Tim Cortese

Adding casdatifan to Cabometyx showed encouraging activity and in previously treated ccRCC: © stock.adobe.com.

In patients with previously treated clear cell renal cell carcinoma, a specific kind of kidney cancer, adding casdatifan to Cabometyx (cabozantinib) treatment showed encouraging activity and was generally well tolerated, according to results from an expansion group in the phase 1 ARC-20 trial presented at the 

In the group of patients who received 50 milligrams (mg) of Welireg twice daily (32 patients), at the median follow-up of 15 months, the confirmed overall response rate was 25%. The best overall response rate was 31%; zero patients had a complete response, 31% had a partial response, 50% had stable disease, and 19% had progressive disease.

In patients who received 50 mg once daily (28 patients), at the median follow-up of 12 months, the confirmed overall response rate was 29%. The best overall response rate was 32%; 4% of patients had a complete response, 29% had a partial response, 54% had stable disease, and 14% had progressive disease.

In those who received 100 mg once daily (27 patients), at the median follow-up of five months, the confirmed overall response rate was 33%. The best overall response rate was 33%; 0% of patients had a complete response, 33% had a partial response, 52% had stable disease, and 7% had progressive disease.

Patients who received the 100 mg dose demonstrated a trend of decreasing sum of target lesion diameters as well as rapid response.

Preliminary efficacy from the cohort of patients who received Welireg plus Cabometyx (24 patients) showed, with a median follow-up of 5.3 months, the confirmed overall response rate was 46%; 4% had a complete response, 42% had a partial response, 50% had stable disease, and 4% had progressive disease.

“Treatment with Welireg showed meaningful clinical activity and disease control across doses,” wrote presenting study author, Dr. Toni K. Choueiri, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School, said during the presentation. “Welireg was well tolerated across all monotherapy doses and in combination with Cabometyx.”

In the dose expansion phase of ARC-20, approximately 30 patients were enrolled in each of the 3 cohorts. In cohort 1, patients received 50 mg of Welireg twice daily; in cohort 2, patients received 30 mg of Welireg once daily; and in cohort 3, patients received 100 mg of Welireg once daily. Eligible patients had clear cell renal cell carcinoma, were in at least the second line of therapy, had at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors version 1.1, and had adequate organ and marrow function.

The median age of patients in cohorts 1, 2, and 3 were 62 years, 65 years, and 60 years; an Eastern Cooperative Oncology Group performance status of 1 was observed in 52%, 42%, and 52%, respectively; the most common International Metastatic Renal Cell Carcinoma Database Consortium risk score was intermediate in 64%, 55%, and 66%; and 2 or more prior regimens were received by 94%, 84%, and 83%. All patients in all cohorts received both a vascular endothelial growth factor receptor–tyrosine kinase inhibitor and a programmed death-ligand 1 inhibitor.

The trial’s primary end points were side effects and dose-limiting toxicities. Secondary end points were overall response rate assessed by the investigator per Response Evaluation Criteria in Solid Tumors version 1.1 and pharmacokinetics and pharmacodynamics; exploratory end points were progression-free survival, overall survival, and biomarkers.

With Welireg monotherapy, any treatment-emergent side effect related to the study drug occurred in 94% of cohort 1, 90% of cohort 2, and 93% of cohort 3; of grade 3 or higher occurred in 49%, 32%, and 28%, respectively; and serious side effects occurred in 3%, 10%, and 7%.

Grade 3 or higher side effects that occurred in more than 5% of patients in cohort 1 were anemia (42%) and hypoxia (9%); in cohort 2, they were 32% and 7%; and in cohort 3, they were 17% and 10%.

In patients who received 100 mg of Welireg plus Cabometyx (42 patients), with a median follow-up of 3.7 months, any side effects related to Welireg occurred in 98%, grade 3 or higher side effects occurred in 31%, and serious side effects in 7%. Any side effects related to Cabometyx occurred in 93%, grade 3 or higher side effects occurred in 38%, and serious side effects occurred in 12%. Any side effects related to any study drug occurred in 98%, grade 3 or higher side effects occurred in 48%, and serious side effects occurred in 17%.

In the combination group, side effects related to Welireg were anemia (24%), hypoxia (7%), and decreased neutrophil count (2%); side effects related to Cabometyx were anemia (14%), hyponatremia (7%), hypertension (5%), and decreased neutrophil count (5%); and side effects related to any study drug were anemia (24%), hyponatremia (7%), hypoxia (7%), hypertension (5%), and decreased neutrophil count (5%).

Further, in the monotherapy group, 9% of patients in cohort 1, 3% in cohort 2, and 7% in cohort 3 experienced any side effect leading to dose reduction. In the combination group, side effects leading to dose reduction were related to Welireg in 24%, related to Cabometyx in 38%, and related to any study drug in 52%. It was noted that most patients who had a dose reduction of either agent were reduced by only 1 level.

The phase 3 PEAK-1 trial evaluating 100 mg of daily Welireg plus 60 mg of daily Cabometyx compared with placebo plus Cabometyx in patients with advanced or metastatic clear cell renal cell carcinoma was announced, as well as the phase 1b/3 eVOLVE-RCC02 trial evaluating volrustomig plus Welireg in frontline advanced clear cell renal cell carcinoma.

“Combination casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma: results from an expansion cohort of ARC-20 (NCT05536141),” by Dr. Toni Chouieri, et al. Presented at the 2025 Kidney Cancer Research Summit; July 17-18, 2025; Boston, MA.

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Articles

The addition of casdatifan to Cabometyx (cabozantinib) in patients with previously treated clear cell renal cell carcinoma demonstrated promising efficacy and tolerability in the phase 1 ARC-20 trial. Different dosing regimens of Welireg were evaluated, with varying response rates and side effect profiles. The combination of Welireg and Cabometyx showed a higher overall response rate compared to monotherapy. The trial's primary endpoints focused on side effects and dose-limiting toxicities, while secondary endpoints included overall response rate and pharmacokinetics. Future trials, such as PEAK-1 and eVOLVE-RCC02, are planned to further investigate these treatments.

Adding casdatifan to Cabometyx therapy showed encouraging activity and was generally well tolerated in previously treated clear cell renal cell carcinoma. 

Welireg Plus Cabometyx Shows Tumor Control in Kidney Cancer Trial 

Stereotactic body radiotherapy costs less and has shown better safety compared with immunotherapy and tyrosine kinase inhibitors in patients kidney cancer: © stock.adobe.com

Metastasis-directed radiotherapy alone showed encouraging results, including favorable survival rates and low side effects, for patients with oligometastatic clear cell renal cell carcinoma, a specific type of kidney cancer, according to a phase 2 trial presented at the 

With a median follow-up of 36.3 months, median progression-free survival was 34 months; median systemic therapy-free survival was 17.7 months; and 3-year overall survival was 86.5%.

Investigators noted that surveillance was associated with a median systemic therapy-free survival of 14.9 months in a phase 2 trial published in 

At baseline, 60% of patients (47 of 78) were minimal residual disease positive; among these, the median tumor fraction was 22.5 ppm. After 3 months, 25% of initially minimal residual disease-positive patients converted to negative.

Patients who were minimal residual disease negative showed improved systemic therapy-free survival compared with those who were positive since enrollment and since the 3-month assessment.

“Metastasis-directed therapy without systemic therapy offers advantages in costs, side effects, and clinic visits over frontline systemic therapies,” wrote study author Dr. Chad Tang, associate professor at the University of Texas MD Anderson Cancer Center, and coauthors. “[Metastasis-directed therapy] without systemic therapy showed favorable overall survival and side effect profiles. Biomarkers are needed at baseline to select patients and after therapy to guide surveillance versus systemic treatment. Circulating tumor DNA using a second-generation assay may help inform both roles.”

The trial enrolled patients with oligometastatic renal cell carcinoma with clear cell histology, up to five metastases, and no prior systemic therapy or more than one month off prior systemic therapy. Treatment included standard imaging and biopsy, blood draw, stereotactic radiation with or without local surgery to all disease sites, followed by imaging and blood draw. If progression occurred, the cycle restarted; otherwise, systemic therapy began.

Co-primary endpoints were progression-free survival per RECIST 1.1 and systemic therapy-free survival, defined as median systemic therapy-free survival greater than 25 months.

Immunotherapy alone or in combination and tyrosine kinase inhibitors cost approximately $150,000 to $300,000 annually, while stereotactic body radiation therapy costs about $15,000 to $40,000 per round; grade 3 or higher side effects occur in 45% to 85% and 5% to 10%, respectively; clinic visits occur at least monthly and one to two visits per radiation round.

Regarding safety, grade 2 or higher side effects were seen in 20.8% of patients, grade 3 or higher side effects in 6.7%, and grade 3 side effects in only one patient. Most common grade 2 side effects included musculoskeletal pain (10 patients), pneumonitis (five patients), cough (three patients), and shortness of breath (two patients). Most common grade 3 side effects were musculoskeletal pain (five patients), increased white blood cells (two patients), pleural effusion (one patient), and abdominal distension (one patient). The only grade 4 side effect was high blood sugar (one patient).

“Phase 2 trial of metastasis directed radiotherapy without systemic therapy (MRWS) for oligometastatic clear cell renal cell carcinoma (ccRCC) and investigation of circulating tumor DNA (ctDNA) as a personalized biomarker,” by Dr. Chad Tang. Presented at the 2025 Kidney Cancer Research Summit; July 17, 2025; Boston, MA.

“Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial,” by Dr. Brian I. Rini. 

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A phase 2 trial demonstrated promising outcomes for metastasis-directed radiotherapy in oligometastatic clear cell renal cell carcinoma, showing favorable survival rates and minimal side effects. With a median follow-up of 36.3 months, the study reported a median progression-free survival of 34 months and a 3-year overall survival rate of 86.5%. The trial highlighted the potential of metastasis-directed therapy to reduce costs and side effects compared to systemic therapies. Biomarkers, particularly circulating tumor DNA, may guide patient selection and treatment strategies.

Stereotactic body radiotherapy costs less and has shown better safety compared with immunotherapy and tyrosine kinase inhibitors in patients kidney cancer. 

Metastasis-Directed Radiotherapy Shows Improved Kidney Cancer Outcomes

Imlunestrant alone or in combination with Verzenios improved patient-reported outcomes in ER+, HER2– advanced breast cancer following endocrine therapy: © stock.adobe.com.

Imlunestrant alone or in combination with Verzenios (abemaciclib) improved patient-reported outcomes among those with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer who progressed after endocrine therapy.

Notably, these data were derived from the phase 3 EMBER-3 trial presented at the 2025 ASCO Annual Meeting. In patients with an ESR1 mutation, based on changes in baseline in the EORTC QLQ-C30 global health status/quality of life score, treatment with imlunestrant was favored compared with standard of care endocrine therapy. At treatment cycle seven, the difference between groups was 9.9 points. The global health status/quality of life score was typically maintained across both treatment arms.

In patients with an ESR1 mutation, the median time to deterioration of global health status/quality of life score with imlunestrant was 5.6 months, with 53 events, compared with 3.8 months and 50 events, with endocrine therapy. The investigators noted that estimates were limited by a high rate of censoring.

Additionally, in patients with an ESR1 mutation, overall global health status/quality of life score and functional domains remained consistent. Imlunestrant was superior regarding the physical, role, social, emotional, and cognitive functional domains. Regarding symptom domains, worse scores were observed with endocrine therapy for fatigue, pain, dyspnea, insomnia and appetite loss; worse scores were observed with imlunestrant for nausea/vomiting, constipation, and diarrhea. It was noted that symptom domains were broadly similar between treatment groups.

In all patients, the overall changes in global health status/quality of life score and functional domains were typically maintained across all treatment arms. In order from worst to best, the mean change from baseline for global health status/quality of life score was imlunestrant plus Verzenios, endocrine therapy and imlunestrant; for physical function, social function, emotional function and cognitive function, it was the same, and for role function, it was endocrine therapy, imlunestrant plus Verzenios, and imlunestrant.

Regarding symptom domains, imlunestrant plus Verzenios demonstrated clinically meaningful worse scores regarding nausea/vomiting and diarrhea. The average proportion of time with “frequent” or “almost constant” diarrhea was 22% with imlunestrant plus Verzenios, 3% with imlunestrant, and 2% with endocrine therapy.

“Consistent with the primary results from EMBER-3, these patient-reported outcomes results reinforce the benefit of imlunestrant, as monotherapy or combined with Verzenios, as an all-oral targeted therapy option after progression on [endocrine therapy] for patients with ER-positive, HER2-negative [advanced breast cancer],” wrote lead study author Dr. Giuseppe Curigliano, a professor of medical oncology at the University of Milano, and of the European Institute of Oncology, National Institute of Hospitalization and Scientific Care in Milano, Italy, and coauthors, in the presentation.

The trial enrolled approximately 859 patients who were randomly assigned to receive either imlunestrant monotherapy (327 patients), imlunestrant plus Verzenios (208 patients) or endocrine therapy (324 patients). Imlunestrant was given at 400 milligrams (mg) every day in both groups; Verzenios was given at the labeled dose; and endocrine therapy, which was the investigator’s choice between Faslodex (fulvestrant) or Aromasin (exemestane), was also given at the labeled dose.

Eligible patients had ER-positive, HER2-negative advanced disease. Regarding prior therapies, in the adjuvant setting, patients had recurrence on or within 12 months of completion of an aromatase inhibitor with or without a CDK4/6 inhibitor; for advanced breast cancer, patients had progression on a first-line aromatase inhibitor with or without a CDK4/6 inhibitor and no other therapy for advanced breast cancer.

The trial’s primary end points were investigator-assessed progression-free survival across all treatment groups. Secondary end points included overall survival, blinded independent committee review-assessed PFS, overall response rate, and safety; exploratory end points were patient-reported outcomes.

The patient-reported outcomes measures used and their respective schedules are as follows: the EORTC QLQ-C30 global health status/quality of life score, function domains, and symptom domains were assessed on day one and then every eight weeks after with short-term follow-up; the EORTC IL-19 physical functioning was assessed every eight weeks opposite the EORTC QLQ-C30; the Patient-reported Outcomes version of the Common Terminology Criteria for Adverse Events (a patient-reported outcome measurement system developed by the National Cancer Institute to capture symptomatic adverse events in patients on cancer clinical trials; PRO-CTCAE) for frequency of diarrhea was assessed on day one then every week after with short-term follow-up; and the PRO-CTCAE injection site reaction occurrence was assessed every week of cycle one then the first two weeks of all other cycles.

It was reported that 72% of patients receiving Faslodex experienced injection site reaction at any time of treatment; 20% of them had an incidence of less than 25%, 32% had an incidence from 25% to 50%, 30% had an incidence from 50% to 75%, and 17% had an incidence of greater than 75%.

The median investigator-assessed progression-free survival, in all patients, was 9.4 months with imlunestrant plus Verzenios and 5.5 months with imlunestrant alone. In patients with an ESR1 mutation, the median progression-free survival was 5.5 months with imlunestrant alone versus 3.8 months with endocrine therapy.

Regarding safety, treatment-emergent side effects of any grade occurred in 83% of patients with imlunestrant, 98% of patients with imlunestrant plus Verzenios, and 84% of patients with endocrine therapy; of grade 3 or higher, treatment-emergent side effects occurred in 17%, 49%, and 21%, respectively.

In patients with imlunestrant, dose reductions, treatment discontinuations, and death due to side effects occurred in 2%, 4%, and 2%; in patients with imlunestrant plus Verzenios, they occurred in 39%, 6%, and 1%, respectively; and in patients with endocrine therapy, they occurred in 0%, 1%, and 1%.

“Patient-reported outcomes (PROs) in patients with ER+, HER2- advanced breast cancer (ABC) treated with imlunestrant, investigator’s choice standard endocrine therapy, or imlunestrant + abemaciclib: Results from the phase III EMBER-3 trial" by Dr. Curigliano G, et al., 

Imlunestrant, alone or with Verzenios (abemaciclib), improved patient-reported outcomes in ER-positive, HER2-negative advanced breast cancer patients post-endocrine therapy. The phase 3 EMBER-3 trial showed that imlunestrant was favored over standard endocrine therapy, particularly in patients with an ESR1 mutation, with better global health status/quality of life scores. Imlunestrant demonstrated superiority in functional domains, though symptom domains varied between treatments. The trial's primary endpoint was progression-free survival, with imlunestrant plus Verzenios showing a median of 9.4 months compared to 5.5 months with imlunestrant alone.

Imlunestrant alone or in combination with Verzenios improved patient-reported outcomes in ER+, HER2– advanced breast cancer following endocrine therapy. 

Imlunestrant Alone or With Verzenios Improved PROs in Advanced Breast Cancer

Second-line Enhertu improved key survival end points versus Cyramza plus paclitaxel for HER2+ gastric cancer or gastroesophageal junction adenocarcinoma: © stock.adobe.com.

Among patients with HER2-positive unresectable or metastatic gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJ), second-line treatment with Enhertu (fam-trastuzumab deruxtecan-nxki) had a clinically meaningful and statistically significant benefit when compared with Cyramza (ramucirumab) plus paclitaxel. The investigative combination specifically improved overall survival rates among patients.

These findings were generated by the phase 3 DESTINY-Gastric04 trial, data from which was simultaneously shared during a press briefing during the 

At a median follow-up of 16.8 months for Enhertu and 14.4 months for Cyramza plus paclitaxel, the median overall survival was 14.7 months versus 11.4 months , respectively, with a 30% reduction in risk of death. The 6-month overall survival rates were 83.5% versus 74.4%, respectively, the 12-month overall survival rates were 57.6% versus 48.9%, and the 24-month overall survival rates were 29.0% versus 13.9%.

The median progression-free survival with Enhertu was 6.7 months (95% CI, 5.6-7.1) versus 5.6 months with Cyramza plus paclitaxel. The six-month progression-free survival rate was 52.6% versus 41.5%, respectively, and the 12-month progression-free survival rate was 22.9% versus 13.6%.

The confirmed overall response rate was 44.3% in all patients who received Enhertu and 29.1% in all patients who received Cyramza plus paclitaxel; the difference was 15.1%. The duration of response was 7.4 months versus 5.3 months, respectively. At six months, the duration of response rate was 58.4% versus 35.7%, respectively, and at 12 months, it was 29.7% versus 15.0%.

The disease control rate was 91.9% with Enhertu; 3.0% of patients (seven patients) achieved a complete response, 41.3% (97 patients) achieved a partial response, 47.7% (112 patients) achieved stable disease, 5.5% (13 patients) had progressive disease, and 2.6% (six patients) were not evaluable. In patients who received Cyramza plus paclitaxel, the disease control rate was 75.9%; 1.3% of patients (three patients) achieved a complete response, 27.8% (66 patients) achieved a partial response, 46.8% (111 patients) achieved stable disease, 9.3% (22 patients) had progressive disease and 14.8% (35 patients) were not evaluable.

“Enhertu demonstrated a statistically significant and clinically meaningful improvement in overall survival compared with [Cyramza plus paclitaxel] in patients with HER2-positive metastatic GC/GEJ in the second line setting,” stated presenting study author Dr. Kohei Shitara, director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, in the presentation. “DESTINY-Gastric04 confirmed Enhertu as the global [second line] standard-of-care therapy for patients with HER2-positive metastatic GC/GEJ.”

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

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

Overall response rate (ORR): the proportion of patients who have a partial or complete response to therapy.

DESTINY-Gastric04 was a global, multicenter trial that randomly assigned approximately 494 patients to receive either 6.4 milligrams per kilogram (mg/kg) of intravenous Enhertu once every three weeks (246 patients) or intravenous Cyramza at 8 mg/kg on days one and 15 of each 28-day cycle and paclitaxel at 80 mg/m

 on days one, eight and 15 of each 28-day cycle (248 patients).

Eligible patients had HER2-positive GC/GEJ with HER2 status confirmed locally or centrally on a biopsy obtained after progression on Herceptin (trastuzumab). Patients also had no clinically active central nervous system metastases.

Exclusion criteria included a history of noninfectious interstitial lung disease or pneumonitis that was treated with glucocorticoids, active interstitial lung disease or pneumonitis, or suspected of having interstitial lung disease or pneumonitis that could not be ruled out by imaging.

The trial’s primary end point was OS. Key secondary end points included progression-free survival per investigator assessment, confirmed overall response rate per investigator assessment, duration of response per investigator assessment and safety.

Drug-related treatment-emergent side effects of any grade affected 93.0% (227 of 244 patients) of patients who received Enhertu and 91.4% (213 of 233 patients) of patients who received Cyramza plus paclitaxel; drug-related treatment-emergent side effects of grade 3 or higher affected 50.0% and 54.1% of patients. The most common drug-related side effects that were grade 3 or higher for Enhertu was neutropenia (28.7%), anemia (13.7%) and leukopenia (12.4%) ramucirumab.

It was also noted that interstitial lung disease/pneumonitis occurred in 13.9% of patients who received Enhertu and 1.3% who received Cyramza plus paclitaxel.

Drug-related treatment-emergent side effects were associated with dose discontinuation, dose interruption, dose reduction, and death, respectively, in 11.5%, 38.5%, 31.1%, and 1.6% of patients who received Enhertu, and in 13.3%, 51.1%, 36.1%, and 0.9%, respectively, of patients who received Cyramza plus paclitaxel.

“These results warrant further evaluation of Enhertu in the context of first-line therapy,” wrote the authors of the study in the paper.

Shitara K, Gumus M, Pietrantonio F, et al. Trastuzumab deruxtecan (T-DXd) vs ramucirumab (RAM) + paclitaxel (PTX) in second-line treatment of patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) unresectable/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA): Primary analysis of the randomized, phase 3 DESTINY-Gastric04 study. Presented at: 2025 American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2025. Chicago, IL. Abstract 4002.

Shitara K, Van Cutsem E, Gümüş M, et al. Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer. 

. Published online May 31, 2025. doi:10.1056/NEJMoa2503119

Enhertu (fam-trastuzumab deruxtecan-nxki) demonstrated significant clinical benefits over Cyramza (ramucirumab) plus paclitaxel in second-line treatment for HER2-positive unresectable or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. The DESTINY-Gastric04 trial showed improved overall survival, progression-free survival, and response rates with Enhertu. Enhertu's safety profile included notable side effects such as neutropenia and interstitial lung disease. These findings suggest Enhertu as a new global standard for second-line therapy, with potential for first-line treatment evaluation.

Second-line Enhertu improved key survival end points versus Cyramza plus paclitaxel for HER2+ gastric cancer or gastroesophageal junction adenocarcinoma.

Tim Cortese

Welireg Plus Cabometyx Shows Tumor Control in Kidney Cancer Trial

Metastasis-Directed Radiotherapy Shows Improved Kidney Cancer Outcomes

Imlunestrant Alone or With Verzenios Improved PROs in Advanced Breast Cancer

Enhertu Improves Survival End Points Vs Cyramza/Paclitaxel in HER2+ GC/GEJ

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