Bridget Hoyt

Zanzalintinib is currently being investigated in colorectal, kidney, head and neck and neuroendocrine tumors.

New positive data for zanzalintinib plus Tecentriq (atezolizumab) shows statistically significant improvements in overall survival versus Stivarga (regorafenib) in patients with previously treated non-microsatellite instability (MSI)-high metastatic colorectal cancer who were enrolled on a clinical trial, according to a news release.

Results come from the STELLAR-303 phase 3 pivotal trial’s intent-to-treat population.

“The STELLAR-303 results, which showed a survival benefit with the combination of zanzalintinib and atezolizumab versus regorafenib across all randomized patients with previously treated metastatic colorectal cancer, marks an important first milestone for our zanzalintinib pivotal development program,” Dr. Amy Peterson said in the news release. “We look forward to discussing the findings with regulatory authorities and presenting the detailed results at an upcoming medical conference.”

Peterson is the executive vice president of Product Development & Medical Affairs, and chief medical officer at Exelixis, the company that produces zanzalintinib.

The safety of zanzalintinib in combination with Tecentriq and of Stivarga were generally consistent with what has been seen in previous studies, and no new safety signals were identified.

The trial will continue to the planned final analysis for the other dual primary endpoint of overall survival in patients without liver metastases (also referred to as the non-liver metastases subgroup), as per the release.

The intent-to-treat population included all randomized patients, regardless of whether they had liver metastases. The non-liver metastases subgroup included patients who did not have active liver metastases at the start of the study, as determined by the investigator.

Microsatellite instability (MSI)-high: genetic feature of some cancers linked to better response to immunotherapy; non-MSI-high cancers often respond differently.

Overall survival: time from treatment start or diagnosis until death from any cause.

Progression-free survival: time during and after treatment that a patient lives without cancer growing or spreading.

Overall response rate: percentage of patients whose cancer shrinks or disappears after treatment.

Duration of response: length of time a treatment keeps cancer under control after it first responds.

Secondary endpoints of the STELLAR-303 study include progression-free survival, objective response rate, and duration of response in both the intent-to-treat population and the non-liver metastases subgroup. Exelixis plans to present full results from STELLAR-303 at an upcoming medical conference.

Colorectal cancer is the third most common cancer in the U.S. and often spreads to the liver, where survival drops significantly, especially when diagnosed at a metastatic stage, as per the release. The 16.2% 5-year survival rate of metastatic colorectal cancer drops under 14% with the presence of liver metastases when treated with palliative chemotherapy.

More Information on the STELLAR-303 Trial

STELLAR-303 is a global, multicenter phase 3 study evaluating treatment options for people with previously treated metastatic colorectal cancer that is not MSI-high. In this open-label trial, 901 patients were randomly assigned to receive either the investigational drug zanzalintinib (100 milligrams) plus Tecentriq or Stivarga, according to the release.

The study had two primary endpoints which are overall survival in both the full study population and in the subgroup of patients without liver metastases, as assessed by investigators at the start of the trial.

Zanzalintinib is an investigational third-generation oral tyrosine kinase inhibitor designed to block several key receptor tyrosine kinases involved in cancer development and progression, including VEGF receptors, MET, AXL and MER, as per the release. These targets play roles in both normal cellular activity and cancer-related processes such as tumor growth, metastasis, new blood vessel formation (angiogenesis), and resistance to treatments like immune checkpoint inhibitors.

This experimental therapy builds on the established target profile of Cabometyx and Cometriq (cabozantinib), aiming to improve certain characteristics — such as pharmacokinetic half-life — while potentially offering broader anti-tumor activity. Zanzalintinib is being evaluated in clinical trials for a range of advanced solid tumors, including colorectal, kidney, head and neck and neuroendocrine cancers.

As of now, zanzalintinib has not been approved for any indication and remains under investigation in ongoing studies.

“Zanzalintinib in Combination with an Immune Checkpoint Inhibitor Improved Overall Survival in STELLAR-303 Phase 3 Pivotal Trial in Patients with Metastatic Colorectal Cancer” Exelixis press release via Business Wire. https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-zanzalintinib-combination-immune-checkpoint

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New data indicates that the combination of zanzalintinib and atezolizumab significantly improves overall survival compared to regorafenib in patients with previously treated non-MSI-high metastatic colorectal cancer. The STELLAR-303 phase 3 trial demonstrated these results in the intent-to-treat population. The safety profile of the combination was consistent with previous studies, with no new safety signals. The trial will continue to assess overall survival in patients without liver metastases. Zanzalintinib, a third-generation tyrosine kinase inhibitor, remains investigational and is being evaluated for various advanced solid tumors.

Zanzalintinib plus Tecentriq significantly improved overall survival versus Stivarga in previously treated metastatic colorectal cancer, phase 3 data show.

Zanzalintinib Combo Improves Survival in Metastatic Colorectal Cancer

Dr. Rita Mukhtar sits down for a conversation with Dr. Joshua Sabari to discuss the potential use of ctDNA to guide breast cancer therapy: © stock.adobe.com.

The ability to use circulating tumor DNA (ctDNA) to guide surgical decision-making following neoadjuvant chemotherapy was explored in a presentation by researchers at the 

In an interview following the meeting, Dr. Rita Mukhtar, one of the trial investigators, sat down for an interview with Dr. Joshua K. Sabari, editor-in-chief of CURE, to further explore ctDNA in this space. ctDNA are small pieces of DNA which can be detected and are released by tumor cells into a person’s blood; if detected early, they have the potential to guide treatment decisions, according to the National Cancer Institute website.

Mukhtar specializes in breast and general surgery and serves as an associate professor of surgery in the Division of Surgical Oncology at the University of San Francisco (UCSF), UCSF Health. Sabari serves as an assistant professor in the Department of Medicine at NYU Grossman School of Medicine and director of High Reliability Organization Initiatives at Perlmutter Cancer Center.

: Hello, I am Dr. Joshua Sabari. I’m a thoracic medical oncologist at NYU Langone Health, Perlmutter Cancer Center in New York. I’m excited to be joined by Dr. Rita Mukhtar, a breast surgeon. Rita, please introduce yourself.

: Thank you so much, I’m happy to be here. As you mentioned, my name is Rita Mukhtar, and I am a breast surgeon at UCSF. I also co-chair the local regional working group for the I-SPY2 trial, which is a neoadjuvant chemotherapy trial for patients with molecularly high-risk and low-risk breast cancer. We heard a lot of information at the meeting about the role of ctDNA in breast cancer, and it’s very exciting; there’s a lot of interest in ctDNA to guide systemic therapy and possibly for surveillance.

What I talked about was some exciting data where we actually looked at whether or not ctDNA can help us plan our surgical approach for patients with breast cancer. We looked at patients who had neoadjuvant chemotherapy, and ctDNA was measured before chemotherapy, during and after. Then people went to the operating room, and typically for breast cancer surgery, at least a few lymph nodes are removed. If any of those lymph nodes still have tumor after chemotherapy, then patients undergo axillary lymph node dissection, which involves removing the majority of lymph nodes in the axilla or armpit area, and that can cause significant morbidity, such as lymphedema.

What we really want to find is a way to figure out which patients are only going to have maybe one or two positive lymph nodes. When you do that sentinel node biopsy, you’ve already gotten everything out, and you don’t need to go on and remove any more lymph nodes. We don’t have a great way of figuring that out right now, but it turns out that ctDNA can predict whether or not someone has a high chance or a low chance of having many lymph nodes that are still positive after chemotherapy. This is a model that we developed using machine learning; it’s something that we’re going to have to validate for sure. We looked retrospectively at patients who have participated in the I-SPY trial, but we are in the process of validating this further.

These data kind of open the door to the idea that we might be checking ctDNA before we go to the operating room, and based on the result of that, deciding if we’re going to do just a sentinel node biopsy or the full axillary dissection. The other exciting thing is that we could also change the endpoints in the model. In the model that we used, we really predicted having a high nodal burden, but you could also predict having negative nodes.

If we could use ctDNA to help us be highly confident that people did not have any involved lymph nodes, we maybe could even omit all axillary surgery in these high-risk patients who are getting neoadjuvant chemotherapy.

: Thank you, Dr. Mukhtar, that was a phenomenal presentation and truly important for guiding patient care, particularly in the operating room. I know in the lung cancer space, we use a lot of ctDNA in both the early-stage and metastatic settings. How sensitive are the assays that you’re using in patients with breast cancer?

: There’s been a huge evolution in the use of ctDNA assays, starting with the genotyping assays often used in the metastatic setting. What we’re using now are these MRD, or minimal residual disease, assays in the non-metastatic setting. These new generation assays can detect tumor DNA in the blood down to one part per million.

Certainly, assessing the sensitivity of the assay being used is important when evaluating the data and also when considering which assays to use going forward, depending on the setting. We used the Signatera assay. The Signatera assay is a tumor-informed assay, meaning the patient’s primary tumor is sequenced, and up to 16 tumor-specific mutations can be used to create a probe to look for that circulating tumor DNA in the blood.

If patients have detection of at least two of those mutations, we classify that as positive. We used positive or negative as the endpoint or predictor in our study, but you could also look at the quantity because these are quantitative assays.

: That is so important. Thank you for your work; I’m looking forward to seeing ongoing validation so that it can change practice for our patients with breast cancer. I’m joined again by Dr. Rita Mukhtar, breast surgeon, and thank you for joining us and for participating and educating our CURE readers. Thank you.

: Thank you so much. It’s a pleasure to be here.

Circulating tumor DNA (ctDNA) is being explored as a tool to guide surgical decisions in breast cancer patients undergoing neoadjuvant chemotherapy. Dr. Rita Mukhtar discussed the potential of ctDNA to predict lymph node involvement, potentially reducing the need for extensive axillary surgery. The study utilized machine learning models and the Signatera assay to assess ctDNA's predictive capabilities. This approach could refine surgical strategies, minimizing morbidity. Ongoing validation is necessary to confirm these findings and potentially change clinical practice in breast cancer treatment.

Dr. Rita Mukhtar sits down for a conversation with Dr. Joshua Sabari to discuss the potential use of ctDNA to guide breast cancer therapy.

How a Blood Test May Help Guide Breast Cancer Treatment  

Daraxonrasib has received breakthrough therapy designation from the FDA for KRAS G12+, previously treated, metastatic PDAC: © stock.adobe.com.

The investigative agent daraxonrasib (RMC-6236) has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) with KRAS G12 mutations, according to a news release from Revolution Medicines, Inc.

The breakthrough therapy designation aims to accelerate the development and review of new therapeutic agents for individuals with serious conditions that have significant unmet medical needs. To qualify, the investigative therapy — in this case, daraxonrasib — must show preliminary clinical evidence indicating a substantial improvement for patients compared with existing treatments.

This regulatory decision is based on early clinical evidence with daraxonrasib in the phase 1 RMC-6236-001 study evaluating daraxonrasib in patients with PDAC. Notably, the registrational, phase 3 RASolute 302 study is expanding the evaluation of daraxonrasib and is examining the use of daraxonrasib in patients with previously treated, metastatic PDAC. This trial is expected to substantially complete enrollment this year.

“This breakthrough therapy designation underscores the enormous need for new treatments for patients with pancreatic cancer and highlights the potentially important role the investigational drug, daraxonrasib, may have in helping patients living with this disease,” Dr. Mark A. Goldsmith, PhD, chief executive officer and chairman of Revolution Medicines, stated in the news release. “We look forward to substantially completing enrollment of the RASolute 302 study this year to enable an expected readout in 2026 and, should the results support it, working closely with the FDA and other regulatory agencies around the world to bring daraxonrasib to patients as quickly as possible.”

Understanding the Trial Data and Daraxonrasib

The oral, direct RAS(ON) multi-selective inhibitor, daraxonrasib, has the potential to treat various cancers driven by oncogenic RAS mutations. This is done by stopping RAS signaling, thereby blocking common oncogenic RAS mutations, which are the key drivers of several major cancers, including PDAC, non-small cell lung cancer and colorectal cancer. Notably, more than 90% of individuals with PDAC have tumors driven by RAS mutations; approximately 85% harbor a KRAS G12 mutation.

Progression-free survival (PFS): The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse.

Overall survival (OS): The length of time from either the date of diagnosis or the start of treatment that patients diagnosed with the disease are still alive.

To combat the unmet needs within this patient population, the global RASolute 302 trial is underway, seeking to continue to the evaluation of daraxonrasib in previously treated metastatic PDAC. The trial focuses on patients with PDAC containing RAS mutations like RAS G12X, while an expanded cohort is evaluating patients with RAS G13X and RAS Q61X. The primary end points of the upcoming trial are progression-free survival and overall survival in the main patient population, while secondary end points include progression-free survival and overall survival in the expanded population.

What is the Difference Between Pancreatic Cancer and PDAC?

Pancreatic cancer is among the most lethal cancers, as an estimated 60,000 people were diagnosed with pancreatic cancer and approximately 50,000 died from it in 2024 in the United States alone. The disease is marked by a tendency for late diagnosis, resistance to conventional chemotherapy, and a high mortality rate.

PDAC is a type of pancreatic cancer and is the most common form of the disease. PDAC and its variants represent approximately 92% of all pancreatic cancer cases. Due to the absence of early symptoms and effective screening methods, approximately 80% of PDAC cases are diagnosed at an advanced or metastatic stage. Metastatic PDAC continues to be a leading cause of cancer-related deaths in the U.S., with a five-year survival rate of approximately 3%.

“Revolution Medicines Announces FDA Breakthrough Therapy Designation for Daraxonrasib in Previously Treated Metastatic Pancreatic Cancer with KRAS G12 Mutations." News Release. Revolution Medicines, Inc. June 23, 2025. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-fda-breakthrough-therapy

Daraxonrasib (RMC-6236) has been granted breakthrough therapy designation by the FDA for treating metastatic pancreatic ductal adenocarcinoma (PDAC) with KRAS G12 mutations. This designation aims to expedite the development of therapies for serious conditions with unmet needs. The decision is based on promising phase 1 trial results, with a phase 3 trial, RASolute 302, underway. Daraxonrasib targets RAS mutations, prevalent in over 90% of PDAC cases. PDAC, a highly lethal cancer, often presents at advanced stages, contributing to its high mortality rate.

Daraxonrasib has received breakthrough therapy designation from the FDA for KRAS G12+, previously treated, metastatic pancreatic ductal adenocarcinoma.

Daraxonrasib Gains FDA Status for Certain Metastatic Pancreatic Cancer 

The treatment offers a non-surgical option for patients who may not be candidates for repeat procedures.

The U.S. Food and Drug Administration has approved UGN-102 (mitomycin intravesical solution) for the treatment of adult patients with recurrent low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC).

The drug’s efficacy was based on data from the phase 3 ENVISION trial, which evaluated 240 enrolled patients with low-grade NMIBC recurring following previous transurethral resection, or surgical removal, of bladder tumor (TURBT).

Out of 223 evaluable patients, 78% had a 

, which, in this case, indicates that patients had no cancer left in the bladder according to an internal visual analysis called cystoscopy and a microscope urine evaluation called urine cytology, along with a biopsy if needed. Among those who responded, 79% remained cancer-free for at least one year.

To be part of the study, patients needed to meet at least one of the following: have multiple tumors, have a single tumor larger than 3 cm or have a cancer recurrence within one year.

The most common side effects that patients experienced were pain or burning with urination (dysuria), urinary tract infections, blood in the urine, fatigue and changes in lab values like kidney function or blood counts.

Serious side effects occurred in 12% of patients. Less than 1% of participants experienced urinary retention or urethral narrowing. One patient died from heart failure during the study, although it is not currently public information whether the death was caused by UGN-102.

Previous data from the phase 3 ATLAS trial showed that UGN-102 may also benefit patients regardless of whether they had TURBT. In that study, newly diagnosed patients who received UGN-102 had a 15-month disease-free survival rate of about 77%. Patients with recurrent disease had a 63% disease-free rate over the same period.

Complete response rates remained high at one year in both groups—nearly 88% in newly diagnosed patients and about 69% in those with recurrent cancer.

The most common treatment-related side effects in ATLAS included dysuria, frequent urination, urgent urination, and nighttime urination.

For more news on cancer updates, research and education, 

The FDA has granted approval to UGN-102 for use in patients with low-grade intermediate-risk non-muscle-invasive bladder cancer.

Bridget Hoyt

Zanzalintinib Combo Improves Survival in Metastatic Colorectal Cancer

How a Blood Test May Help Guide Breast Cancer Treatment

Daraxonrasib Gains FDA Status for Certain Metastatic Pancreatic Cancer

FDA Approves UGN-102 For Some With Bladder Cancer

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