Jason Broderick

Treatment with Herceptin (trastuzumab) and Perjeta (pertuzumab) with endocrine therapy but without chemotherapy has been shown to potentially be an effective treatment for patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer. Furthermore, the addition of Kisqali (ribociclib) might improve patient outcomes even more.

These findings come from the second interim efficacy analysis of the phase 3 DETECT V trial presented at the 2024 ESMO Congress.

In the study, 270 patients with metastatic HR/HER2–positive breast cancer receiving a first to third line of treatment were randomized to one of two arms. In the chemotherapy arm, patients received physician’s choice of chemotherapy plus Herceptin/Perjeta followed by maintenance Herceptin/Perjeta and endocrine therapy. In the chemotherapy-free arm, patients received physician’s choice of endocrine therapy plus Herceptin/Perjeta. After 124 patients enrolled, the study was amended to add Kisqali to endocrine therapy in both arms. 

The combination of Herceptin, Perjeta, and endocrine therapy without chemotherapy showed promising results in patients with HR+/HER2+ metastatic breast cancer.

Adding Kisqali to the treatment regimen further improved patient outcomes, reducing the risk of disease progression or death.

The DETECT V trial suggests that a chemotherapy-free regimen with Herceptin, Perjeta, and endocrine therapy, potentially with the addition of Kisqali, may be a promising treatment option for patients with HR+/HER2+ metastatic breast cancer.

Overall survival (OS, the time a patient lives, regardless of disease status) and progression-free survival (PFS, the time a patient lives without their disease spreading or worsening) was similar between the arms. In the chemotherapy-free arm, the median OS was not reached (meaning more than half of the patients in that arm were still alive) versus 46.1 months in the chemotherapy arm. For PFS, the median was 19.1 months in the chemotherapy-free arm versus 22.4 months in the chemotherapy arm.

The addition of Kisqali improved PFS and OS, with patients treated with Kisqali being 48% less likely to experience disease progression or death and being 58% less likely to die of any cause.

Dr. Wolfgang Janni emphasized that this was a comparison of subsequent study cohorts, not a randomized comparison for the addition of Kisqali. Janni is a professor at the University of Ulm in Ulm, Germany.

Regarding safety of the chemotherapy versus chemotherapy-free arms, the most common side effect in both arms was diarrhea, with 100 all-grade incidences in the chemotherapy-free arm and 146 in the chemotherapy arm.

“We did observe a higher amount of diarrhea in the chemotherapy containing arm, while we saw more prolonged neutropenia [low count of neutrophils, a type of white blood cell] in the chemo[therapy]-free arm, possibly due to longer exposure to [Kisqali],” Janni explained. In the chemotherapy-free arm, there were 64 incidences of all-grade neutropenia and 48 grade 3 (severe) or higher.

For the safety analysis of Kisqali versus no Kisqali, 55 patients (37.4%) receiving Kisqali experienced at least one serious side effect versus 43 patients (34.7%) in the no Kisqali arm. Ninety-five patients (64.6%) and 62 patients (50%) in the Kisqali and no Kisqali arms, respectively, experienced at least one grade 3 or higher side effect.

“The tolerability comparison between the two cohorts did not show a difference in the overall incidence of serious [side effects], but in [side effects] with grade 3 or higher, which was mainly caused by the higher incidence of neutropenia and liver enzyme abnormalities in the [Kisqali] cohort. There were no treatment-associated deaths in this study,” Janni said.

The final results from this study are pending, as are longer-term findings from the Kisqali cohort, which had shorter follow-up due to its later addition into the study regimens.

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

subscribe to CURE®’s newsletters here.

Articles

Among patients with HR+/HER2+ breast cancer, Herceptin and Perjeta plus endocrine therapy proved to be beneficial without chemotherapy.

Herceptin, Perjeta Regimen May Be Effective Without Chemo in Breast Cancer

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.

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

A treatment combination of Braftovi (encorafenib), Erbitux (cetuximab) and chemotherapy showed promising anti-tumor activity in patients with BRAF V600E-mutant metastatic colorectal cancer who were previously treated with at least one line of systemic therapy, according to a presentation at the 

A presentation at the conference highlighted updated safety results from the phase 3 BREAKWATER study, which included three components: a safety portion, a phase 3 randomization and a second randomization labeled as cohort 3.

The safety portion included two cohorts: Braftovi plus Erbitux and FOLFIRI chemotherapy (cohort 1); and Braftovi plus Erbitux and mFOLFOX6 chemotherapy (cohort 2). The phase 3 component randomized patients to three treatment groups: Erbitux alone; Erbitux plus mFOLFOX6 chemotherapy; or the control group of three chemotherapy regimens: FOLFIRI, mFOLFOX6, or capecitabine and oxaliplatin (CAPOX) with or without Avastin (bevacizumab). Cohort 3 randomly assigned patients to either Erbitux/FOLFIRI chemotherapy or FOLFIRI chemotherapy with or without Avastin.

A treatment combination of Braftovi, Erbitux and chemotherapy showed promising anti-tumor activity in patients with BRAF V600E-mutant metastatic colorectal cancer.

Among previously treated patients receiving Braftovi, Erbitux and chemotherapy as a second-line therapy, the ORR was 44.4%.

In patients receiving Braftovi, Erbitux and chemotherapy as a second-line therapy, the median DOR was 12.5 months, the median PFS was 12.6 months, and the median OS was 19.7 months.

Patients must have confirmed stage 4 colorectal cancer and be ineligible if they have tumors that are microsatellite instability-high or mismatch repair-deficient.

Of note, the presentation of the BREAKWATER study at ESMO mainly focused on the safety portion, which included patients from cohort 1.

There were 30 patients enrolled in cohort 1. The median age was 56.5 years and 66.7% were men. The ECOG performance status was either 0 (ability to independently perform daily tasks; 73.3%) or 1 (ability to perform most daily tasks independently; 26.7%). Twelve patients had not received prior therapy, and 18 patients had one prior line of therapy.

In a presentation at the 2024 ESMO Congress, Dr. Josep Tabernero, head of the Department of Medical Oncology, Vall d’Hebron University Hospital and director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain, discussed findings from the trial. Tabernero reported that only one dose-limiting toxicity (DLT; side effects from drugs that prevent an increase in dose) occurred with the Erbitux/chemotherapy combination, which was grade 4 (life-threatening) neutropenia (lower levels of a white blood cell type) that lasted more than seven days.

Treatment-related side effects of any grade were experienced by 93.3% of patients, with 50% of patients experiencing grade 3 (severe)/4 treatment-related side effects, and 16.7% of patients experiencing a serious side effect related to study treatment. There were no deaths related to the study treatment.

Efficacy data showed an objective response rate (ORR; percentage of patients whose cancer shrunk or disappeared) of 83.3% in patients from cohort 1 receiving Braftovi, Erbitux plus chemotherapy in the first-line metastatic setting. There were two complete responses (CRs; disappearance of cancer), eight partial responses (PRs; cancer shrunk) and one patient with stable disease (SD; cancer did not improve or worsen). The median duration of response (DOR) was not estimable. The median progression-free survival (PFS; time patients are alive without their disease worsening) was not evaluable, meaning not enough patients had their disease worsened by the data collection date, and the median overall survival (OS; time patients live regardless of disease status) was not evaluable.

Among previously treated patients from cohort 1 receiving treatment as a second-line therapy, the ORR was 44.4%. There was one CR, seven PRs and seven patients with SD. The median DOR was 12.5 months. The median PFS was 12.6 months, and the median OS was 19.7 months.

“The combination of [Braftovi, Erbitux] plus chemotherapy was tolerable without new safety signals in patients with BRAF V600E-mutant metastatic colorectal cancer … [and] showed promising improvement in key efficacy measures,” said Tabernero.

The BREAKWATER trial assessed the combination of Braftovi and Erbitux with or without chemotherapy in patients with metastatic colorectal cancer. Patients must have confirmed stage 4 colorectal cancer harboring a BRAF V600E mutation. Patients were ineligible if they had tumors that are microsatellite instability-high or mismatch repair-deficient.

Safety Among Patients With Metastatic Colorectal Cancer

At the 2024 ESMO Congress, Tabernero shared data from cohort 1 of the safety portion, which evaluated the combination of Braftovi, Erbitux and chemotherapy. The primary goal of the safety portion of the trial was DLTs, with secondary goals including safety and antitumor activity. 

Additional safety data showed that all patients experienced treatment-emergent side effects, with 63.3% and 46.7% experiencing grade 3/4 treatment-emergent side effects and serious treatment-emergent side effects, respectively. Treatment-emergent side effects leading to dose reduction, dose interruption or permanent discontinuation of any drug occurred in 53.3%, 73.3% and 30% of patients, respectively. Treatment-emergent side effects were associated with two patient deaths.

Treatment-emergent side effects across all grades occurring in at least 30% of patients included nausea (50%), diarrhea (46.7%), constipation (43.3%), fatigue (43.3%), dermatitis acneiform (acne-like bumps; 40%), rash (33.3%) and skin hyperpigmentation (30%). Treatment-emergent side effects of grade 3 or worse included two cases of dermatitis acneiform and one case each of diarrhea, constipation and fatigue.

Erbitux combination is currently approved by the FDA

 for use in patients previously treated for BRAF V600E-mutated metastatic colorectal cancer.

“Currently, there are no specifically targeted first-line treatments for BRAF V600E-mutant metastatic colorectal cancer, which highlights the unmet need for novel treatment options for this patient population,” said Tabernero.

In his concluding remarks, Tabernero said, “These results support the continued evaluation of Erbitux plus chemotherapy as a treatment option for patients with BRAF V600E-mutated metastatic colorectal cancer in cohort 3 of the BREAKWATER study.”

In patients with BRAF V600E-mutant metastatic colorectal cancer, a combination of Braftovi, Erbitux and chemotherapy showed promising antitumor activity.

Braftovi Regimen Is Promising in Metastatic Colorectal Cancer

Patients who had BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) and were urinary minimal residual disease (uMRD)-negative after treatment of Adstiladrin (nadofaragene firadenovec) did not experience cancer recurrences, according to a phase 2 trial.

Findings from the phase 2 trial were presented in a poster at the 2024 

Beyond being highly predictive of future recurrence, uMRD was also shown to enable quantitative evaluation of molecular response to Adstiladrin, according to first author Dr. Vikram M. Narayan and co-investigators. Narayan is an assistant professor in the department of urology at Emory University School of Medicine.

“uMRD profiling uses next-generation sequencing to identify mutations associated with urothelial carcinoma and can be used to predict recurrence and assess response to therapy,” Narayan and co-investigators wrote on their poster.

Patients with a specific type of non-muscle invasive bladder cancer (NMIBC) called BCG-unresponsive, who were treated with Adstiladrin, showed no cancer recurrences if they were urinary minimal residual disease (uMRD)-negative after treatment.

The study used a technique called uMRD profiling, which used advanced genetic analysis to identify mutations associated with the cancer, helping predict the likelihood of recurrence and assess the response to Adstiladrin therapy.

The uMRD analysis involved 43 patients in a phase 2 trial, with urine samples collected before treatment and at three months follow-up. The primary goal of the study was to achieve high-grade recurrence-free survival at one year.

The analysis found that patients with uMRD-negative status had significantly better recurrence-free survival rates compared to uMRD-positives, indicating the potential effectiveness of Adstiladrin in preventing cancer recurrence.

The researchers’ uMRD analysis was from the phase 2 trial that included 43 patients with BCG-unresponsive (relapsed/refractory) NMIBC treated with the novel intravesical therapy Adstiladrin. To enroll in the trial patients had to have an ECOG performance status of 2 or lower, meaning eligible patients were able to perform tasks independently. Patients with upper tract bladder cancer were not eligible.

The uMRD analysis included all patients in the trial who had been treated with at least one dose of Adstiladrin, which included 35 patients. Urine samples were collected from patients before induction and at three months follow-up.

The primary endpoint (main result measured at the end of a study to see if treatment worked) of the study was high-grade recurrence-free survival (RFS; time after primary treatment when cancer does not return) at one year.

Initial pathological stages for the 35 evaluable patients were Ta in three patients, T1 in nine patients and Tis in 23 patients. Six patients also had concomitant carcinoma in situ (CIS). For the 32 patients with pre-treatment urine samples available, the most frequently mutated genes included TP53, TERT, PIK3CA, ARID1A, PLEKHS1, ELF3 and ERBB2. CNVs occurred most in SOX4and NIT1.In both pre- and post-induction collections, “uMRD identified patients with high (72%) and low (28%) recurrence risk,” the authors wrote.

The12-month pre-induction RFS rates were 71% and 20% for MRD-negatives and MRD-positives, respectively.Also at 12 months, the post-induction RFS rates were 100% and 20% for MRD-negatives and MRD-positives, respectively.

The researchers measured quantitative drug response using pre- and post-induction urine in 15 patients and categorized patients’ MRD status as negative (7%), complete responder (13%), partial responder (27%), stable (20%) or refractory (33%).The researchers then determined a broad correlation between recurrence and response groups, with no recurrence in the MRD negative and complete responder groups and recurrence in seven of the 12 patients that comprised the other groups.

“uMRD enables quantitative assessment of molecular response to drug treatment. uMRD-determined pre-treatment disease burden assessment can support stratification of control and intervention arms in future treatment trials,” the authors wrote in their poster conclusion.

Earlier this month, Ferring Pharmaceuticals, the developer of Adstiladrin, announced that the therapy is now fully available across the United States for the treatment of adult patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors. In December 2022, the 

 Adstiladrin for use in this patient population.

Urinary minimal residual disease-negative status was related to preventing the return of cancer when certain patients with bladder cancer received Adstiladrin.

Jason Broderick

Herceptin, Perjeta Regimen May Be Effective Without Chemo in Breast Cancer

Keytruda Improves Disease-Free Survival in Some With Urothelial Carcinoma

Braftovi Regimen Is Promising in Metastatic Colorectal Cancer

Adstiladrin Leads to Beneficial Outcomes in Some Bladder Cancers

Latest News