Gina Mauro

Patients with relapsed/refractory acute myeloid leukemia (AML) will now be assesses with the off-the-shelf cell therapy CYNK-001 after a case of conversion to minimal residual disease (MRD) negativity at its highest dose level, announced the clinical-stage biotechnology company, Celularity, in a press release. The new cohort expands on an existing population of patients with MRD-positive disease.

-negative AML who had received 5.4 billion CYNK-001 cells, did not experience a dose-limiting toxicity (DLT), and converted from MRD-positive disease to MRD-negative disease upon assessment. The patient also had good-risk cytogenetics.

After primary induction treatment with 7+3 chemotherapy failed, the patient received second induction treatment followed by high-dose cytarabine consolidation. The patient experienced a complete clinical response (CR); however, the MRD was persistent and did not clear after 4 months of azacitidine; MRD was confirmed on a marrow biopsy.

The patient then entered on the phase 1 trial and received lymphodepletion before receiving 1.8 billion CYNK-001 cells on days 0, 7, and 14 in the outpatient setting, totaling to 5.4 billion CYNK-001 cells. On day 28, the patient not only had confirmed conversion from MRD-positive to MRD-negative disease, but CYNK-001 cells were present in both the peripheral blood and bone marrow.

“The absence of DLT to date in the phase 1 trial enables us to continue with our scheduled dose escalation and to expand the trial to include patients with [relapsed/refractory] AML,” said Robert J. Hariri, MD, PhD, founder, chairman, and chfficerief executive o of Celularity. “In addition, the demonstrated ability to deliver a total [natural killer] cell dose of 5.4 billion cells in the outpatient setting without DLT and the observation of achieving a conversion from an MRD-positive to MRD-negative state on bone marrow examination with CYNK-001 cells persisting in bone marrow and blood at 28 days after day 0 infusion, is compelling and supports our trial dose escalation and indication expansion.”

To date, no DLTs have been observed at any of the dose levels, including the total dose levels of 1.8 billion, 3.6 billion, and 5.4 billion CYNK-001 cells on days 0, 7, and 14, respectively, the company noted.

Celularity is developing off-the-shelf allogeneic therapies that are derived from postpartum human placenta. CYNK-001 is an allogeneic unmodified natural killer (NK) cell being investigated in solid and hematologic malignancies, as well as infectious diseases. The cryopreserved allogeneic off-the-shelf cell therapy is enriched for CD56+/CD3– NK cells that are expanded from human placental CD34+ cells.

In the open-label, multi-dose, phase 1 trial, investigators are evaluating the maximum-tolerated dose (MTD) or maximum-planned dose of CYNK-001 in an estimated 22 patients with AML.2 The estimated completion date of the trial is January 3, 2022.

To be eligible for enrollment, patients must have primary or secondary AML who are in first of second morphological CR, morphological CR with incomplete hematologic recovery, or morphologic leukemia-free state as defined by the European LeukemiaNet recommendations for AML Response Criteria. Additional eligibility criteria include MRD positivity, between the ages of 18 and 80 years old, an ECOG performance status of 2 or lower, and the ability to be off immunosuppressive therapy for at least 3 days prior to CYNK-001 infusion.

Prior central nervous system involvement is permitted if it was treated, and cerebral spinal fluid is clear for at least 2 weeks prior to start of lymphodepletion.

Those who have any significant medical conditions that would prevent them from participating on the trial, laboratory abnormalities, bi-phenotypic acute leukemia, acute promyelocytic leukemia, inadequate organ function, autoimmune disease, and uncontrolled graft-vs-host disease or GVHD requiring corticosteroids, among other factors, were excluded from enrollment.

Patients are administered cyclophosphamide and fludarabine followed by CYNK-001 at 3 varying dose levels on days 0, 7, and 14. The primary end points of the trial are the number of patients who experience a DLT, MTD, and frequency and severity of adverse effects. Secondary outcome measures include the number of patients who convert from MRD positivity to negativity, time to and duration of MRD response, progression-free survival, time to progression, duration of morphologic complete remission, and overall survival.

In their announcement, Celularity noted that it intends to continue dose escalation in the MRD indication to a total 9.0 billion CYNK-001 cells in addition to expanding the study to include those with relapsed/refractory AML.

To enhance the persistence of CYNK-001 therapy, the trial’s expansion arms of MRD and relapsed/refractory AML will comprise an augmented lymphodepletion protocol of 3600 mg of cyclophosphamide and 120 mg of fludarabine given over the course of 4 days compared with 900 mg of cyclophosphamide and 75 mg of fludarabine over 3 days. The dosing schedule analysis is used as a method to increase post-lymphodepletion interleukin (IL)-15 levels and to also add subcutaneous IL-2.

Celularity announces expansion of human placental hematopoietic stem cell derived natural killer cells (CYNK-001) phase 1 trial in patients with acute myeloid leukemia. News release. Celularity. June 29, 2021. Accessed June 29, 2021.

Articles

Patients with relapsed/refractory acute myeloid leukemia will now be assesses with the off-the-shelf cell therapy CYNK-001 after a case of conversion to minimal residual disease negativity at its highest dose level.

Early Study of CYNK-001 Expands to Include R/R Acute Myeloid Leukemia Cohort

Without requiring red blood cell (RBC) transfusions, luspatercept-aamt (Reblozyl) led to a mean  increase in hemoglobin (Hb) from baseline levels in 77.1% of patients compared with in 0% treated with placebo in patients with non-transfusion–dependent β-thalassemia (NTDT) in the phase 2 BEYOND trial (NCT03342404; EudraCT 2015-003225-33), according to a presentation during the European Hematology Association 2021 Virtual Congress.

Results showed that beyond the significant improvement of 1.0 g/dL or higher from baseline over a continuous 12-week interval during weeks 13 to 24 in the overall population (n = 145; 

 < .0001), the benefit with the agent was also observed regardless of baseline mean Hb level.

In patients whose baseline mean Hb was lower than 8.5 g/dL (n = 84), the mean Hb increase of 1.0 g/dL or higher from baseline was achieved in 72.7% of patients on luspatercept vs 0% of those on placebo (

 < .0001). In those whose baseline mean Hb was 8.5 g/dL or greater (n = 61), these rates were 82.9% and 0%, respectively (

Additionally, luspatercept was found to be well tolerated over a prolonged period of time, and was associated with improvements in quality of life in this patient population.

“Treatment with luspatercept resulted in clinically significant and sustained improvements of anemia in adults with NTDT, as measured by hemoglobin levels, with more than 50% of patients [who received] luspatercept achieving and maintaining a hemoglobin increase of more than 1.5 g/dL or greater,” Ali Taher, MD, lead study author; and professor of medicine, hematology & oncology, at American University of Beirut Medical Center in Lebanon, said in a virtual presentation of the findings. “Clinical benefit of luspatercept treatment, previously observed in patients with transfusion-dependent thalassemias [TDTs] through significant reduction in RBC transfusion burden, has now also been observed in patients with NTDT, as measured by meaningful improvement of anemia.”

β-thalassemia is a hereditary blood disorder that is characterized by impaired hemoglobin production and chronic anemia of varying severity. Tailored RBC transfusions, iron chelation therapy, and novel treatments target the key pathophysiologic mechanisms in TDTs and NTDT. NTDT is made up of a diverse group of patients who do not require lifelong regular RBC transfusions as a means to survival but may require occasional transfusions during surgeries or infections.

Furthermore, patients with NTDT who have a baseline Hb of 10 g/dL or higher are known to have significantly longer morbidity-free survival vs those whose Hb is less than 10 g/dL (

 There is also a significant correlation between the improvement in Hb levels by 1 g/dL and decreased odds of developing morbidities in patients with NTDT whose baseline Hb was less than 10 g/dL.

Treatments that can improve anemia and disease complications in the NTDT population continue to represent an unmet need, Taher noted.

Luspatercept is a first-in-class erythroid maturation agent that binds select TGF-β superfamily ligands to diminish Smad2/3 signaling and enhance late-stage erythropoiesis. In 2019, the FDA approved luspatercept as a treatment of anemia in adult patients with TDT. The agent was subsequently approved by the European Medicines Agency for this indication in 2020.

The decision for those approvals came from the phase 3 BELIEVE trial (NCT02604433), in which 21.4% of patients with TDT who received luspatercept achieved at least a 33% reduction in RBC transfusion burden during weeks 13 to 24 compared with 4.5% for those who received placebo.

 Taher added that luspatercept may have clinical benefit to treat the anemia and improve outcomes in the NTDT patient population.

In the multicenter, double-blind, placebo-controlled BEYOND study, investigators sought to evaluate the safety and efficacy of luspatercept compared with placebo in adult patients with NTDT. Patients were randomized 2:1 to receive luspatercept subcutaneously at 1.0 mg/kg every 3 weeks (n = 100) or placebo subcutaneously every 3 weeks (n = 50). The study was then unblinded to include an open-label treatment period for patients on luspatercept, which is an estimated 15-month period.

The data cutoff date was September 14, 2020. The primary end point of the trial was achievement of at least 1.0 g/dL mean Hb increase from baseline over a continuous 12-week interval during weeks 13 to 24 in the absence of RBC transfusions. A key secondary end point was mean change from baseline in NTDT–patient-reported outcome (PRO) Tiredness/Weakness (T/W) domain score over a continuous 12-week interval during weeks 13 to 24.

Additional secondary end points included achievement of 1.5 g/dL or higher mean Hb increase from baseline over a continuous 12-week interval during weeks 13 to 24 in the absence of RBC transfusions; proportion of patients who remained RBC transfusion free over 24 weeks; mean change in NTDT-PRO T/W domain score by visit; achievement of 1.0 g/dL or higher mean Hb increase from baseline over a continuous 12-week interval during weeks 37 to 48 in the absence of RBC transfusions; duration of mean Hb increase from baseline of at least 1.0 g/dL during any 12-week interval; as well as safety and tolerability with luspatercept.

The baseline characteristics were similar between the luspatercept (n = 96) and placebo (n = 49) arms. Overall (n = 145), the median age was 40.0 years (range, 18.0-71.0) and 43.4% of patients were male. Moreover, 66.9% of patients had β-thalassemia, the median baseline Hb was 8.2 g/dL (range, 5.3-10.1), and 57.9% of patients’ baseline Hb were lower than 8.5 g/dL. The median baseline NTDT-PRO T/W score was 4.3 (0-9.5), and 69.7% of patients’ had a baseline NTDT-PRO T/W score that was 3 or higher. Furthermore, 86.2% of patients received 0 RBC transfusion units in the 24 weeks before the first luspatercept or placebo dose.

The mean serum ferritin level was 554.6 µg/L (standard deviation, 496.9), and the mean liver iron concentration was 6.0 mg/g.

Results also showed that the benefit with luspatercept with achievement of mean Hb increase from baseline to weeks 13 to 24 in the absence of RBC transfusions vs placebo was seen regardless of patients’ splenectomy status (yes, least squares [LS] mean difference 1.09; 95% CI, 0.72-1.45; 

 < .0001 vs no, LS mean difference 1.53; 95% CI, 1.20-1.86; 

 < .0001), sex (male, LS mean difference 1.39; 95% CI, 0.96-1.81; 

 < .0001 vs female, LS mean difference 1.42; 95% CI, 1.12-1.72), baseline Hb level (< 8.5 g/dL, LS mean difference, 1.46; 95% CI, 1.10-1.82; 

 < .0001 vs ≥ 8.5 g/dL, LS mean difference 1.36; 95% CI, 1.01-1.70; 

 < .0001), baseline NTDT-PRO T/W domain score (< 3 points, LS mean difference 1.30; 95% CI, 0.89-1.71; 

 < .0001 vs ≥ 3 points, LS mean difference 1.47; 95% CI, 1.15-1.78; 

 < .0001), and β-thalassemia genotype (without a-thalassemia, LS mean difference 1.45; 95% CI, 1.15-1.75; 

 < .0001 vs with a gene duplication, LS mean difference 1.48; 95% CI, 1.12-1.85; 

Also, during weeks 13 to 24, 52.1% (n = 50) of patients on luspatercept achieved a mean Hb increase of 1.5 g/dL or higher from baseline. An improvement in NTDT-PRO T/W scores from baseline were also seen more frequently with luspatercept at -0.92 compared with -0.47 with placebo (LS mean difference -0.48; 95% CI, -1.03 to 0.08; 

 = .0924) in weeks 13 to 24. The improvement was also seen in weeks 37 to 48 with luspatercept (-1.0) over placebo (-0.16; LS mean difference -0.79; 95% CI, -1.58 to 0; 

The NTDT-PRO T/W domain scores improved with luspatercept correlated with Hb increase Taher said, and added that the mean change from baseline in NTDT-PRO T/W score by visit showed a gradual and consistent improvement with luspatercept and was maintained through week 78.

Luspatercept also met the other secondary end points on the BEYOND study, including proportion of patients who stayed RBC transfusion-free over 24 weeks (89.6% with luspatercept vs 67.3% with placebo; 

 = .0013), achievement of 1.0 g/dL or more mean Hb increase from baseline over a continuous 12-week interval during weeks 37 to 48 in the absence of RBC transfusions (70.8% vs 2.0%, respectively; 

 < .0001), and total duration of the mean Hb increase from baseline 1.0 g/dL during any 12-week interval (243.3 days vs 132.9 days; 

Regarding safety, at least 1 treatment-related treatment-emergent adverse event (TEAE) occurred in 76.0% and 36.7% of luspatercept- and placebo-treated patients, respectively; grade 3 or higher TEAEs occurred in 28.1% and 24.5% of patients, respectively. One or more serious TEAE occurred in 11.5% of those on luspatercept and 24.5% of patients on placebo. Thromboembolic events did not occur in any patients, and 2 malignant events were reported on the placebo arm; these included 1 case each of diffuse large B-cell lymphoma and hepatocellular carcinoma.

The most common, all-grade TEAEs reported in 5% or more of patients on luspatercept and placebo, respectively, included bone pain (36.5% vs 6.1%), headache (30.2% vs 20.4%) and arthralgia (29.2% vs 14.3%). No deaths occurred.

In April 2020, the FDA also approved luspatercept for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

1. Taher AT, Cappellini MD, Kattamis A, et al. The BEYOND study: results of a phase 2, double-blind, randomized, placebo-controlled multicenter study of luspatercept in adult patients with non-transfusion-dependent β-thalassemia. Presented at: European Hematology Association 2021 Virtual Congress; June 9-19, 2021; virtual. Abstract S101.

2. Musallam KM, et al. Morbidity-free survival and hemoglobin level in non-transfusion-dependent β-thalassemia: a 10-year cohort study. 

. Published online January 20, 2021. doi:10.1007/s00277-020-04370-2

3. Reblozyl (luspatercept-aamt). Prescribing information. Bristol Myers Squibb; 2019. Accessed June 11, 2021.

Without requiring red blood cell transfusions, luspatercept-aamt led to a mean  increase in hemoglobin from baseline levels in 77.1% of patients compared with in 0% treated with placebo in patients with non-transfusion–dependent β-thalassemia in the phase 2 BEYOND trial, according to a presentation during the European Hematology Association 2021 Virtual Congress.

Luspatercept Leads to Hemoglobin Increase in Patients With Non-Transfusion–Dependent Beta-Thalassemia

Pimitespib, a heat shock protein 90 (HSP90) inhibitor doubled the progression-free survival (PFS) and prolonged the overall survival (OS) compared with placebo in patients with advanced gastrointestinal stromal tumor (GIST) that is refractory to imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga), according to results from the phase 3 CHAPTER-GIST-301 trial (JapicCTI-184094) that were presented during the 2021 ASCO Annual Meeting.

Findings showed that the median PFS with pimitespib was 2.8 months (95% CI, 1.6-2.9) compared with 1.4 months (95% CI, 0.9-1.8) with placebo, leading to a 49% reduction in the risk of disease progression or death and meeting the study’s primary end point (HR, 0.51; 95% CI, 0.30-0.87; stratified log-rank 

A PFS improvement was also observed in patients with 

 exon 13/14 and 17/18 mutations (HR, 0.52).

“This trial demonstrated that pimitespib significantly improved PFS [and prolonged] OS [with] a tolerable safety profile, as an HSP90 inhibitor, for the first time,” lead study author Yoshitaka Honma, MD, of the National Cancer Center Hospital in Tokyo, Japan, said in a poster presentation on the findings. “Pimitespib represents a potential new standard treatment in patients with GIST in the salvage-line setting, with a mechanism of action [that differs] from traditional therapies.”

An estimated 90% of GIST cases harbor driver mutations in 

, which promotes continuous oncogenic signaling. Although ripretinib (Qinlock) and avapritinib (Ayvakit) are both available in the treatment of patients with GIST and target 

, they may have limited efficacy due to secondary 

 mutations, such as exon 13/14 and exon 17/18, or in those with other mutations beyond 

Pimitespib is a novel HSP90 inhibitor that has shown prior antitumor activity in molecularly defined subgroups of solid tumors.2 In a phase 2 study (JapicCTI-163182), pimitespib demonstrated a median progression-free survival of 4.4 months (95% CI, 2.8-6.0) in patients refractory to imatinib, sunitinib, and regorafenib.

In the double-blind, placebo-controlled CHAPTER-GIST-301 study, investigators enrolled patients with histologically confirmed advanced GIST that was refractory to imatinib, sunitinib, and regorafenib. Patients had to have at least 1 measurable lesion and an ECOG performance status of 0 or 1.

Participants were randomized in a 1:2 fashion to receive pimitespib (n = 54) at 160 mg on a 5-days-on/2-days-off schedule in 21-day cycles or placebo (n = 27), also at a 5-days-on/2-days-off schedule in 21-day cycles.

Notably, those who experienced disease progression via blinded central radiological review (BCRR) were unblinded and then permitted to cross over to receive open-label pimitespib.

The primary end point of the trial was PFS by BCRR based on modified RECIST v1.1 criteria; secondary end points included OS, PFS in patients who crossed over to pimitespib (known as secondary PFS), pharmacogenomics, and safety. Crossover-adjusted OS was calculated through the rank preserving structural failure time (RPSFT) model.

Patients were stratified by the number of prior systemic anticancer therapies (3 vs 4 or more) and age (less than 65 years vs 65 years or older).

The primary analysis was planned at an estimated 70 PFS events per BCRR and was performed using a stratified log-rank test. A sample size of 81 patients was calculated to provide 90% power to detect a difference in PFS between pimitespib and placebo, with a 1-sided significance level of 0.025.

Patients were enrolled to the trial from October 2018 to April 2020 across 6 sites in Japan. The data cutoff date was June 23, 2020. Of the 58 patients who received pimitespib, 50 discontinued due to either progressive disease (PD; n = 39), adverse effects (AEs; n = 4), physician decision (n = 3), withdrawal of consent (n = 2), because they did not take the study drug for more than 21 days (n = 1), or death due to tumor hemorrhage that was unrelated to pimitespib (n = 1). One patient started open-label pimitespib but then discontinued due to PD.

Of the 28 patients who received treatment with placebo, 24 discontinued due to either PD (n = 22) or AEs (n = 2). Seventeen patients on this arm then started open-label pimitespib, 16 of whom discontinued the HSP90 inhibitor because of PD (n = 13), they didn’t take the study drug for more than 21 days (n = 2), or withdrawal of consent (n = 1)

Eight patients are on ongoing treatment with pimitespib compared with 4 patients who remain on placebo. One patient from the placebo arm is still receiving open-label pimitespib.

Baseline characteristics were similar in both arms. The median age of patients was 61.75 years, and 38.6% of patients were older than 65 years; more than half of patients were male (56.1%) and 85.1% had an ECOG performance status of 0. Moreover, 38.7% of patients had received more than 4 prior therapies.

Across both arms, 60.6% of patients had detectable KIT mutations in exon 9 (13.3%), exon 11 (49.5%), and exon 13/14 or exon 17/18 (52.7%). Moreover, 10.3% of patients had detectable 

Additional data showed that the secondary PFS with the HSP90 inhibitor was 2.7 months (95% CI, 0.7-4.1). No complete or partial responses were reported in either arm. The stable disease rate was 62.1% on the pimitespib arm and 35.5% on the placebo arm per BCCR.

The median OS was 13.8 months (95% CI, 9.2–not reached [NR]) with pimitespib vs 9.6 months (95% CI, 5.5–NR) with placebo (HR, 0.63; 95% CI, 0.32-1.21). When adjusting the placebo OS via RPSFT, the median OS was 7.6 months (95% CI, 5.3-14.9), which translated to a 58% reduction in the risk of death with pimitespib (HR, 0.42; 95% CI, 0.21-0.85).

Regarding safety, all-grade and grade 3 or higher AEs occurred in 96.6% and 43.1% of patients on pimitespib, respectively, and in 78.6% and 28.6% of those on placebo, respectively.

Treatment-related AEs (TRAEs) that were all grade or grade 3 or higher occurred in 93.1% and 25.9% of those on the pimitespib arm, respectively, and 39.3% and 3.6% of those on the placebo arm, respectively. The grade 3 or higher TRAEs reported in those who received pimitespib included diarrhea (13.8%), decreased appetite (1.7%), malaise (1.7%), renal impairment (3.4%), and anemia (5.2%).

AEs that led to dose reductions on the pimitespib and placebo arms occurred in 38.2% and 3.6% of patients, respectively, while AEs that led to dose interruptions were reported in 67.2% and 32.1% of patients, respectively. Moreover, AEs that resulted in study discontinuation occurred in 6.9% and 7.1% of patients on the investigative and control arms, respectively.

1. Honma Y, Kurokawa Y, Sawaki A, et al. Randomized, double-blind, placebo (PL)-controlled, phase III trial of pimitespib (TAS-116), an oral inhibitor of heat shock protein 90 (HSP90), in patients (pts) with advanced gastrointestinal stromal tumor (GIST) refractory to imatinib (IM), sunitinib (SU) and regorafenib (REG). 

. 2021;39(suppl 15):11524. doi:10.1200/JCO.2021.39.15_suppl.11524

2. Garcia-Carbonero R, Carnero A, Paz-Ares L. Inhibition of HSP90 molecular chaperones: moving into the clinic. 

. 2013;14(9):e358-369. doi:10.1016/S1470-2045(13)70169-4

3. Doi T, Kurokawa Y, Sawaki A, et al. Efficacy and safety of TAS-116, an oral inhibitor of heat shock protein 90, in patients with metastatic or unresectable gastrointestinal stromal tumour refractory to imatinib, sunitinib and regorafenib: a phase II, single-arm trial. 

. 2019;121:29-39. doi:10.1016/j.ejca.2019.08.009

Pimitespib, a heat shock protein 90 inhibitor doubled the progression-free survival and prolonged the overall survival compared with placebo in patients with advanced gastrointestinal stromal tumor that is refractory to imatinib, sunitinib, and regorafenib, according to results from the phase 3 CHAPTER-GIST-301 trial.

Pimitespib Shows Significant PFS Improvement in Advanced Refractory GIST

-expressed, mutated, or -amplified uterine cancer, the combination of pertuzumab (Perjeta) and trastuzumab (Herceptin) led to a 37% (95% CI, 21%-50%) disease control rate (DCR), according to results from the Targeted Agent Profiling and Utilization Registry (TAPUR) study that were presented during the 2021 ASCO Annual Meeting.

Data showed that the objective response rate was 7% (95% CI, 1%-24%). Two patients had partial responses and 8 patients achieved stable disease (SD) at 16+ weeks, which translated to 10 patients meeting the prespecified criteria as responders to the combination.

“Pertuzumab and trastuzumab demonstrated antitumor activity in heavily pretreated patients with uterine cancer with 

 amplification and/or specific mutations,” Eugene R. Ahn, MD, an investigator on the study and deputy medical director of clinical research at Cancer Treatment Centers of America, said in a presentation on the findings. “Additional study is warranted to confirm the efficacy of pertuzumab and trastuzumab in this patient population, and…to identify biomarkers for patients likely to respond to trastuzumab/pertuzumab; [this] will be an important step to advancing the benefits of precision medicine in this population.”

The TAPUR trial, which is conducted by ASCO, is a nonrandomized, phase 2 basket trial testing 18 commercially available treatments in more than 85 molecular targets across advanced solid tumors with specific genomic alterations. All cohorts follow a Simon’s optimal two-stage design.

The clinical significance of ERBB2 expression or 

 amplification in endometrial cancer as a predictive marker for response to HER2-directed therapies has been controversial, Ahn said. Prior data have showed that the percentage of patients with high-grade endometrial cancer and 

 gene amplification ranges from 17% to 30%, and up to 80% of this patient population has ERBB2 protein expression.

Uterine serous carcinoma is the most likely subtype to have 

 positivity; however, previous research has shown that 45% of patients with 

-positive primary tumors had metastatic lesions that were also 

 positive via immunohistochemistry or chromogenic in situ hybridization.

 Additionally, trastuzumab monotherapy has showed limited efficacy in 

In this arm of the TAPUR trial, investigators evaluated the combination of pertuzumab and trastuzumab in 28 patients with 

-positive uterine cancer. To be eligible for enrollment on this cohort, patients needed to have advanced uterine cancer with an ECOG performance status of 0 to 2, adequate organ function, measurable disease, and have their genomic test performed in a CLIA-certified, CAP-accredited laboratory. Patients’ tumors must have harbored 

 amplification or overexpression, or any of the 13 prespecified 

Pertuzumab was given intravenously at an initial dose of 850 mg over 1 hour, followed by 420 mg IV over 30 minutes to 1 hour, every 3 weeks. Trastuzumab was given IV at an initial dose of 8 mg/kg over 90 minutes, followed by 6 mg/kg every 30 minutes to 1 hour, every 3 weeks.

The primary end point of the trial is DCR, defined as objective response or SD at 16+ weeks via RECIST v1.1 criteria. Additional end points include progression-free survival (PFS), overall survival (OS), and potentially serious or treatment-related adverse events that are grades 3 to 5 in severity.

Of the 28 patients enrolled between August 2017 and November 2019, the median age was 69 years (range, 44-90+). Moreover, 21 patients were White, 2 were Black, 1 was Asian, 1 was more than 1 race, 2 were recorded as other, and 1 patient preferred not to answer. Eighty-nine percent (n = 25) of patients were non-Hispanic or non-Latino. More than half (n = 16) of patients had an ECOG performance status of 1, followed by 9 patients with a status of 0 and 11 with a status of 2. Twelve patients had received 1 to 2 prior lines of treatment, while 16 received 3 or more prior lines.

In the breakdown of genomic alterations, patients had either 

Additional findings showed that the median PFS was 28.1 weeks and the median OS was 60.9 weeks.

Regarding safety, 1 grade 3/4 adverse event (AE) was reported, which was grade 3 muscle weakness, and was considered to potentially be related to pertuzumab/trastuzumab. No other serious AEs or treatment-related toxicities were reported.

Ahn discussed additional clinical trials of HER2-directed treatments in 

-amplified uterine cancer. For example, results from the phase 2 GOG181Btrial of trastuzumab in women with stage III/IV HER2-positive endometrial cancer showed no objective responses in the 33 patients enrolled.

Secondly, a phase 2 study (NCT01367002) randomized 58 patients with 

-overexpressing uterine serous carcinomas to receive carboplatin/paclitaxel alone or with trastuzumab. Results showed that the median PFS was 12.9 months with the addition of trastuzumab compared with 8.0 months for chemotherapy alone (HR, 0.44; 90% CI, 0.26-0.76; 

 = .005).5 The median OS was 24.4 months and 19.6 months, respectively (HR, 0.58; 90% CI, 0.34-0.99; 

1. Ali-Ahmad HM, Roth M, Mangat PK, et al. Pertuzumab plus trastuzumab (P+T) in patients (Pts) with uterine cancer (UC) with 

amplification, overexpression or mutation: results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. 

. 2021;39(suppl 15):5508. doi:10.1200/JCO.2021.39.15_suppl.5508

2. Konecny GE, Santos L, Winterhoff B, et al. HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer. 

. 2009;100(1):89-95. doi:10.1038/sj.bjc.6604814

3. Halle MK, Tangen IL, Berg HF, et al. HER2 expression patterns in paired primary and metastatic endometrial cancer lesions.

. 2018;118(3):378-387. doi:10.1038/bjc.2017.422

4. Fleming GF, Sill MW, Darcy KM, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. 

. 2010;116(1):15-20. doi:10.1016/j.ygyno.2009.09.025

5. Fader AN, Roque DM, Siegel E, et al. Randomized phase ii trial of carboplatin-paclitaxel compared with carboplatin-paclitaxel-trastuzumab in advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress Her2/Neu (NCT01367002): updated overall survival analysis. 

. 2020;26(15):3928-3935. doi:10.1158/1078-0432.CCR-20-0953

In patients with ERBB2/ERBB3-expressed, mutated, or -amplified uterine cancer, the combination of pertuzumab and trastuzumab led to a 37%  disease control rate, according to results from the Targeted Agent Profiling and Utilization Registry study.

Gina Mauro | Authors

Articles

Early Study of CYNK-001 Expands to Include R/R Acute Myeloid Leukemia Cohort

Luspatercept Leads to Hemoglobin Increase in Patients With Non-Transfusion–Dependent Beta-Thalassemia

Pimitespib Shows Significant PFS Improvement in Advanced Refractory GIST

Pertuzumab Plus Trastuzumab Demonstrates Clinical Activity in ERBB2/ERBB3+ Uterine Cancer