Chris Ryan

There was no clinical benefit observed by adding the novel drug oleclumab to Imfinzi (durvalumab) and chemotherapy for frontline, advanced triple-negative breast cancer treatment, according to findings from the phase 2 SYNERGY clinical trial.

The findings showed that the 24-week clinical benefit rate (percentage of patients whose disease shrinks, disappears or stabilizes) for patients in the oleclumab group was 43% compared with 44% in the control group.

Patients in the control group received Imfinzi plus chemotherapy without the addition of oleclumab.

More patients in the oleclumab group achieved a complete response (complete disappearance of cancer), while more patients in the control group had a partial response (cancer shrinking as a result of treatment). Additionally, the rate of progressive disease was higher in the oleclumab group.

“We have ongoing translation analysis that will shed light on the mechanism associated with response and resistance to the combination (of oleclumab, [Imfinzi] and chemotherapy), and we hope to identify predictive biomarkers of response,” lead study author Dr. Laurence Buisseret, a medical oncologist at the Institut Jules Bordet of Hôpital Universitaire de Bruxelles in Brussels, Belgium, said in a presentation of the data at the European Society of Medical Oncology 2022 Congress.

Oleclumab Plus Immunotherapy Previously Showed Promise

Oleclumab works by binding to CD73, an enzyme found on tumor cells, and stops the production of immunosuppressive adenosine, which helps cancer cells escape the immune system.

Previous results with mouse models showed that the inhibition of the adenosine pathway synergizes with PD-1/PD-L1 checkpoint inhibitors. Data from the phase 2 COAST (NCT03822351) and phase 2 NeoCOAST (NCT03794544) trials showed that the addition of the anti-CD73 monoclonal antibody oleclumab to the anti–PD-L1 monoclonal antibody Imfinzi 

 in patients with non–small cell lung cancer.

 when PD-1/PD-L1 checkpoint inhibitors have been added to chemotherapy in frontline treatment of patients with triple-negative breast cancer. However, that benefit has only favored patients with tumors that express high levels of PD-L1, the protein that checkpoint inhibitors like Imfinzi and Keytruda (pembrolizumab) target.

The SYNERGY trial evaluated the efficacy and safety of the oleclumab/Imfinzi/chemotherapy triplet in adults with locally advanced or metastatic triple-negative breast cancer who had measurable disease.

To be eligible for participation in the trial, patients must have: no prior treatment in the metastatic setting, at least six months since the end of adjuvant treatment, an ECOG performance status of 0 or 1 (indicating that their disease has little to no impact on their daily functioning) and adequate organ function.

According to the National Cancer Institute, adjuvant therapy is additional cancer treatment administered following the initial treatment to lower the risk that the disease returns.

Patients were not permitted to have prior treatment with a checkpoint inhibitor or to have a major autoimmune disease.

The main goal of the trial was clinical benefit rate at week 24. Moreover, the investigators aimed to assess overall response rate (percentage of patients whose disease shrunk or disappeared as a result of treatment), duration of response, progression-free survival (time from treatment until disease worsens), overall survival (time from treatment until death by any cause) and clinical benefit rate per PD-L1 and CD73 expression.

In the oleclumab and control groups, the rates of baseline PD-L1 positivity were 52.4% and 56.3%, respectively. The rates of CD73 positivity were 27% and 32.8%, respectively.

In patients who were PD-L1 positive, the clinical benefit rate was higher in the oleclumab groups (16 of 33 patients experienced benefit) compared to the control group (14 of 36 patients experienced benefit). However, the difference in clinical benefit was not statistically significant between these two groups, meaning that the researchers could not be sure that it was the difference in treatment regimens — not chance — that one group outperformed the other.

In patients who were PD-L1 negative, the clinical benefit rate was higher in the control group (14 or 28 patients benefitted) versus the oleclumab group (11 of 30 patients benefitted).

The clinical benefit rate for patients who were CD73 positive was higher in the control group (11 of 21 patients) compared with the oleclumab group (4 of 17 patients). Patients who were CD73 negative experienced a higher clinical benefit rate in the oleclumab group (23 of 46) versus the control group (17 of 43).

None of the differences in clinical benefit were found to be statistically significant.

Patients treated in the control group achieved a median progression-free survival of 7.7 months compared with six months in the oleclumab group. Nine patients in each group remained on immunotherapy maintenance at data cutoff.

Notably, two patients stopped treatment with oleclumab after the interim analysis.

Regarding side effects, all patients in both groups experienced at least one side effect of any severity, and all patients reported at least one any-severity side effect during the first 12 weeks of treatment. The rates of serious or severe side effects in the oleclumab and control groups were 79.4% and 68.8%, respectively.

Mild to moderate blood-related side effects occurred in 23.8% and 26.6% of patients in the oleclumab and control groups, respectively. The rates of serious or severe blood-related side effects were 60.3% and 46.9%, respectively. Rates of any-severity and serious or severe anemia, neutropenia (decrease in neutrophils, a type of white blood cell), thrombocytopenia (decrease in thrombocytes, a type of white blood cell) and fatigue were similar across the two groups.

Mild to moderate immune-related side effects occurred in 73% of patients in the oleclumab group, compared with 68.8% of patients in the control group. The serious or severe rates of immune-related side effects were 15.9% and 12.5% in the oleclumab and control groups, respectively.

No toxicity-related deaths were reported. Four patients in the oleclumab group and five patients in the control group discontinued treatment due to side effects, including two patients in each group prior to week 24.

"Optimal chemotherapy duration with immunotherapy needs to be further investigated, and we need to develop new therapeutic combinations for (patients with advanced triple-negative breast cancer),” Buisseret concluded.

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Adding the novel drug oleclumab to Imfinzi and chemotherapy for the frontline treatment of advanced triple-negative breast cancer did not improve clinical outcomes, according to recent study findings.

Adding the Novel Drug Oleclumab to Imfinzi and Chemotherapy Fails to Improve TNBC Outcomes

Brukinsa led to higher complete response (no evidence of cancer left) or very good partial response rates than Imbruvica (ibrutinib) for patients with Waldenström macroglobulinemia that harbored a 

 mutation, according to long-term follow-up from the phase 3 ASPEN trial.

At a median follow-up of 44.4 months, findings showed that patients with 

-mutated Waldenström macroglobulinemia who were enrolled to cohort 1 achieved a complete response or very good partial response rate of 36.3% with Brukinsa (98 patients) compared with 25.3% with Imbruvica (101 patients). Notably, the response rate of complete response or very good partial response was noted to be numerically higher at all time points with Brukinsa compared to Imbruvica in this population.

Moreover, the median time to complete response or very good partial response was shorter in the Brukinsa group compared to the Imbruvica group, at 6.7 months and 16.6 months, respectively. The event-free rate for the duration of complete response or very good partial response at 24 months was also found to be higher in the investigative group than the control arm, at 90.6% and 79.3%.

“Although not statistically significant at (the previously reported) primary analysis, a consistent trend of deeper, earlier, and more durable responses complete response or very good partial response was observed (with Brukinsa compared with Imbruvica),” lead study author Dr. Constantine S. Tam, the program lead for Chronic Lymphocytic Leukemia and Low-Grade Lymphoma at Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues, wrote in a poster on the findings.

Prior ASPEN data showed that at a median follow-up of 19.4 months 

Brukinsa elicited a complete response or very good partial response rate of 28.4%

 compared with 19.2% with Imbruvica in patients with 

-mutated Waldenström macroglobulinemia. In September 2021, 

FDA approved Brukinsa for the treatment of adult patients with Waldenström macroglobulinemia

To enroll on ASPEN, patients were required to be at least 18 years of age and have a diagnosis of Waldenström macroglobulinemia. They also needed to have measurable disease requiring treatment; an ECOG performance status (which measures a patient’s ability to complete daily tasks) of 0 to 2; adequate bone marrow, renal and hepatic function; and a life expectancy of more than four months. Patients who had not received prior treatment for their disease were required to be considered inappropriate candidates for a standard chemoimmunotherapy regimen.

-mutated Waldenström macroglobulinemia were enrolled to cohort 1, and 28 patients with 

Patients in cohort 1 were randomly assigned to receive oral Brukinsa at a twice-daily dose of 160 mg (102 patients), or oral Imbruvica at a once-daily dose of 420 mg (99 patients). Treatment continued in both arms until disease progression. All patients in cohort 2 were administered 160 mg of Brukinsa twice daily until disease progression.

The main goal of the trial was complete response or very good partial response in cohort 1. Secondary end points included further comparison of efficacy, clinical benefit, anti-lymphoma effects, and safety of Brukinsa vs Imbruvica in cohort 1. The efficacy and safety of Brukinsa in cohort 2 served as exploratory end points.

Additional data from cohort 1 showed that both the median overall survival (time from treatment until death of any cause) and progression-free survival (time from treatment until disease gets worse) were not reached. However, investigators noted that statistical estimates favored Brukinsa for overall survival and progression-free survival.

The 42-month overall survival rates were 87.5% and 85.2% for Brukinsa and Imbruvica, respectively; the 42-month PFS rates were 78.3% and 69.7%, respectively.

-mutated disease were noted to achieve deeper and faster responses with Brukinsa (20 patients), as well as favorable progression-free survival over Imbruvica (33 patients). The 42-month PFS rates in the investigative and control arms were 73.2% and 49.0%, respectively. Among this subset, 21.2% of patients achieved a very good partial response or better with Brukinsa, compared to 10.0% of those who received Imbruvica. Major responses occurred in 78.8% and 65.0% of patients, respectively, and overall responses occurred in 90.9% and 95.0% of patients, respectively.

 wild-type disease, Brukinsa (65 patients) elicited a very good partial response or better rate of 44.6% and 30.6% with Imbruvica (72 patients). Major responses were experienced by 83.1% and 84.7% of patients, respectively. Lastly, the overall response rate achieved with Brukinsa in this subset was 96.9% compared to 94.4% with Imbruvica.

In cohort 2, Brukinsa elicited one complete response, a complete response or very good partial response rate of 31%, and a major response rate of 65%. Event-free rates of overall survival and progression-free survival at 42 months were 83.9% and 53.8%, respectively.

Regarding safety in cohort 1, 99% and 100% of patients, respectively, experienced at least one side effect of any grade in the Brukinsa and Imbruvica groups. The rates of grade 3 or higher side effects were 74.3% and 72.4%, respectively. Moreover, 3.0% and 5.1% of patients who received Brukinsa and Imbruvica, respectively, experienced side effects that resulted in death; 8.9% and 20.4% of patients experienced side effects leading to treatment discontinuation; and 15.8% and 26.5% of patients had side effects that led to a dose reduction.

In cohort 1, grade 3 or higher side effects reported in the Imbruvica and Brukinsa arms, respectively, included diarrhea (2.0% vs 3.0%), upper respiratory tract infection (1.0% vs 0%), muscle spasms (1.0% vs 0%), arthralgia (0% vs 3.0%), hypertension (19.4% vs 9.9%), nosebleeds (0% vs 1.0%), atrial fibrillation (6.1% vs 2.0%), fatigue (1.0% vs 1.0%), pneumonia (10.2% vs 1.0%) and fainting (6.1% vs 5.0%).

Grade 3 or higher side effects of interest reported in the control and investigative arms, respectively, comprised infection (27.6% vs 21.8%), bleeding (10.2% vs 8.9%), diarrhea (2.0% vs 3.0%), hypertension (20.4% vs 9.9%), atrial fibrillation/flutter (8.2% vs 2.0%), anemia (6.1% vs 11.9%), neutropenia (10.2% vs 23.8%), thrombocytopenia (6.1% vs 10.9%), second primary malignancy (3.1% vs 5.9%) and non–skin cancers (3.1% vs 4.0%).

“Fewer (side effects) leading to treatment discontinuation, dose reductions, and deaths occurred in the (Brukinsa) arm,” the study authors concluded. “Cumulative incidences of atrial fibrillation, diarrhea, hypertension, muscle spasm, and pneumonia were lower in patients receiving (Brukinsa). Despite a higher rate of neutropenia in the (Brukinsa) arm, infection rates were similar and more patients in the (Imbruvica) arm had grade (3 or higher) infections.”

Brukinsa, which was approved in September 2021, resulted in better ouctomes for certain patients with with Waldenström macroglobulinemia, according to the ASPEN clinical trial. 

Brukinsa Continues to Outperform Imbruvica for MYD88-Mutant Waldenström Macroglobulinemia

Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer who were assigned to receive a three-drug regimen of Tukysa (tucatinib), Ibrance (palbociclib) and letrozole saw an increase in the amount of time it took for their disease to progress to the central nervous system, known as central nervous system (CNS) progression-free survival (PFS), according to recent research.

Previous results from the trial showed that the combination had an acceptable safety profile and encouraging antitumor activity in this population, while this poster presentation presented during the 2021 San Antonio Breast Cancer Symposium focused on data from an exploratory analysis of intracranial efficacy in patients who had CNS metastases.

Findings from the phase 1b/2 clinical trial showed that in 15 patients with CNS metastases (where disease had spread to the brain and/or spinal cord), the average CNS-PFS was eight months with the triplet regimen. Additionally, at the one-year mark, 20% of patients did not experience disease progression to the CNS, and at the two-year mark 13% of patients did not have CNS progression.

“The majority of patients had treated (non-measurable) CNS lesions, limiting the evaluation of CNS response and biasing outcome towards stable disease [SD],” lead study author Dr. Elena Shagisultanova, of the University of Colorado Cancer Center, and colleagues, wrote in a poster on the data. “Moreover, we demonstrate the ability to get prolonged clinical benefit with this regimen post first CNS progression in carefully adjudicated cases.”

For the trial, researchers examined the combination of a HER2-targeted tyrosine kinase inhibitor (TKI), a CDK4/6 inhibitor, and an anti-hormonal agent in patients with hormone receptor-positive, HER2-negative metastatic breast cancer who had untreated asymptomatic or treated stable CNS metastases.

To be eligible for enrollment, patients needed to be post-menopausal or premenopausal on ovarian suppression. Moreover, they must have received two or more HER2 inhibitors at any time of their disease, one or more HER2-targeted agents in the metastatic setting and up to two endocrine agents for metastatic disease. Patients were allowed to have received prior treatment with letrozole. However, if patients received prior treatment with HER2-targeted TKIs or CDK4/6 inhibitors, they were excluded.

Study participants received Tukysa twice a day; daily Ibrance for 21 days on and seven days off; and daily letrozole. Researchers examined the drugs’ activity and CNS-PFS, which was defined as intracranial (within the skull) progression or death, and bi-compartmental PFS.

Within the 15 patients with CNS metastases, the average age was 47 years (range, 22 to 70), and the average number of prior lines of therapy received for metastatic disease was two (range, 1 to 5). Additionally, nine patients (60%) received prior CNS radiation, one patient (7%) underwent neurosurgery alone, three patients (20%) underwent neurosurgery and radiation, and two patients (13%) did not receive any prior treatment for CNS disease. All patients had previously received HER2-targeted therapy with Herceptin (trastuzumab) and Perjeta (pertuzumab) and five patients received Kadcyla (ado-trastuzumab emtansine; T-DM1).

Of the 15 patients enrolled to the trial, 14 were evaluable for disease; one patient was determined to have non-evaluable disease because they had no evidence of disease in the CNS for 24 months. At a data cutoff date of Nov. 1, 2021, 12 patients had received treatment; five of these patients had stable disease (SD) for six months or longer with the combination, six had SD for fewer than six months and one experienced a complete response.

Two patients were not treated; one patient who had a non-measurable dural lesion (meaning that it was found on the dura, the outer layer covering the brain and spinal cord) had SD for five months, and the other patient had a measurable lesion and had SD for eight months.

Regarding safety, prior data showed that the most common severe side effects reported with the triplet regimen included neutropenia (a decrease in white blood cells called neutrophils; 58%), leukopenia (white blood cell reduction; 24%), diarrhea (17%) and fatigue (14%). Notably, these side effects were determined to be manageable. Moreover, no cases of brain swelling were reported in patients with CNS metastases, including those who received radiation for isolated CNS progression during the study.

A version of this article was originally published on OncLive as, “

Tucatinib Plus Palbociclib/Letrozole Prolongs CNS-PFS in HR+/HER2+ Breast Cancer

A three-drug regimen was shown to lengthen the amount of time before cancer progressed to the central nervous system — known as central nervous system progression-free survival — in certain patients with breast cancer.

Triplet Regimen Extends Time Before Brain, Spinal Cord Metastases Worsen in Patients With Breast Cancer

Data from an early-phase trial demonstrated that the use of datopotamab deruxtecan was associated with promising and long-lasting treatment responses in patients with advanced or metastatic triple-negative breast cancer (TNBC).

The study authors noted that standard treatment options for patients with advanced or metastatic TNBC which has relapsed or is refractory to therapy are lacking.

To address the scarcity of options, researchers initiated the TROPION-PanTumor01 study, where investigators are assessing the safety and efficacy of datopotamab deruxtecan — an antibody drug conjugate that targets the transmembrane glycoprotein trophoblast cell surface antigen 2 (TROP2) — in patients with a variety of solid tumors. Of note, TROP2 can promote tumor growth and its overexpression is common in many solid tumors, including breast cancer.

, Dr. Ian E. Krop and colleagues presented data from the TNBC patient cohort of the phase 1 trial.

Patients enrolling in the trial were required to have relapsed/refractory advanced or metastatic solid tumors. Additionally, patients needed to be at least 18 years old in the United States or 20 years old in Japan and be unselected for TROP2 expression. Patients with stable and treated brain metastases were permitted to enroll in the trial.

In the TNBC cohort, 42 of 44 patients (median age, 53 years; range, 32 to 82 years) received datopotamab deruxtecan intravenously at 6 mg/kg every three weeks, while the other two patients received the study drug delivered via IV at 8 mg/kg every three weeks. The decision to use the 6-mg/kg dose, which has been selected for expansion across other tumors in this study, as well as in the phase 3 TROPION-Lung01 (NCT04656652) and TROPION-Breast01 (NCT05104866) studies, was based on clinical results and exposure-response analyses for safety and efficacy.

Analyzing safety and tolerability was the main goal of this study. Additional goals included assessing the efficacy of the study drug, as well as how the drug is absorbed into the body and the presence of anti-drug antibodies.

Most of the patients (70%) were residents of the U.S. Moreover, 11% of the TNBC cohort had brain metastases.

The median number of prior therapies among patients with TNBC in the metastatic setting was three (range one to 10), and 68% of patients had received at least two prior lines of treatment.

At a median follow-up of 7.6 months, the overall response rate (the proportion of patients whose disease partially or completely responded to treatment) among the TNBC cohort was 34%. The data indicated that one patient achieved a complete response, 14 patients achieved a partial response and 17 patients had stable disease.

The study results also noted that at a median follow-up of 8.8 months, treatment with the study drug led to an overall response rate of 52% in patients with TNBC who had not received prior treatment with a TOPO1 inhibitor-based antibody drug conjugate (27 patients).

A median duration of treatment response had not yet been reached, as most responses were still ongoing as of July 30, 2021 (the data cutoff for reporting).

“There are clear responses or clear tumor regressions in those patients who had prior Topo-based (antibody drug conjugates) with at least one confirmed partial response,” lead study author Krop, associate chief of the Susan F. Smith Center for Women’s Cancer at Dana-Farber Cancer Institute in Boston, said in a presentation during the conference. “However, because a full 30% of the patients on this study had a prior Topo I inhibitor(-based) (antibody drug conjugate), and that is the same class of payload as (datopotamab deruxtecan), there is a possibility of cross resistance. Therefore, we did want to look at specifically the subset of patients who had not had one of these prior (antibody drug conjugates).”

At the data cutoff date, 31 patients had discontinued treatment, including 30 due to disease progression, and one patient due to a side effect. Of note, 13 patients remained on treatment as of the time of data presentation.

Furthermore, treatment with datopotamab deruxtecan was associated with a manageable safety profile with no new safety signals. The most frequent treatment-emergent side effects included nausea, stomatitis (painful swelling and sores inside the mouth), vomiting and fatigue. Neutropenia and diarrhea, however, were both uncommon.

Overall, 98% of patients experienced at least one treatment-emergent side effect, 45% of which were considered serious or severe. Side effects led to dose reductions in 18% of patients and 14% of patients experienced a treatment interruption because of side effects.

Krop added that the hormone receptor-positive, human epidermal growth factor receptor 2-negative cohort of TROPION-PanTumor01 is now fully enrolled and data are forthcoming. Datopotamab deruxtecan is also being explored in the phase 1b/2 BEGONIA trial (NCT03742102), which is testing the agent in combination with Imfinzi (durvalumab) as a first-line treatment for patients with metastatic TNBC.

Additionally, the phase 3 TROPION-Breast01 trial is investigating datopotamab deruxtecan in HR-positive, HER2-negative breast cancer. A phase 3 trial of datopotamab deruxtecan in patients with TNBC is being planned, Krop said.

“We have come a long way in TNBC when we're talking about comparing different targeted therapies, when up until a few years ago, there were no targeted therapies at all,” Krop concluded. “This is good progress. There is potential room for looking at this drug both in pretreated patients, like what was seen here, as well as earlier lines of therapy.”

Early-phase study results showed that treatment with a novel drug elicits promising outcomes in patients with advanced or metastatic triple-negative breast cancer.

Chris Ryan

Adding the Novel Drug Oleclumab to Imfinzi and Chemotherapy Fails to Improve TNBC Outcomes

Brukinsa Continues to Outperform Imbruvica for MYD88-Mutant Waldenström Macroglobulinemia

Triplet Regimen Extends Time Before Brain, Spinal Cord Metastases Worsen in Patients With Breast Cancer

Novel Drug Elicits Favorable Outcomes in Advanced, Metastatic TNBC

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