Jason Broderick

A Tecentriq regimen did not improve event-free survival in patients with triple-negative breast cancer.

For patients with triple-negative breast cancer (TNBC), Tecentriq (atezolizumab) plus neoadjuvant chemotherapy followed by adjuvant Tecentriq did not significantly improve event-free survival (EFS), missing the primary end point of the phase 3 NSABP B-59/GBG-96-GeparDouze trial.

2024 San Antonio Breast Cancer Symposium (SABCS)

 showed that at a median follow-up of 46.9 months, the four-year EFS rate was 85.2% with Tecentriq plus chemotherapy versus 81.9% with placebo plus chemotherapy. This difference was not considered statistically significant, according to the researchers.

This lack of benefit was consistent across all patient subgroup except clinical nodal status, in which there was a significant difference favoring Tecentriq in patients with positive node status.

Neoadjuvant: treatment given before surgery.

Event-free survival (EFS): time without disease progression or relapse.

Primary end point: main goal measured at the end of a study to see if treatment worked.

Pathological complete response (pCR): no detectable cancer after treatment.

Disease-free survival: the time after treatment without cancer recurrence.

Overall survival (OS): time until death from any cause.

Distant disease-free survival: time without cancer spread to other organs.

Area under the curve: a measure of the drug concentration in the blood over time.

There was no overall survival (OS) benefit with Tecentriq at four years, with a rate of 90.2% versus 89.5% with placebo. The researchers noted that the addition Tecentriq to neoadjuvant chemotherapy boosted the pathological complete response (pCR) rate at 63% versus 57% with placebo.

“While not meeting efficacy criteria for the primary end point, the results support translational studies for potential biomarkers to identify subsets of patients with TNBC who may benefit from the addition of checkpoint inhibitors to neoadjuvant or adjuvant therapy,” said presenting author Dr. Charles Geyer from the University of Pittsburgh Medical Center.

The safety analysis for the trial included 1,532 of the 1,550 initially randomized patients. The results showed little difference between the two groups regarding rates of treatment-emergent side effects.

Across the entire safety population, nearly all patients experienced at least one treatment-emergent side effect, with 74.3% having grade 3 or 4 (severe or life-threatening) treatment-emergent side effects and 32.7% having serious treatment-emergent side effects.

Treatment-emergent side effects resulting in treatment discontinuation occurred at 12.1% versus 11.4% for paclitaxel in the Tecentriq versus chemotherapy arms, respectively; 8.5% versus 7.3%, respectively, for carboplatin; 5.2% versus 3.5%, respectively, for Adriamycin (doxorubicin) plus cyclophosphamide with epirubicin plus cyclophosphamide; and 21.2% versus 10.6%, respectively, for Tecentriq plus placebo. Treatment-emergent side effects were considered the cause of death for two patients in the Tecentriq group and three patients in the placebo group.

The trial enrolled 1,550 patients with TNBC. Across the whole population, the median age was 49 years and all patients except one were female. Forty-one percent of patients were node-positive, 59% had a primary tumor size between 1.1 and 3.0 centimeters (cm) and 41% had a primary tumor size greater than 3 cm. Sixty-four percent of patients were PD-L1 negative.

Ninety-five percent of patients had invasive ductal/invasive carcinoma of no special type, 81% of patients had grade 3 tumors. About half (52.8%) of patients had BRCA1/

and PALB-2 wild-type. Specifically, 8.3% had a BRCA1 mutation, 2.5% had a BRCA2 mutation and 0.8% had a PALB-2 pathogenic variant.

Patients were randomized to Tecentriq or placebo with paclitaxel plus carboplatin, followed by investigator’s choice of cyclophosphamide with Adriamycin or epirubicin. After surgery, patients resumed Tecentriq at the same dose or placebo as adjuvant therapy for six months. Radiotherapy was administered with Tecentriq and placebo.

The primary end point of the trial was EFS, with secondary end points including OS, pCR in the breast and lymph nodes, distant disease-free survival, disease-free survival and toxicity.

“GS3-05: NSABP B-59/GBG-96-GeparDouze: A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy with atezolizumab or placebo followed by adjuvant atezolizumab or placebo in patients with Stage II and III triple-negative breast cancer.” By Dr. Geyer C, et al. Presented at: San Antonio Breast Cancer Conference; December 10-14, 2024; Abstract GS3-05.

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Articles

Tecentriq (atezolizumab) combined with neoadjuvant chemotherapy did not significantly improve event-free survival (EFS) in patients with triple-negative breast cancer (TNBC) in the phase 3 NSABP B-59/GBG-96-GeparDouze trial. The four-year EFS rate was 85.2% with Tecentriq versus 81.9% with placebo, lacking statistical significance. No overall survival benefit was observed, though Tecentriq increased the pathological complete response rate. Safety analysis showed similar treatment-emergent side effects between groups. Translational studies are suggested to identify TNBC patient subsets that may benefit from checkpoint inhibitors.

Tecentriq plus chemotherapy did not improve event-free survival in triple-negative breast cancer but increased rate of complete tumor removal.

Tecentriq Regimen Misses End Goal in Triple-Negative Breast Cancer

Several biomarkers were linked to improved outcomes in patients with high-risk, early-stage triple-negative breast cancer, with Keytruda plus chemotherapy.

Several biomarkers, including the T-cell inflamed 18-gene expression profile, were associated with improved pathologic complete response and event-free survival, both with and without Keytruda (pembrolizumab) therapy.

Results from an exploratory analysis of the KEYNOTE-522 study in high-risk, early triple-negative breast cancer were presented at 2024 San Antonio Breast Cancer Symposium.

Tumor mutational burden also correlated with improved event-free survival in the Keytruda plus chemotherapy arm, but not in the placebo plus chemotherapy arm. There were few patients with high tumor mutational burden in this patient population of those with triple-negative breast cancer.

Further, the Keytruda/chemotherapy regimen offered an efficacy advantage compared with chemotherapy alone, regardless of subgroups defined by several biomarkers such as tumor mutational burden, T-cell inflamed 18-gene expression profile and more.

T-cell inflamed 18-gene expression profile: a panel of 18 genes used to predict the response to immunotherapy in patients with cancer.

Pathologic complete response: the lack of all signs of cancer in tissue samples after treatment.

Event-free survival: the time after primary treatment when a patient is free from complications or events that treatment was meant to delay or prevent.

Tumor mutational burden: the total number of mutations in the DNA of cancer cells, which is information that may help with treatment plans. Patients with a high number of mutations may be more likely to respond to certain types of immunotherapy.

Neoadjuvant: the first treatment given to shrink a tumor before the main treatment like surgery.

Adjuvant: additional treatment for cancer given after the primary treatment to reduce the risk for cancer recurrence.

Overall survival: the time from diagnosis or treatment initiation when a patient with cancer is still alive.

Whole-exome sequencing: a laboratory method to learn how the building blocks of a person’s DNA are organized, and can be used to find mutations in genes that may preclude a patient to disease.

RNA sequencing: a laboratory method to learn the exact order in which RNA molecules are situated in a cell, which helps care teams determine which genes are expressed in different types of cells.

PTEN loss signature: a gene that regulates cell growth and survival, and, when lost, can lead to uncontrolled cell growth and potentially tumor formation.

Proliferation: the process of cell division and growth.

Glycolysis: when glucose, or sugar, is broken down in cells via reactions that do not require oxygen, which is a way that cells produce energy.

About the KEYNOTE-522 Exploratory Analysis

 sought to evaluate the combination of neoadjuvant Keytruda with chemotherapy and adjuvant Keytruda in patients with newly diagnosed, previously untreated, high-risk, early-stage triple-negative breast cancer. Previously reported findings have shown that neoadjuvant Keytruda with chemotherapy followed by adjuvant Keytruda significantly improved pathologic complete response, event-free survival and overall survival versus neoadjuvant placebo plus chemotherapy with adjuvant placebo in patients with high-risk, early triple-negative breast cancer.

In this exploratory biomarker analysis, the end points included evaluating the association of tumor mutational burden, T-cell inflamed 18-gene expression profile and a set of non-T-cell inflamed 18-gene expression profile consensus signatures with pathologic complete response and event-free survival. Secondary end points included evaluating RNA sequence-based molecular subtypes, BRCA/HRD status, HER2 gene expression/signature, and PTEN loss signature associations with pathologic complete response and event-free survival.

Patients with newly diagnosed, previously untreated, high-risk, early triple-negative breast cancer and evaluable pretreatment tumor samples were enrolled in the study. A total of 1,172 patients were randomly assigned and treated, including 783 in the Keytruda plus chemotherapy arm and 389 in the placebo and chemotherapy arm. There were 946 patients who had whole-exome sequencing data, with 641 who received Keytruda/chemotherapy and 305 given placebo/chemotherapy, and 904 had RNAseq data, consisting of 618 and 286 across the study arms.

Tumor mutational burden was assessed through whole-exome sequencing, while T-cell–inflamed 18-gene expression profile and non–T-cell-inflamed 18-gene expression profile consensus signatures were evaluated using RNA sequencing.

Among the non–T-cell-inflamed 18-gene expression profile consensus signatures, proliferation and glycolysis were positively associated with pathologic complete response in both arms but did not correlate with event-free survival.

For the secondary end points of the study, positive associations of PTEN loss signature and BRCA/HRD status with pathologic complete response were observed in both treatment arms. HER2 gene expression was linked with the T–cell-inflamed 18-gene expression profile; however, it did not show significant associations with pathologic complete response or event-free survival in the Keytruda/chemotherapy arm after adjustment for the T-cell–inflamed 18-gene expression profile.

Subgroup analyses of secondary biomarkers using prespecified cutoffs consistently confirmed the benefit of the Keytruda and chemotherapy combination over the chemotherapy and placebo combination.

The KEYNOTE-522 study explored the efficacy of Keytruda combined with chemotherapy in high-risk, early-stage triple-negative breast cancer. Biomarkers like the T-cell inflamed 18-gene expression profile and tumor mutational burden were linked to improved pathologic complete response and event-free survival. The Keytruda/chemotherapy regimen showed superior efficacy over chemotherapy alone, regardless of biomarker-defined subgroups. Secondary analyses revealed associations of PTEN loss and BRCA/HRD status with pathologic complete response. HER2 expression correlated with the T-cell inflamed profile but not with improved outcomes in the Keytruda arm.

Several biomarkers may predict improved treatment responses and outcomes in patients with triple-negative breast cancer.

Understanding Genetics May Predict Treatment Response in Triple-Negative Breast Cancer

Uproleselan did not improve overall survival in relapsed/refractory AML patients in a phase 3 trial, though it may benefit patients with primary refractory AML.

A phase 3 international clinical trial evaluating the efficacy of uproleselan (GMI-1271) in combination with chemotherapy versus chemotherapy alone in patients with relapsed/refractory acute myeloid leukemia (AML) did not demonstrate a statistically significant improvement in overall survival (OS) in the intent-to-treat (ITT) population.

These findings presented at the 2024 ASH Annual Meeting.

At a median follow-up of 37.9 months, the median OS for the ITT population was 13 months among those in the uproleselan arm (194 patients) versus 12.3 months in the placebo plus chemotherapy arm (194 patients). This difference was not statistically significant. However, OS survival probabilities at 48 months were 34.1% for the uproleselan group and 25.5% for the placebo group.

Despite not meeting the primary OS end point, uproleselan showed encouraging results in certain subgroups, particularly for patients with primary refractory AML, who experienced a survival advantage.

“Unfortunately, this large international phase 3 study did not meet its overall primary end point of overall survival. However, I think there are some clinically meaningful benefits observed in the uproleselan arm across multiple predefined subgroups,” explained Dr. Daniel J. DeAngelo, chief of the Division of Leukemia at Dana-Farber Cancer Institute, during a presentation of the data.

Overall survival: the time from diagnosis or the start of treatment when a patient with cancer is still alive.

Intent-to-treat population: all patients who are randomly assigned to a treatment group regardless of whether they received the assigned treatment or completed the trial.

Oral mucositis: a side effect that causes painful sores and inflammation in the mouth and throat.

Complete response: the disappearance of all signs of cancer from treatment.

Complete response with incomplete count recovery: all signs of cancer have disappeared from the body, but the patient’s blood cell counts have not fully recovered.

Median duration of response: the midpoint of the time period during which patients experience a positive response to treatment.

Minimal residual disease: a very small number of cancer cells in the body after treatment.

CYP inhibition: when a medication interferes with the activity of an enzyme called CYP, which are crucial for metabolizing various substances in the body including drugs. 

QTc prolongation: an indication on an electrocardiogram that can increase the risk for dangerous heart rhythms.

Differentiation syndrome: a side effect caused by a rapid release of cytokines from leukemia cells affected by anticancer drugs.

Patients with primary refractory AML, which consisted of 33% of enrolled patients, had a substantial benefit from uproleselan. The median OS in this patient population was 31.2 months with uproleselan (62 patients) versus 10.1 months with the placebo arm (66 patients).

The survival benefit was consistent regardless of the chemotherapy backbone used. For patients treated with fludarabine, cytarabine, idarubicin (FAI) chemotherapy combined with uproleselan, the hazard ratio was 0.53, indicating a survival advantage. For those treated with mitoxantrone, etoposide, cytarabine (MEC) chemotherapy plus uproleselan, the hazard ratio was 0.68, suggesting a trend toward benefit.

Uproleselan is an E-selectin antagonist that works by disrupting AML cell survival pathways and overcoming chemotherapy resistance. The agent can potentially deepen chemotherapy response.

This trial enrolled 388 patients aged 18 to 75 years, with either primary refractory AML or first or second relapse. Patients were required to be eligible for intensive salvage treatment.

Once enrolled, patients were randomly assigned to receive uproleselan with chemotherapy or chemotherapy alone, with MEC or FAI as the chemotherapy backbone, based on investigator choice. Uproleselan was administered during the induction phase and continued through up to three cycles of consolidation, with the option of proceeding to transplant.

The primary end point was OS. Key secondary end points were severe oral mucositis during induction, complete response (CR) and remission rates.

The median duration of response (DOR) among the uproleselan-treated primary refractory patients was not reached, compared with a median DOR of 12.7 months in the placebo group.

Minimal residual disease (MRD) status at the end of induction was a key secondary end point of the study. In patients who achieved CR or CR or CR with incomplete count recovery (CRi), uproleselan showed a higher rate of MRD negativity. Among patients achieving CR, 67.1% of those treated with uproleselan were MRD-negative versus 61.5% in the placebo group.

Further, over 50% of patients in both arms underwent allogeneic stem cell transplantation (allo-SCT) after treatment. Notably, patients who underwent transplantation experienced a marked survival benefit when treated with uproleselan. Of those who achieved CR and proceeded to allo-SCT, the median OS was not reached (NR) for the uproleselan group compared with 24.8 months for the placebo group. The five-year survival probabilities for transplanted patients were 57.5% in the uproleselan arm versus 27.7% in the placebo arm.

Looking at safety, there was no increase in serious side effects or any grade 3 (severe) or higher treatment-emergent side effects observed with uproleselan. No discontinuations due to side effects were seen.

“There was no known CYP inhibition, QTc prolongation or differentiation syndrome seen in this study. The safety profile was consistent with what we expect from the chemotherapy backbone, with no significant differences,” explained DeAngelo, sharing that uproleselan did not add any extra toxicity to the chemotherapy backbone.

“While the study did not meet the primary endpoint of overall survival, the findings show clinically meaningful benefits in primary refractory AML and post-transplant survival, suggesting that uproleselan has the potential to improve outcomes in this challenging population,” added DeAngelo.

Uproleselan, an E-selectin antagonist, was evaluated in a phase 3 trial for relapsed/refractory AML patients, showing no significant improvement in overall survival (OS) in the intent-to-treat population. However, it demonstrated potential benefits in specific subgroups, particularly primary refractory AML patients, with a notable survival advantage. The trial involved 388 patients, with uproleselan administered alongside chemotherapy. Despite not meeting the primary OS endpoint, uproleselan showed improved minimal residual disease negativity and post-transplant survival, without increasing severe side effects or treatment-emergent toxicities.

A Phase 3 trial of uproleselan failed to improve overall survival in relapsed/refractory AML, though it may benefit primary refractory patients.

Uproleselan Fails to Improve Survival in AML, Although Some Subgroups May Benefit

Newly diagnosed patients with multiple myeloma may have higher MRD-negativity rates when treated with Tecvayli alone or with Revlimid. 

Patients with newly diagnosed multiple myeloma experienced robust clinical activity when treated with Tecvayli (teclistamab) alone or in combination with standard Revlimid (lenalidomide) as maintenance therapy after induction and autologous stem cell transplantation (ASCT), study results have shown.

Initial results from the safety run-in component of the phase 3 MajesTEC-4/EMN30 trial were presented at 

. Of note, a safety run-in part of a trial is a preliminary phase designed to assess the safety of a new treatment before it moves into larger-scale studies.

The safety run-in consisted of three maintenance cohorts: two administering Tecvayli-Revlimid (cohorts 1 and 2) and one administering Tecvayli monotherapy (cohort 3). The main difference behind cohorts 1 and 2 is that the Tecvayli dosing was less intense in cohort 2.

The minimal residual disease (MRD)-negativity rate (10

 sensitivity) was 100% among evaluable patients in all three cohorts. This was measured at 12 months in cohort 1 and at six months in cohorts 2 and 3. Evaluable patients consisted of those with a baseline sample and at least one sample during maintenance. The median progression-free survival (PFS) had not been reached in any of the cohorts.

“Unprecedented efficacy was observed, with all evaluable patients achieving MRD negativity,” said presenting author Dr. Elena Zamagni, associate professor of hematology at the Bologna University, Italy.

Zamagni also reported that responses to treatment deepened during maintenance in all three cohorts. All patients in cohort 1 achieved a complete remission (CR) or better, as did 90.6% of patients in cohort 2 and 93.3% of patients in cohort 3. In cohort 1, the CR rate was 9.4% and the stringent CR (sCR) rate was 90.6%. In cohort 2, 9.4% of patients achieved a very good partial response (VGPR), 25% of patients achieved a CR, and 65.6% of patients achieved an sCR. The corresponding rates were 6.7%, 23.3% and 70%, respectively, in cohort 3.

Regarding hematologic toxicity, the most frequently occurring treatment-emergent adverse event (TEAE, side effect) was neutropenia. Across all time points, the overall rate of grade 3 (severe)/4 (life-threatening) neutropenia was 93.8% in cohort 1, followed by 62.5% in cohort 2, and 46.7% in cohort 3.

Zamagni further explained, “If we look at the cumulative incidence of grade 3/4 neutropenia at six months, we can see that the incidence decreased significantly from 81% in cohort 1 — which had a more intense [Tecvayli] dosing schedule — down to 56% in cohort 2 and 40% in cohort 3.”

Zamagni added that, “Febrile neutropenia, anemia and eosinophilia were very rare, as was the rate of treatment discontinuation due to TEAEs, which was low at 5.3% overall.”

With nonhematologic TEAEs (excluding infection), grade 3/4 TEAEs were rare, with the most frequently occurring being cytokine release syndrome (CRS), which occurred in approximately half of the patients overall. Most CRS cases occurred during Tecvayli step-up dosing, with 37.2% occurring after step-up dose 1, 8.5% occurring after step-up dose 2, and 5.3% occurring after treatment dose 1. There were no cases of grade 3/4 CRS and no discontinuations due to CRS. Also of note, there were no cases of immune effector cell–associated neurotoxicity syndrome. “We also had some diarrhea, mainly related to [Revlimid], and some injection site reaction,” added Zamagni.

Incidents of infections and hypogammaglobulinemia were frequent, according to Zamagni. Grade 3/4 infections occurred in 37.5%, 28.1%, and 20% of cohorts 1, 2 and 3, respectively. The most common infections were upper respiratory tract infections, COVID-19, pneumonia and nasopharyngitis. Hypogammaglobulinemia occurred in 96.9%, 78.1% and 93.3% of cohorts 1, 2 and 3, respectively. All of these patients received at least one dose of intravenous or subcutaneous immunoglobulin. Infection prophylaxis was also strongly recommended.

Design and Demographics of the Safety Run-In of MajesTEC-4/EMN30

There were two Tecvayli-Revlimid cohorts and one single-agent Tecvayli cohort in the safety run-in. In cohort 1 (32 patients), patients received Tecvayli at 1.5 mg/kg weekly for cycles 1 and 2, and then 3 mg/kg every two weeks for cycles 3 to 6, and thereafter 3 mg/kg monthly for up to two years of fixed-duration maintenance. For cohort 2 (32 patients), Tecvayli was given at 1.5 mg/kg on days 8 and 15, and then immediately after it was given at 3 mg/kg monthly. In the single-agent cohort 3 (30 patients), the dose of Tecvayli was the same as in cohort 2. For patients also receiving Revlimid (cohorts 1 and 2), Revlimid was initiated at 10 mg/day in 28-day cycles from cycles 2 to 4. If Revlimid was well tolerated, the dose could be raised to 15 mg/day for cycles 5 to 26. All patients were scheduled to receive fixed-duration maintenance for two years; however, for patients receiving Tecvayli-Revlimid who were at least in CR at one year, Tecvayli was stopped.

Overall, 81 (86.2%) of the 94 randomized patients remained on treatment as of September 2024. Side effects (five patients) and patient withdrawal (three patients) were the two main reasons for discontinuation. There were two patients who discontinued due to progressive disease. Cohort 1 started earlier and thus had a longer median follow-up of 21.1 months. The median follow-up was 9.2 months for both cohorts 2 and 3.

The results of the safety run-in now inform the main randomization phase of the phase 3 MajesTEC-4/EMN30 Trial.

The MajesTEC-4/EMN30 trial is enrolling patients with newly diagnosed multiple myeloma with an ECOG performance status of 0 to 2, who have received four to six cycles of a triplet or quadruplet induction therapy (PI and/or IMiD with or without an anti-CD38 antibody) and a single or double ASCT with or without consolidation. Patients have to have at least a partial response following these initial treatments.

The enrollment goal is 1,500 patients. Patients will be randomized evenly to fixed-duration maintenance therapy with Tecvayli-Revlimid, Tecvayli alone or Revlimid alone.

The MajesTEC-4/EMN30 trial is actively recruiting patients.

“Phase 3 Study of Teclistamab (Tec) in Combination with Lenalidomide (Len) and Tec Alone Versus Len Alone in Newly Diagnosed Multiple Myeloma (NDMM) As Maintenance Therapy Following Autologous Stem Cell Transplantation (ASCT): Safety Run-in (SRI) Results from the Majestec-4/EMN30 Trial” by Dr. Elena Zamagni et al., 

Tecvayli (teclistamab) demonstrated significant clinical efficacy in newly diagnosed multiple myeloma patients when used alone or with Revlimid (lenalidomide) as maintenance therapy post-induction and ASCT. The phase 3 MajesTEC-4/EMN30 trial's safety run-in phase showed 100% MRD-negativity among evaluable patients across all cohorts. Complete remission rates were high, with cohort 1 achieving the highest stringent CR. Neutropenia was the most common severe adverse event, with its incidence decreasing with less intense Tecvayli dosing. The trial's main randomization phase is now informed by these findings.

Tecvayli alone or plus Revlimid has been found to be safe and may result in high MRD-negativity rates.

Jason Broderick

Tecentriq Regimen Misses End Goal in Triple-Negative Breast Cancer

Understanding Genetics May Predict Treatment Response in Triple-Negative Breast Cancer

Uproleselan Fails to Improve Survival in AML, Although Some Subgroups May Benefit

Tecvayli Effective Maintenance Therapy in Newly Diagnosed Multiple Myeloma

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