in Oncology. Ovarian cancer, version 3.2025. Accessed November 26, 2025. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf