Kristi Rosa

The dual-targeting CAR T-cell therapy KITE-363 showed positive response rates and manageable side effects in relapsed or refractory B-cell lymphoma.

Among patients with relapsed/refractory B-cell lymphoma, the anti-CD19/CD20 CAR T-cell therapy KITE-363 showcased high response rates with a manageable safety profile, according to results from a first-in-human phase 1 study presented during the 

Safety data indicated that no dose-limiting toxicities were reported in phase 1a. Grade 3 (severe) or higher side effects were experienced by 2 patients who received the agent at dose level 1 (DL1; 3 patients), which was 0.5 x 10⁶ CAR T cells/kg. Grade 3 or higher side effects were reported in six patients who received dose level 2 (DL2; 8 patients), which was 1 x 10⁶ CAR T cells/kg. In those who received dose level 3 (DL3; 26 patients), which was 2 x 10⁶ CAR T cells/kg, the most common grade 3 or higher side effects included decreased white blood cell count (11 patients), neutropenia (8 patients) and decreased neutrophil count (11 patients).

Moreover, one grade 3 case of cytokine release syndrome (CRS) was reported in a patient with nodular lymphocyte-predominant Hodgkin lymphoma; the duration of the event was one day. Three grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) events were observed: one in the DL2 group, which had a duration of four days, and two in the DL3 group, which had durations of one and two days, respectively. Notably, no grade 3 or higher CRS or ICANS events were observed in those with primary refractory large B-cell lymphoma who received the CAR T-cell therapy at DL3 (15 patients).

In patients without prior exposure to CAR T-cell therapy who received KITE-363 at DL3 (23 patients), the objective response rate was 87%, and this was comprised of a complete response rate of 78% and a partial response rate of 9%. Four percent of patients had stable disease and 9% had progressive disease. Within this group, those with large B-cell lymphoma who had previously received at least two lines of therapy (seven patients) experienced an objective response rate and complete response rate of 100% each. Those with primary refractory large B-cell lymphoma (15 patients) experienced an objective response rate of 80% and a complete response rate of 67%. Of the 3 patients who had prior CAR T exposure and received DL3, one achieved a complete response.

Among those who received KITE-363 at DL1 and DL2 (11 patients), the objective response rate was 64%, with a complete response rate of 36% and a partial response rate of 27%. Nine percent experienced stable disease and 27% had progressive disease.

“These results support KITE-363 as a promising therapeutic approach for patients with relapsed/refractory B-cell lymphoma including those with highly refractory large B-cell lymphoma,” Saurabh Dahiya, MD, FACP, an associate professor of medicine at Stanford University School of Medicine in Stanford, California, said in a presentation of the data.

Keeping Up With KITE-363 and Its Evaluation in R/R B-Cell Lymphoma
The bicistronic, lentiviral-encoded autologous CAR T-cell therapy, KITE-363, is dual targeted. The anti-CD19 and anti-CD20 CAR possess a CD28 costimulatory domain and a 4-1BB costimulatory domain, respectively. “Dual targeting has the potential to address tumor heterogeneity and improve the durability of responses by preventing CD19-negative relapses,” Dahiya noted.

The open-label, multicenter, phase 1 study utilized a 3 plus 3 study design. It was comprised of a phase 1a dose-escalation portion and a phase 1b dose-expansion portion. For phase 1a, patients had histologically confirmed relapsed/refractory B-cell lymphoma by World Health Organization criteria following more than two lines of therapy or second-line primary refractory disease. Phase 1b only enrolled patients with relapsed/refractory large B-cell lymphoma, which included those with second-line primary refractory disease. All patients were at least 18 years of age and had an ECOG performance status of 0 or 1.

They were excluded if they had Richter transformation, central nervous system involvement of lymphoma, active infection, or a central nervous system disorder of clinical significance. Those with clinically significant autoimmune or cardiac disease were also excluded.

The primary end points for phase 1a and phase 1b were incidence of dose-limiting toxicities and objective response rate, respectively. Secondary end points included complete response rate, duration of response, progression-free survival, time to next treatment, overall survival, safety, and levels of CAR T cells and cytokines in the blood.

After screening, patients were enrolled and underwent leukapheresis. This was followed by optional bridging therapy, which was comprised of corticosteroids with or without local radiation therapy per investigator discretion. From day –five to –three, patients received lymphodepleting chemotherapy comprised of cyclophosphamide at 300 milligrams per square meter (mg/m²) daily and fludarabine at 30 mg/m² daily for three days. On day 0, patients were infused with KITE-363 at one of the three dose levels. For DL3, the median time from leukapheresis to infusion with the CAR T-cell therapy was 27 days. The first post-infusion response assessment was conducted on day 28.

A total of 41 patients were enrolled and underwent leukapheresis. Three of these patients were not treated, and the remaining 38 went on to receive lymphodepleting chemotherapy. Because one patient did not meet protocol-required eligibility to receive KITE-363, a total of 37 patients received the CAR T-cell therapy.

At the data cutoff date of March 18, 2025, the median follow-up in those who received treatment (37 patients) was 12.4 months. The median follow-up for those in the DL3 group was 11.1 months.

The median age for all treated patients was 62 years, with 46% aged 65 years or older and 11% aged 75 years or older. In the DL3 group, the median age was 60.5 years, with 42% aged 65 years or older and 12% aged 75 years or older. More than half of patients were male (65%), most were White (78%), most were not Hispanic or Latino (86%) and had an ECOG performance status of 1 (60%). Moreover, 73% of all treated patients had stage III or 4 disease at study entry, as did 65% of those in the DL3 group.

In all treated patients, the most common histologic subtype was large B-cell lymphoma (92%), followed by indolent non-Hodgkin lymphoma (5%) and nodular lymphocyte-predominant Hodgkin lymphoma (3%). In the DL3 group, the most common histologic subtype was also large B-cell lymphoma (96%), followed by nodular lymphocyte-predominant Hodgkin lymphoma (4%). Nineteen percent of all treated patients and 15% of those in the DL3 group had bulky disease, which was defined as at least 7.5 centimeters. Dahiya noted that patients had tumors that were positive for CD19 and/or CD20, with most patients (78%) having tumors that were positive for both. Thirteen percent of patients had tumors that were positive for 1 antigen.

In all treated patients, 46% were primary refractory and 54% had received two or more prior regimens. Nineteen percent received prior CD19-targeted CAR T-cell therapy, 14% previously underwent autologous stem cell transplant and 57% had received bridging therapy. In the DL3 group, 58% were primary refractory and 42% had received at least two prior lines of treatment. In the 15 patients who were primary refractory, four experienced partial responses as best response to frontline treatment and 11 experienced progressive disease. Prior CD19-targeted CAR T-cell therapy and prior autologous stem cell transplant were received by 12% and 15% of patients, respectively. Fifty-eight percent of patients in this group received bridging therapy.

The median duration of complete response, defined as duration of response of all patients who achieved a complete response as best response, was not reached. The duration of complete response rate at 6 months was 71.4%. “Data beyond 6 months is heavily impacted by censoring,” Dahiya noted. “Longer follow-up is needed.” Nine of the 37 patients who received treatment died; 8 died due to progressive disease.

Among those who received the CAR T-cell therapy at DL3, all patients experienced any-grade side effects. Eighty-one percent of these effects were grade 3 or higher. Any-grade and grade 3 or higher serious side effects were reported in 54% and 38% of patients, respectively. Any-grade cardiac disorders were experienced by 35% of patients; 4% were grade 3 or higher. Any-grade infections occurred in 42% of patients; 15% were grade 3 or higher. Hematologic side effects included neutropenia (any grade, 38%; grade 3 or higher, 31%), thrombocytopenia (8%; 4%) and anemia (31%; 15%). Hypogammaglobulinemia occurred in 15% of patients.

In those who received KITE-363 at DL1 or DL2, grade 1 or 2 CRS occurred in 64% of patients and grade 3 ICANS occurred in 9%. The median time to onset of CRS was six days and the median duration was three days. The median time to onset of ICANS was also 6sixdays and the median duration was six days. CRS was managed with Actemra in 45% of patients and corticosteroids in 27%. ICANS was managed with corticosteroids in 9% and Kineret in 9%.

In those who received the agent at DL3, grade 1 (mild) or 2 (moderate) CRS occurred in 88% and grade 3 CRS occurred in 4%. The median time to onset was 3.5 days and the median duration was five days. Most events were managed with Actemra (88%), followed by corticosteroids (65%) and Kineret (4%). Grade 1 or 2 ICANS was experienced by 38%; this effect was grade 3 for 8%. The median time to onset was six days and the median duration was 4.5 days. These effects were largely managed with corticosteroids (38%) followed by Kineret (15%).

Additional Revelations and Take-Home Message

“KITE-363 cell expansion was dose dependent, with markedly robust expansion observed in DL3, appearing greater than 3- to 5-fold higher than with Yescarta,” Dahiya said. Post-infusion peak levels of serum analytes were also linked with KITE-363 pharmacokinetics and reduced toxicity.

Due to these early results, the robust CAR T-cell expansion and the acceptable toxicity profile, the agent is also under development for patients with autoimmune disease, Dahiya concluded.

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Articles

KITE-363, an anti-CD19/CD20 CAR T-cell therapy, demonstrated high response rates and a manageable safety profile in relapsed/refractory B-cell lymphoma patients during a phase 1 study. The study revealed no dose-limiting toxicities, with varying side effects across different dose levels. The therapy showed promising efficacy, particularly at dose level 3, with high objective and complete response rates. The dual-targeting approach of KITE-363 aims to address tumor heterogeneity and improve response durability. The study's findings support further development of KITE-363 for relapsed/refractory B-cell lymphoma and autoimmune diseases.

KITE-363 Shows High Response in B-Cell Lymphoma With Manageable Safety

Imdelltra improved survival and quality of life versus chemotherapy as second-line treatment for small cell lung cancer, reinforcing it as a new SOC.

Among patients with small cell lung cancer, second-line treatment with Imdelltra (tarlatamab-dlle) led to statistically significant and clinically meaningful improvements in progression-free survival and overall survival versus chemotherapy, according to data from the primary analysis of the phase 3 DeLLphi-304 trial presented at the 

Findings showed that at a median follow-up of 11.2 months for patients treated with Imdelltra (254 patients) and 11.7 months for those given chemotherapy (255 patients), Imdelltra led to a median overall survival of 13.6 months compared with 8.3 months for chemotherapy. In the Imdelltra arm, the 6- and 12-month overall survival rates were 76% and 53%, respectively. These respective rates were 62% and 37% in the chemotherapy arm.

“Taking the efficacy and safety data together, these data clearly support Imdelltra as a preferable therapy for patients in the second-line setting for small cell lung cancer,” lead study author Dr. Charles M. Rudin said in a presentation of the data. “Beyond redefining the standard of care for these patients, this study also establishes a new paradigm for the use of bispecific, T-cell engager immunotherapies for our patients with lung cancer.”

Rudin is deputy director of the Cancer Center, co-director of the Druckenmiller Center for Lung Cancer Research, and the Sylvia Hassenfeld Chair in Lung Cancer Research at Memorial Sloan Kettering Cancer Center in New York, New York.

In May 2024, the FDA granted accelerated approval to Imdelltra for the treatment of patients with extensive-stage small cell lung cancer with disease progression on or after platinum-based chemotherapy. This regulatory decision was supported by data from the phase 2 DeLLphi-301 trial.

More Efficacy, Patient-Reported Outcomes and Safety Data

Findings also demonstrated that the median progression-free survival was 4.2 months for the Imdelltra arm versus 3.7 months for the chemotherapy arm. The 6-month progression-free survival rates in the Imdelltra and chemotherapy arms were 31% and 23%, respectively; the respective rates at 12 months were 20% and 4%.

Patients in the Imdelltra arm achieved an objective response rate of 35% compared with 20% for those given chemotherapy. In the experimental arm, the rates of complete response, partial response, stable disease, and progressive disease were 1%, 34%, 33% and 22%, respectively. In the chemotherapy arm, these respective rates were 0%, 20%, 44% and 20%. Ten percent and 16% of patients in the Imdelltra and chemotherapy arms, respectively, were not evaluable for response.

The median duration of response was 6.9 months in the Imdelltra arm compared with 5.5 months in the chemotherapy arm. The respective 6- and 12-month duration of response rates were 56% and 41% for Imdelltra compared with 29% and 13% for chemotherapy. The median time to response was 1.5 months versus 1.4 months for Imdelltra and chemotherapy, respectively. At data cutoff, response was ongoing in 47% of patients in the experimental group versus 15% of the control group.

Regarding patient-reported outcomes, the mean improvement in dyspnea score from baseline to week 18 was 1.94 in the Imdelltra arm versus –7.20 in the chemotherapy arm. At week 18, cough score improvements were reported in 16.1% of patients in the Imdelltra group versus 9% of patients in the control group. Improvements in chest pain at week 18 were reported in 8.7% and 3.5% of patients, respectively.

The median treatment duration was 4.2 months in the Imdelltra arm (252 patients) versus 2.5 months in the chemotherapy arm (244 patients). Any-grade treatment-emergent adverse effects occurred in 99% of patients in the experimental arm versus all patients in the chemotherapy arm. The rates of any-grade treatment-related adverse effects were 93% and 91%, respectively.

Grade 3 (severe) treatment-related adverse effects were reported in 27% of patients in the Imdelltra group compared with 62% of patients in the chemotherapy group. The respective rates of serious treatment-related adverse effects were 28% and 31%. These effects led to dose interruption and/or reduction in 19% of patients treated with Imdelltra versus 55% given chemotherapy, and led to treatment discontinuation in 3% and 6% of patients, respectively. One patient experienced a grade 5 (death) treatment-related adverse effect in the Imdelltra arm compared with four patients in the chemotherapy arm.

In the experimental arm, treatment-emergent cytokine release syndrome occurred during the first 2 cycles of Imdelltra in 60% of patients who were monitored for 48 hours (209 patients) at grade 1 (45%), grade 2 (13%), and grade 3 (1%). Nineteen percent of patients had serious cytokine release syndrome, and it led to treatment discontinuation in 0.5% of patients. The median time to intervention was 27 hours from the last Imdelltra dose.

In patients who were monitored for cytokine release syndrome for at least six to eight hours during the first 2 cycles of treatment with Imdelltra (43 patients), cytokine release syndrome was reported in 37% of patients at grade 1 (28%) and in 9% of patients at grade 2. Seven percent of instances in this group were serious, although none led to treatment discontinuation. The median time to intervention was 17 hours.

Although treatment-emergent adverse effects such as cytokine release syndrome, dysgeusia, fever, and decreased appetite were more common with Imdelltra, chemotherapy was associated with increased incidence of anemia, neutropenia, thrombocytopenia, and decreased platelet counts. The rates of grade 3 or higher adverse effects such as anemia, neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, decreased platelet count, decreased neutrophil count, fatigue, pneumonia and low sodium levels were all higher with chemotherapy versus Imdelltra.

The open-label, randomized, controlled study enrolled patients at least 18 years of age with histologically or cytologically confirmed small cell lung cancer who experienced disease progression following a first-line, platinum-based regimen with or without an immune checkpoint inhibitor. Patients were required to have an ECOG performance status of 0 or 1. Patients with asymptomatic, previously treated or untreated brain metastases were allowed to enroll.

Investigators randomly assigned patients in a 1:1 fashion to receive Imdelltra or chemotherapy comprising lurbinectedin (47 patients), topotecan (185 patients), or amrubicin (23 patients). Stratification factors included prior treatment with a PD-(L)1 inhibitor (yes versus no), chemotherapy-free interval (less than 90 days versus at least 90 days to less than 180 days versus at least 180 days), brain metastases (yes versus no), and intended chemotherapy (topotecan/amrubicin versus lurbinectedin).

Overall survival served as the trial’s primary end point. Progression-free survival and patient-reported outcomes were key secondary end points. Other secondary objectives included objective response rate, duration of response, disease control rate and safety.

At baseline, the median age was 64 years in the Imdelltra arm versus 66 years (range, 26-84) in the chemotherapy arm. The majority of patients in both arms were male (Imdelltra, 72%; chemotherapy, 66%), were White (60%; 55%), were current or former smokers (91%; 88%), had an ECOG performance status of 1 (67%; 68%), received prior anti–PD-(L)1 therapy (71%; 71%), and received prior radiotherapy (63%; 63%). A chemotherapy-free interval of less than 90 days was most common in both arms (43%; 45%), followed by at least 90 days and less than 180 days (33%; 31%) and at least 180 days (24%; 25%).

Brain metastases were present in 44% of patients in the Imdelltra arm versus 45% of patients in the chemotherapy arm. The rates of patients with liver metastases were 33% and 37%, respectively. Among evaluable patients, 95% in the Imdelltra arm (217 patients) and 93% in the chemotherapy arm (214 patients) were positive for DLL3 expression.

“Tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer: primary analysis” by Dr. Charles M. Rudin, et al., 2025 ASCO Annual Meeting.

Imdelltra (tarlatamab-dlle) demonstrated significant improvements in progression-free and overall survival compared to chemotherapy in small cell lung cancer patients, as shown in the phase 3 DeLLphi-304 trial. The median overall survival was 13.6 months with Imdelltra versus 8.3 months with chemotherapy. Imdelltra also showed better patient-reported outcomes and a favorable safety profile, despite higher rates of cytokine release syndrome. The trial supports Imdelltra as a preferable second-line therapy, establishing a new paradigm for bispecific T-cell engager immunotherapies in lung cancer treatment.

Imdelltra Shows Survival Benefit in Small Cell Lung Cancer

Kisqali plus hormone therapy improved 4-year outcomes across age and menopausal status in early hormone receptor–positive, HER2-negative breast cancer.

Among patients with stage 2/3 hormone receptor–positive, HER2-negative early breast cancer, Kisqali (ribociclib) plus nonsteroidal aromatase inhibitor (NSAI) showed consistent benefits in invasive disease-free survival (iDFS), distant disease-free survival (DDFS), recurrence-free survival (RFS) and distant relapse-free survival (DRFS), according to an analysis of the phase 3 NATALEE trial presented at the 

At a median follow-up of 44.2 months, results showed that the 4-year iDFS rates in premenopausal patients were 90.6% with the Kisqali-plus-NSAI regimen with letrozole or anastrozole (1115 patients) versus 85.3% with a NSAI alone (1123 patients). In postmenopausal patients, the 4-year iDFS rates were 86.8% with the Kisqali-plus-NSAI regimen versus 82.2% with NSAI alone, which was a Δ4.6% absolute improvement.

“This analysis showed that [Kisqali] in combination with letrozole or anastrozole lowered the chance of the cancer returned was safe to use in a broad population of patients with HR-positive, HER2-negative early breast cancer,” lead study author Dr. Kevin Kalinsky, professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, and the director of the Glenn Family Breast Center at Winship Cancer Institute, said in an oral presentation during the meeting. “[Kisqali] plus a NSAI provides treatment benefit to a broad range of patients with stage 2/stage 3 HR-positive, HER2-negative early breast cancer across menopausal status and age.”

Although survival outcomes in patients with hormone receptor–positive, HER2-negative early breast cancer have improved with the use of adjuvant endocrine therapy, there is still a risk of recurrence, influenced by menopausal status and age, Kalinsky explained.

Invasive disease-free survival (iDFS): time after treatment during which no invasive breast cancer returns or spreads.

Distant disease-free survival (DDFS): time after treatment without cancer returning in distant parts of the body.

Recurrence-free survival (RFS): time after treatment during which cancer does not come back in any form.

Distant relapse-free survival (DRFS): time after treatment that a patient lives without the cancer coming back in distant organs.

Nonsteroidal aromatase inhibitor (NSAI): type of hormone therapy that lowers estrogen levels to slow or stop hormone receptor–positive breast cancer.

ECOG performance status: scale used to measure how a disease affects a patient’s daily living abilities.

Time to deterioration (TTD): how long it takes for a patient’s health or physical function to worsen.

EORTC QLQ-C30: a questionnaire used to assess quality of life in people with cancer.

Δ (Delta): symbol used to show the difference in percentage points between two treatment outcomes.

To be eligible for NATALEE, patients must have had hormone receptor–positive/HER2-negative early breast cancer and prior endocrine therapy was permitted within 12 months prior to randomization. Patients had to have:

anatomical stage 2a disease, which could be N0 with grade 2 and evidence of high risk, a Ki-67 of at least 20%, Oncotype DX Breast Recurrence Score at least 26 or high risk via genomic risk profiling, or grade 3, or N1 disease;

or anatomical stage 3, which was N0, N1, N2 or N3.

Patients who were premenopausal were required to undergo ovarian suppression.

A total 5101 patients were randomized 1:1 to receive 400 milligrams of daily Kisqali on a three-weeks-on/1-week-off schedule for three years plus an NSAI regimen of letrozole or anastrozole for at least five years plus goserelin in men and premenopausal women, or the NSAI regimen alone.

The primary end point was iDFS using STEEP criteria; secondary end points were RFS, DDFS, overall survival, safety and tolerability, patient-reported outcomes and pharmacokinetics.

Stratification factors included anatomical stage (2 versus 3), menopausal status (men and premenopausal women versus postmenopausal women), receipt of prior neo(adjuvant) chemotherapy (yes versus no), and geographic location (North America/Western Europe/Oceania versus rest of world).

Prior NATALEE data showed a statistically significant benefit with iDFS with Kisqali plus NSAI versus NSAI alone in a larger population of patients with hormone receptor–positive/HER2-negative early breast cancer at risk of recurrence. Additionally, the absolute iDFS benefit had increased to 4.9% in a 4-year landmark analysis and was observed across subgroups.

In the analysis presented at the 2025 ASCO Annual Meeting, investigators reported on 4-year efficacy, safety and quality-of-life (QOL) outcomes with Kisqali plus NSAI specific to menopausal status and age from the NATALEE study.

Kalinsky noted that more premenopausal patients versus postmenopausal had an ECOG performance status of 0 (86.8% versus 80.1%, respectively), Ki-67 greater than 20% (39.9% versus 34.4%), stage 3 (62.2% versus 58.3%), N1 to N3 nodal stage (63.4% versus 56.9%) and T3/T4 tumors (28.7% versus 24.0%) at diagnosis.

The data cutoff date was April 29, 2024. Efficacy outcomes were further explored via menopausal status and then grouped by age. Overall, in premenopausal patients, the 4-year DDFS rates were 91.6% with Kisqali/NSAI and 86.6% with NSAI alone, 4-year RFS rates were 92% and 86.6%, respectively, and 4-year DRFS rates were 92.7% and 87.6%, respectively.

When examined in premenopausal patients younger than 40 years, the absolute benefit rate with Kisqali (237 patients) versus NSAI alone (276 patients) across iDFS, DDFS, RFS and DRFS end points were Δ6.3%, Δ7%, Δ5.5% and Δ6.5%, respectively.

These rates were slightly lower in premenopausal patients 40 years or older with Kisqali (878 patients) versus NSAI alone (847 patients): iDFS (Δ5%); DDFS (Δ4.4%), RFS (Δ5.3%) and DRFS (Δ4.7%).

The same analysis was conducted in postmenopausal patients. Overall, in this subgroup, the 4-year DDFS rates were 87.7% versus 83.6% with Kisqali or NSAI, respectively (Δ4.1%). The 4-year RFS rates were 88.8% versus 84.5% (Δ4.3%), and the 4-year DRFS rates were 89.2% versus 85.6% (Δ3.6%).

The outcomes were explored further in postmenopausal patients younger than 60 years. The absolute benefit rate with Kisqali (703 patients) versus NSAI alone (735 patients) across iDFS, DDFS, RFS and DRFS end points were Δ2.7%, Δ2.2%, Δ2.8% and Δ2.1%, respectively.

These absolute benefit rates were higher in postmenopausal patients 60 years or older with Kisqali (721 patients) versus NSAI alone (685 patients): iDFS (Δ6.4%); DDFS (Δ5.9%), RFS (Δ5.8%) and DRFS (Δ5%).

Kalinsky emphasized that the trial was not powered to detect differences with these exploratory analyses, adding that the data should be interpreted with caution.

Safety and dose modifications due to adverse effects (AEs) were examined by menopausal status. Kalinsky highlighted that in premenopausal patients overall (2178 patients), the Kisqali discontinuation rate due to AEs was 16.1%, and 75.4% discontinued without dose reductions; in patients younger than 40 years, these respective rates were 10.5% and 52%, and in patients 40 years and older, they were 17.5% and 79.2%, respectively.

The Kisqali dose reduction rate due to AEs was 22.4% in all premenopausal patients, followed by 27% and 21.1% in patients younger than 40 years and at least 40 years old, respectively.

“Premenopausal women were more likely to discontinue [Kisqali] without having had a dose reduction,” Kalinsky said.

In postmenopausal patients overall (2771 patients), the Kisqali discontinuation rate was 22.9% and 67.5% stopped treatment without experiencing dose reductions. These rates were 17.8% and 68% in patients younger than 60 years and 27.9% and 67.2% in patients 60 years and older. The Kisqali dose reduction rate due to AEs was 23.6% in all postmenopausal patients, followed by 24.2% and 22.9% in patients younger than 60 years and at least 60 years old, respectively.

Time to deterioration (TTD) in global health status (GHS) and physical functioning scales of the EORTC QLQ-C30 was similar between arms for all patient subgroups.

“Efficacy and safety of Kisqali plus nonsteroidal aromatase inhibitor in NATALEE: analysis across menopausal status and age” by Dr. Kevin Kalinsky, et al., 

“Kisqali plus endocrine therapy in early breast cancer” by Dr. Dennis Slamon, et al., 

“Adjuvant Kisqali plus nonsteroidal aromatase inhibitor in hormone receptor–positive/HER2-negative early breast cancer: 4-year outcomes from the NATALEE trial” by Dr. Peter Fasching, et al., 

Kisqali (ribociclib) combined with a nonsteroidal aromatase inhibitor (NSAI) demonstrated significant benefits in invasive disease-free survival (iDFS), distant disease-free survival (DDFS), recurrence-free survival (RFS), and distant relapse-free survival (DRFS) for patients with stage 2/3 hormone receptor-positive, HER2-negative early breast cancer. The phase 3 NATALEE trial showed improved outcomes across menopausal status and age groups, with notable efficacy in premenopausal patients. Safety profiles were consistent, with manageable adverse effects. The trial's exploratory analyses suggest caution in interpreting subgroup differences, emphasizing the need for further research.

Kisqali plus aromatase inhibitor improved outcomes across age and menopausal status in early hormone receptor–positive, HER2-negative breast cancer.

Kisqali Benefit Lasts Across Age in Breast Cancer Subset

Trodelvy plus Keytruda, when given in the frontline, extended survival without progression versus chemo plus Keytruda in PD-L1+ metastatic TNBC: © stock.adobe.com.

Trodelvy (sacituzumab govitecan-hziy) and Keytruda (pembrolizumab), when given as a first-line treatment, significantly improved survival without progression versus chemo plus Keytruda among patients with PD-L1–positive, advanced or metastatic triple-negative breast cancer (TNBC).

These primary findings were generated from the phase 3 ASCENT-04/KEYNOTE-D19, which were shared during the 

At a data cutoff date of March 3, 2025, out of the 221 patients treated with Trodelvy plus Keytruda, there was a median progression-free survival of 11.2 months by blinded independent central review (BICR) versus 7.8 months in the 222 patients treated with chemotherapy plus Keytruda, translating to a 35% reduction in the risk of disease progression or death. The six- and 12-month progression-free survival rates in the Trodelvy arm were 72% and 48%, respectively; in the chemotherapy arm, these respective rates were 63% and 33%.

“Results from ASCENT-04/KEYNOTE-D19 support the use of Trodelvy plus Keytruda as a potential new standard of care for patients with previously untreated, PD-L1–positive, locally advanced unresectable or metastatic TNBC,” Dr. Sara M. Tolaney, chief of the division of Breast Oncology at Dana-Farber Cancer Institute, in Boston, Massachusetts, said in the briefing. She is also an associate professor of medicine at Harvard Medical School.

Data from previous studies showed that median progression-free survival achieved with chemotherapy with immune checkpoint inhibition ranges from 7.5 months to 9.7 months in patients with PD-L1–positive metastatic TNBC; however, most patients will experience progressive disease and approximately half of those treatment for metastatic TNBC in the first line do not go on to receive second-line treatment.

Trial Design: Eligibility, Treatment, Objectives

The global, randomized, phase 3 study enrolled patients with treatment-naive, locally advanced unresectable or metastatic TNBC who had PD-L1 positivity defined as a combined positive score of at least ten per the 22C3 assay. At least six months must have passed since treatment in the curative setting, where prior anti–PD-(L)1 inhibition was permitted.

A total of 443 participants were randomly assigned to receive either 10 milligrams per kilogram (mg/kg) of intravenous Trodelvy on days one and eight, plus 200 mg of Keytruda on day one of 21-day treatment cycles versus Keytruda at the same dose and schedule combined with chemotherapy. Treatment continued until progressive disease and intolerable toxicity. All patients who experienced disease progression by BICR were permitted to cross over to receive single-agent Trodelvy in the second line.

Stratification factors comprised region (US/Canada/Western Europe vs the rest of the world), previous exposure to PD-(L)1 inhibition (yes versus no), and curative treatment-free interval (de novo TNBC versus recurrence within six to 12 months from treatment completion in the curative setting versus recurrence longer than 12 months from completion of treatment in the curative setting).

The primary end point of the study was progression-free survival by BICR, and secondary end points included overall survival, objective response rate and duration of response by BICR, safety and quality of life.

All patients were female and had a PD-L1 combined positive score of 10 or higher. Most patients were White (Trodelvy arm, 63%; chemotherapy arm, 63%), from the rest of the world (62%; 62%) and had an ECOG performance status of 0 (71%; 69%). Regarding curative treatment-free interval, most patients were recurrent in over 12 months (48%; 48%), followed by de novo (34%; 34%) and recurrent within 6 to 12 months (18%; 18%). Metastatic sites included lymph nodes (72%; 69%), lung (50%; 43%), other (37%; 32%), bone (28%; 20%), liver (25%; 26%) and brain (4%; 3%).

The chemotherapy selected before randomization in the Trodelvy arm was taxane for 52% of patients and gemcitabine/carboplatin for 48% of patients; in the chemotherapy arm, these respective rates were 51% and 49%. Four percent of patients in the antibody-drug conjugate arm vs 5% of those in the chemotherapy arm had prior exposure to PD-(L)1 inhibition.

Although overall survival data were immature at the time of the report, with a maturity rate of only 26%, a positive improvement was observed for the Trodelvy plus Keytruda arm vs chemotherapy plus Keytruda arm — despite a high crossover rate. Specifically, 43% of those on the chemotherapy arm crossed over to receive the antibody-drug conjugate as a single agent in the second line, which accounted for 81% of those who were subsequently given treatment after chemotherapy/Keytruda was discontinued.

The median overall survival was not reached in the Trodelvy arm, and it was also not reached in the chemotherapy arm; 53 and 61 events were reported in the arms, respectively. The hazard ratio for overall survival was 0.89.

Trodelvy plus Keytruda induced an objective response rate of 60% vs 53% with chemotherapy plus Keytruda. In the antibody-drug conjugate arm, 13% of patients achieved a complete response and 47% had a partial response; 32% had stable disease, 4% progressed and 5% were not response evaluable. In the chemotherapy arm, the complete response and partial response rates were 8% and 45%, respectively; 32% of patients had stable disease, 12% experienced disease progression and 4% were not evaluable.

The median time to response in the Trodelvy arm was 1.9 months (range, 1.0-9.3); it was also 1.9 months (range, 1.1-11.4) in the chemotherapy arm. Notably, the median duration of response was 16.5 months in the antibody-drug conjugate arm and 9.2 months in the chemotherapy arm.

Any-grade treatment-emergent side effects occurred in over 99% of those in the Trodelvy and chemotherapy arms; these effects were grade 3 or higher for 71% and 70% of patients, respectively. Treatment-emergent serious side effects were experienced by 38% of those who received the antibody-drug conjugate vs 31% of those given chemotherapy; 28% and 19% of cases, respectively, were treatment related.

In the Trodelvy plus Keytruda arm, treatment-emergent side effects led to dose reductions or interruptions in 35% and 77% of patients, respectively; treatment-emergent side effects led to treatment discontinuation for 12% of patients and proved fatal for 3% of patients. Three of the 7 treatment-emergent side effects that led to death were determined to be related to treatment. In the chemotherapy plus Keytruda arm, treatment-emergent side effects led to dose reductions and interruptions for 44% and 74% of patients, respectively; treatment-emergent side effects led to discontinuation for 31% of patients. treatment-emergent side effects led to death for 3% of those in this arm; 1 of these cases was related to treatment.

“Overall, the safety profile of Trodelvy plus Keytruda was consistent with the known safety profiles of each drug,” Tolaney said. “The rate of serious side effects was higher in the Trodelvy plus Keytruda group compared with the chemotherapy plus Keytruda group; however, the rate of treatment-emergent side effects leading to dose reduction or treatment discontinuation was lower.”

Dr. Jane L. Meisel, professor in the Departments of Hematology and Medical Oncology and Gynecology & Obstetrics, and codirector of Breast Medical Oncology at Emory University School of Medicine in Georgia, commented on the significance of the findings.

“I do think this is really such potentially practice-changing data. We've seen in previous studies how Trodelvy works so well for patients with metastatic TNBC later on in their treatment. And now, to see this combined with Keytruda and compared with chemotherapy plus Keytruda with such both statistically and clinically meaningful benefits for patients, I think it really does change the game for this subgroup,” she said. “This is very exciting, and I look forward to seeing this potentially make its way into clinical practice. I think the nice thing too, is that as clinicians, many of us have used both of these agents — Trodelvy and Keytruda — quite a bit, and so the fact that there were no additional toxicities seen [beyond what we have] seen before, will help people get used to using this and feel comfortable with it once it makes its way into the clinic.”

Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109

Trodelvy combined with Keytruda as a first-line treatment significantly improved progression-free survival in patients with PD-L1–positive, advanced or metastatic triple-negative breast cancer compared to chemotherapy plus Keytruda. The phase 3 ASCENT-04/KEYNOTE-D19 trial demonstrated a 35% reduction in disease progression or death risk. The study's primary endpoint was progression-free survival, with secondary endpoints including overall survival and response rates. Safety profiles were consistent with known data, though serious side effects were more frequent in the Trodelvy plus Keytruda group.

Trodelvy plus Keytruda, when given in the frontline, extended survival without progression versus chemo plus Keytruda in PD-L1+ metastatic TNBC.

Kristi Rosa

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