Kyle Doherty joined MJH Life Sciences in 2021 and is the lead editor for 

as well as news and conference updates for OncLive.com. Email: kdoherty@mjhlifesciences.com

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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 

®. “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.

 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.

, 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 

 made to the latest versions of the guidelines in other disease areas as of December 2025.

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

Datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) was added as a preferred second-line regimen for patients with 

-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 

 exon 19 deletions or L858R mutations, 

S768, L861Q, and/or G79X mutations, as well as 

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 

-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 

 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 

. “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)

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.

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

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 

. “[There was also a] recommendation for FOLFOX plus encorafenib/cetuximab or panitumumab as first-line therapy for 

 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)

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)

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 

Entrectinib (Rozlytrek), larotrectinib (Vitrakvi), and repotrectinib were added as category 2A recommendations to the useful in certain circumstances section for patients with 

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

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 

“[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.”

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

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.

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

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 

. “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 

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.

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

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.

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

Ziftomenib (Komzifti) was added as a category 2A recommendation for the treatment of patients with relapsed or refractory AML harboring an 

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.

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

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.

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

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 

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 

Erdafitinib (Balversa) was added as a category 2A, useful in certain circumstances recommendation for patients with stage IV (M1) disease harboring an 

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

Maintenance olaparib (Lynparza) was added as a category 2B treatment for patients with 

 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 

“[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 

. “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.

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

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

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

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

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

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

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

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

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

Articles

Read the most notable updates to the latest versions of the NCCN Clinical Practice Guidelines in Oncology across tumor types ahead of 2026.

Experts Unpack the Most Notable NCCN Guideline Changes Heading Into 2026

Ashling Wahner joined MJH Life Sciences in 2022. She produces 

, and helps ensure timely publication of news content and announcements from the FDA approval pipeline. She also attends conferences live and virtually to conduct video interviews and produce written coverage. Email: awahner@mjhlifesciences.com

Rapid advances in systemic therapy, perioperative treatment strategies, and biomarker science are reshaping muscle-invasive bladder cancer (MIBC) management, with circulating tumor DNA (ctDNA) emerging as a pivotal tool for guiding treatment and predicting outcomes.

“MIBC [management is] changing quickly, and ctDNA does have a role to play,” 

® Peer Exchange. “It’s going to revolutionize the outcome of our patients. We're going to cure more patients, and I hope you see that in your clinics as well.”

During the panel discussion, bladder cancer experts discussed the strengths and limitations of current standards of care (SOCs) for patients with MIBC across the neoadjuvant, adjuvant, and perioperative settings. They contextualized these standards in light of updates to the treatment paradigm, which were presented at the 

2025 European Society for Medical Oncology (ESMO) Congress

What up-front regimen should patients with MIBC receive in the neoadjuvant setting?

“[In] the current treatment paradigm for MIBC, it’s still the case that one needs to look at platinum eligibility to start with in the neoadjuvant setting,” Powles said. “For those eligible for platinum-based chemotherapy, the [phase 3] NIAGARA [trial (NCT03732677)] approach is a SOC.”

NIAGARA showed that the addition of durvalumab (Imfinzi) to neoadjuvant gemcitabine and cisplatin, followed by radical cystectomy and adjuvant durvalumab, significantly improved event-free survival (EFS; HR, 0.68; 95% CI, 0.56-0.82; 

< .0001) and overall survival (OS; HR, 0.75; 95% CI, 0.59-0.93; 2-sided 

= .0106) compared with gemcitabine and cisplatin alone in the neoadjuvant setting, followed by radical cystectomy and no adjuvant treatment in patients with cisplatin-eligible MIBC.

the FDA approved perioperative durvalumab plus chemotherapy

What do the SunRISe trials show about the expanded potential for gemcitabine intravesical systems in bladder cancer management?

The panelists were quick to highlight that although NIAGARA has reshaped the current MIBC treatment arsenal, innovations beyond immunotherapy are fast approaching, particularly in the neoadjuvant setting. A recent notable development for non-MIBC (NMIBC) hints at what may come for MIBC down the line. In September 2025, 

the FDA approved the gemcitabine intravesical system

 (formerly TAR-200; Inlexzo) for the treatment of adult patients with Bacillus Calmette-Guérin–unresponsive NMIBC with carcinoma in situ with or without papillary tumors.

 This regulatory decision was supported by findings from the phase 2b SunRISe-1 trial (NCT04640623).

The phase 2 SunRISe-4 study (NCT04919512) evaluated the efficacy and safety of the gemcitabine intravesical system plus cetrelimab in patients with cisplatin-ineligible MIBC. Data presented at ESMO 2025 showed that patients who received the combination (n = 88) achieved a pathologic complete response (pCR) rate of 38% (95% CI, 28%-49%) vs 28% (95% CI, 16%-44%) with cetrelimab monotherapy (n = 46).

 The 12-month recurrence-free survival (RFS) rates were 77% (95% CI, 67%-85%) and 64% (95% CI, 47%-77%), respectively.

“It's an interesting approach, and…the response rate is really high,” 

said. “It's a good device. The paradigm is now crowded, and it's going to be difficult to decide the best way to go.”

Exploratory analyses also showed that urinary tumor DNA (utDNA) and ctDNA may be effective biomarkers for detecting residual disease after neoadjuvant therapy. utDNA-positive minimal residual disease (MRD) rates decreased after 12 weeks of neoadjuvant therapy across both arms. In particular, in the gemcitabine intravesical system arm, this rate dropped from 77.8% at baseline to 50.0% at week 12. utDNA MRD negativity at week 12 was associated with pCR, and ctDNA MRD negativity was linked with longer RFS.

“When it comes to muscle-invasive disease, the big question is: Can [the intravesical gemcitabine device] contribute to a potential increase in pCR rate if it's given in the context of even more effective systemic therapies?” 

“SunRISe-4 is interesting and hypothesis-generating, but my sense is that the systemic therapy was probably not adequate in the context of what we see from the NIAGARA regimen and recent data from [the phase 3 KEYNOTE-905 trial (NCT03924895)] with enfortumab vedotin-ejfv [Padcev] plus pembrolizumab [Keytruda]. But I can see a future where [the gemcitabine intravesical system] could be investigated to boost pCR rates in the context of more effective systemic therapies. Could we select patients with durable clinical CRs who can keep their bladders? I can see the future there to be tested in clinical trials with [the gemcitabine intravesical system] in muscle-invasive disease.”

What perioperative regimens are gaining ground in cisplatin-ineligible MIBC?

The panelists noted that the management of cisplatin-ineligible MIBC is also evolving based on data from KEYNOTE-905. In the trial, patients who received enfortumab vedotin plus pembrolizumab followed by radical cystectomy and standard pelvic lymph node dissection (RC + PLND; n = 170) achieved a median EFS that was not reached (NR; 95% CI, 37.3-NR) compared with 15.7 months (95% CI, 10.3-20.5) with RC + PLND followed by observation alone (n = 174; HR, 0.40; 95% CI, 0.28-0.57; 1-sided 

 The respective pCR rates were 57.1% (95% CI, 49.3%-64.6%) and 8.6% (95% CI, 4.9%-13.8%).

What do data show about the effect of ctDNA status on survival outcomes in MIBC?

Shifting to the core of the discussion, the experts took on the topic of ctDNA’s growing role in bladder cancer treatment decision-making. They provided context by spotlighting findings from the ctDNA analysis of the phase 3 IMvigor010 trial (NCT02450331) of adjuvant atezolizumab (Tecentriq) vs observation in patients with MIBC. In this trial, among patients who were ctDNA positive, treatment with atezolizumab was associated with an OS benefit vs observation (HR, 0.59; 95% CI, 0.42-0.83).

 Furthermore, greater levels of ctDNA clearance with atezolizumab correlated with longer OS.

“IMvigor010 started all the excitement with ctDNA in basically all of genitourinary oncology,” 

said. “[It is] compelling that if [a patient is] ctDNA positive, [they] are destined to recur. These are the patients who need to [receive] intensified [treatment].”

The IMvigor010 findings were validated in updated data from the phase 3 CheckMate 274 trial (NCT02632409) of adjuvant nivolumab (Opdivo) vs placebo in patients with high-risk MIBC, which were presented at ESMO 2025 

 The ctDNA analysis—though the panelists cautioned about the relatively small sample size—showed that baseline undetectable ctDNA status (n = 79) was associated with improved survival outcomes vs detectable ctDNA status (n = 54). Among all patients with ctDNA-undetectable disease, the median disease-free survival (DFS) was 52.1 months (95% CI, 19.4-not evaluable [NE]) vs 5.0 months (95% CI, 2.8-6.5) among those with detectable ctDNA (HR, 0.30; 95% CI, 0.18-0.48). The respective median OS values were NR (95% CI, 62.0 months-NE) and 28.2 months (95% CI, 19.4-36.1; HR, 0.44; 95% CI, 0.25-0.76).

However, trends toward improved DFS and OS outcomes were observed with nivolumab vs placebo, regardless of ctDNA status. Among patients with ctDNA-detectable disease, the median DFS with nivolumab (n = 27) was 7.4 months (95% CI, 2.8-19.2) vs 2.8 months (95% CI, 2.4-5.0) with placebo (n = 27; HR, 0.35; 95% CI, 0.18-0.66). The median DFS values among patients in these respective arms with ctDNA-undetectable disease were 91.9 months (95% CI, 19.2-NE; n = 50) and 52.2 months (95% CI, 16.9-NE; n = 29; HR, 0.99; 95% CI, 0.51-1.93). The median OS among patients with ctDNA-detectable disease was 36.2 months (95% CI, 23.0-NE) with nivolumab vs 19.3 months (95% CI, 8.1-28.2) with placebo (HR, 0.41; 95% CI, 0.20-0.83). The median OS values among patients in these respective arms with ctDNA-undetectable disease were NR (95% CI, 62.0 months-NE) and NR (95% CI, 40.7 months-NE; HR, 0.87; 95% CI, 0.41-1.84).

The panelists explained that the hypothesis regarding the use of ctDNA testing in bladder cancer was further confirmed in IMvigor011 (NCT04660344), which they later elaborated on in the context of growing evidence supporting ctDNA testing in MIBC.

What are some of the recent advances in systemic therapy, unmet needs, and the importance of ctDNA testing in MIBC?

“Patients with bladder cancer die of metastatic disease, not local disease,” Powles said. “The purpose of surgery is to catch the cancer early enough before the cancer spreads. If it's later than that, and the cancer has already spread, the role of surgery becomes somewhat academic. In the end, the MRD—the disease that's already spread—is going to define the outcome of the patients, and the question will be: Have you given systemic therapy [that is] effective to cure those patients? What are the early features after cystectomy that can tell you whether the patient is going to relapse?”

Powles opened the floor to a larger discussion about the role of ctDNA testing in bladder cancer and when it is best predictive of disease recurrence, calling for insights on both the benefits and limitations of this method for choosing optimal treatment strategies.

“We live in an era where we have an emergence of new, more effective systemic therapies that aim not only to [target] the primary tumor but also the micrometastases, which are the invisible enemy,” Grivas said. “The more effective systemic therapies may enable us to try to cure more patients, especially [those] with localized disease, and maybe a few with advanced metastatic disease. [They may] also, down the road, enable us to do more bladder preservation.”

Grivas noted the efficacy of immune checkpoint inhibition that the NIAGARA data uphold, as well as the increasing relevance of antibody-drug conjugates exemplified in KEYNOTE-905, explaining that “checkpoint inhibition by itself is probably not as effective in the context of combination therapy but may have a role in the adjuvant setting, and ctDNA [testing] can help refine that discussion.”

The panelists unanimously acknowledged that, although several advances have been made in the systemic management of MIBC, patient outcomes still need improvement, and MRD remains an area of largely untapped potential.

“We need biomarkers, and we need better drugs, so we need a combination of MRD and a biomarker that predicts the activity of the drug,” 

said. “In my mind, MRD is still a biomarker for microscopic disease.”

Tan explained the promise of treatment response monitoring, which allows for a close look at how disease may be progressing in a patient, noting that “with treatment response monitoring, we have insight into the ctDNA kinetics of the tumor and when resistance starts to develop if [a patient does not] clear ctDNA. This is an avenue that needs to be explored further.”

He emphasized that implementing adaptive treatment approaches based on ctDNA levels and biomarker expression following completion of standard regimens, such as enfortumab vedotin plus pembrolizumab, may be the next step in helping patients live longer.

“We need to recognize the heterogeneity of this disease,” Tan said. “We're helping a lot of patients, but we need better biomarker recognition and MRD treatment response monitoring to raise that tail of the curve that we're already seeing.”

How do the IMvigor011 trial data begin to add to the conversation about the role of ctDNA testing in MIBC?

The phase 3 IMvigor011 trial prospectively evaluated ctDNA-guided treatment outcomes with adjuvant atezolizumab vs placebo in patients with MIBC. Data presented at ESMO 2025 showed that patients who tested ctDNA positive at any time point through ctDNA testing had improved DFS and OS with atezolizumab vs placebo.

 The median DFS was 9.9 months (95% CI, 7.2-12.7) with atezolizumab (n = 167) vs 4.8 months (95% CI, 4.1-8.3) with placebo (n = 83; HR, 0.64; 95% CI, 0.47-0.87; stratified 

= .0047). The median OS values in these respective arms were 32.8 months (95% CI, 27.7-NE) and 21.1 months (95% CI, 14.7-NE; HR, 0.59; 95% CI, 0.39-0.90; stratified 

 Similar efficacy was observed between patients who tested ctDNA positive at baseline vs those who converted to ctDNA-positive status upon repeat testing.

“IMvigor011 makes the landscape [and] the decision-making more interesting,” Sonpavde said. “In the setting where IMvigor011 was done, which is with or without neoadjuvant chemotherapy alone and no chemoimmunotherapy beforehand, it makes sense to use the IMvigor011 approach…. [However], I don't think you can make the case that if [a patient has ctDNA-]positive [disease], we give [this regimen, and if they have ctDNA-]negative [disease], we don't.”

What factors are needed for more widespread implementation of ctDNA testing in clinical practice?

“There are panel-based testing approaches in specific tumor types, such as colorectal cancer, lung cancer, and breast cancer, but that has not happened in urothelial cancer, prostate cancer, kidney cancer, and other tumor types,” Powles said. “Instead of using those panel-based approaches, we're probably better off using a personalized approach, where we're tracking specific mutations that are identified within this particular cancer.”

Powles explained that this approach may lead to more specificity to inform individualized treatments, as well as fewer false positive results. Tan added that future tests should have improved sensitivity to help with treatment decision-making, especially in the perioperative setting, where curative-intent treatment may still be an option for certain patients. However, he cautioned that one main limitation of ctDNA testing in bladder cancer is that it cannot detect cancer in the central nervous system. The role of ctDNA assays in metastatic disease also remains unclear, Grivas added.

“We have opportunities to design trials for escalation and de-escalation, building upon IMvigor011 in the localized setting, but also [to] try to answer questions in the metastatic disease setting,” Grivas said. “As these assays become more readily available, we'll have the opportunity to do that.”

Sonpavde concluded the discussion with insights into the issue of overtreatment, explaining that this may occur in many patients who receive perioperative treatment, as it is possible for certain patients to be cured with cystectomy alone. He emphasized that identifying better biomarkers may help determine which patients would benefit most from adjuvant treatment and pave the way for improved bladder cancer outcomes in the future.

“Patients who are ctDNA negative before neoadjuvant therapy, postneoadjuvant therapy, and then again post cystectomy have good outcomes,” he said. “Now, I've been wondering [whether] we're overtreating [these patients] with even more adjuvant components of the therapy. This all needs to be proven, and more studies need to be done…. Could we use ctDNA to have a bladder-preservation approach in patients who achieve clinical CR or [who are] ctDNA negative? These are all [topics] to explore. [ctDNA testing] could have a role in the bladder-preservation setting post neoadjuvant therapy.”

Thomas Powles, MD, MRCP, MBBS, is a professor of genitourinary oncology, director of the Barts Cancer Centre, and lead for solid tumor research at St Bartholomew’s Hospital in London, United Kingdom.

Joaquim Bellmunt, MD, PhD, is director of the Bladder Cancer Center in the Genitourinary Oncology Program and a senior physician at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

Petros Grivas, MD, PhD, is a professor in the Clinical Research Division, medical director of local/regional outreach, and medical director of the International Program at Fred Hutchinson Cancer Center in Seattle, Washington. He is also a professor in the Division of Hematology and Oncology at the University of Washington School of Medicine.

Guru P. Sonpavde, MD, is the medical director of genitourinary oncology, assistant director of the Clinical Research Unit, and the Christopher K. Glanz Chair for Bladder Cancer Research at the AdventHealth Cancer Institute in Orlando, Florida.

Alan Tan, MD, is an associate professor of medicine in the Division of Hematology and Oncology in the Department of Medicine at Vanderbilt University Medical Center, as well as a genitourinary oncology specialist at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

FDA approves durvalumab for muscle invasive bladder cancer. FDA. March 28, 2025. Accessed November 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer

US FDA approval of Inlexzo (gemcitabine intravesical system) set to transform how certain bladder cancers are treated. News release. Johnson & Johnson. September 9, 2025. Accessed November 18, 2025. https://www.multivu.com/johnson-and-johnson/9342851-en-johnson-and-johnson-fda-approval-inlexzo-gemcitabine-intravesical-system

Necchi A, Guerrero-Ramos F, Crispen PL, et al. Neoadjuvant gemcitabine intravesical system (TAR-200) + cetrelimab (CET) or CET alone in patients (pts) with muscle-invasive bladder cancer (MIBC): SunRISe-4 (SR-4) primary analysis and biomarker results. 

. 2025;36(suppl 2):S1767-S1768. doi:10.1016/j.annonc.2025.09.131

Vulsteke C, Kaimakliotis H, Danchaivijitr P, et al. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: the phase III KEYNOTE-905 study. 

. 2025;36(suppl 2):S1763. doi:10.1016/j.annonc.2025.09.124

Powles T, Assaf ZJ, Degaonkar V, et al. Updated overall survival by circulating tumor DNA status from the phase 3 IMvigor010 trial: adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma. 

. 2024;85(2):114-122. doi:10.1016/j.eururo.2023.06.007

Galsky MD, Gschwend JE, Milowsky MI, et al. Adjuvant nivolumab versus placebo for high-risk muscle-invasive urothelial carcinoma: 5-year efficacy and ctDNA results from CheckMate 274. 

. Published online October 17, 2025. doi:10.1016/j.annonc.2025.09.139

Powles TB, Kann A, Castellano Gauna DE, et al. IMvigor011: a phase III trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer. 

. 2025;36(suppl 2):S1749. doi:10.1016/j.annonc.2025.09.109

In a recent Peer Exchange, bladder cancer experts reviewed the current treatment paradigm for muscle-invasive bladder cancer (MIBC) and discussed updates from ESMO 2025.

ctDNA Insights Stand at the Forefront of Data-Driven, Individualized MIBC Management

Image by Ashling Wahner & MJH Life Sciences Using AI

Inhibiting the oxidative phosphorylation (OXPHOS) pathway with novel agents such as lixumistat (IM156) could suppress the growth of cancer cells and decrease resistance to available therapies, positioning it as an attractive treatment approach in pancreatic cancer, according to Shubham Pant, MD, MBBS, and Ryan W. Huey, MD, MS.

“OXPHOS is a pathway [that] basically provides nutrition to the cancer cells,” Pant, director of clinical research and professor in the Department of Investigational Cancer Therapeutics and Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with 

®. “In pancreatic cancer, it’s a source of adenosine triphosphate [ATP], and it’s very sensitive.”

“The OXPHOS pathway plays an important role in the survival of pancreatic cancer cells and may offer a mechanism in which it can grow and ultimately become resistant to therapeutics such as chemotherapy,” Huey, associate professor in the Department of GI Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, added in a separate interview with 

. “We have some drugs that work in pancreatic cancer, but unfortunately, they don’t work as well or for as long as we would like. If we can inhibit OXPHOS [and] suppress the growth of tumor cells, [we can] conceivably help the drugs that we are giving work for a longer period.”

Lixumistat is a novel biguanide mitochondrial PC1 inhibitor of OXPHOS.

 PC1 is a key component in the electron transport chain of the OXPHOS pathway that binds and oxidizes nicotinamide adenine dinucleotide hydride prior to the electron transfer that forms ATP.

The OXPHOS pathway provides ATP and metabolic precursors to cancer cells, making it a potentially attractive target for anticancer therapies.

Lixumistat is a novel biguanide PC1 inhibitor; PC1 is a key component of the OXPHOS pathway. 

Data from the phase 1b COMBAT-PC trial showed that patients with PDAC who received lixumistat at the RP2D of 400 mg daily (n = 10) plus gemcitabine and nab-paclitaxel experienced a DCR of 80%, an ORR of 50%, a median PFS of 7.4 months, and a median OS of 18 months.

What data have been reported with lixumistat?

Lixumistat was initially examined for the treatment of patients with advanced solid tumors in a phase 1 first-in-human study (NCT03272256). The dose-escalation study enrolled adult patients with advanced solid tumors refractory to standard therapies with an ECOG performance status of 2 or less, including those with gastric, colorectal, and breast cancers, as well as glioblastoma multiforme.

Among efficacy-evaluable patients (n = 16), no objective responses were observed with lixumistat monotherapy. However, 7 patients achieved stable disease for a disease control rate (DCR) of 32%. The median progression-free survival (PFS) was 54 days (95% CI, 47-71).

Lixumistat, a novel OXPHOS pathway inhibitor, shows potential in treating pancreatic cancer by suppressing tumor growth and enhancing chemotherapy efficacy. Initial studies revealed modest single-agent activity but promising results when combined with gemcitabine and nab-paclitaxel, achieving a disease control rate of 80% and a median overall survival of 18 months. Safety profiles were favorable, with no grade 4 or 5 toxicities. Lixumistat has received orphan drug designations for pancreatic cancer and glioblastoma multiforme. Another OXPHOS inhibitor, ME-344, is under investigation for metastatic colorectal cancer.

Shubham Pant, MD, MBBS, and Ryan W. Huey, MD, MS, discuss OXPHOS pathway inhibition in pancreatic cancer with lixumistat.

Yasmeen Qahwash

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