Tony Berberabe, M.P.H.

Patients with high-risk muscle-invasive urothelial carcinoma (MIUC) who underwent radical surgery experienced notable improvements in disease-free survival (DFS, the time a patient lives without signs of cancer) when treated with adjuvant (postsurgical) Keytruda (pembrolizumab) when compared with patients who underwent observation after a 45-month follow-up, study findings have shown.

Findings from the phase 3 AMBASSADOR trial were presented during the 2024 ESMO Annual Congress by Dr. Andrea B, Apolo, a senior investigator in the Genitourinary Malignancies Branch of the National Cancer Institute in Bethesda, Maryland.

Adjuvant Keytruda significantly extended disease-free survival (DFS) in patients with high-risk muscle-invasive urothelial carcinoma (MIUC) compared to observation.

The benefit of Keytruda was observed regardless of PD-L1 expression and lymph node status, suggesting its potential effectiveness for a wide range of patients.

Patients with lower tract MIUC, primarily bladder cancer, demonstrated a more significant improvement in DFS with Keytruda compared to those with upper tract disease.

While the final analysis of overall survival is pending, interim data suggest a potential benefit of Keytruda in extending the lives of patients with high-risk MIUC.

The study reported manageable toxicity associated with Keytruda, making it a promising treatment option for patients with MIUC.

Urothelial carcinoma, as defined by the National Cancer Institute, begins in the urothelial cells lining the urethra, bladder, ureters, renal pelvis and other organs, and almost all bladder cancers are urothelial carcinomas.

“In this setting, [Keytruda] doubled the median DFS at 29.6 months compared with 14.2 months in the observation arm,” Apolo said during a presentation of the data in the intention-to-treat population that was published in 

A total of 702 enrolled patients were randomly assigned to receive 200 milligrams of Keytruda every three weeks (354 patients) versus observation (348 patients) with dual primary end points of DFS and overall survival (OS, the time a patient lives regardless of disease status). Across both cohorts, the median age was 68 years, and the majority of patients were men (74.6%).

In the Keytruda arm, 57.3% of patients were PD-L1 positive compared with 57.8% of patients in the observation arm. In the Keytruda arm, the primary tumor sites were bladder (75.4%), upper tract (22.9%) and urethra (1.7%) compared with the observation arm: 75.6%, 21% and 3.4%, respectively.

When evaluating subgroups, Apolo noted that DFS in patients who were PD-L1 positive showed a benefit in terms of prognosis. “The marker was prognostic, but not predictive because both arms, PD-L1–positive and –negative, benefited from adjuvant [Keytruda],” Apolo added.

Turning to DFS for primary tumor sites in the upper and lower tract, investigators reported small numbers, “so it is hard to draw conclusions from these cohorts,” Apolo said. Exploratory DFS subgroups were also evaluated and included an evaluation of lymph node status (if the cancer has spread to the lymph nodes), upper tract neoadjuvant therapy, ECOG performance status (evaluating a patient’s ability to perform daily tasks) and histologic variants.

In all patients with N0 stage disease (cancer has not spread to the lymph nodes, with higher numbers indicating increasing spread to the lymph nodes), the hazard ratio (HR) for DFS was 0.53, meaning there was a 47% likelihood the disease would return compared with the observation group. In N1, the HR was 0.81, and for patients with N2/N3 stage disease, the HR was 0.71. “This was prognostic, but adjuvant Keytruda benefited all groups including N0 and N1, and N2 and N3,” she continued.

Evaluation of lymph node stage by lower tract versus upper tract demonstrated that “patients with disease present in the lower tract, which were predominantly bladder patients, showed benefit from adjuvant [Keytruda], regardless of N0 or N-plus status,” Apolo said. “Looking at patients with upper tract disease, we noted that the [DFS] numbers are very small and the data are inconclusive,” Apolo continued.

The investigators reported that the most common sites of metastatic disease occurrence (702 patients) were abdominal lymph nodes (40%), pelvic lymph nodes (30%), bone (22%), chest/neck lymph nodes (20%) and liver (18%). Apolo noted that these recurrence sites were “interesting and hypothesis-generating.”

In the primary analysis of the AMBASSADOR study, Keytruda showed a significant improvement in DFS versus observation after a 22-month follow-up.

DA approval of Opdivo (nivolumab) in high-risk MIUC after surgery

. At that point, 34% of patients in the observation arm and 20% of patients in the Keytruda arm had received a non-protocol checkpoint inhibitor or withdrew consent. “The interim OS had been presented, although the final analysis of OS had not been performed because only 8% of events had been reached,” Apolo said.

Apolo concluded the presentation noting that subgroup analysis showed a DFS benefit with Keytruda versus observation regardless of PD-L1 expression and lymph node status.

“Based on the doubling of the median DFS and the previously presented manageable toxicity, this trial supports adjuvant [Keytruda] as a therapeutic option in patients with high-risk MIUC,” Apolo said.

For more news on cancer updates, research and education, don’t forget to 

Articles

Among patients with high-risk muscle-invasive urothelial carcinoma, postsurgical Keytruda extended the time some lived without signs of cancer.

Keytruda Improves Disease-Free Survival in Some With Urothelial Carcinoma

Minimal residual disease may offer treatment insights for patients with AML.

After patients with acute monocytic leukemia (AML) undergo induction chemotherapy (treatment with the goal of killing all or most cancer cells to induce remission), molecular minimal residual disease (MRD) assessments (tests for malignant cells remaining in the patient’s body following treatment) may be helpful in determining which patients have NPM1-mutated disease. This distinction can guide treatment decisions — especially in those with FLT3 internal tandem duplication (ITD), according to data presented at the 2023 

American Society of Hematology Annual Meeting

Of note, at first remission, the role of allogeneic stem cell transplant (ASCT) in NPM1-mutated AML remains controversial as there is significant variation in practice.

Historically, the benefit of ASCT was observed in patients with NPM1-mutated AML in the presence of FLT3 ITD; however, with the increased understanding of MRD and its improvement on survival, the need to identify the primary determinant of benefit has grown. Although ASCT can benefit patients with AML, research suggests that patients with favorable risk generally do better with chemotherapy and that the risks and adverse events from ASCT outweigh the benefits in these patients. Alternatively, in patients who are at adverse risk with AML generally do poorly with chemotherapy and are likely to benefit from transplant.

“In general, an allogeneic transplant is offered in first remission to patients with AML who have an adverse risk. It is not offered in favorable risk,” lead author Dr. Jad Othman, of Guy’s and St Thomas’ NHS Foundation Trust in London, said in a presentation of the data. “The question of (offering transplant) in intermediate risk has always been one that has been controversial.”

To determine if patients who were MRD-positive had improved survival when they received an ASCT compared with patients who were MRD-negative, data were compared from two large United Kingdom studies, AML17 and AML19. A total of 737 patients who achieved complete remission, meaning that there was no remaining detectable disease, and had a valid MRD result were evaluated. In AML17, 17% of patients were MRD-positive and 21% in AML19 were MRD-positive. Overall, ASCT was performed in 20% of patients in AML17 and 25% of patients in AML19.

“Importantly, the selection of patients for transplant in the two studies were very different,” Othman said. “In AML17, patients were selected based on a validated risk score, as determined by age, sex, secondary disease, cytogenetics, white cell count and response after one course of chemotherapy.” In AML19, patients underwent ASCT only if they were MRD-positive in the peripheral blood after chemotherapy cycle 2.

Time-to-event variables were analyzed using the Kaplan-Meier method, and the impact of ASCT was assessed using Cox regression and visualized with Simon-Makuch plots, said Othman.

It had been previously reported in AML17 that patients who were MRD-positive had poor outcomes with a three-year cumulative incidence of relapse (CIR) rate of 84% and a three-year overall survival (OS; percentage of patients who are still alive) rate of 25%.In AML19, the three-year CIR was 50% and 3-year OS rate of 51%.

A significant survival advantage was observed in patients who had detectable MRD after the first two courses of chemotherapy if they received a transplant in their first remission compared with patients who were MRD-negative after chemotherapy.

“Those patients who were MRD-negative after chemotherapy did not derive any survival advantage from having a transplant in their first remission,” Othman said.

MRD also predicts ASCT benefit in patients with NPM1-mutated AML and FLT3 ITD, which has traditionally been considered to be a strong indication for transplant, Othman said. In this patient population, patients who were MRD-positive benefited from ASCT versus no ASCT compared with patients who were MRD-negative.

“This held true even if it was limited to those patients with a high allelic ratio for FLT3 ITD,” Othman said. In other subgroups, the investigators “weren’t able to identify any MRD-negative population in whom a transplant and chemotherapy provided a survival advantage,” Othman added.

Based on this analysis, the investigators concluded that MRD after induction chemotherapy identifies patients with NPM1-mutated AML who benefit from ASCT in first remission. Further, after second induction, patients who were MRD-negative show no benefit from transplant, even with FLT3 ITD co-mutation.

Molecular minimal residual disease status may offer clues as to which patients with acute monocytic leukemia will benefit from certain therapies. 

MRD Status Can Help Guide Treatments in NPM1-Mutated AML

Findings from the phase 3 EMRALD trial showed that all relevant subgroups of patients with ER-positive/HER2-negative, 

-mutated advanced or metastatic breast cancer tended to experience improved progression-free survival (PFS; time from treatment until disease progression or death) with orserdu (elacestrant) compared to standard of care.

The study analysis — which was presented at the 2023 

 — revealed that exposure to CDK4/6 inhibitors plus estrogen therapy for at least 12 months improved PFS, suggesting that the estrogen receptor (ER) pathway could be the main driver of disease, regardless of the metastatic site or coexistence of 

“We evaluated eigh subsets, including patients with bone, liver and lung metastases, HER2-low expression and HER2-zero expression, 

 mutation,” coauthor Dr. Janice Lu, professor, Northwestern University Lurie Comprehensive Cancer Center, Chicago, Illinois, said during the presentation of data.

Patients (478) were randomly assigned to receive Orserdu (239 patients) or standard of care (239 patients) and 228 patients were identified with an 

 mutation group, 159 patients were treated with prior CDK4/6 inhibitors for 12 months, 71% had liver and or lung metastases, 39% had a 

 mutation and 48% had HER2-low expression.

 mutation, median PFS in the treatment arm was 8.61 months, compared to 1.91 months in the control arm.

In the current analysis, in patients with accompanying liver and/or lung metastases, the median PFS among patients in the Orserdu arm was 7.26 months compared with 1.87 months among patients treated with standard of care. In patients with 

 mutation, median PFS was 5.45 months compared to 1.94 months, respectively. In patients with 

 mutation, median PFS was 8.61 months vs 1.87 months, respectively. In patients with HER2-low expression, median PFS was 9.03 months vs 1.87 months, respectively.

The EMERALD trial enrolled patients with ER-positive/HER2-negative metastatic breast cancer who were previously treated with one to two lines of endocrine therapy and an CDK4/6 inhibitor. Investigators allowed for previous treatment with Faslodex (fulvestrant). In the trial, patients either received 345 mg Orserdu or investigator’s choice of Faslodex or an aromatase inhibitor.

 mutation status (detected vs not detected), prior treatment with Faslodex (yes vs no), and visceral metastasis (yes vs no). The major efficacy outcome measure was PFS, assessed by a blinded imaging review committee. A statistically significant difference in PFS was observed in the intention to treat (ITT) population and in the subgroup of patients with 

 mutations. Efficacy results from the EMERALD study led to the 

Regarding safety, most side effects, including nausea, were grade 1 and 2, and no grade 4 (severe) treatment-related side effects were reported. Investigators reported that quality of life was maintained between treatment groups and no differences were observed between all patients and patients with 

No hematologic safety signal was observed, and no patients in either treatment arm exhibited sinus bradycardia. Further, no deaths were reported as treatment-related in either arm of the trial.

The most common all-grade side effects (10% or greater) reported in patients with 

 mutation in the treatment arm were musculoskeletal pain (50%), nausea (38.5%) and fatigue (25.6%). In the control arm, the most common all grade side effects (10% or greater) were musculoskeletal pain (37.3%), nausea (14.7%) and fatigue (22.7%).

“A clinically meaningful improvement in PFS favoring (Orserdu) compared with standard of care was consistent across all relevant subgroups with 

-mutation tumors and assumed endocrine-sensitivity,” concluded Lu.


Patients with ER-positive, HER2-negative, ESR1-mutant advanced breast cancer experienced improvements in progression-free survival when being treated with Orserdu, study results showed. 

Orserdu Boosts PFS in ESR1-Mutated Metastatic Breast Cancer Subgroups

A watch-and-wait approach remains the standard of care for patients with early-stage chronic lymphocytic leukemia. 

A watch-and-wait approach remains the standard of care for patients with early-stage chronic lymphocytic leukemia (CLL) with inactive disease, according to findings from a recent phase 3 trial.

In particular, the final analysis of the phase 3 CLL12 trial was presented by Dr. Petra Langerbeins at the 2023 

Findings from a previous analysis demonstrated that Imbruvica (ibrutinib) improved event-free survival in patients with early-stage disease.

Patients with Binet stage A disease (meaning no anemia, no thrombocytopenia and fewer than three areas of lymphoid tissue enlargement) were screened for eligibility for the trial and underwent risk assessment. Patients with low risk (152 patients) were assigned to the watch-and-wait arm, and those determined to be at increased risk were assigned to receive Imbruvica (182 patients) versus placebo (181 patients).

The primary focus of this trial was event-free survival, defined as time to symptomatic progression, CLL treatment or death. Other areas of interest included progression-free survival (the time during and after treatment when a patient with cancer lives without disease worsening), time to next treatment (the time from initiating one treatment to the initiation of another line of therapy) and overall survival (the time when a patient with cancer is alive).

“(Event-free survival), (progression-free survival) and (time to next treatment) were significantly longer for patients in the (Imbruvica) group,” said Langerbeins, of the division of hematology, immunology, infectiology, intensive care and oncology at the University of Cologne in Germany. “But (Imbruvica) did not prolong survival as compared with placebo.”

The overall response rate (the percentage of patients with a partial or complete response to treatment) was 72.5% in the Imbruvica group at a median of 69.3 months of observation time. Further, event-free survival, progression-free survival and time to next treatment were not reached (meaning that more than half of patients in a trial were still alive or did not meet a certain outcome) in the treatment group compared with 14 months, 51.6 months and 68.5 months, respectively, in the placebo group.

Regarding safety, 9.9% of patients in the Imbruvica group (170 patients) reported a serious side effect versus 14.9% in the placebo group (168 patients).

Mild to life-threatening second malignancies were reported in 12.9% of patients in the Imbruvica group versus 21.4% in the placebo arm. Second malignancies that caused death were reported in 1.2% and 3%, respectively. In the watch-and-wait group (152 patients), 9.9% of patients reported a mild to life-threatening second malignancy and 1.3% of patients reported a second malignancy that led to death.

The median number of treatment cycles was 39 in the Imbruvica group and 27.5 in the placebo group. The main reason for early treatment discontinuation was side effects in the Imbruvica group (72.4%) compared with progressive disease (48.5%) in the placebo group.

Regarding subsequent therapies administered, 9.9% of the watch-and-wait group received subsequent treatment, with the majority receiving targeted therapies (86.7%) or chemoimmunotherapy (13.3%). In the Imbruvica group, 15.9% received subsequent treatment. Patients received targeted therapies or chemoimmunotherapy equally (48.3%) or anti-CD20 monoclonal antibody (3.4%). In the placebo group, 43.6% received subsequent treatment. Patients received chemoimmunotherapy (53.2%), targeted therapies (45.6%) or anti-CD20 monoclonal antibody (1.3%).

The mortality rate was 6.6% in the Imbruvica group, 7.7% in the placebo group and 3.9% in the watch-and-wait group.

When comparing the overall survival between the treatment and placebo groups, overall survival was not reached for both arms. Investigators reported that overall survival from diagnosis was not reached and revealed no significant differences in the median when comparing treatment, placebo and watch-and-wait groups.

“The CLL12 study demonstrates that in patients with early stage CLL, (Imbruvica) is associated with relevant cardiovascular toxicity and increased susceptibility to bleeding,” Langerbeins said. “The median survival is fantastic for untreated patients with risk features and is estimated to be more than 20 years,” Langerbeins concluded.

Patients with inactive early-stage chronic lymphocytic leukemia may benefit from a wait-and-watch approach compared with immediate treatment with Imbruvica, findings from a phase 3 trial showed. 

Tony Berberabe, M.P.H.

Keytruda Improves Disease-Free Survival in Some With Urothelial Carcinoma

MRD Status Can Help Guide Treatments in NPM1-Mutated AML

Orserdu Boosts PFS in ESR1-Mutated Metastatic Breast Cancer Subgroups

Standard Approach for Inactive, Early CLL Remains a Wait-and-Watch Strategy

Latest News