Patients with breast cancer that harbors 

 fusions achieved deep and durable responses following treatment with entrectinib (Rozlytrek), according to updated data from the phase 2 STARTRK-2 trial (NCT02568267) presented at the ESMO Breast Cancer Congress 2022.

At a median duration of survival follow-up of 35.3 months in patients with 

 fusion–positive disease (n = 7), entrectinib elicited a 71% (95% CI, 29.0%–96.3%) overall response rate (ORR); 2 patients achieved a complete response (CR) and 3 patients had a partial response (PR). Response data were missing on the other 2 patients. Both patients who achieved a CR had secretory disease, and among the 3 patients to have a PR, 2 had secretory disease and 1 had non-secretory disease. Among the 5 responders, the median duration of response (DOR) was 12.9 months (95% CI, 4.2-not evaluable [NE]).

 gene fusions are drivers in many solid tumors, including breast cancer.

 Though less than 1% of all breast cancer cases harbor 

 fusions, they are present in more than 90% of secretory breast carcinomas.

Prior data from the ALKA-372-001 trial (EudraCT 2012-000148-88), the phase 1 STARTRK-1 trial (NCT02097810), and STARTRK-2 showed entrectinib demonstrated deep and durable responses in patients with 

 Prior data from STARTRK-2 showed patients with 

 fusion–positive breast cancer achieved an ORR of 83% (n = 5 of 6), a median DOR of 12.9 months (95% CI, 4.2-NE), a median progression-free survival (PFS) of 10.1 months (95% CI, 5.1-NE), and a median overall survival (OS) of 23.9 months (95% CI, 5.1-23.9).

STARTRK-2 enrolled patients with locally advanced or metastatic solid tumors that harbored an 

 fusion–positive breast cancer. Moreover, patients were eligible regardless of central nervous system (CNS) metastases, and patients were required to be naïve to TRK inhibitors.

Enrolled patients received 600 mg of entrectinib once daily. Tumor burden was assessed following the first cycle of therapy, followed by every 8 weeks after by blinded independent central review per RECIST v1.1 criteria. Notably, regular brain scans were required for patients with baseline CNS metastases.

The primary end points were ORR and DOR per blinded independent central review. Secondary end points included PFS, OS, intracranial efficacy, CNS progression, and safety.

 fusion–positive breast cancer, all were female with a median age of 61 years (range, 36-67), and 5 patients were White. Patients had an ECOG performance status of 0 (n = 3), 1 (n = 2), or 2 (n = 2). All patients had received prior chemotherapy, radiotherapy, and hormonal therapy, and 5 patients were administered prior targeted therapy. One patient had previous radiotherapy of the brain.

Prior lines of therapy for metastatic disease included 0 (n = 3), 1 (n = 1), 3 (n = 1), and 4 or more (n = 2). Two patients presented with CNS metastases at baseline, and the median time since diagnosis for all patients was 130.1 months (range, 32.6-309.1). Histology included non-secretory (n = 2), secretory (n = 4), and not specified (n = 1).

Additional data showed the median PFS was 10.1 months (95% CI, 5.1-NE), and the median OS was 19.2 months (95% CI, 5.1–NE).

In the 2 patients with CNS metastases at baseline, the first had HER2-positive, estrogen receptor (ER)–positive, PGR-negative disease and received whole brain radiation 2-6 months prior to beginning entrectinib. This patient received no prior lines of systemic therapy for metastatic disease, and she achieved a PR and an intracranial non-CR and non–progressive disease. The second patient had HER2-negative, ER-positive, PGR-positive disease and received 6 prior lines of systemic therapy for metastatic disease. This patient did not have response data after dying 1.7 months following the first dose of entrectinib, though her death was not considered related to treatment.

Notably, no patients experienced a CNS progression event, regardless of baseline status.

Among 12 patients who received at least 1 dose of entrectinib and were evaluable for safety, 4 patients experienced a grade 3 or higher treatment-related adverse effect (TRAE). These included anemia (n = 2), fatigue (n = 1), and increased alanine aminotransferase (n = 1). There were no grade 5 TRAEs recorded. Only 1 patient had a series TRAE.

The most common TRAEs of any grade included dizziness (n = 5), nausea (n = 5), anemia (n = 4), constipation (n = 4), vomiting (n = 4), dysgeusia (n = 3), diarrhea (n = 3), increased alanine aminotransferase (n = 3), increased aspartate aminotransferase (n = 3), increased blood creatinine (n = 3), paresthesia (n = 3), and increased weight (n = 3).

Treatment-related adverse events resulted in the dose interruptions in 6 patients, dose reductions in 5 patients, and treatment discontinuations in 1 patient.

“In line with previous reports, entrectinib was associated with a manageable safety profile in patients with 

 fusion-positive breast cancer,” lead study author Min Janice Lu, MD, of USC Norris Comprehensive Cancer Center, wrote in the poster.

Lu J, Blakely CM, Barve M, et al. Entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer: updated data from STARTRK-2. Presented at: 2022 ESMO Breast Cancer Congress; May 3-5, 2022; Berlin, Germany. Poster 173P.

Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. 

. 2015;5(1):25-34. doi:10.1158/2159-8290.CD-14-0765

Wu S, Shi X, Ren X, Li K, Pang J, Liang Z. Evaluation of NTRK gene fusion by five different platforms in triple-negative breast carcinoma. 

. 2021;8:654387. doi:10.3389/fmolb.2021.654387

Demetri GD, Braud FD, Drilon A, et al. Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors. 

. 2022;28(7):1302-1312. doi:10.1158/1078-0432.CCR-21-3597

Lu J, Blakely CM, Le Tourneau C, et al. Efficacy and safety of entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PS11-28.

Basket study of entrectinib (RXDX-101) for the treatment of patients with solid tumors harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK gene rearrangements (fusions) (STARTRK-2). ClinicalTrials.gov. Updated May 3, 2022. Accessed May 11, 2022. 

https://clinicaltrials.gov/ct2/show/NCT02568267

This article was originally published on OncLive as “Entrectinib Continues to Yield Promising Data in NTRK Fusion–Positive Breast Cancer”

Articles

Entrectinib elicited encouraging responses in patients with breast cancer that harbors NTRK fusions, according to updates from the phase 2 STARTRK-2 trial.

Entrectinib Generates Favorable Outcomes in NTRK Fusion+ Breast Cancer

Not only did ARO-HIF2, an investigational RNA interference (RNAi) therapy, reduce levels of hypoxia inducible factor-2 alpha (HIF2α) expression in patients with clear cell renal cell carcinoma (RCC), the agent was also found to have a manageable safety profile, according to data from the phase 1b AROHIF21001 trial (NCT04169711).

Findings from the trial, which were presented during the 2022 Genitourinary Cancers Symposium, showed that of 26 evaluable patients, 9 experienced a median reduction in HIF2α mRNA of 30% (range, -19% to -59%) by qPCR.

In the subset of patients who received ARO-HIF2 at 225 mg (n = 7) the median reduction in HIF2α mRNA was 46% (range, -22 to -47). In those who were administered 525 mg of ARO-HIF2 (n = 10), the median reduction in HIF2α mRNA was 27% (range, -19 to -39). In the subset of patients who were given 1050 mg of the agent (n = 9), the median reduction in HIF2α mRNA was 44% (range, -28 to -49).

Additionally, 14 patients achieved a median reduction in HIF2α protein of 26% (range, -1700 to -98) by immunohistochemistry (IHC). The HIF2α protein reduction rates in the 225-mg, 525-mg, and 1050-mg cohorts were 26% (range, -26 to -82), 47% (range, 0 to -90), and 0% (range, 1700 to -98), respectively.

“This ongoing phase 1 study provides initial proof of target engagement based on reductions in HIF2α expression, as well as an acceptable safety profile in response to escalating doses of ARO-HIF2,” lead study author James Brugarolas, MD, PhD, of UT Southwestern Medical Center, and colleagues, wrote in a poster on the findings.

HIF2α is usually expressed at low levels and targeted for degradation by the von Hippel-Lindau (VHL) tumor suppressor protein. However, VHL inactivation, which is a causative event of clear cell RCC, prompts tumorigenesis through uncontrolled HIF2α accumulation. The synthetic double-stranded RNAi trigger, ARO-HIF2, which includes an alpha-v beta3 targeting ligand, was developed to silence HIF2α expression.

The AROHIF21001 trial enrolled patients with advanced or metastatic clear cell RCC that progressed during or after at least 2 prior regimens which must have included a VEGF-targeted therapy and a checkpoint inhibitor therapy.

 To be eligible for participants, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, a life expectancy that was longer than 3 months, and organ function that was considered to be acceptable at the time of the screening.

Exclusion criteria included a history of untreated brain metastases, having received prior systematic therapy or radiation therapy within 2 weeks of the first dose of study treatment, or having previously undergone solid organ or stem cell transplantation. Moreover, patients could not be receiving current treatment with immune checkpoint inhibitors, nor could they have received prior HIF2 inhibitors within 6 months before their first dose of study treatment.

Intravenous ARO-HIF2 was administered weekly at 225 mg in cohort 1 (n = 7), 525 mg in cohort 2 (n = 10), and 1050 mg in cohort 3 (n = 9). Moreover, tumor growth was evaluated by biopsy at baseline and again at 2 weeks. Additionally, patients were evaluated for safety each week. Every 8 weeks, participants were examined for tumor response by RECIST criteria.

The primary end point of the study was to evaluate treatment-emergent adverse effects (TEAEs) associated with ARO-HIF2. Secondary end points included pharmacokinetics and preliminary efficacy per RECIST v1.1 criteria.

Exploratory end points included the assessment of post-dose tumoral expression of HIF genes in response to treatment with the agent, change in tumor integrin expression, correlation of integrin expression with changes in HIF gene expression, and the examination of serum biomarkers of agent activity. The correlation of disease-related gene expression to the activity of the agent is also under exploration. Plasma and urine metabolites will also be assessed.

Spanning cohorts, the mean age was 65.1 years (range, 44-87). Seventy-seven percent of patients were male. Regarding performance status, 42.3% of patients had an ECOG performance status of 0, and 57.7% had a status of 1. Most patients (53.8%) had intermediate-risk disease per International Metastatic RCC Database Consortium criteria; 23.1% had good-risk disease and 15.4% had poor-risk disease.

Additionally, 30.8% of patients received 2 prior lines of therapy, 30.8% received 3 prior lines, and 11.5% received 4 prior lines of therapy. Notably, 26,9% of patients received 5 or more prior lines of treatment. Prior treatment included anti-VEGF therapy (100%) and checkpoint inhibition (100%). Regarding 

 mutation status, 17.6% of patients had frame shift mutations, 29.4% had missense mutations, 5.9% had in frame deletion, 11.8% had no variant, and 35.3% did not have this information available.

Prior data from the trial showcased early signals of activity with ARO-HIF2 in the 225 mg and 525 mg cohorts.

 Specifically, 7 of 9 patients who had evaluable tumor samples and received treatment experienced reductions in HIF2α per IHC H-score. Notably, these reductions ranged from -9% to -82%, with a mean reduction of -48%.

Additional data presented during the 2022 Genitourinary Cancers Symposium showed that ARO-HIF2 elicited an objective response rate of 7.7% in all patients, with 2 patients experiencing a partial response. Furthermore, 30.8% of patients achieved stable disease and 50.0% experienced disease progression. One patient was not evaluable for response, and response data were missing for 2 patients. Overall, the disease control rate with the agent was 38.5%.

At least 1 TEAE of any grade occurred in 96.2% of patients. Specifically, 57.7% of patients experienced at least 1 grade 1 or 2 TEAE, 30.8% reported at grade 3 TEAE, 3.8% experienced a grade 4 TEAE, and 3.8% experienced a grade 5 TEAE. Serious TEAEs were reported in 34.6% of patients. Moreover, treatment-related AEs of any grade occurred in 65.4% of patients. One patient discontinued treatment due to TEAEs.

TEAEs of any grade that occurred in more than 4 patients included fatigue (50.0%), dizziness (26.9%), dyspnea (26.9%), nausea (23.1%), abdominal pain (23.1%), neuropathy (19.2%), and constipation (19.2%).

Enrollment for the phase 1 trial remains open and enrollment is ongoing.

Brugarolas J, Beckermann KE, Rini BI, et al. Initial results from the phase 1 study of ARO-HIF2 to silence HIF2-alpha in patients with advanced ccRCC (AROHIF21001). 

 2022;40(suppl 6):339. doi:10.1200/JCO.2022.40.6_suppl.339

Study of ARO-HIF2 in patients with advanced clear cell renal cell carcinoma. ClinicalTrials.gov. Updated April 19, 2021. Accessed May 3, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04169711

Arrowhead announces positive interim results from phase 1b study of ARO-HIF2 for treatment of clear cell renal cell carcinoma. News release. Arrowhead Pharmaceuticals, Inc. July 6, 2021. Accessed May 3, 2022. 

This article was originally published on OncLive as “ARO-HIF2 Lowers HIF2α Expression and Demonstrates Favorable Safety Profile in Clear Cell RCC”

Patients with clear cell renal cell carcinoma experienced reduced levels of hypoxia inducible factor-2 alpha expression following treatment with ARO-HIF2. 

Investigational RNA Interference Therapy, ARO-HIF2, Yields Encouraging Phase 1 Results in Clear Cell RCC

Patients with hematologic malignancies identifying as White had a significantly higher uptake of telemedicine use throughout the COVID-19 pandemic compared with those who identified as Black, according to data from a retrospective observational study. These findings, the study authors argued, demonstrate a need for further exploration into these disparities.

Overall, patients with hematologic malignancies were found to reduce their in-person visits and increase their telemedicine use, according to the analysis, which was presented during the 2021 ASH Annual Meeting & Exposition.

However, telemedicine uptake was reportedly disparate between Black patients and White patients. This was found to be consistent across all diseases and combine treatments (t = 9.5; 

 < .01, including acute myeloid leukemia [AML] inpatient treatments (t = 2.4; 

 = .04), multiple myeloma oral treatment (t = 6.0, 

 < .01), and in multiple myeloma inpatient treatments (t = 2.3; 

 = .04). This trend was observed throughout the study duration, which lasted from March 2020 to February 2021.

However, although a statistically significant 18% reduction in in-person visits was observed among patients who identified as White and were receiving oral medication (95% CI, 9.9%-25%) between March 2020 and May 2020 compared with the projected rates, there was no observed reductions in in-person visit rates for patients who identify as Black. For White patients, the projected rate was 2.0 visits per patient per month, and the actual visit rate was 1.61 visits per patient per month (95% CI, 1.8-2.2).

“These patterns in documented visits reflect potential telemedicine use disparities, which requires further study into possible compound causes, including economic and societal factors,” Natalia Neparidze, MD, lead study author and an associate professor of Internal Medicine and Hematology at Yale School of Medicine, said in a poster presentation on the data.

The onset of the COVID-19 pandemic impacted healthcare delivery by reducing the number of in-person visits and pushing telemedicine to the forefront of care. Differences in these trends across racial groups are not clear. The study presented during the meeting was conducted to further explore racial disparities in visit throughout the pandemic for those with documented active treatment for hematologic malignancies.

To do this, investigators leveraged data from the nationwide Flatiron Health electronic health record–derived deidentified database, which included information from approximately 280 cancer clinics and around 800 sites of care across the United States.

The analysis included patients with AML, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, or multiple myeloma. Patients needed to be at least 18 years of age and documented receipt of at least 1 systemic therapy that they received between March 1, 2016, and February 28, 2021.

Treatment types within lines of therapy were stratified based on race (White vs Black/African American) and treatment type within lines of therapy (orals vs inpatient). Oral treatments include oral agents plus outpatient infusions with orals. Inpatient treatment could comprise chemotherapy, bone marrow transplant, and CAR T-cell therapy.

To estimate projected counterfactual monthly visit rates between March 2020 and February 2021, fit time-series forecasting models to pre-pandemic monthly visit rate data were leveraged. The differences between projected and actual visits were calculated by using cross-correlation analysis to assess for significant differences in visits between Black and White patient populations.

The analysis included a total of 24,432 patients; this included 2,343 Black patients and 16,218 White patients. Among patients receiving oral treatment in-person, 6.6% were Black and 32.0% were White; 0.9% and 4.7% of patients, respectively received oral treatment via telemedicine. Moreover, 4.8% and 46.0% of patients who received in-person inpatient treatment were Black and White, respectively; 0.5% and 4.7% of patients, respectively, received inpatient treatment via telemedicine.

Neparidze N, Lau KW, Wang X, et al. Racial disparities in telemedicine uptake during the COVID-19 pandemic among patients with hematologic malignancies in the United States. 

. 2021;138(suppl 1):1973. doi:10.1182/blood-2021-153787

This article was originally published on OncLive as “Analysis Reveals Racial Disparities in Telemedicine Use During COVID-19 Pandemic Among Patients With Hematologic Malignancies”

The disparate use in telemedicine between White and Black patients warrants further exploration into compound cases, such as economic and societal factors. 

Telemedicine Use During COVID-19 Disparate Between White and Black Patients With Hematologic Cancers

Because varying levels of keratopathy have been associated with treatment with belantamab mafodotin-blmf (Blenrep), patients with relapsed/refractory multiple myeloma often require coordinated adverse event (AE) management when receiving this therapy, according to Sarah Sunshine, MD.

Patients who receive belantamab mafodotin can encounter mild, moderate, or severe forms of keratopathy, and Sunshine said management of these AEs should begin before the start of treatment. Between the care of oncologists and consultations with ophthalmologists, a multidisciplinary approach can benefit patients, she added.

“If I am concerned that there is a higher grade of keratopathy or that there has been an acute change in [vision in] these patients, I reach out directly to the oncologist and let them know,” Sunshine said. “The ophthalmologist has to see these patients within a few days before [each infusion], so [oncologists and ophthalmologists] need to be in close communication.”

®, Sunshine, assistant professor, Ophthalmology and Visual Sciences, and member, Program in Oncology, University of Maryland School of Medicine, discussed the management of keratopathy associated with belantamab mafodotin treatment in patients with multiple myeloma and explained why ophthalmologists play a vital role in addressing these AEs.

®: What are the differences between mild, moderate, and severe keratopathy associated with belantamab mafodotin treatment in multiple myeloma?

: Belantamab mafodotin is a BCMA-directed treatment for treatment-refractory multiple myeloma. About 75% of the patients experience some sort of corneal toxicity, which is keratopathy, and it is usually described as either microcystic-like epithelial changes or superficial punctate keratopathy. [Keratopathy] can cause either no symptoms, blurry vision, or dry-eye symptoms.

Mild-to-moderate keratopathy is described as nonconfluent, microcystic-like changes that are predominantly in the periphery. What is interesting about these changes is they start in the periphery, and they work their way in. When you stop treatment or [a patient’s] symptoms get better, [the symptoms retreat to the periphery before resolving].

The other [aspect of how we define mild-to-moderate keratopathy involves] best-corrected visual acuity. If there has only been a change in 1 line of the Snellen visual acuity, which is our standard way of measuring vision, then that is still considered mild [keratopathy]. Moderate [keratopathy] is [defined by] 2 to 3 lines [of change] on the Snellen Chart but no worse than 20/200 vision.

Severe keratopathy is more of a diffuse, confluent corneal change; it is a combination of these microcystic epithelial cysts and punctate keratopathy, which is a breakdown of the epithelial cells, the skin of the cornea. Because [the cornea] is central, [severe keratopathy] is accompanied with a worsening of vision of at least 2 to 3 lines on the Snellen Chart.

The most severe form of [keratopathy] is when there is an epithelial defect or loss of the skin of the cornea. That js usually accompanied with worse than 20/200 vision. That is what we are trying to prevent here.

What steps should be taken to manage these AEs in this patient population? Is there a one-size-fits-all approach for these patients?

This is where I find it challenging as an ophthalmologist. We do not have great treatment options [for keratopathy]. The only thing that has been helpful is lubrication with artificial tears. The other treatments have not been shown to work. Steroids, antibiotics, and other treatment has not helped patients [manage keratopathy].

From a treatment standpoint, artificial tears and lubrication are the most important things. I try to get these patients on artificial tears preemptively. At the first visit before patients start treatment, I start artificial tears to increase the lubrication, and then we can increase its use from there. My personal favorite is preservative-free artificial tears because [patients] can use them as often as they want.

The only other option that we have is holding treatment. What is promising is that when you do hold treatment, those corneal changes tend to regress. The exact timing is variable, but the [keratopathy] does regress.

Can dose modifications affect keratopathy events in this patient population?

Dose modifications can help, [including] lengthening the time between the treatments. The standard is 3 weeks, but if you go further than that, it tends to give the cornea time to resolve somewhat.

How does multidisciplinary management between oncologists and ophthalmologists play a role in monitoring these AEs?

[The management of corneal toxicity] is a great example of collaborating, working together, and making sure you have a great team. At the University of Maryland, we are lucky that we have such a coordinated care system. I have a clinic in the cancer center, so it makes it a much easier, integrated system for the patients. That is not standard at most institutions, but it is a great model for how closely ophthalmology and oncology should try to work together.

How involved should ophthalmologists be throughout the course of treatment? How frequent should those visits be to help manage AEs?

We see [patients] initially before they start the treatment. We see them at their baseline exam to find out if there are any underlying ophthalmic conditions and what their baseline vision is, so we can use that to monitor them as they move forward.

We need to see [patients] every 3 weeks if they’re on [belantamab mafodotin] or 4 to 6 weeks if they are on a longer regimen, but it tends to be every 3 weeks. The most challenging part is the scheduling because it can sometimes be hard to ensure that we can get [the visit] in exactly [at the 3-week mark] around the infusion schedule.

What else would you like to add about treatment-related keratopathy?

The biggest point I would like to emphasize is the collaboration between ophthalmology and oncology and how critical that is for patient care. [It is also important] to understand and educate the patients on [keratopathy]. Even if there is a vision change or corneal changes, we do have good options. [Keratopathy] is not a long-term toxicity, and we can stop treatment or increase lubrication [to mitigate it].

This article was originally published on OncLive as “Proactive Care Is Required to Manage Belantamab Mafodotin–Associated Keratopathy in Myeloma”

A proactive, multidisciplinary approach is the best way to address belantamab mafodotin—related keratopathy in patients with multiple myeloma. 

Coordination With Ophthalmologists Ideal for Mitigating Belantamab Mafodotin–Related Vision Problems in Multiple Myeloma

The ongoing phase 1/2 FELIX trial (NCT04404660) will assess the safety and efficacy of the CD19-targeted CAR T-cell therapy obecabtagene autoleucel (obe-cel; previously referred to as AUTO1) as a treatment option for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

“With obe-cel, [investigators] tried to develop a low-affinity CD19 binder that would allow the CAR T cells to rapidly bind and then release,” Bijal Shah, MD, MS, explained. “The hope was this would do 2 things. The first was that it would decrease [some of] the toxicity associated with CAR T-cell therapy, specifically cytokine release syndrome [CRS] and neurologic adverse effects. [The second is that it] would improve the health of the T cell and limit T-cell exhaustion so now the T cells can stay active for a longer period.”

Previously, in the multicenter phase 1 ALLCAR19 trial (NCT02935257), 20 adult patients with relapsed/refractory B-ALL were infused with obe-cel as part of a split-dose schedule, titrated to pre-lymphodepletion bone marrow disease burden.

 Those with blasts of greater than 20% received 10 x 10

 CAR T cells, and those with blasts that were 20% or less received 100 x 10

 CAR T cells. At an interval of 9 days, if CRS and immune effecter cell–associated neurotoxicity syndrome (ICANS) was not observed, dose 2 was administered to a total dose of 410 x 10

Eighty-five percent of the patients achieved a minimal residual disease (MRD)–negative complete response (CR) at month 1, and 3 of these 17 patients underwent allogeneic stem cell transplantation while in remission. Moreover, the 6-month event-free survival (EFS) rate with the product was 68.3% (95% CI, 42.4%-84.4%); at 12 months, this rate was 48.3% (95% CI, 23.1%-69.7%).

The FELIX trial, which is currently recruiting, will further explore the autologous product in this patient population.

 To be eligible for enrollment, patients will need to be at least 18 years of age, have an ECOG performance status of 0 or 1, documented CD19 positivity within 1 month of screening, and acceptable renal, hepatic, pulmonary, cardiac function.

After preconditioning with a chemotherapy regimen comprised of cyclophosphamide and fludarabine, participants will be given a total target dose of 410 x 10

 CD19-positive CAR T cells as a split dose on day 1 and day 10 plus or minus 2 days. The primary objectives are to examine the frequency and severity of adverse effects (AEs) and serious AEs following infusion and to evaluate the overall response rate with the product. Secondary end points include duration of response, progression-free survival, overall survival, and safety, among others.

®, Shah, associate member of the Department of Malignant Hematology at Moffitt Cancer Center, shed light on advances made with CAR T-cell therapies in adult patients with B-ALL, the promise of obe-cel as an emerging option, and the key objectives of the recently launched FELIX trial.

®: Could you discuss the evolution of CAR T-cell therapy in ALL treatment? Where does obe-cel fit into the mix? How does it differ from other available products?

: We have 2 approved CAR T-cell products for B-cell ALL. We have tisagenlecleucel [Kymriah], which has been approved for use in children and young adults up to the age of 25 years. More recently, we [saw] the approval of brexucabtagene autoleucel [Tecartus] for all adult patients with relapsed or refractory B-ALL. The setting for the approvals differs a little bit. Tisagenlecleucel was approved [for use] after 2 prior lines of therapy, or after failure or intolerance of a second-generation TKI. The approval for brexucabtagene autoleucel was for any stage of relapse. Patients in first relapse could also be eligible for CAR T-cell [therapy], based on the FDA approval.

We are seeing new CAR T-cell approaches move into multicenter testing, with the goal of FDA approval. The obe-cel product is one that merits some discussion. When we talk about tisagenlecleucel and brexucabtagene autoleucel, we [see] a high-affinity CD19 binder. With obe-cel, [investigators] tried to develop a low-affinity CD19 binder that would allow the CAR T cells to rapidly bind and then release.

[The agent] has been tested in the phase 1 ALLCAR19 study, [which was] recently presented by Claire Roddie, MD, PhD, of the University College of London Hospitals NHS Foundation Trust, [and published] in the 

. [Data] demonstrated that [the agent] was highly effective. The CR rate was about 85%, and these were MRD negative by [flow cytometry].

The challenge [with this] is going to be twofold: relapse overall, but in particular, CD19-negative relapses. At this point, we are left to speculate why we see this phenomenon. Although we did see this with CD28-based CAR T-cell therapy, the rates seemed to be somewhat [lower]. Preclinical data suggest that for 4-1BB–associated signaling, which is part of the co-stimulatory domain for obe-cel and tisagenlecleucel, these cells may be less sensitive to low CD19 antigen burden on the leukemic blasts. This may allow for the escape of low antigen burden or evolution toward CD19-negative status.

Taking a deeper dive into obe-cel, could you discuss the FELIX trial? What makes this research unique?

FELIX is a phase 1/2 multicenter international trial that is examining [this] low-affinity CAR T-cell product in patients with relapsed and refractory B-cell ALL. What really distinguishes [this trial from others] is the inclusion of a MRD cohort. This is important [because] we have multiple studies and retrospective observations supporting the idea that the best outcomes in terms of response, response duration, and toxicity are associated with a low, and ideally undetectable, disease burden. This is what came out of the pediatric real-world CAR T consortium that Liora M. Schultz, MD, of Stanford University, and colleagues, recently published in the 

. However, even getting that disease burden to less than 5% seems to be very important in helping to improve outcomes in the context of CAR T-cell therapy.

To some degree, this was unexpected. Although we know that T-cell exhaustion, which can occur when there is high tumor cell burden, could limit the impact of CAR T-cell therapy, the expectation was that even with higher blast burdens, we would not see that play out with the degree of expansion and the other things we see with CAR T-cell therapy. [Conversely], there was a concern that there would not be enough antigen to drive the CAR T cells to grow and kill if we put them into this low MRD setting. However, none of that has borne out. We can see that the CAR T cells remain highly active—even with very low disease burdens. You can draw your cutoff almost anywhere—5%, 10%, 50%—with these 4-1BB–based CAR T-cell therapies, and you start to see a drop-off in response.

When we look at CD28-based CAR T, such as the recently approved brexucabtagene autoleucel, the cutoff may be a little higher. We did not see a drop off in response rate until we got to more than 75% blast. However, it will be interesting to see with longer-term follow-up how these different blast-burden thresholds impact the duration of response. One of the unique things [we saw with] the phase 1/2 ZUMA-3 trial [NCT02614066], which is reflective of an older adult cohort, was the low rate of allogeneic stem cell transplant. We will get a cleaner signature, in terms of durability response, looking across these different blast-cutoff thresholds. FELIX is unique in allowing [those with] low blast burden to enroll.

The other thing that distinguishes the FELIX trial is [that it is utilizing] fractionated infusion. We saw some of this data come from Frey and colleagues when they were using tisagenlecleucel in adult patients. They would give the CAR T-cell product on day 1, day 2, and day 3, but the dose would be fractionated so that if [the patients] experienced severe CRS before the second or third day, they would not receive the full dose of the product. This was to improve safety, particularly as they went up on the total cell dose. They did succeed in that regard, and this set the stage for other approaches looking at fractionated infusion.

[Patients] will receive a dose on day 1, [which will depend] on whether they are coming onto [the trial] with MRD vs more than 20% blasts. For those who have higher blast burden, they will receive a lower starting dose. However, at day 10, provided that any CRS that has occurred has resolved, they will go on to receive a higher cell dose. That is [an important] approach in terms of dosing of the CAR T to try to mitigate toxicity, but also to improve the total dose of cells infused, which may be especially important when we talk about the 4-1BB–based products.

What data have been reported thus far with obe-cel?

Roddie and colleagues published [data from the phase 1 ALLCAR19 trial in 

. They enrolled 25 patients and treated 20. Of those who were treated, 17 achieved an MRD-negative remission. An 85% CR [rate] with MRD negativity is outstanding. That is a good signal already.

What they are seeing with follow-up is that many of these responses are maintained. The EFS looks like it is going to be about 1 year [based on the] curves, and that is outstanding; it is a signal for an effective CAR T-cell product. The CAR T cells also seem to persist over time, which seems to be encouraging in terms of helping to mitigate against subsequent relapse. We need to prove that, but the early data are certainly promising.

What should be known about the safety of obe-cel that has been observed to date?

They did see lower toxicity than we are accustomed to seeing with CAR T-cell therapy in adults. CRS and ICANS were not commonly observed, and when they were seen, they seemed to occur more often in those patients who had higher tumor burden going into the CAR T-cell therapy, as we have seen in other trials. Particularly for those patients who are enrolled with very low tumor burden, so less than 5% blasts, the [safety] outcomes were quite good.

These are encouraging data. We are seeing a signal for CD19 antigen loss on the lymphoblasts. This may be a feature of 4-1BB–based CARs, or all CARs. We know that whether it is 4-1BB or CD28, thrombocytosis can occur. There may be other mechanisms in terms of CD19 antigen downregulation, or the ability of these CAR T cells to ferret out low CD19 antigen–bearing blasts, that may also impact this phenotype of CD19-antigen negativity. However, this is something that we will have to follow and contend with.

Therefore, it is important that we also have the evolution of other CAR T-cell therapies occurring in the background, such as the [ones targeting] CD22, and I am sure there are others [under exploration] in B-cell ALL. That may help us initially to manage the CD19-negative relapses, but hopefully at some point, we consider how we can combine our therapies to prevent any relapse from occurring, and [potentially] avoiding this phenomenon altogether.

What other research efforts are generating excitement?

We are seeing the development of humanized CAR T-cell agents, as well as an evolution in CD22-based CAR T-cell therapy. For example, Noelle V. Frey, MD, of Penn Medicine, [recently] presented [data] from a phase 1 trial [NCT03620058] that combined a humanized CD19 CAR T-cell product with CD22-targeted CAR T in patients who had relapsed after prior CAR T-cell therapy. [This approach had] intriguing efficacy. You get what you expect in terms of early CD19 CAR T-cell peak, but as the CD19 CAR T cells faded, you see this second peak of the CD22 CAR T cells. [We need to learn more about] what is driving that CD22 CAR T-cell expansion…and try to put that whole picture together [to have better understand what to expect] post–CAR T-cell therapy. We still have a lot to learn in that space.

I am excited to see how some of these novel approaches are further developed. Data out of Memorial Sloan Kettering Cancer Center, suggest that taking this CD28-based CAR with a CD19 target and then combining it with a CD22-based CAR with a 4-1BB co-stimulatory domain may be the optimal recipe for clearing the leukemic blasts and [may have] that activity to avoid antigen escape. These kinds of approaches where we mix and match our CARs are what I am keeping a close eye on, because there may be some real opportunities to improve outcomes for our patients.

A study of CD19 targeted CAR T cell therapy in adult patients with relapsed or refractory B cell acute lymphoblastic leukaemia (ALL). ClinicalTrials.gov. Updated January 5, 2022. Accessed February 8, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04404660

Roddie C, Dias J, O’Reilly MA, et al. Durable responses and low toxicity after fast off-rate CD19 chimeric antigen receptor-t therapy in adults with relapsed or refractory B-cell acute lymphoblastic leukemia. 

. 2021;39(30):3352-3363. doi:10.1200/JCO.21.00917

An expert with Moffitt Cancer Center comments on the ongoing FELIX trial, and the potential of the novel CAR T-cell therapy, obecabtagene autoleucel, to change the B-cell acute lymphoblastic leukemia treatment paradigm. 

Investigators Seek to Evaluate Obe-Cel’s Role in Relapsed/Refractory B-Cell ALL 

There is a higher rate of high-risk uterine cancers among Black women compared with White women, according to Cortney Eakin, MD. Furthermore, although obesity is 1 potential underlying risk factor, investigation into other potential underlying causes is necessary if the oncology community plans to address this disparity, she added.

“The risk of high-risk histologies in Black women is increasing at a very high rate, at 4% every year,” Eakin said. “If we don’t find a reason for this trend, and we don’t do something to abate it, we’re looking at Black women being at a 2.8-times higher risk of being diagnosed with a high-risk cancer compared with a low-risk cancer. These disparities that we’re seeing today are only bound to get worse if we don’t do something about it.”

 during the 2022 SGO Winter Meeting, Eakin, a gynecologic oncology research fellow at the University of California, Los Angeles (UCLA), discussed alarming trends in uterine cancer histologies in Black women and some of the potential underlying risk factors at play.

: What prompted this research into trends in uterine cancer histology in Black women in the United States?

: I have some phenomenal mentors as a fellow. John K. Chan, MD, [of the University of California, San Francisco] is certainly one of them. One of the things that is important for great mentorship is being able to challenge [existing] paradigms and to ask the [important] questions. One day, we were having a conversation about the dualistic approach to type 1 vs type 2 endometrial cancer, and we questioned how accurate that [paradigm was].

We have access to these national databases where we can see obesity and histology trends. If this paradigm really exists, shouldn’t we see that on a national scale? That question is what started this project.

What did you find when looking into this topic?

There have been several studies thus far that have showed that Black women tend to be at higher risk for high-risk histologies. That’s nothing new. What we really wanted to do was to [observe] what obesity trends are doing [in this population] and understand how they compare with those of White women. We also wanted to understand what happens if these trends continue.

We found that the rate of uterine cancer is not increasing significantly in White women, but it’s increasing very significantly—about 2.5% every year—in Black women. If those were all low-risk, grade 1, endometrioid tumors that typically have a good prognosis, that’s 1 [thing]. But we wanted to break down the histology to understand what cancers [these women] are getting. [It turns out Black women are getting] higher-risk cancers.

When you look at obesity, [Black women] are significantly more obese [compared with White women]. The main finding of the study was that Black women are significantly more impacted by those high-risk cancers [and] that they’re increasing at a high rate. If you look at all type 2 cancers, they’re increasing at about 4% annually, which is worrisome in and of itself. When you look at serous carcinomas in particular, they have been increasing over 6% every year for almost the past 20 years. If this trend continues over the next 10 years, when a Black woman gets diagnosed with uterine cancer, they’re going to be almost 3 times as likely to get a high-risk cancer compared with a low-risk, grade 1 tumor. That’s a trend that we have to pay attention to.

We know that these racial disparities exist. What can we do to modify them? When [a patient] gets diagnosed with uterine cancer, we can say it’s an access to care issue, and we can [ask] whether they are getting the best treatment available, but we can’t change the histology. The histology is what they present with, and there have to be some sort of modifiable risk factors out there that can account for some of these racial disparities. Maybe obesity is 1 of them.

What is the likelihood that obesity is responsible for these trends?

The main question we had with this study was whether obesity could potentially be a [risk] factor. Obesity is rising in both Black and White women. Obesity is rising [at a faster rate] in White women than it is in Black women, but Black women are also traditionally more obese.

By 2017, 47% of Black women were obese. Forty seven percent of an entire population is high. Ultimately, [we didn’t collect] patient-level data, so we can’t say [definitively] that obesity plays a role. All we can say is that when we look at the national trends, it’s a question that is worth proposing and looking into further in future studies.

Have any comparative studies been done on a global scale on this topic?

On a global scale, [there have not been any studies done on this topic]. Our study had over 778,000 endometrial cancers. The vast majority were endometrioid. Serous cancers made up about 6%, and clear cell and carcinosarcomas collectively made up about another 6.5%. Globally, you’re talking about [approximately] 10% of cancers. It’s hard for us to have studies that have the power to find these risk factors when endometrial tumors are traditionally much more common.

The studies that have been done that have proposed these questions are things like the Women’s Health Initiative. Some data are coming out of [that study]. There’s also the Epidemiology of Endometrial Cancer Consortium. Those studies have shown that body mass index [BMI] and obesity have more of an impact on type 1 tumors, but the impact that [obesity] has on type 2 tumors is also not 0.

The data are out there, and people are paying more attention to this now. Now it’s a matter of, on a national and global scale, what we do about it.

What are some of the next steps that should be taken to further this research?

One thing that we can do about it is ask: What is driving this? Race is not just Black and White. Genetically at our core, we’re much more similar than we think. Race is a proxy for so many other social determinants of health and environmental factors. Are there environmental factors, are there epigenetic factors, or are there biomarkers that are impacting this population at a higher rate than they’re impacting other populations that can explain why Black women are being diagnosed with higher-risk cancers? Those are the questions that we need to start asking ourselves so we can start to drive down this disparity.

At the end of the day, our job as oncologists is to ask the tough questions, go back to the original paradigms, and question whether there a way that we can rethink them.

Ultimately, that’s all we’re proposing. Can we rethink about the way that we have approached endometrial cancer that will allow us to improve disparities that we’re seeing today? Hopefully, we can start to drive that conversation forward, and if that’s what happens, we’ve done our job.

This article was originally published on OncLive as “Increasing Rate of High-Risk Endometrial Cancer in Black Women Prompts Questions Into Underlying Causes”

An expert from the University of California Los Angeles (UCLA) discusses the alarming rate of high-risk uterine cancers among Black women and how researchers are investigating the underlying risk factors at play.

 High Rate of High-Risk Endometrial Cancer in Black Women Demands Attention and Further Research Into Underlying Disparities 

Many researchers are assessing the use of novel immunotherapies against chemotherapy to determine the ideal treatment strategy for frontline endometrial cancer, according to Bradley R. Corr, MD.

“Some of the most exciting trials that are coming out are going to look [at how to best leverage immunotherapy agents as] up-front therapy,” Corr said. “One of the questions that [we hope to] answer in the not-too-distant future is: Is immunotherapy better, equivalent, or worse than chemotherapy? Combination therapy or single-agent [treatment] with immunotherapy could end up replacing chemotherapy.”

The phase 3 LEAP-001 (NCT03884101) and GOG-3064 (NCT05173987) trials are comparing the use of immunotherapy approaches with chemotherapy in those with endometrial cancer. Specifically, LEAP-001 is comparing the efficacy of frontline pembrolizumab (Keytruda) plus lenvatinib (Lenvima) vs chemotherapy in patients with stage III, IV, or recurrent disease.

The GOG-3064 study is evaluating the safety and efficacy of pembrolizumab vs carboplatin/paclitaxel in patients with mismatch repair–deficient (dMMR) advanced or recurrent disease who did not previously receive systemic chemotherapy.

® during the 2022 SGO Winter Meeting, Corr, an assistant professor of the gynecologic oncology team in the Division of Gynecologic Oncology at University of Colorado (UC) Anschutz Medical Campus, of UCHealth, discussed practice-changing developments and active clinical trials that are being done in endometrial cancer.

What research efforts are active clinical trials are focused on in the realm of endometrial cancer?

: [Several] active clinical trials are [being done] in endometrial cancer, [and they really give us] a sense of where treatment is [headed]. In [this disease], a big focus is on immunotherapy, and specifically checkpoint blockade. Several clinical trials are evaluating immunotherapy in either combination with chemotherapy or as single-agent therapy.

What factors should be considered when determining whether immunotherapy, chemotherapy, or a combination of the two should be leveraged?

Right now, we see a lot of biomarker-driven therapies, [and with these, we are] thinking about mismatch repair deficiency or microsatellite instability [MSI]. These markers [can potentially dictate] whether combination strategies or single-agent immunotherapy checkpoint blockade will be effective or not.

Adding in the instrumental aspect of combining [immunotherapy] with standard chemotherapies like carboplatin and paclitaxel is where a lot of the questions [exist, and we hope they] are going to be answered. Alongside that, [we want to see whether] any of the combination therapies or single-agent therapies that we already have approved [for use] in recurrent cancers, [and be moved] into up-front therapy.

What ongoing trials are you most excited about?

Right now, the landscape of endometrial cancer trials is quite robust; it is an exciting time [for research]. Some of the trials that I am most interested in are [examining] up-front [approaches]—specifically immunotherapy vs chemotherapy, rather than combination. The [phase 3] LEAP-001 trial and the [phase 3] GOG-3064 trial are [both] evaluating [immunotherapy vs chemotherapy] in those with this disease.

I'm also interested in [the work that is being done with] small molecule inhibitors, some of the single-agent targeted therapies [that are under investigation] in the recurrent setting in various endometrial cancers. [Data on these approaches are anticipated], far as efficacy and tolerability [goes].

What would you say is the most significant recent advancement that has been made in this disease?

As far as FDA-approved advances, the combination of pembrolizumab and lenvatinib has been game changing; it is standard of care for recurrent microsatellite stable tumors. Where I see all the shifting is how much to incorporate chemotherapy in up-front therapy [and whether we should incorporate chemotherapy at all]. That's where [research is being] focused.

How will molecular profiling help inform clinician decisions?

Molecular profiling is quickly becoming a standard of care for all endometrial cancers because it is dictating appropriate therapies. This field is advancing significantly. Currently, the National Comprehensive Cancer Network guidelines has recommendations for standard mismatch repair, as well as 

As this develops, we are finding new molecular markers, and we are finding efficacious therapies [targeting these] molecular markers. It is helping not only dictate which therapies work, but also which tumors do not need [treatment]. That is helping our clinical trial development, as well as what therapies to offer our patients.

This article was originally published on OncLive as “Active Clinical Trials of Interest in Endometrial Cancer Explore Novel Up-Front Approaches”

An expert from the University of Colorado (UC Health) comments on ongoing clinical trials which promise to shake up the treatment paradigm of endometrial cancer. 

Ryan Scott

Articles

Entrectinib Generates Favorable Outcomes in NTRK Fusion+ Breast Cancer

Investigational RNA Interference Therapy, ARO-HIF2, Yields Encouraging Phase 1 Results in Clear Cell RCC

Telemedicine Use During COVID-19 Disparate Between White and Black Patients With Hematologic Cancers

Coordination With Ophthalmologists Ideal for Mitigating Belantamab Mafodotin–Related Vision Problems in Multiple Myeloma

Investigators Seek to Evaluate Obe-Cel’s Role in Relapsed/Refractory B-Cell ALL

High Rate of High-Risk Endometrial Cancer in Black Women Demands Attention and Further Research Into Underlying Disparities

Potentially Game-Changing Clinical Trials in Endometrial Cancer Seek to Evaluate Immunotherapeutic Approaches

Oral Decitabine and Cedazuridine Holds Potential to Reduce Clinic Visits, Infusion Time for Patients With Lower-Risk MDS

Ruxolitinib Remains Backbone in Myelofibrosis and MPN Treatment

Understanding Translocation RCC Biology, Genomic Drivers May Provide Answers Needed for Better Targeted Treatments Options