Tim Cortese

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., 

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Articles

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.

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

GLP-1 drugs reduced obesity-related cancer and death rates versus DPP-4s with no increased cancer risk, a large real-world study shows.

In an assessment of more than 170,000 patients, GLP-1 drugs were not linked with higher cancer rates, and led to a decrease in obesity-related cancers and deaths, according to a 

study presented during the 2025 American Society of Clinical Oncology Annual Meeting

There was a 7% decrease in obesity-related cancer among patients who used GLP-1 receptor agonists with 2501 events vs 2671 events in patients who were DPP-4 users. For females, events observed were 1754 for GLP-1 and 1898 for DPP-4. For males, there were 747 events with GLP-1 and 773 with DPP-4.

There was an 8% decrease in all-cause mortality with 2783 events with GLP-1 vs 2961 for DPP-4. For females, there were 1219 events with GLP-1 and 1514 events with DPP-4. For males, events were 1564 with GLP-1 and 1447 with DPP-4.

Investigators assessed 14 types of cancer and found that the protective association between GLP-1 and cancer incidence was driven by those of the colon and the rectum. Of note, there was no evidence of adverse association with pancreatic cancer.

GLP-1 receptor agonists: medicines that help control blood sugar and weight in people with type 2 diabetes.

DPP-4 inhibitors: diabetes drugs that help lower blood sugar by preventing the breakdown of a natural hormone called GLP-1.

Obesity-related cancers: types of cancer more likely to occur in people with obesity, including colon and rectal cancer.

All-cause mortality: death from any cause, not just a specific disease or condition.

Target trial emulation: research method that uses real-world data to mimic a clinical trial for more accurate comparisons.

Medullary thyroid cancer: a rare form of thyroid cancer included in warning labels for some GLP-1 drugs due to possible risk.

Medullary thyroid cancer could not specifically be assessed in this study due to the small sample size and is included in the warning labels for multiple GLP-1 medications, however, there was a lack of association between GLP-1 use and thyroid cancer as a whole in this assessment.

“Findings extend the value of GLP-1 medicines beyond blood sugar control, weight, heart, and kidney health to potential cancer prevention in adults who are high-risk,” Lucas A. Mavromatis, research assistant in the Division of Precision Medicine in the Department of Medicine at NYU Grossman School of Medicine, said during the presentation. “The effect size is small, follow-up was short, and assessed medications are primarily weaker, ‘diabetes dose’ formulations; long-term studies are needed to confirm the durability of effect and safety.”

Data were collected between 2013 and 2023 from 43 health system networks and included electronic health records and insurance claims. Those included in the analysis were adults with type 2 diabetes and had a body mass index of 30 kilograms per square meter or more, and were started with either a GLP-1 medicine or a DPP-4 inhibitor for the first time.

Comparison groups included 85,015 pairs, and each GLP-1 starter was paired with 1 DPP-4 starter of similar age, sex, race, weight, laboratory values, year of prescription and medical history. This followed the target trial emulation framework.

Outcomes included the first diagnosis of any 14 obesity-related cancers or death from any cause. Follow-up was from the first prescription until cancer, death, or the last recorded visit, with an average coverage of 3.9 years.

The background for the study was the gap in knowledge of the long-term impact of GLP-1 medications on the risk of cancer.

“GLP-1 treatments remain a strong option for people with diabetes and obesity and may favorably affect cancer risk. Decisions should balance benefits, costs, and [adverse] effects in discussion with clinicians,” Mavromatis concluded.

GLP-1 receptor agonists were associated with a reduction in obesity-related cancers and all-cause mortality in a study of over 170,000 patients, without increasing overall cancer rates. The protective effect was notably observed in colon and rectal cancers, with no adverse association with pancreatic cancer. The study, presented at the 2025 ASCO Annual Meeting, highlighted the potential of GLP-1 drugs in cancer prevention for high-risk adults. However, the effect size was small, and further long-term studies are needed to confirm these findings and assess safety.

GLP-1 drugs lowered rates of obesity-related cancers and death versus DPP-4s, with no increased cancer risk, study finds.

GLP-1 Drugs Linked to Fewer Obesity-Related Cancers

Opdivo plus Cabometyx resulted in a benefit versus Sutent in the first-line of advanced renal cell carcinoma treatment. © stock.adobe.com

Among patients with previously untreated, advanced renal cell carcinoma (RCC), treatment with Opdivo (nivolumab) plus Cabometyx (cabozantinib) resulted in long-term efficacy and manageable safety versus treatment with the standard of care, Sutent (sunitinib), study results have shown.

Progression-free survival: How long a patient lives without their disease spreading or worsening.

Overall survival: The time a patient lives, regardless of disease status.

Duration of response: How long a patient responds to treatment.

Overall response rate: Patients who responded partially or completely to treatment.

Complete response: The disappearance of cancer.

International Metastatic RCC Database Consortium (IMDC) risk group: A classification system to predict the prognosis and drive treatment decisions for patients with metastatic renal cell carcinoma.

Palmar-plantar erythrodysesthesia: Hand-foot syndrome.

Final follow-up results from the phase 3 

 were presented at the 2025 ASCO Genitourinary Cancer Symposium.

At the median follow up of 67.6 months for the intention to treat population, the median progression-free survival (PFS) was 16.4 months for patients who received Opdivo/CabometyxCabometyx and 8.3 months for those who received Sutent; median overall survival (OS) was 46.5 months versus 35.5 months, respectively, and median duration of response (DOR) was 22 months versus 15.2 months.

The overall response rate (ORR) was 55.7% versus 27.4% for patients in the Opdivo versus Sutent arms, respectively. Of patients who received Opdivo/Cabometyx, 20.1% experienced a partial response (PR) with 60% or more tumor reduction, and 21.7% received a PR with less than 60% tumor reduction. In the Opdivo/Cabometyx arm versus the Sutent arm, complete responses were observed in 45 and 15 patients, PRs in 135 and 75, stable disease in 104 and 136, progressive disease in 21 and 47 and unknown in 18 and 55.

“Long term efficacy benefit was observed with [Opdivo plus Cabometyx] over [Sutent] in these final results from the CheckMate 9ER trial, with a median of 67.6 months follow-up,” presenting author Dr. Robert J. Motzer, section head of Kidney Cancer in Genitourinary Oncology Service and Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, and coauthors, wrote in the presentation. “The results continue to support [Opdivo plus Cabometyx] as a standard of care for previously untreated advanced RCC.”

A total of 651 patients were enrolled in the trial and randomly assigned to receive 240 mg of intravenous Opdivo every two weeks plus 40 mg of oral Cabometyx daily (323 patients) or 50 mg of oral Sutent daily on four weeks on, two weeks off schedule (328 patients). Eligible patients had previously untreated advanced or metastatic RCC with a clear cell component who were in any International Metastatic RCC Database Consortium (IMDC) risk group.

Of patients in the IMDC favorable risk group, the median PFS in the Opdivo/Cabometyx group (74 patients) was 21.4 months versus 12.8 months in the Sutent group (72 patients); median OS was 53.7 months versus 58.9 months, respectively, and ORR was 66.2% versus 43.1%.

In the IMDC intermediate or poor risk group, the median PFS in the Opdivo/Cabometyx group (249 patients) was 15.4 months versus 7.1 months in the Sutent group (256 patients); median OS was 43.9 months versus 29.2 months, respectively, and ORR was 52.6% versus 23%.

Patients with liver metastases had a median PFS was 10.9 months in the Opdivo/Cabometyx group (73 patients) and 6.2 months in the Sutent group (56 patients); median OS was 37.6 months and 22.1 months, respectively; ORR was 52.1% and 21.4%.

Of patients with bone metastases, the median PFS was 13.8 months in the Opdivo/Cabometyx group (79 patients) and 5.3 months in the Sutent group (75 patients); median OS was 34.8 months and 20.7 months, respectively; ORR was 49.4% and 9.3%.

Those with lung metastases demonstrated a median PFS was 16.4 months in the Opdivo/Cabometyx group (241 patients) and 8.3 months in the Sutent group (251 patients); median OS was 47.5 months and 32.4 months, respectively; ORR was 57.3% and 27.9%.

Additionally, 93% of patients in the Opdivo/Cabometyx group and 95% in the Sutent group discontinued treatment; 43% and 55%, respectively, received subsequent systemic therapies; 26% and 31% received two or more subsequent systemic therapies; and the most common was any VEGFR inhibitor (79%) in the Opdivo/Cabometyx group and any PD-L1 inhibitor (81%) in the Sutent group.

The median duration of therapy was 21.8 months in the Opdivo/Cabometyx group and 8.9 months in the Sutent group; 62% and 55% of patients had at least one dose reduction; and the median time to first dose reduction was 4.1 months and two months.

Regarding safety, common treatment-related side effects of any grade occurred in 98% of patients in the Opdivo/Cabometyx group and 93% of the Sutent group, and grade 3 (severe)/4 (life-threatening) treatment-related side effects occurred in 68% and 55%, respectively. The most common treatment-related side effects of any grade were diarrhea (60% and 46%, respectively), palmar-plantar erythrodysesthesia (39% and 42%), hypertension (34% and 35%) and hypothyroidism (37% and 31%). Also, 22% of patients to receive Opdivo/Cabometyx were administered corticosteroids to manage immune-mediated side effects of any grade. Any grade treatment-related side effects led to discontinuation in 28% and 11%, respectively.

Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Final follow-up results from the CheckMate 9ER trial.” By Dr. Robert J. Motzer et al., 

The combination of nivolumab and cabozantinib demonstrated superior long-term efficacy and manageable safety compared to sunitinib in untreated advanced renal cell carcinoma (RCC). The CheckMate 9ER trial showed improved progression-free survival, overall survival, and response rates with nivolumab/cabozantinib. The study included 651 patients, with significant benefits observed across various risk groups and metastatic sites. Common side effects included diarrhea and hypertension, with a higher incidence of severe side effects in the nivolumab/cabozantinib group. These findings support nivolumab/cabozantinib as a standard treatment for advanced RCC.

Opdivo plus Cabometyx resulted in a significant progression and survival benefits compared with Sutent in the first-line treatment of patients with advanced renal cell carcinoma.

Tim Cortese

Imlunestrant Alone or With Verzenios Improved PROs in Advanced Breast Cancer

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

GLP-1 Drugs Linked to Fewer Obesity-Related Cancers

Opdivo Plus Cabometyx Safe, Effective in Advanced Renal Cell Carcinoma

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