Long-term treatment with luspatercept-aamt (Reblozyl) elicited the longest duration of reduced red blood cell (RBC) transfusion dependence among patients with β-thalassemia, according to updated data from the phase 3 BELIEVE trial (NCT02604433), presented at the 2022 EHA Congress.

Response was assessed as reduction of RBC transfusion burden by at least 33% from baseline and by at least 50% from baseline among patients who received luspatercept vs placebo during any rolling 12- or 24-week interval. With a long-term data cutoff of January 5, 2021, among the 224 patients in the luspatercept arm, 173 patients (77.2%) had at least 33% response during any 12-week interval and 116 (51.8%) had a response during any 24-week interval. A transfusion burden reduction of at least 50% was reported among 112 patients (50%) and 53 patients (23.7%) during any 12- and 24-week interval, respectively.

These outcomes were compared with prior data cutoff landmarks: May 11, 2018 (primary data cutoff) and January 7, 2019 (intermediate data cutoff). In the primary analysis, 70.5% and 41.1% of patients had at least a 33% reduction in transfusion burden at the 12- and 24-week intervals. These rates were 76.3% and 45.1% in the intermediate analysis, respectively. Reduction of at least 50% were reported at any 12- and 24-week intervals among 40.2% and 16.5% of patients, respectively, in the primary analysis and 44.6% and 20.5% in the intermediate analysis.

“In terms of transfusion independence, at the cutoff of 3 years 12% of patients [who received] luspatercept, achieved transfusion independence, equal to or more than [8] weeks. And that, of course, implies the longest interval of this condition of transfusion in dependence,” said Maria Domenica Cappellini, MD, FRCP, FACP, professor of internal medicine at the University of Milan and chief of the Rare Diseases Centre at the Fondazione IRCCS Policlinico Hospital in Italy, during a presentation of the data.

The median longest duration of RBC transfusion independence was 72 days (95% CI, 62-103) with longer-term luspatercept treatment. At the primary and intermediate analysis cutoffs, the rates of RBC transfusion independence lasting at least 8 weeks were 10.7% and 11.2%, respectively, compared with 12.1% in the longer-term analysis.

“Continuous treatment with the luspatercept allowed for more patients to experience a reduction in RBC transfusion burden, with longer durations of responses compared [with] the previous cutoff,” Cappellini said. “We are confident that these [benefits] will be even more clear with longer follow-up and patients with transfusion dependent β-thalassemia treated in the BELIEVE study will continue to benefit from luspatercept with over 3 years of treatment.”

Additional data showed that the median duration of RBC transfusion burden reduction was 114 days (95% CI, 107-137) and 99 days (95% CI, 95-104) for those with 33% reduction and 50% reduction, respectively, at the long-term analysis cutoff. In the primary data cutoff analysis, the median duration of RBC transfusion burden reduction was 104 days (95% CI, 84-588) for those with at least 33% reduction and 97.5 days (95% CI, 84-588) for those with at least 50% reduction. In the intermediate analysis the median duration was 105 days (95% CI, 84-825) and 99 days (95% CI, 84-825), respectively.

The median treatment duration during the primary, intermediate, and long-term landmark analyses were 64.1 days (95% CI, 3-97), 95.7 days (95% CI, 1.7-128.1), and 153.6 days (95% CI, 1.7-215).

Further, the mean cumulative duration of RBC transfusion burden reduction during any rolling 12-week interval was 627.3 (standard deviation, 390.5) for patients who received luspatercept.

In terms of RBC transfusion burden change from baseline, Cappellini noted that patients receiving luspatercept required fewer units of blood over time. The mean change in RBC units every 48 weeks from baseline was –4.8 (weeks 1-48), –5.6 (weeks 49-96), –6.2 (weeks 97-144), and –6.4 (weeks 145-192) compared with a 1.1 unit increase reported in weeks 1-48 with placebo.

Cappellini also highlighted that patients achieving an RBC transfusion burden reduction of 50% or higher experienced a greater interval between the transfusions compared with the baseline over time at a mean of +9.9 days (standard deviation, 22.0).

Luspatercept, an erthyroid maturation agent, is approved for the treatment of anemia in patients with β-thalassemia who require regular red blood cell (RBC) transfusions. Additionally, it received an indication for patients who require 2 or more RBC units over 8 weeks for patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts or with MDS/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

BELIEVE was a randomized, double-blind, study comparing luspatercept with placebo.

 Investigators enrolled adults with β-thalassemia who required regular transfusions of 6 to 20 RBC units in the 24 weeks prior to random assignment, with no transfusion-free period (35 days). Patients were randomly assigned 2:1 to luspatercept (n = 224) plus best supportive care or placebo plus best supportive care (n = 112). Luspatercept was administered subcutaneously 1.0 mg/kg (up to a maximum dose of 1.25 mg/kg) every 3 weeks. Best supportive care included RBC transfusions to maintain baseline hemoglobin levels and iron chelation therapy.

The primary end point was reduction of RBC transfusion burden by at least 33% from baseline with a reduction of at least 2 units in weeks 13 to 24 compared with the 12 weeks prior to randomization.

Baseline characteristics between the experimental and control arm were well balanced. The median age was 30 years (range, 18-66). Median hemoglobin levels at 24 weeks were 9.31 g/dL (range, 4.5-11.4) and 9.15 g/dL (range, 5.8-11.7) in the luspatercept arm and placebo arm, respectively. The median RBC transfusion burden was 6.12 units (range, 3-14) every 12 weeks in the luspatercept arm and 6.27 (range, 3-12) in the placebo arm. The median burden every 24 weeks was 14 units (range, 6-24) and 15 (range, 6-26), respectively. Further, over half of patients (57.6% and 58.0%, respectively) had a splenectomy.

In terms of liver iron concentration (LIC), at baseline the median LIC in the luspatercept arm was 6.4 mg/g dry weight (range, 0.8-125.0) and 5.05 mg/g dry weight (range, 0.2-53.2) in the placebo arm. An analysis of LIC is ongoing, according to Cappellini.

At data cutoff 127 patients (56.7%) remained on study treatment and 2.7% (n = 6) have completed 192 weeks of treatment. Of the 224 patients in the luspatercept arm, 96 (42.9%) discontinued treatment. The most common reasons for discontinuation were physician decision (23.7%), adverse event (10.3%), or other (5.4%).

Cappellini MD, Taher AT, Porter JB, et al. Longer-term analysis of efficacy of luspatercept in patients with transfusion-dependent β-thalassemia enrolled in the BELIEVE study. Presented at: 2022 EHA Congress; June 9-17, 2022; Vienna, Austria. Abstract S270.

Reblozyl. Prescribing information. Celegene; 2020. Accessed June 11, 2022. bit.ly/3c0E2sj

An efficacy and safety study of luspatercept (ACE-536) versus placebo in adults who require regular red blood cell transfusions due to beta (β) thalassemia (BELIEVE). ClinicalTrials.gov. Updated January 25, 2022. Accessed June 11, 2022. 

https://clinicaltrials.gov/ct2/show/NCT02604433

Articles

Updated data from the phase 3 BELIEVE trial revealed a sustained reduction in the need for red blood cell transfusions among patients with β-thalassemia who received treatment with luspatercept-aamt.

Luspatercept Linked With Maintained Reduction in Transfusion Dependence Among Patients With β-Thalassemia

Viable long-term responses with tisagenleleucel (Kymriah) were observed among pediatric and young adult patients with heavily pretreated relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), according to a 5-year follow-up of the phase 2 ELIANA trial (NCT02435849) presented at the 2022 EHA congress.

Among 79 patients, with a median age of 11 years (range, 3-24), the overall remission rate (ORR) was 82% with a complete remission (CR) rate of 62% and a CR with incomplete blood count recovery (CRi) rate was 20%. Additionally, 98% of patients who achieved remission had minimal residual disease (MRD) negativity at 3 months.

Among 65 responders, the median relapse-free survival (RFS) was 43 months (95% CI, 12- not estimable [NE]). The 5-year RFS rate was 44% (95% CI, 31%-56%).

“Long term remission rates up to 5.9 years of follow up from ELIANA demonstrate that tisagenlecleucel may be a curative treatment option for heavily pretreated pediatric and young adult patients with relapsed or refractory B-ALL,” Susana Rives, MD, PhD, said in a presentation of the data. Rives is a specialist physician in the Pediatric Oncology Department of Sant Joan de Déu Barcelona Children’s Hospital and head of the Hematopoietic System Tumors Unit at the Sant Joan de Déu Hospital, in Spain.

ELIANA enrolled patients with relapsed or refractory B-cell ALL between the ages of 3 and 21 years with bone marrow lymphobasts of at least 5% who had not received prior CD19-directed therapy. Patients received lymphodepleting chemotherapy prior to infusion comprising 30 mg/m2 of intravenous (IV) fludarabine daily for 4 doses with cyclophosphamide 500 mg/m2 IV daily for 2 doses.

Patients proceeded to a single infusion of tisagenlecleucel based on weight at the time of infusion. For patients weighing over 50 kg, the dose range was 0.1 to 2.5 × 108 cells and for those weighing 50 kg or less the dose range was 0.2 to 5.0 × 106 cells. The primary end point was ORR within 3 months, and 4-week maintenance of remission by independent review committee assessment. Secondary end points included MRD status, duration of response, RFS, event-free survival (EFS), overall survival (OS), cellular kinetics, and safety.

At baseline, the median number of prior lines of therapy was 3 (range, 1-8) and 61% of patients has prior allogeneic stem cell transplantation (alloSCT). Most patients had primary refractory disease status (92%) and the median morphologic blast count in bone marrow was 74% (range, 5%-99%).

At the time of last evaluation, 31 patients were in remission with a median follow-up of 60.1 months (range, 25.3-68.5).

The median EFS was 15 months (95% CI, 10-45) with a 5-year EFS rate of 36% (95% CI, 25%-47%). When censoring for patients who underwent alloSCT the median EFS was 13 months (95% CI, 9-35) with a 5-year EFS rate of 34% (95% CI, 23%-45%).

Further, at the time of the final analysis the median OS was not reached (95% CI, 46- NE). At 5 years, 55% of patients were alive (95% CI, 43%-66%).

Investigators reported that the probability of B-cell aplasia was 83% (95% CI, 71%-91%) at 6 months and 71% (95% CI, 57%-82%) at 12 months. The median time to B-cell recovery was 39 months and among those who achieved B-cell recovery the cumulative incidence of relapse was 40%.

Following infusion with tisagenlecleucel, 25% of patients underwent alloSCT. Investigators noted that 4 patients had alloSCT within 3 months of receiving the CD19-directed CAR T-cell therapy. In total, 10 patients underwent transplant in remission and 7 had alloSCT and the remaining 14 underwent transplant after 3 months.

Investigators noted that results for OS and EFS between pediatric (< 18 years) vs young adult patients (≥ 18 years) were comparable. Among 65 pediatric patients the median OS was not reached (95% CI, 44-NE) vs 57 months (95% CI, 10-NE) among 14 young adult patients. The median EFS was 15 months for both populations.

Rives noted that no new long-term treatment-related safety events were reported in the long-term analysis. Adverse effects of special interest (AESIs) observed after 1 year post infusion were reported at the meeting.

Among patients who achieved remission at any time during the study, including those who received a response at any time (n = 70), 39% had at least 1 AESI of any grade and 21% had an AESI grade 3 or higher.

The most commonly reported AESI was infection with any-grade incidence of 33% and grade 3 or higher incidence reported among 20% of patients. All-grade hemaphagocytic lymphohistiocytosis or cytokine release syndrome was reported in 1 patient and was grade 3 or higher. Serious neurologic events occurred in 3% of patients with 1 event grade 3 or higher. Hematological disorders, including cytopenias, were reported in 10% of patients, and 4 events were grade 3 or higher.

“We had a patient with a secondary malignancy—a myelodysplasia—this patient had a prior [allogeneic] transplant with [total body irradiation] TBI and with and high cumulative doses of etoposide, cyclophosphamide, and tricyclines, but still she had moderate cytopenias with severe dysplastic signs in peripheral blood and bone marrow,” Rives said adding that the patient received no further therapy and the cytopenias are stable.

A majority of patients (82%) received immunoglobulin IV at any time post infusion with 33% of patients receiving the infusion after 1 year and 16% after 2 years. Further, 88% of patients in remission received immunoglobulin IV during persistent B-cell aplasia.

Tisagenlecleucel was approved for use in pediatric and young adult patients with B-ALL in 2017 based on earlier data from the ELIANA study.2 In data that led to the approval, the ORR was 83% (95% CI, 71%-91%) among 63 evaluable patients and the median duration of remission was not reached. MRD negativity was reported in all responders.

Rives S, Maude AL, Hiramatsu H, et al. Tisagenlecleucel in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia: final analyses from the ELIANA study. Presented at: 2022 EHA Congress. June 9-17, 2022; Vienna, Austria. Abstract S112.

FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. Updated September 7, 2017. Accessed June 13, 2022. bit.ly/3aWMs6o

Heavily pretreated pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia maintained response with tisagenlecelucel according to long-term follow-up data from the phase 2 ELIANA trial. 

Pediatric/Young Adult Patients With B-ALL Continue to Derive Benefit From Tisagenlecluecel at 5-Year Follow-Up

Among 14 patients with stage II/III mismatch repair–deficient (dMMR) locally advanced rectal cancer, the clinical complete response rate (cCR) following treatment with single-agent dostarlimab-gxly (Jemperli) was 100%, according to data from a phase 2 trial (NCT04165772) presented at the 2022 ASCO Annual Meeting and simultaneously published in the 

“No patients have required chemotherapy, radiation, or surgery [and] there has been no disease recurrence observed during the follow-up period,” Andrea Cercek, MD, said in a presentation of the data. “Longer follow-up is certainly required to establish the durability of this treatment. In conclusion we believe these data provide the framework for immunoablative therapies. It highlights the clinical impact of biomarker-driven therapy, in other words of moving precision medicine into early-stage disease.” Cercek is section head of colorectal cancer and codirector of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center in New York, New York, where the trial was conducted.

The median follow-up for the analysis was 6.8 months (range, 0.7-23.8). “The majority of our patients [achieve cCR] at 6 months, but we did have a few at 3 months as well. [We have] quite a bit of a range from 0.7 to nearly 24 months and all patients remain disease free,” Cercek said.

“Standard of care for T3, T4, or node-positive rectal cancer involves trimodality therapy,” explained Kimmie Ng, MD, MPH, associate chief of the Division of Gastrointestinal Oncology, director of the Young-Onset Colorectal Cancer Center, codirector of the Colon and Rectal Cancer Center, and director of Translational Research in the Division of Gastrointestinal Oncology at Dana-Farber Cancer Center in Boston, Massachusetts in a discussion of the data.

“However, because components of the standard of care may lead to significant morbidity and quality-of-life issues, many recent studies have tried to eliminate components of the standard of care while still maintaining efficacy,” said Ng, who is also an associate professor of medicine at Harvard Medical School.

Approximately 5% to 10% of rectal cancers are dMMR, which confers resistance to chemotherapy. Investigators hypothesized that PD-1 blockade may replace chemotherapy, chemotherapy and radiation, or replace the trimodality approach of chemotherapy, radiation, and surgery.

Patients enrolled on the trial received the PD-1 monoclonal antibody dostarlimab at 500 mg intravenously every 3 weeks for 6 months, equaling 9 total cycles. At baseline and through treatment, patients were closely monitored and assessed for response at 6 weeks, 3 months, and 6 months. At these key timepoints patients underwent endoscopic and digital rectal exams. Upon treatment completion at 6 months patients then underwent comprehensive radiologic and endoscopic evaluation including tumor biopsy collection and T2-weighted and diffusion-weighted MRI of the rectum, 18F-fluorodeoxyglucose positron emission tomography, and CT scan of the chest, abdomen, and pelvis.

A cCR was defined as no evidence of residual tumor on both the digital and endoscopic rectal exams and on the rectal MRI results. Specifically, there must be visual evidence of primary rectal tumor disappearance on a normal digital exam and lack of signal on diffusion-weighted imaging with scar on T2-weighted imaging. Further, each target lymph node must have decreased short axis to less than 0.5 cm diameter.

If patients achieved cCR they entered a nonoperative follow-up window and underwent evaluation every 4 months. Patients with residual disease would proceed to chemoradiation until cCR was observed. If this was not achieved patients would proceed to surgery. Target enrollment is 30 patients.

The primary objective was overall response rate of PD-1 blockade with or without chemoradiation and pathologic complete response (pCR) or cCR at 12 months following treatment with dostarlimab with or without chemoradiation. Secondary outcomes include safety and tolerability.

The null hypothesis was that an overall response rate would be less than 25%, a numerical determination made based on the response rate to neoadjuvant chemotherapy of patients with dMMR colon cancer which is approximately 7%. “The rejection of null hypothesis required a response of 11 or more patients,” Cercek said.

At the time of the presentation 18 patients had been accrued to the trial. A majority were women (67%) and had a median age of 54 years (range, 26-78). In terms of tumor staging 22% had T1/2 tumors and 78% had T3 or T4 tumors. The mean tumor mutational burden was 67 mut/Mb (range, 36-106).

A majority (94%) of patients had node-positive disease and 100% of patients had 

 V600E wild-type disease, which Cercek noted during a question-and-answer session is because these are patients with left-sided tumors.

“What I’d like to highlight is that the majority of these patients had big bulky tumors [with] 94% node positive,” Cercek said. “The standard of care for these patients would have very likely required all 3 modalities—chemotherapy, radiation and surgery.”

Cercek presented an overview of the first 2 patients enrolled and treated with dostarlimab. The first patient was a woman aged 38 years who presented with a large, node-positive tumor. “After completion of 6 months of [dostarlimab], we noted disappearance of tumor on endoscopy, and no evidence of tumor on MRI; she achieved a cCR, which was a very exciting start to the trial.”

The second patient was a woman aged 30 years who presented with approximately 3 months of rectal bleeding, a change in the caliber of her stool, and pelvic pain for approximately 2 weeks prior to diagnosis. Cercek noted that she subsequently received a diagnosis with Lynch syndrome. A clear response was noted at 6-week follow-up, but Cercek added that a clinical benefit was observed as well. “After just 2 doses, she felt significantly better, her bowels had normalized, and she no longer had pelvic pain. At 3 months, she achieved a cCR [on endoscopy] and on MRI she had a near complete response, so there was still some visible tumor there. On PET [evidence of disease] had also completely disappeared. Her final examination, after completion of 6 months of therapy was notable for a cCR and I’m very happy to say that this has been sustained now in follow-up for nearly 2 years.”

In terms of safety no grade 3 or 4 adverse events were observed. “This has the potential to be translated rapidly into areas where access to modern chemotherapy and even more importantly, radiation and surgery may not be available,” Cercek said in her concluding remarks.

In August 2021, dostarlimab was approved by the FDA for the treatment of patients with dMMR recurrent or advanced solid tumors who have progressed on or following prior therapy and who have no satisfactory treatment options.3

“Neoadjuvant dostarlimab for 6 months represents a promising new treatment for patients with stage II/III dMMR rectal cancer [and] larger multicenter clinical trials with longer follow-up and disease-free survival and overall survival end points are needed,” Ng said. “It is going to be critical that we identify predictive biomarkers of pathologic complete response to help guide the treatment for our patients.”

Cercek A, Lumish MA, Sinopoli JC, et al. Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer. 

. 2022;40(suppl 17):LBA5. doi:10.1200/JCO.2022.40.17_suppl.LBA5

Cercek A, Lumish MA, Sinopoli JC, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. 

. Published online June 5, 2022. doi:10.1056/NEJMoa2201445

FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated February 1, 2022. Accessed June 6, 2022. bit.ly/3whe2C6

At data cutoff, all treated patients in a phase 2 trial experienced a clinical complete response with single-agent dostarlimab-gxly.

All Patients With dMMR Rectal Cancer Experience Clinical Complete Response With Dostarlimab In Phase 2 Trial

Findings from the phase 3 TROPiCS-02 trial (NCT03901339) demonstrated that sacituzumab govitecan-hziy (Trodevly) improved progression-free survival outcomes vs standard-of-care single-agent chemotherapy for patients with hormone receptor–positive, HER2-negative breast cancer with endocrine therapy resistance.

Findings which were presented during a press briefing at the 

by Hope S. Rugo, MD, FASCO, showed that the antibody-drug conjugate reduced the risk of progression by 34%.

At a median follow-up of 10.2 months, the median progression-free survival (PFS) was 5.5 months (95% CI, 4.2-7.0) with sacituzumab govitecan vs 4.0 months (95% CI, 3.1-4.4) with investigator’s choice chemotherapy (HR, 0.66; 95% CI, 0.53-0.83; 

 < .0003). The overall survival (OS) data were not mature at the time of the primary analysis; however, investigators noted a numeric trend toward improvement with the antibody-drug conjugate vs standard care.

“A subset of these heavily pretreated patients had rapid progression in the first 2 months on treatment,” Rugo said. “Therefore, we analyzed PFS at several key landmark time points. The Kaplan-Meier curves separated early and were consistent over time with a higher proportion of patients alive and progression free at all landmark time points.”

Specifically, at 6 months, 46% of patients who received sacituzumab govitecan (n = 272) were alive without worsening disease compared with 30% who received chemotherapy (n = 271). At 12 months the PFS rates were 21% vs 7%, respectively.

“Sacituzumab govitecan demonstrated significant clinical benefit and manageable safety compared with chemotherapy in patients with heavily pretreated, endocrine-resistant hormone receptor–positive, HER2-negative advanced breast cancer, and should be considered a potential treatment in this heavily pretreated population,” said Rugo, who is a professor of medicine and director, breast oncology and clinical trials education at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

For patients who develop progressive disease following sequential treatment with endocrine therapies, including CDK4/6 inhibitors, mTOR inhibitors, and PI3K inhibitors, the standard of care consists of single-agent chemotherapy such as capecitabine, vinorelbine, gemcitabine or eribulin.1,2 Because of acquired resistance, outcomes for patients who receive chemotherapy in later-line setting are not favorable with a PFS of approximately 4 months.

Investigators of TROPiCS-02 evaluated the safety and efficacy of single-agent sacituzumab govitecan, an antibody-drug conjugate targeting Trop-2, a calcium signal transducer, which is highly expressed in hormone receptor–positive, HER2-negative breast cancer compared with other subtypes.

The agent comprises a humanized anti–Trop-2 monoclonal antibody with an SN-38 payload attached via a proprietary hydrolyzable linker.

TROPiCS-02 enrolled patients with hormone receptor–positive, HER2-negative metastatic breast cancer who were refractory to or relapsed after at least 2 prior systemic chemotherapy regimens for metastatic disease including at least 1 prior anticancer hormonal treatment and at least 1 CDK4/6 inhibitor administered in the metastatic setting.

Patients could not have received more than 4 prior lines of chemotherapy prior to enrollment. Investigators noted that therapy administered in the neoadjuvant or adjuvant setting for early-stage disease qualified as a prior line of chemotherapy if disease recurred within 12 months. Further, patients must have had measurable disease per RECIST 1.1 criteria.

Patients were randomly assigned 1:1 to receive sacituzumab govitecan at 10 mg/kg via intravenous infusion on days 1 and 8 of a 21-day cycle or investigator’s choice chemotherapy until progression or unacceptable toxicity. The primary end point was PFS with secondary end points including OS, response, duration of response, quality of life, and safety. Stratification factors included the following: visceral metastases (yes vs no), endocrine therapy in metastatic setting for at least 6 months (yes vs no), and prior lines of chemotherapies (2 vs 3-4).

Baseline characteristics were well balanced between the 2 arms. The median age in the investigative arm was 57 years (range, 29-86) and 55 years (range, 27-78) in the control arm. Most patients had liver metastases at baseline (84% and 87%, respectively), had an ECOG performance status of 1 (57% and 54%), and had received prior CDK4/6 inhibitor within 12 months (59% and 61%).

The median number of prior lines of chemotherapy in the metastatic setting were 3 (range, 0-8) for those who received sacituzumab govitecan and 3 (range, 1-5) for those who received chemotherapy.

In terms of safety, no new toxicity signals were observed in with sacituzumab govitecan and were manageable based on observations in prior studies. The most common adverse effects were diarrhea and neutropenia. Among the 6 deaths reported in the sacituzumab govitecan arm, 1 was related to treatment.

“No other specific pattern was identified following detailed review of all safety events leading to death,” Rugo said, noting that other events included COVID-19 infection, pneumonia, and other illnesses.

Rugo HS, Bardia A, Marmé F, et al. Primary results from TROPiCS-02: a randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer. 

. 2022;40(suppl 17):LBA1001. doi:10.1200/JCO.2022.40.17_suppl.LBA1001

Rugo HS, Bardia A, Tolaney SM, et al. TROPiCS-02: a phase III study investigating sacituzumab govitecan in the treatment of HR+/HER2- metastatic breast cancer. 

. 2020;16(12):705-715. doi:10.2217/fon-2020-0163

Study of sacituzumab govitecan-hziy versus treatment of physician’s choice in participants with HR+/HER2- metastatic breast cancer (TROPiCS-02). ClinicalTrials.gov. Updated May 5, 2022. Accessed June 4, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03901339

Sacituzumab govitecan elicited a statistically significant and clinically meaningful benefit among patients with hormone receptor–positive, HER2-negative metastatic breast cancer.

Sacituzumab Govitecan Outperforms Chemotherapy in HR+/HER2- Metastatic Breast Cancer

Addressing access to care is the first steps to improving patient outcomes, according to investigators with Yale Cancer Center and Moffitt Cancer Center. Ensuring that patients reach the right providers at the right team is key in being able to provide potentially life-saving agents and personalized treatments.

“Access is a multifaceted construct. It’s not just about the onboarding process or the amount of time that it takes to get that first appointment. It also ensures that the patient can reach a live person when they make a phone call, that they can be seen in a convenient location be seen by a clinician who is an expert in their specific disease, that they [can] access information about their diagnosis that’s readily available, and be able to afford their care,” Sarah Mougalian, MD, said during the 2022 National Comprehensive Cancer Network (NCCN) Annual Conference.

 She added that treatment should not only be prompt, but also have seamless transitions from the first appointment through every phase of the cancer care continuum. Mougalian is chief ambulatory officer at Yale Cancer Center/ Smilow Cancer Hospital and an associate professor of medicine in medical oncology at Yale School of Medicine in New Haven, Connecticut.

Sustainable care following the first point of contact the management of logistics of care affects both the patient and the provider. “The moment that one has a diagnosis [of cancer], they are overcome with a sense of fear and urgency,” Christie Pratt, MA, DHSc, said on a panel at the 2022 NCCN Annual Conference. “At that moment both patients and their loved ones need help. It’s about more than just getting them to the best care. It’s deeper than that,” Pratt is the senior director of Moffitt Medical Group at Moffitt Cancer Center in Tampa, Florida.

Data from a recent meta-analysis of mortality rates across the most common cancer types— bladder, breast, colon, rectum, lung, cervix, and head and neck—demonstrated that delays in cancer treatment initiation were associated with increased risk of death if delayed by 4 weeks or more.2 For example, a 13% increased risk of death was associated with a 4-week delay in adjuvant systemic treatment for patients with colorectal cancer.2 Hazard ratios for delays in systemic treatments had singificant associations with delays of 4 weeks in neoadjuvant treatment of bladder cancer (HR, 1.24; 95% CI, 1.03-1.50), adjuvant treatment of breast cancer (HR, 1.09; 95% CI, 1.07-1.11). Additionally, radiotherapy delays in head and neck cancer (HR, 1.09; 95% CI, 1.05-1.14) and cervical cancer (HR, 1.23; 95% CI, 1.00-1.50) were deemed significant.

Investigators cited patient, disease, and system factors all play a role in delays to care, the most cited reasons being workups and specialist consultations. To alleviate the burden of even one of these factors could significantly improve delays in treatment.

Mougalian and Pratt presented 2 initiatives to improve new patient access to cancer care at Yale Cancer Center/Smilow Cancer Hospital and Moffit Cancer Center, respectively.

 The programs focused on systemic hurdles, namely reducing delays for patient appointments with disease specialists.

Developing a system with a patient-centric focus, investigators at Yale Cancer Center initiated a pilot program to offer patients next day access to care following a diagnosis of cancer. Mougalian and her colleagues began with 2 subspecialty clinics at the institution—breast and gynecologic oncology. “We want it to be easy [for the patient following their] initial consultation to self-refer [and] for the scheduling process to be efficient,” Mougalian said. “We want the patient to be able to see a provider who is expert in their diagnosis in a timely fashion or institutional goal is within 5 days. Both before and after the first appointment, the patient should be able to speak with someone knowledgeable in the process and understanding of the plan of care.”

Investigators in the breast and gynecologic clinics were tasked with developing individual implementation plans that included an algorithm to define which patients were eligible for next day access (

). Selected patients typically included those who had received a diagnosis of cancer or suggestion of cancer prior to referral. The institutional goal of the pilot program was to have patients obtain appointments within 5 days. Early findings of the program were presented at the 2021 American Society of Clinical Oncology Quality Care Symposium.

The analysis included 3107 new patients who had a referral meeting across 4 sites of the institution. The primary efficacy measures of the program were to evaluate the number of patients who were seen within 1 business day of their referral, time to their first visit, the number of patients who accepted a next day appointment, and to obtain a descriptive analysis of the reasons why a next day appointment was not taken. Among the entire population of patients seen, 900 were eligible for next day visits with 12% of patients accepting the appointment. More patients with breast cancer (17%) accepted next day visits than those who received a diagnosis of gynecologic cancer (9%).

The median time to first visit was measured at 2 time points: December 2019 through February 2020, and December 2020 through February 2021. The median time to next visit in the first year was 13 days vs 9 days in the second year.

Mougalian stressed the importance of care team coordination through the process. “For providers who refer to us, the process should also be seamless and efficient,” she said. “Appointments should be scheduled quickly and follow-up and notes from the first consultation should be relayed back to the referring physician.” Mougalian added that special attention should also be paid to internal staffing challenges with even distribution of patient cases among appropriate specialists within the disease state. “Each team reviewed historical data to estimate the volume of new patient slots [and] made the appropriate adjustments in scheduling,” she said.

In contrast with their internal goal, investigators also strived to meet patient where they were. “The patient was at the center of this initiative and the No. 1 goal was to honor the patient’s choice, offering an appointment as soon as the patient wants it, and where the patient prefers,” Mougalian said. In tandem with this, she noted that managing patient expectations was also a critical component of the process, including the limitations that come with a next day appointment and other options that were available to them. An example roadmap for implementation is outlined in 

In an analysis of patients with a data cutoff of February 2021, reasons why patients did not accept a next day appointment included the availability of a specific provider (49%) or a specific date was requested (27%). These rates dropped in an analysis between August 2021 and January 2022 to 38% and 20%, respectively.

Overall patients were satisfied with their scheduling through the next day access program with 92% of respondents (n = 864) stating that they were satisfied with their appointment choices. Further, 67% said the appointments exceeded their expectations with 29% stating that the appointment met their expectations. “We also asked on a scale of 1 to 10: How would you rate your first visit? The average was 9.4, and the median was 10 [ range, 4-10],” Mougalian said.

Oncologist feedback was also collected during the process with some providers noting that the appointments often felt inefficient and harder to navigate, especially if they did not have a comprehensive snapshot of the patient’s records for clinical review. “In general, the feedback was positive, and it was [noted] that patient satisfaction [as well as] excellent responses from providers who referred [patients] was a market differentiator and was going to drive referrals going forward,” Mougalian said.

At Moffit Cancer Center, a similar program, First Connect, was initiated to establish care expectations for patients, enhance multidimensional approaches to care including access to clinical trials and personalized medicine, and improve access to visits with a 1-day turnaround from intake to appointment with a clinical subject matter expert.

 “The goal of First Connect was to not only create and provide patients with access, but [execute] it in a very meaningful way,” Pratt said.

The First Connect program starts with a call during which 3 main components are tackled: clinical assessment to support additional work-up requests and initiate a suspected clinical pathway; accelerate access to care by aligning the right provider with the right patient; and to build a foundational component with the patient. A key differentiator of the construct of the Moffit Cancer Center program is an increased focus on the emotional bond with the patient to help alleviate anxiety and build connections with the clinical team, Pratt said.

“The First Connect call is scheduled 24 hours after a patient has entered into our system,” Pratt said. “These calls are prior to a destination visit and serve as the connection that that patient can make with the clinic [and with] a provider who has the knowledge base about the disease can help set expectations. The most important piece is that the patient feels comfortable, understands, and is prepared for the destination visit.” In addition to establishing that connection, Pratt noted that these calls are aimed at patient retention. “Approximately 12% of patients who call into our system, get put into a queue to be scheduled, and then we lose them, they never complete a new patient appointment,” Pratt said. “And that could be because they cancelled the appointment or because we were unable to ever get a hold of them, or that they [were a no show]. We really wanted this to be a way to make that connection and let the patient know, we care, we want to begin the process, and start collecting records to show you that we’re invested in your care and getting you to that consulate visit to start the journey.”

An important component of the pilot program is also generating an increased awareness of the institution’s offerings. “We want to make sure that we market to providers, so that if you’re [a clinician] who’s messaging to your patients is that their cancer diagnosis is your top priority, we now offer the opportunity to speak to a cancer expert within 1 day,” Timothy A. Price, MBA, FACHE, director of patient access at Moffitt Cancer Center said.

Overcoming Barriers to Implementation and Care

Operational and cultural barriers present hurdles for both referring physicians and institutional teams to overcome. Multilevel problems are affecting diversity in clinical trial enrollment from a patient, health system, provider, and community aspect. Should the pilot programs reach the community in their intended ways, increased engagement between providers and referring clinicians may open the door for improved institutional infrastructure across sites to promote enrollment and recruitment. Although the changes may be minimal at this level, these programs afford the treating institutions data sets they did not previously have access to.

“These [programs are] important for the organization because they become a very rich data set,” Price said. “Really understanding patient preference and what’s actually happening with our scheduling data, [we can] harness the power [and] leverage that information for modality planning and looking at our clinical pathways for developing better clinical trial matching.”

Both Price and Mougalian drew attention to turnover and staffing issues which may affect the consistency of these programs to meet their objectives. “We saw that the number of available slots declined over time to and that we largely attribute to faculty departures,” Mougalian said.

“For us, from a [registered nurse] RN perspective, across the nation we have nursing challenges,” Price said. “They have clinical responsibilities [so we must] monitor to see if it is still appropriate delegation of responsibilities knowing some of the constraints that the departments. We wanted to call this out because post pandemic we have seen a rise in calls. How do we deal with those volumes?” One avenue Price noted is maintaining the high-quality call and providing training to get the most out of the interaction and establish that meaningful connection.

“We really need to be thinking about the capacity and the scalability of this,” Price said. “We need to take a look at how they manage their clinical duties and making sure that they’re getting credit for the work that they’re doing.”

Mougalian agreed noting that the minimum data that a patient and the referred physician receive prior to the first appointment should be meaningful. “The team should work together to ensure that the patient understands the plan of care that follow-up is established and that the patient is satisfied with the interactions, the process, and the care that’s delivered,” she said.

“There is no silver bullet for access,” Price said. “We really need to be doing things that have an upstream effect and [can change] the system.”

Mougalian S, Pratt C, Price TA. Strategies and initiatives to improve new patient access to cancer care. Presented at: 2022 National Comprehensive Cancer Network Annual Conference. March 30-April 2, 2022; Accessed May 3, 2022. bit.ly/3wj3RgH

Hanna TP, King WD, Thibodeau S, et al. Mortality due to cancer treatment delay: systematic review and meta-analysis. 

Mougalian SS, Shomsky L, Campos MM, Chiang AC. “The waiting is the worst”: development of a next day access (NDA) program for patients with cancer. 

. 2021;39(suppl 28):205. doi:10.1200/JCO.2020.39.28_suppl.205

This article was originally published on 

 as “New Programs Unlock Patient Access to Oncology Care.”

Pilot programs based out of Yale Cancer Center and Moffitt Cancer Center seek to improve access for newly diagnosed patients with cancer. 



New Strategies Provide Faster Access To Cancer Care For Patients

Patients with metastatic triple-negative breast cancer (TNBC) maintained clinical benefit with sacituzumab govitecan-hziy (Trodelvy), according to a post hoc analysis of the phase 3 ASCENT trial (NCT02574455). Furthermore, the efficacy results, which were presented at the European Society for Medical Oncology Breast Cancer Congress 2022, showed that the benefit was consistent across all groups, regardless of HER2 expression. 

In the analysis, investigators stratified patients by HER2 expressions measured by immunohistochemistry (IHC) score. HER2-low expressors were defined those who had an IHC score of 1+ or 2+; those with IHC0 were defined as HER2-negative.

Among patients with HER2-low expressing TNBC, sacituzumab govitecan significantly improved progression-free survival (PFS) vs chemotherapy of physicians’ choice (TPC) of either capecitabine, eribulin, vinorelbine, or gemcitabine. The median PFS was 6.2 months with the antibody-drug conjugate (n = 63) vs 2.9 months with TPC (n = 60; HR, 0.44; 95% CI, 0.27-0.72; 

 = .002). For those with HER2-negative disease, the median PFS with sacituzumab govitecan (n = 149) was 4.3 months vs 1.6 months with TPC (n = 144; HR, 0.38; 95% CI, 0.28-0.50; 

Sacituzumab govitecan also improved overall survival (OS), reducing the risk of death in patients with HER2-low expressing TNBC by 57% compared with TPC. Specifically, among this patient population the median OS in the investigative arm was 14.0 months vs 8.7 months in the control arm (HR, 0.43; 95% CI, 0.28-0.67; 

 < .001). In the HER2 nonexpressors the median OS with sacituzumab govitecan was 11.3 months vs 5.9 months with TPC (HR, 0.51; 95% CI, 0.39-0.66; 

“Sacituzumab govitecan should be considered an effective treatment option for patients with metastatic TNBC eligible for second-line or later therapy, irrespective of HER2 status,” the study authors wrote.

These data were comparable to the reported findings for the intention-to-treat (ITT) population which resulted in the approval of sacituzumab govitecan for those with unresectable or locally advanced TNBC who have received at least 2 prior systemic therapies, 1 of which must have been for metastatic disease.

 In the overall population 267 patients received sacituzumab govitecan and 262 received TPC. The median PFS was 4.8 months (95% CI, 4.1-5.8) vs 1.7 months (95% CI, 1.5-2.5), respectively (HR, 0.43; 95% CI, 0.35-0.54; 

 < .0001). The median OS was 11.8 months (95% CI, 10.5-13.8) vs 6.9 months (95% CI, 5.9-7.6), respectively (HR, 0.51; 95% CI, 0.41-0.62; 

Investigators of ASCENT randomly assigned patients with metastatic TNBC with relapsed or refractory disease following 2 or more prior lines of chemotherapy to either sacituzumab govitecan 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle or TPC. Of note, patients with known HER2-positive disease were ineligible for enrollment and investigators determined the cutoff for HER2-negative status as HER2 IHC1+. Those who had HER2 IHC2+ must have had in situ hybridization negative status. Stratification factors included number of prior therapies, geographic region, and the presence of absence of known brain metastases.

The primary end point was PFS in the population of patients without brain metastases with secondary end points of PFS in the ITT population, OS, overall response rate (ORR), quality of life, duration of response (DOR), and time to response.

In terms of response, the ORR was comparable across populations for patients who received sacituzumab govitecan—HER2-low expression (32%), HER2-negative (31%), ITT (31%)—vs TPC— HER2-low expression (8%), HER2-negative (3%), ITT (4%).

The complete response (CR) rate for patients in the HER2-low expression population who received sacituzumab govitecan was 5% vs 2% among those who received TCP; the partial response (PR) rate was 27% vs 7%, respectively. More patients in the TPC arm had achieved stable disease (SD; 40%) compared with sacituzumab govitecan (37%). The median DOR was 5.6 months (95% CI, 4.3-not estimable [NE]) in the investigational arm vs 3.6 months (95% CI, 2.9-NE) in the control arm. The clinical benefit rate (CBR) was 68% and 45%, respectively.

In the HER2-negative population the CR rate was 2% vs 0% with sacituzumab govitecan and TPC, respectively. The PR rate was 29% and 3%, respectively, with 37% and 23% of patients achieving SD, respectively. The median DOR was 6.9 months (95% CI, 5.4-9.0) vs 2.9 (95% CI, 2.8-NE) in the investigational and control arms with CBRs of 68% vs 26%, respectively.

In the ITT population the CR rate was 4% vs 1%, the PR rate was 27% vs 3%, and SD was achieved in 36% vs 27% of patients who received sacituzumab govitecan and TPC, respectively. The median DOR was 6.3 months (95% CI, 5.5-9.0) with sacituzumab govitecan vs 3.6 months (95% CI, 2.8-NE). The CBR was 67% vs 31%, respectively.

Hurvtiz A, Bardia A, Punie K, et al. Sacituzumab govitecan (SG) efficacy in patients with metastatic triple-negative breast cnacer (mTNBC) by HER2 immunohistochemistry (IHC) status: findings from the phase 3 ASCENT study. Presented at: European Society for Medical Oncology Breast Cancer Congress 2022. May 3-5, 2022; Berlin, Germany.

FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. Updated April 8, 2021. Accessed May 5, 2022. bit.ly/3vJMSVW

This article was originally published on OncLive as “Sacituzumab Govitecan Maintains Clinical Benefit Across HER2 Expressions in TNBC”

Sacituzumab govitecan-hziy significantly improved progression-free survival in patients with HER2-low expressing TNBC and HER2-negative disease.

Regardless of HER2 Expression, Responses Are Showcased With Sacituzumab Govitecan in TNBC

HER2-positive breast cancer who also harbor brain metastases and were enrolled in the phase 2 TUXEDO-1 trial (NCT04752059) derived clinical benefit from treatment with fam-trastuzumab deruxtecan-nxki (Enhertu), according to data presented at the European Society for Medical Oncology Breast Cancer Congress 2022.

Among the 15 patients in the intention-to-treat (ITT) population, the objective response rate (ORR) via response assessment in neuro-oncology criteria was 73.3% (95% CI, 48.1%-89.1%). Bartsch noted that in the analysis 1 patient was found to have dural brain metastases only resulting in 14 patients meeting protocol requirements. The ORR among these patients was 78.6%. The clinical benefit rate in the ITT population was 86.7% and 92.9% in the per-protocol population.

“Brain metastases are a common and devastating complication of HER2-postitive breast cancer,” Rupert Bartsch, MD, associate professor, codirector of the Brain Metastases Program, and a consultant for hematology and medical oncology in the Department of the Medicine I, Clinical Division of Oncology at the Medical University of Vienna in Austria, said. “Local therapy has long been the main stay of treatment, but recent years have seen growing interest in systemic treatments as well.”

Data from combination regimens of HER2 tyrosine kinase inhibitors (TKIs), such as lapatinib (Tykerb) or neratinib (Nerlynx) plus capecitabine, have yielded clinically relevant activity for patients with HER2-positive breast cancer and brain metastases who progress after local therapy.

The standard of care for these patients was defined in results of the HER2CLIMB trial (NCT02614794), in which tucatinib (Tukysa) plus trastuzumab (Herceptin) and capecitabine reduced the risk of intracranial progression with a median central nervous system (CNS) progression-free survival (PFS) of 9.9 months (95% CI, 8.0-13.9) vs 4.2 months (95% CI, 3.6-5.7) with trastuzumab and capecitabine alone (HR, 0.32; 95% CI, 0.22-0.48; 

 < .00001).4 A 42% reduction in the risk of death was also observed among the 198 patients with brain metastases who received the investigational approach vs the 98 patients who received placebo (HR, 0.58; 95% CI, 0.40-0.85; 

Data from trials such as the DEBBRAH trial (NCT04420598) have suggested a role for antibody-drug conjugates in patients with brain metastases, Bartsch said.

TUXEDO-1 is a single-center, single-arm trial for patients with histologically confirmed HER2-positive breast cancer with newly diagnosed brain metastases or brain metastases progressing after local therapy for whom there is no indication for immediate local therapy available. Prior exposure to trastuzumab and pertuzumab (Perjeta) were required and prior exposure to ado-trastuzumab emtansine (T-DM1; Kadcyla) was permitted.

Patients received trastuzumab deruxtecan at the recommended dose of 5.4 mg/kg intravenously once every 3 weeks until progression or unacceptable toxicity.

At baseline, patients had a median age of 69 years (range, 30-76) with 80% of patients having the presence of visceral metastases and 80% of patients having HER2-positive/Luminal B disease. Prior treatment with T-DM1 was reported among 60% of patients and prior laptatinib was reported among 26.7%. In terms of prior treatment for brain metastases, 60% of patients had progressive brain metastases after local therapy at baseline. The median number of prior lines of therapy was 2 (range, 1-5).

Investigators also reported other secondary outcome measures. The median overall survival was not reached and the median PFS was 14 months (95% CI, 11–not reached) at a median follow-up of 11 months (range, 3-17). The extracranial response rate among 13 patients with extracranial metastases was 27.8% and was 62.5% among 8 patients who had measurable extracranial disease at baseline.

In terms of safety, most adverse effects (AEs) were grade 1/2 the most common of which were fatigue (66.7%), nausea (46.7%), anemia (46.6%) neutropenia (46.6%), and constipation (40%). Grade 3 AEs included fatigue (15.3%), anemia (6.7%), diarrhea (6.7%), dyspnea (6.7%), and urinary tract infection (6.7%).

AEs of special interest included 1 instance of ejection fraction decrease which was grade 3 and 1 instance interstitial lung disease which was grade 2 and was resolved after 6 weeks of corticosteroid treatment, according to Bartsch. Further, 6 serious AEs were reported in a total of 4 patients and 1 patient experienced grade 5 urosepsis which was not related to treatment.

“Global health status, physical function, and emotional function were maintained over the entire treatment period with an initial drop seen in the first weeks of therapy,” Bartsch said. “Importantly, in a trial conducted in patients with active brain metastases, cognitive function was maintained over the entire treatment period.”

Bartsch R, Berghoff AS, Furtner J, et al. Trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients with active brain metastases: primary outcome analysis from the TUXEDO-1 trial. Presented at: European Society for Medical Oncology Breast Cancer Congress 2022. May 3-5, 2022; Berlin, Germany.

Lin NU, Diéras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. 

. 2009;15(4):1452-1459. doi:10.1158/1078-0432.CCR-08-1080

Freedman RA, Gelman RS, Anders CK, et al; Translational Breast Cancer Research Consortium. A phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. 

. 2019;37(13):1081-1089. doi:10.1200/JCO.18.01511

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. 

. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775

This article was originally published on OncLive as “Evidence Grows to Support Trastuzumab Deruxtecan in Patients With HER2+ Breast Cancer and Active Brain Metastases”

Patients with HER2-positive breast cancer who also have brain metastases experienced clinical benefit with fam-trastuzumab deruxtecan-nxki in the phase 2 TUEXEDO-trial.

Trastuzumab Deruxtecan Continues to Elicit Responses in HER2+ Breast Cancer With Active Brain Metastases

Acute myeloid leukemia (AML) currently holds the lowest 5-year survival rate of all the leukemias at 29.5%, compared with 70.6% for those with chronic lymphocytic leukemia, 87.2% for those with chronic myeloid leukemia, and 69.9% for those with acute lymphocytic leukemia. Researchers have noted that the 2 most pressing barriers to improving the survival rate include helping patients achieve complete remission (CR) and maintaining the depth of that remission.

Furthermore, in order to develop effective treatments for this patient population, investigators will need to overcome acquired resistance to standard therapies, such as induction chemotherapy with anthracycline and cytarabine, as well as the persistence of leukemia stem cells tracked in minimal residual disease (MRD).

“Remissions can be achieved with both intensive and non-intensive therapies in sometimes up to 70% of patients [with AML], but a major issue with a vast majority of patients is [relapse] unless they are bridged to allogeneic stem cell transplant,” David Sallman, MD, said in an interview with 

®. “A big issue is having some leftover amount of disease after frontline therapies, which [is] predictive of poor outcomes even in [individuals] who are ultimately bridged to transplant. Improving the depth of remission and targeting leukemic stem cells that may be left behind [are] of paramount importance to further improve outcomes to therapy.”

Sallman is an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

A recent avenue of exploration for investigators is to inhibit the activity that promotes the self-renewal of leukemic stem cells and draw out persistent cells masked in the bone marrow tumor microenvironment. Specifically, investigators are exploring novel agents engineered to target adhesion factors, which can mobilize persistent leukemic stem cells from the bone marrow niche.

“Normal hematopoietic stem cells reside in the bone marrow in these specialized microenvironments, which refer to the stem cell niche,” Geoffrey L. Uy, MD, said in an interview. “Evidence suggests that leukemia stem cells occupy specific niches within the bone marrow. This interaction confers protection against genotoxic stresses, such as chemotherapy.”

Uy is a professor of medicine in the Division of Oncology, Section of Bone Marrow Transplantation at Washington University School of Medicine in St Louis and a bone marrow transplant specialist and medical oncologist at Siteman Cancer Center in Missouri.

One adhesion molecule and associated pathway of interest is E-selectin, which is expressed on the vascular endothelium and has known interactions with leukemic stems cells through binding with ligands such as CD44. Activation of the E-selectin pathway induces activity that can result in the protection of these cells and the promotion of cytotoxic chemotherapy resistance.

“E-selectin is normally expressed on endothelial cells and is upregulated in response to inflammation, which includes IL-1, tumor necrosis factor, and lipopolysaccharide,” Uy explained. “When E-selectin is upregulated, it binds to E-selectin ligands present on leukocytes and is an important mechanism for these leukocytes to traffic to areas of inflammation. In the bone marrow microenvironment, we know that E-selectin is present in the bone marrow sinusoids. It is expressed at high levels, and the E-selectin ligands are expressed on tumor cells. We think that this interaction confers specific protective effects to these AML blasts, and plenty of data have shown that specific pathways are activated, such as PI3K, AKT, and NFκB

 that can be important for leukemia cell survival.”

Disrupting the E-selectin pathway opens the door for investigators to capitalize on the known effects of intensive chemotherapy regimens, such as MEC (mitoxantrone, etoposide, and cytarabine). An agent of interest in this space is the novel E-selectin antagonist uproleselan. Investigators have observed preclinical and clinical activity of uproleselan in combination with MEC, specifically in a phase 1/2 study (NCT02306291) in a cohort of older patients (aged ≥ 60 years) with newly diagnosed AML and in a cohort of patients with relapsed or refractory AML, administered in the salvage setting.

Uproleselan Is Safe to Use With Chemotherapy

The treatment schema for the phase 1/2 trial called for the administration of uproleselan 24 hours prior to chemotherapy, followed by twice daily during chemotherapy, and twice daily 48 hours following induction chemotherapy as a 20-minute intravenous (IV) infusion. Three doses of uproleselan were assessed, and the recommended phase 2 dose (RP2D) was determined as 10 mg/kg because it did not result in dose-limiting toxicities in more than 33% of patients.

Induction chemotherapy regimens in the trial were as follows: Patients with relapsed/refractory AML received standard MEC (daily mitoxantrone 10 mg/m2 via 15-20 minute IV, daily etoposide 100 mg/m2 IV over 60 minutes, and daily cytarabine 1000 mg/m2 IV over 60 minutes for 5 days), and older patients with newly diagnosed AML received conventional 7+3 induction chemotherapy (24-hour continuous daily infusion of cytarabine 200 mg/m2 on days 1-7 in combination with 12 mg/m2 idarubicin on days 1-3 via daily IV bolus).

 Induction therapy lasted 8 days and 10 days, respectively. If remission was achieved, patients were offered optional consolidation therapy.

Investigators are seeking to overcome barriers to help patients with acute myeloid leukemia achieve complete and durable remissions by focusing their attention on novel agents engineered to target adhesion factors. 

Brittany Lovely