ASCO 2025 Preview: Practice-Changing Trials to Watch

Close up of a cancer cell under a microscope: © Anna Baranova - stock.adobe.com

As the oncology community prepares for the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, anticipation is running high over a wave of potential practice-changing data sets to be unveiled.

“ASCO is around the corner, and there are several landmark practice-changing abstracts that will be presented,” said Manmeet Ahluwalia, MD, MBA, FASCO, chief scientific officer and deputy director at Baptist Health Miami Cancer Institute. “I would definitely tell people to follow the ASCO [meeting] closely, because we are not going to have 2 or 3 [practice-changing studies], we are going to have more that will be presented.”

With a focus on immunotherapy, targeted agents, novel antibody-drug conjugates, and more, the 2025 meeting promises to spotlight pivotal trials across multiple tumor types. Here are the key studies to watch out for:

Gastrointestinal Cancers

ATOMIC Trial

A potential new standard is on the table in colon cancer as the phase 3 ATOMIC trial (NCT02912559) is evaluating the addition of atezolizumab (Tecentriq) to adjuvant chemotherapy for stage III mismatch repair deficient colon cancer. This trial could redefine adjuvant strategies for a biomarker-defined subgroup.

MATTERHORN Trial (NCT04592913)

Perioperative durvalumab (Imfinzi) plus FLOT chemotherapy, which consists of fluorouracil, leucovorin, oxaliplatin, and docetaxel, improved event-free survival in patients with resectable gastric and gastroesophageal junction (GEJ) cancers, with a strong trend toward improved overall survival (OS). This is the first global, double-blind trial of its kind and could push checkpoint inhibition into early-stage perioperative settings.

“MATTERHORN is the first global study, a phase 3 randomized trial, totally double-blinded, where patients got perioperative durvalumab [Imfinzi] plus FLOT in resectable cancers vs FLOT alone…Adverse events were similar, and they were well tolerated,” Yanghee Woo, MD, surgical oncologist in the Division of Surgical Oncology, associate professor in the Department of Surgery, vice chair of international affairs, director of the Gastroenterology and Minimally Invasive Therapies Program at City of Hope, previously told Targeted Oncology^TM.

CheckMate 577 (NCT02743494; OS Update)

Long-awaited OS results from this pivotal trial in resected esophageal/GEJ cancers will show whether adjuvant nivolumab (Opdivo) after neoadjuvant chemoradiotherapy delivers not only disease-free survival but OS benefit.

Breast Cancer

SERENA-6 (NCT04964934)

This ctDNA-guided trial tests whether the oral SERD camizestrant combined with a CDK4/6 inhibitor can preempt resistance in HR-positive/HER2-negative breast cancer with emergent ESR1 mutations. Early data show a progression-free survival advantage over standard endocrine therapy.

“If the study [results] are positive and show a significant clinical benefit, it could change how we monitor patients. Detecting the emergence of targetable mutations at a subclonal level—before clear clinical or radiographic progression—might justify changing therapy earlier. This approach could have wide-reaching implications, not just for breast cancer, but also for how we design clinical trials across many solid tumors that harbor targetable alterations,” explained Seth Wander, MD, PhD, medical oncologist at Massachusetts General Hospital and assistant professor at Harvard Medical School, in an interview with Targeted Oncology.

ASCENT-04 (NCT05382286)

In PD-L1–positive TNBC, combining sacituzumab govitecan (Trodelvy) with pembrolizumab has shown superior PFS over chemotherapy plus pembrolizumab. With manageable safety, this combination may soon enter frontline treatment.

“There's definitely an interest in trying to move sacituzumab up even earlier…and ASCENT-04 [is] looking at it in the PD-L1–negative population as well as in the PD-L1–positive population,” Sara Tolaney, MD, MPH, associate director of the Susan F. Smith Center for Women’s Cancers; director of Clinical Trials, Breast Oncology; and senior physician at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, previously told Targeted Oncology.

DESTINY-Breast09 (NCT04784715)

Interim data previously showed that fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) outperforms the longstanding taxane plus trastuzumab plus pertuzumab triplet in first-line HER2-positive metastatic breast cancer, with meaningful benefit and a favorable safety profile.

“With immunotherapy, antibody-drug conjugates, and targeted therapies, we are not only providing better treatments but also targeting the cancer more precisely, often with fewer [adverse events],” said Neel Shah, MD, medical oncologist at Northwest Cancer Centers. “Those are the kinds of drugs I am looking forward to learning more about—getting the latest updates, and hearing about anything new on the horizon.”

Lung Cancer

IMForte (NCT05091567)

This study supports lurbinectedin (Zepzelca) plus atezolizumab (Tecentriq) as maintenance therapy in extensive-stage small cell lung cancer (SCLC), offering a possible new paradigm post-induction chemoimmunotherapy.

“IMforte is a trial of lurbinectedin in combination with atezolizumab after induction with chemotherapy and atezolizumab. If that is a positive trial, then the question would be, are people going to treat first with lurbinectedin in the maintenance setting and when they progress, use tarlatamab in the second line?” said Ariel Lopez-Chavez, MD, medical oncologist, director of precision medicine and developmental therapeutics at Allegheny Health Network Cancer Institute, in a previous Targeted Oncology interview.

DeLLphi-304 (NCT05740566)

Tarlatamab-dlle (Imdelltra), a novel DLL3-targeting bispecific T-cell engager, improves overall survival over chemotherapy in second-line SCLC, marking a breakthrough in a historically hard-to-treat space.

CheckMate-816 (NCT02998528; OS Update)

New data reinforce the long-term survival benefit of neoadjuvant nivolumab plus chemotherapy in resectable non–small cell lung cancer, with event-free survival (EFS), pathologic complete response, and major pathologic response improvements sustained beyond 3 years.

Bladder Cancer

SURE-02 (NCT05535218)

This phase 2 trial explores neoadjuvant sacituzumab govitecan + pembrolizumab, followed by response-adapted therapy, aiming to preserve bladders and deliver systemic control.

NIAGARA (NCT03732677)

Now FDA-approved, the durvalumab (Imfinzi) plus chemotherapy regimen showed improvements in EFS and OS in muscle-invasive bladder cancer (MIBC) without compromising surgical outcomes.

NIAGARA is a phase 3 randomized, open-label, multicenter, global trial which enrolled adult patients with cisplatin-eligible MIBC with a clinical stage of T2-T4aN0/1M0 who were evaluated and confirmed for radical cystectomy and had urothelial carcinoma with or without divergent differentiation or histologic subtypes.

Prostate Cancer

STAMPEDE AI Analysis

An innovative artificial intelligence model identifies which high-risk, non-metastatic prostate cancer patients benefit most from second-generation androgen receptor pathway inhibitors, enhancing precision in hormone therapy selection.

COMRADE (NCT03317392)

Initial efficacy and biomarker findings suggest that olaparib (Lynparza) plus radium-223 may offer benefit in metastatic castration-resistant prostate cancer with bone metastases, supporting further exploration of DNA repair-targeting combinations.

Kidney Cancer

CheckMate-214 Final Analysis (NCT02231749)

Despite deep immune profiling, TIL density did not strongly correlate with outcomes in nivolumab/ipilimumab vs sunitinib (Sutent). However, clinical outcomes continue to support immunotherapy combinations in frontline renal cell carcinoma (RCC).

“Essentially, what we've seen over 8 years now is that you have a continued tail of the curve. About a third of the patients in the intention to treat population are still doing well. They're alive and probably mostly off treatment. So we see a durable remission. The FDA approved this combination for intermediate- and poor-risk only. But interestingly, we now see, after 5 years, that the curves are starting to cross over in even [favorable] risk. So you're still seeing an HR of [0.82], which is probably the better HR that that we're seeing, compared [with] the IO/TKI combinations, which actually are either above 1 or close to 1,” Alan Tan, MD, assistant professor of medicine in the division of hematology and oncology at Vanderbilt University Medical Center, told Targeted Oncology.

KEYNOTE-564 (NCT03142334; 5-Year OS)

Five-year data confirm adjuvant pembrolizumab’s (Keytruda) long-term OS benefit in clear cell RCC—helping solidify its role for patients at high recurrence risk.

Head & Neck Cancer

NIVOPOSTOP (NCT03576417)

Adjuvant nivolumab added to standard chemoradiation is being evaluated in high-risk resected head and neck squamous cell carcinoma, aiming to reduce relapse rates with checkpoint blockade. Patients with locally advanced head and neck squamous cell carcinoma, exhibiting extra capsular extension and/or high risk are randomly assigned 1:1 to receive post-operative nivolumab in combination with 3 cycles of cisplatin during radiation therapy or concomitant cisplatin with radiation therapy.

Hematologic Malignancies

VERIFY

Rusfertide, a hepcidin mimetic, demonstrated dramatic reduction in phlebotomy dependence in polycythemia vera, meeting both US and EU primary and secondary end points.

“Based on this preclinical data, the phase 2 randomized study [REVIVE] was conducted… To confirm the results, we are now conducting a global, phase 3, placebo-controlled, randomized trial,” said Aniket Bankar, MD, of Princess Margaret Cancer Center.

Final Takeaway

ASCO 2025 is shaping up to be another impactful meeting, with multiple abstracts poised to shift clinical standards across solid and hematologic malignancies.

“I could not be more excited to be there in person and to see this practice-changing research being presented.” added Ahluwalia.

Community oncologists should pay close attention to these data as they emerge and prepare to adapt treatment strategies quickly. Whether you’re following from home or on-site in Chicago, ASCO 2025 will be one to remember.