Jessica Hergert

In the phase 3 TOPAZ-1 trial (NCT03875235), patients with advanced biliary tract cancer (BTC), who were treated with the PD-L1 inhibitor durvalumab (Imfinzi) in combination with gemcitabine and cisplatin showed improvement overall survival (OS) compared wi those who received placebo, according to findings presented during the 2022 Gastrointestinal Cancers Symposium.

The findings demonstrated a 20% reduction in the risk of death with durvalumab plus chemotherapy vs placebo plus chemotherapy in this patient population (HR, 0.80; 95% CI, 0.66-0.97; 

At a median follow-up of 13.7 months in the durvalumab/chemotherapy arm and 12.6 months in the placebo/chemotherapy arm, the median OS was 12.8 months (95% CI, 11.1-14) vs 11.5 months (95% CI, 10.1-12.5), respectively. The 18-month OS rates were 35.1% (95% CI, 29.1%-41.2%) vs 25.6% (95% CI, 19.9%-31.7%), respectively. The 24-month OS rates were 24.9% (95% CI, 17.9%-32.5%) vs 10.4% (95% CI, 4.7%-18.8%), respectively.

“TOPAZ-1 is the first phase 3 trial to show that adding immunotherapy to standard chemotherapy can increase survival in [BTC], and importantly, does so without inducing any new serious [adverse] effects [AEs],” lead study author Do-Youn Oh, MD, PhD, a professor in the Division of Medical Oncology of the Department of Internal Medicine at Seoul National University Hospital and Seoul National University College of Medicine in Seoul, South Korea, said in a news release.

BTC is a rare and heterogenous type of cancer that is associated with poor patient outcomes. Checkpoint inhibitors may have clinical utility in BTC based on immunogenic features of the disease; however, limited clinical activity has been observed with single-agent therapy in the advanced setting.

Gemcitabine plus cisplatin has been the standard chemotherapy option for patients with advanced BTC in the United States.

“The current standard of care for inoperable biliary tract cancer is combined chemotherapy. That standard has not changed in over a decade. TOPAZ-1 is the first phase 3 trial to demonstrate the benefit of immunotherapy for improved [OS], in combination with chemotherapy, creating a new standard of care. Patients have a greater reason for hope given the positive results seen with the use of immunotherapy in [BTC],” said Cathy Eng, MD, FACP, FASCO, the David H. Johnson Chair in Surgical and Medical Oncology at Vanderbilt-Ingram Cancer Center.

Moreover, the results of a phase 2 study demonstrated encouraging antitumor activity with durvalumab in combination with gemcitabine and cisplatin for patients with advanced BTC. As such, the TOPAZ-1 trial was developed to further evaluate the immunotherapy-containing regimen compared with chemotherapy alone.

The double-blind study randomized 685 patients with previously untreated, unresectable locally advanced, recurrent, or metastatic BTC 1:1 to receive 1500 mg of durvalumab every 3 weeks vs placebo plus 1000 mg/m2 of gemcitabine and 25 mg/m2 of cisplatin on days 1 and 8 every 3 weeks. Patients were treated for up 8 cycles, which was followed by 1500 mg of durvalumab every 4 weeks or placebo until disease progression or unacceptable toxicity.

Patients were stratified by disease status (initially unresectable vs recurrent) and primary tumor location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer).

The primary end point of the study was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.

Overall, 341 patients were randomized to durvalumab/chemotherapy and 344 were randomized to placebo/chemotherapy. The median age was 64 years in both arms and approximately half of patients were female (50.4% vs 48.8%, respectively) with an ECOG performance status of 0 (50.7% vs 47.4%, respectively).

Notably, 55% of patients had intrahepatic cancers, 19% had extrahepatic cancers, and 25% had gallbladder cancer.

Patients were enrolled from centers in the United States, as well as 17 other countries; over half of patients (55%) were enrolled from centers in Asian countries, including South Korea, Thailand, Japan, and China.

Further results showed that the median PFS was 7.2 months (95% CI, 6.7-7.4) with durvalumab plus gemcitabine and cisplatin vs 5.7 months (95% CI, 5.6-6.7) with placebo plus gemcitabine and cisplatin (HR, 0.75; 95% CI, 0.64-0.89; 

The ORR was 26.7% with durvalumab compared with 18.7% with placebo.

Regarding safety, the most common AEs included anemia (48.2%), neutropenia (31.7%), and nausea (40.2%). Potentially serious AEs were observed in 62.7% of patients receiving the durvalumab-containing regimen compared with 64.9% of patients receiving the placebo-containing regimen. Notably, this suggests that most AEs resulted from the chemotherapeutic agents.

Additionally, grade 3 or 4 AEs were observed in 75.7% of patients who received durvalumab/gemcitabine/cisplatin (n = 338) compared with 77.8% of patients who received placebo/gemcitabine/cisplatin (n = 342). Treatment-related AEs (TRAEs) leading to discontinuation of any drug were observed in 8.9% vs 11.4% of patients, respectively. TRAEs leading to death occurred in 0.6% vs 0.3% of patients, respectively.

“We are hopeful that durvalumab plus gemcitabine and cisplatin will become a new standard of care for advanced [BTC]. Our first task at this time is boosting communication with patients and family members about the potential for this immunotherapy combination and what it may mean for their ongoing care,” concluded Oh.

1. Oh DY, He AR, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. Presented at: 2022 Gastrointestinal Cancers Symposium; January 20-22, 2022; San Francisco, CA. Abstract 378.

2. Durvalumab significantly improves survival for patients with biliary tract cancer compared to chemotherapy alone. News release. ASCO. January 18, 2022. Accessed January 18, 2022. https://bit.ly/33OeU6X

Articles

TOPAZ-1 results reveal promise for durvalumab administered in combination with gemcitabine and cisplatin to patients with advanced biliary tract cancer.

Durvalumab Combined Chemotherapy Extends OS in Advanced Biliary Tract Cancer

One positive outcome of the COVID-19 pandemic has been the increased attention to advocating for change and bridging gaps in oncology care. The social determinants of health disparities have expanded the definition of personalized medicine, Karen Winkfield, MD, PhD, said.

“Unfortunately, the COVID-19 pandemic has shown that in the United States we don’t quite have the public health infrastructure that we need, not yet,” said Winkfield, executive director of the Meharry-Vanderbilt Alliance, the Ingram Professor of Cancer Research, and professor of radiation oncology at Vanderbilt University Medical Center in Nashville, Tennessee, during the Greenspan Lecture at the 39th Annual CFS® hosted by Physicians’ Education Resource®, (PER®), LLC.

Factors of Health Disparities in Cancer Care

Despite the downward trends in cancer-related deaths observed across all racial and ethnic patient populations, health disparities still exist, Winkfi eld explained.

 For example, one of the most widely known disparities in cancer care exists between White and Black patients.

There has been a decline in disparity for overall cancer deaths between Black patients and White patients from 33% in 1990 to 14% in 2016.2 However, achieving health equity remains a key goal in cancer care, Winkfield said.

Although biologic determinants like genetics, biology, and comorbidities inevitably have a role in creating these disparities, Winkfi eld hypothesized that social determinants, such as socioeconomic status, access to care, and sociocultural barriers, are the main contributors to these gaps.

Social determinants of health include economic stability, neighborhood and physical environment, education, food, community, and social context, and health care system factors. Negative social determinants, such as low income, lack of access to transportation, food, and social support, literacy challenges, and limited health care provider availability, are associated with poor health outcomes, including increased mortality and morbidity, lowered life expectancy, increased health care expenditures, decreased health status, and functional limitations.

“The social determinants go beyond just food; it is transportation, employment, literacy, and health literacy,” Winkfield said.

Lessons Learned From the COVID-19 Pandemic 

Although social determinants of health are becoming better understood, significant efforts from a socioeconomic and political context are needed to address them and provide precision medicine to all patients, Winkfi eld said.

Notably, the COVID-19 pandemic required rapid integration of many technologies that may start to bridge some of these gaps influenced by social determinants of health such as accessibility. The utility of telemedicine during the height of the pandemic is 1 takeaway lesson. Winkfield underscored that the pandemic showed the feasibility of localized or virtual care for certain procedures and patient conversations. For instance, clinical trial consent forms now are likely able to be signed virtually rather than having patients come into the clinic.

Importantly, adding virtual elements to cancer care can significantly lower the burden of treatment for patients, particularly for those who live in rural communities or who must rely on public transportation.

“Our ability to innovate the way that we have done with COVID-19 where telehealth is being compensated, these are the sorts of things we need to advocate for because, frankly, it makes it much easier for patients. This is what patient-centric care is about,” Winkfield said.

A study published in the International Journal of Radiation Oncology, Biology, Physics stated that achieving health equity is of critical importance for patients receiving radiation therapy and that the renewed passion to protect vulnerable patients observed during the COVID-19 pandemic should continue to address the disparities in care.

Winkfield advised oncologists to be advocates of bringing more equitable cancer care in clinical trials and policy implications to their institutions and communities. Developing a diverse workforce and working in direct collaboration with community-engaged investigators is a great start to addressing these gaps, she said.

Specifically, Winkfi eld called attention to the need for redesigned and inclusive clinical trials. She highlighted the example of multiple myeloma. Although Black individuals comprise 20% of the multiple myeloma population in the United States, they make up only 5% of FDA registration trials in multiple myeloma.

“If we are only getting the clinical trials in the spaces at the places that are very homogenous or have not done a good job at being inclusive, are we really moving the needle?” Winkfield asked.

Ultimately, developing an understanding of the issues that span the entire cancer care continuum from prevention to detection, diagnosis, and treatment to survivorship and end of life is critical, Winkfi eld said. In addition to health equity, some of these issues include quality of care, communications, and decision-making.

“We need to figure out how we can create an environment where we provide precision oncology, but we provide it for every patient so that every patient gets the right treatment at the right time,” Winkfi eld concluded.

1. Winkfield K. Precision medicine: ensuring every patient gets the right treatment at the right time. Presented at: 39th Annual CFS®: November 3-5, 2021; New York, NY.

2. AACR cancer disparities progress report 2020. AACR. Accessed November 4, 2021. 

https://cancerprogressreport.aacr.org/disparities/

3. Siker ML, Deville C Jr, Suneja G, et al. Lessons from COVID-19: addressing health equity in cancer care. 

. 2020;108(2):475-478. doi:10.1016/j.ijrobp.2020.06.042

4. Loree JM, Anand, Dasari A, et al. Disparity of race reporting and representation in clinical trials leading to cancer drug approvals from 2008 to 2018. 

. 2019;5(10):e191870. doi:10.1001/jamaoncol.2019.1870

The social determinants of health disparities have expanded the definition of personalized medicine, Karen Winkfield, MD, PhD, said.

Pandemic Sparks Increased Advocacy That Bridges Health Disparities in Cancer Care

Phase 1 results show that patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) had favorable survival and responses to the investigational bispecific antibody APVO436, and the agent demonstrated was tolerable according to updated findings from an ongoing phase 1 trial (NCT03647800) presented during the ASH Annual Meeting and Exposition 2021.

Regarding safety, APVO436 was found to have an acceptable tolerability profile with manageable adverse effects (AEs) in patients with AML/MDS. The most common grade 3 or higher AEs observed that were suspected to be related to APVO436 included cytokine release syndrome (CRS; n = 4/46; 8.7%), anemia (n = 2/26; 4.3%), and infusion-related reactions (n = 2/26; 4.3%). No hematologic dose-limiting toxicities (DLTs) were observed with ABVO436 across cohorts.

Serious AEs (SAEs) were observed in 28.3% of patients (n = 13/46); 15.2% (n = 7/13) of these were from CRS and 6.5% (n = 3/17) were from infusion-related reactions. The remaining 3 SAEs included one case each of sepsis, which was possibly related to ABVO436, generalized weakness, and grade 1 neurotoxicity. These events resolved within 5 days, 28 days, and 2 days, respectively.

Notably, regarding efficacy, the median overall survival (OS) was 338.5 days among the 8 patients who obtained favorable responses compared with 100 days for nonresponders (n = 31; log-rank, 5.298; 

 = .0213). Across all patients (n = 39), the median OS was 178 days.

“The off-the-shelf availability of APVO436 combined with its single-agent, anti-leukemic activity, favorable safety profile, ease of administration not requiring continuous infusion but weekly short infusions that can be administered in out-patient settings makes it an attractive option as a bispecific T-cell engager [BiTE] against AML,” lead study author Justin M. Watts, MD, an associate professor of medicine in the Division of Hematology and chief of the Leukemia Section of the Sylvester Comprehensive Cancer Center of the University of Miami Health System, and coauthors wrote in the poster.

APVO436 is a humanized, glycosylated homodimeric bispecific antibody targeted against CD123 CD3ε. The agent is comprised of 2 binding domain sets linked to a human immunoglobulin G1 Fc domain.

“APVO436 is a CD3/CD123-targeted BiTE antibody that brings cytotoxic T lymphocytes [CTLs] into proximity with CD123-expressing AML blasts and leukemic stem cells to allow for increased CTL-mediated cell killing,” said Watts in a presentation of the data.

The phase 1b dose-escalation study utilized a 3+3 design to evaluate multiple doses of APVO436 in patients with relapsed/refractory AML and high-risk MDS.

Overall, the study screened 58 patients with relapsed/refractory AML and MDS. Of these patients, 12 failed screening and the remaining 46 patients were deemed eligible for enrollment to the trial. Patients were enrolled 7 to 39 days following documentation of progressive leukemia or leukemic relapse.

Patients in cohort 1 were started on a 0.3-mcg dose of APVO436, which equated to approximately 0.005 mcg/kg for a patient weighing 60 kg. Moreover, this dose was the Minimum Anticipated Biological Effect Level of APVO436 based on T-cell activation assays.

Cohorts were assigned weekly target dose levels of 1 mcg, 3 mcg, 9 mcg, 18 mcg, 12 mcg, 24 mcg, 36 mcg, 48 mcg, and 60 mcg, respectively.

The maximum tolerated dose was not reached at a weekly flat dose of 60 mcg (cohort 10; n = 4). All patients in cohort 10 tolerated APVO436 and no DLTs or grade 3 or 4 AEs were observed.

The recommended phase 2 dose (RP2D), which served as the primary end point of the study, was identified at 18 mcg as a single, flat dose. This dose level, which was given to cohort 6 and equated to approximately 0.2 mcg/kg based on the body weight of the patients enrolled, comprised 30% of the dose level given to patients in cohort 10.


The cumulative incidence of grade 3 or 4 AEs and SAEs, and the incidence of AEs of interest (≥grade 2: CRS, infusion-related reactions, cardiac toxicity, and neurotoxicity as complications of CRS) were also evaluated. Efficacy served as the secondary end point and included the incidence of composite complete responses (CRs) and the incidence of patients who are able to achieve minimal residual disease–negative CRs and undergo hematopoietic stem cell transplant as post-protocol therapy.

Patients were a median age of 69 years (range, 18-82) and most were White (73.9%) males (52.2%). Regarding diagnosis, 84.8% of patients had AML, including primary AML (56.5%), secondary AML (19.6%), or treatment-related AML (8.7%). The remaining 15.2% of patients had MDS. Patients received a median of 2.5 prior lines of chemotherapy (range, 1-8); 34.8% of patients received 4 or more prior lines.

Patients received a median of 7 APVO436 treatments (standard error, 11±2).

Further safety findings showed that transient neurotoxicity related to APVO436 occurred in 10.9% of patients (n = 5/46). The onset of symptoms occurred during cycle 1 in 4 patients and cycle 8 in 1 patient. Mild, grade 1 symptoms, including headache, tremor, dizziness, lethargy, insomnia, memory loss, and confusion, were observed.

One patient in cohort 7 experienced grade 3 confusion on the first day of treatment; the AE was resolved within 1 day.

Moreover, the incidence of neurotoxicity was not found to be dose-dependent, or predicted by gender, race, age, absolute lymphocyte count, or percentage of lymphocytes in peripheral blood.

Neurotoxicity occurred in 3 patients who did not develop CRS; 7 patients who developed CRS did not experience neurotoxicity.

One grade 5 event of fatal acute renal failure occurred in 1 patient who initially developed grade 2 CRS.

Further efficacy findings revealed that, among responders, the median time to progression was 177 days (range, 87-238). One of 8 responders had clearance of peripheral blasts with a more than 50% decrease in bone marrow blast percentage.

Of 34 of 39 evaluable patients, 64.7% (n = 22) achieved stable disease (SD) as their best overall response with ABVO436. Of responders, 8 patients (23.5%) achieved SD within 31 to 75 days after study entry, and disease stability lasted for more than 3 months; 7 patients had progression on 2 to 4 prior lines of anti-AML therapy.

Two patients with primary AML, more than 25% bone marrow blasts, and unfavorable cytogenetics and/or adverse risk group genomic mutations achieved a partial response (PR) at 58 days and 75 days, respectively. These PRs deepened into complete responses (CRs) with full hematologic recovery at 92 days and 113 days, respectively.

The first patient achieved a CR with full hematologic recovery on day 1 of cycle 5. They relapsed 85 days later but continued to have SD until cycle 10 of treatment. The second patient was in a CR on day 1 of cycle 5 but relapsed 57 days later.

Of the 7 patients with MDS enrolled, 6 patients were evaluated for response. All patients had SD without a significant hematological improvement as their best overall response.

The time to progression among patients with MDS was 104 days, more than 106 days, 138 days, more than 147 days, 211 days, and 321 days. Moreover, 3 patients obtained a bone marrow CR with ABVO346.

“In the open-label, multi-center, dose-expansion phase of the study, we will evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care and obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy and combination therapy modalities,” Watts and coauthors concluded.

Watts JM, Lin TL, Mims AS, et al. Tolerability and single agent anti-neoplastic activity of the CD3xCD123 bispecific antibody APVO436 in patients with relapsed/refractory AML or MDS. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Poster 3415

APVO436 appears to be safe and effective for the treatment of acute myeloid leukemia or myelodysplastic syndrome.

APVO436 Achieves Anti-Neoplastic Activity With Tolerable Safety in R/R AML/MDS

An analysis of the phase 3 BELINDA trial (NCT03570892) demonstrated lack of event-free survival (EFS) advantage when tisagenlecleucel (Kymriah) was administered as second-line treatment for patients relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) and compared with the standard of care (SOC) platinum-based chemotherapy followed by autologous stem cell transplant (ASCT) or additional chemotherapy.

“EFS was identical between the 2 arms,” said lead study author Michael R. Bishop, MD, a professor of medicine and director of the Hematopoietic Stem Cell Transplantation Program at the University of Chicago Medicine, during the press briefing at the ASH Annual Meeting 2021.

“[Therefore], unfortunately, BELINDA did not meet its primary end point of improved EFS with tisagenlecleucel and the therapy was not found to be better than current available SOC,” Bishop added.

Approximately two-thirds of patients with B-cell NHL are essentially cured with frontline chemoimmunotherapy; however, a subset of patients who do not respond to initial therapy or relapse within 12 months following frontline therapy have poor outcomes and an expected survival of less than 12 months, Bishop explained.

In this subset, SOC options include platinum-based chemotherapy followed by ASCT in patients with chemotherapy-sensitive disease. However, more than half of these patients will not receive ASCT because of inadequate responses to second-line therapy.

Tisagenlecleucel, a CD19-directed CAR T-cell therapy, was FDA approved on May 1, 2018 for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after at least 2 lines of prior systemic therapy.

 The regulatory indication included patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOC), high grade B-cell lymphoma (HGBL), and DLBCL arising from follicular lymphoma.

As tisagenlecleucel is an autologous CAR T-cell therapy, patients undergo leukapheresis to remove their T cells, which are then modified to effectively target the cancer. The modified cells are then infused back into the patient.

“Our hypothesis was that based upon the results in more advanced DLBCL that moving tisagenlecleucel treatment into up-front therapy for this poor-risk group of patients would result in improved outcomes, specifically EFS,” Bishop said.

The BELINDA trial randomized patients with confirmed relapsed/refractory aggressive NHL who recurred within 12 months following induction chemoimmunotherapy to tisagenlecleucel vs standard of care platinum-based chemotherapy followed by ASCT.

Overall, 396 patients were included in the screened set, but 74 patients did not complete screening to go onto leukapheresis. Therefore, 322 patients were included in the full analysis and safety sets. These patients were randomized 1:1 to tisagenlecleucel (n = 162; Arm A) or SOC (n = 160; Arm B). Ultimately, the tisagenlecleucel infused patient set included 236 patients comprised of 155 who were randomized to tisagenlecleucel and 81 who crossed over from Arm B.

In Arm A, 6 patients (3.7%) discontinued treatment without undergoing tisagenlecleucel infusion for reasons including physician decision (n = 2; 1.2%), progressive disease (PD; n = 2; 1.2%), manufacturing issue (n = 1; 0.6%), and patient decision (n = 1; 0.6%). In Arm B, 102 patients discontinued treatment without undergoing ASCT for reasons including progressive disease (n = 76; 47.5%), physician decision (n = 14; 8.8%), death (n = 7; 4.4%), patient decision (n = 2; 1.3%), technical problems (n = 2; 1.3%), and protocol deviation (n = 1; 0.6%).

Patients who received tisagenlecleucel underwent optimal bridging therapy with investigator’s choice of protocol-defined platinum-based chemotherapy regimens followed by lymphodepletion with, generally, 25 mg/m

 of daily cyclophosphamide for 3 days. A single infusion of tisagenlecleucel was then given at a dose of 0.6 to 6 x 10

Patients who received SOC received investigator’s choice of platinum-based chemotherapy followed by ASCT in responders or a second platinum-based chemotherapy regimen in nonresponders.

The primary end point of the study was EFS, defined as the time from randomization to stable disease (SD) or PD at or after assessment at 12 weeks or death at any time. Moreover, SD or PD at 6 weeks was not considered an EFS event; however, the 6-week assessment evaluated disease burden before tisagenlecleucel infusion and after bridging therapy in patients enrolled to Arm A and determined whether patients enrolled to Arm B had a sufficient response to platinum-based chemotherapy to undergo ASCT.

Disease assessment was performed at 6 and 12 weeks; additional assessments were planned for every 3 months in the year following therapy and every 6 months in the second year following therapy.

Patients were stratified by first-line duration of response, International Prognostic Index (IPI), and geographic region.

Regarding baseline patient characteristics, disease subtypes in the tisagenlecleucel arm vs SOC arm, respectively, included DLBCL-NOS (62.3% vs 70%), HGBL with 

(19.8% vs 11.9%), primary mediastinal large B-cell lymphoma (7.4% vs 8.1%), HGBL-NOS (4.3% vs 5%), grade 3B follicular lymphoma (3.1% vs 0.6%), and other (3.1% vs 4.4%). DLBCL cell of origin in the tisagenlecleucel arm vs SOC arm, respectively, was germinal center B-cell like (GCB; 28.4% vs 39.4%), non-GCB/activated B-cell (32.1% vs 26.3%), or unclassified/missing (1.9% vs 4.4%).

Remission durations in the tisagenlecleucel arm showed that 66% of patients were refractory, 18.5% relapsed less than 6 months following frontline treatment, and 15.4% of patients relapsed within 6 to 12 months. In the SOC arm, these rates were 66.9%, 20%, and 13.1%, respectively.

Most patients across arms were not based in the United States (70.5%), male (62.5%), younger than 65 years of age (68.9%), had IPI scores of at least 2 (61.5%), and had stage IV disease at the time of study entry (47.2%). Additionally, 43.2% of patients who received tisagenlecleucel vs 40.6% of patients who received SOC had an ECOG performance status of 1.

Most patients in both arms received 1 prior line of therapy for current lymphoma (98.8%) and did not have transformation of prior lymphoma (84.8%).

The median time since initial diagnosis was 8.4 months with tisagenlecleucel (Q1-Q3, 6.8-11.1) vs 8.2 months with SOC (Q1-Q3, 5.9-11.4). The median time since most recent relapse or PD was 1.4 months (Q1-Q3, 0.9-2.2) vs 1.1 months (Q1-Q3, 0.8-1.8), respectively.

The median time to randomization was 92 days (range, 61-158), and the median follow-up was 10 months (range, 2.9-23.2).

The safety profile of tisagenlecleucel was consistent with previously reported studies evaluating the therapy.

“We hope that the results of this study will be used to help design further trials in patients with DLBCL,” said Bishop.

Further details of the study will be published in the 

1. Bishop MR, Dickinson M, Purtill D, et al. Tisagenlecleucel vs standard of care as second-line therapy of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma: analysis of the phase III BELINDA study. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract LBA-6.

2. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. News release. FDA. May 1, 2018. Accessed December 13, 2021. 

Tisagenlecleucel failed to improve event-free survival in the second-line setting of relapsed or refractory aggreesve B-cell non-Hodgkin lymphoma versus standard-of-care.

Tisagenlecleucel Does Not Prolong EFS in R/R Aggressive B-Cell Non-Hodgkin Lymphoma

Real-world data on the use of tisagenlecleucel (Kymriah) showed greater efficacy and a favorable safety profile, according to updated findings 

from a study of the Center for International Blood and Marrow Transplant Research (CIBMTR) registry that were presented during the 

 These findings were consistent with results of the pivotal phase 2 JULIET trial (NCT02445248) of patients with 

relapsed/refractory diffuse large B-cell lymphoma (DLBCL). 

At a median follow-up of 17.2 months (range, 6-34.7), the overall response rate (ORR) in all patients included in the updated analysis (n = 613) was 57.4% (n = 352). Moreover, 42.4% (n = 260) of patients had a best overall response (BOR) of a complete response (CR) and 15% (n = 92) had a BOR of a partial response (PR).

Among JULIET-eligible patients (n = 200), the ORR was 61% (n = 122); 44% (n = 88) had a CR as their BOR and 17% (n = 34) had a PR as their BOR.

Among JULIET-ineligible patients (n = 413), the ORR was 55.7% (n = 230); 41.6% (n = 172) had a CR as their BOR and 14% (n = 58) had a PR as their BOR.

“Data from the CIBMTR registry revealed favorable outcomes in terms of both survival and response, as well as toxicity, for patients treated with commercial tisagenlecleucel. These outcomes were similar to those seen in JULIET,” lead study author Daniel J. Landsburg, MD, vice chief of Quality and Safety in the Division of Hematology/Oncology, medical director of Infusion Services at the Hospital of the University of Pennsylvania, and an associate professor and physician at Penn Medicine, said in a presentation of the data.

DLBCL and HGBL are types of aggressive B-cell non-Hodgkin lymphoma in which patients who are not cured with first-line therapy tend to have poor prognoses.

Tisagenlecleucel is a CD19-directed autologous CAR T-cell therapy that was FDA approved in May 2018 for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after at least 2 prior lines of systemic therapy.

 The indication included patients with DLBCL not otherwise specified, HGBL, and DLBCL arising from follicular lymphoma.

The regulatory decision was based on findings from the JULIET trial, in which tisagenlecleucel induced a 53% ORR and 34.6% 12-month PFS rate in patients with heavily pretreated relapsed/refractory DLBCL (n = 115).

Early data from the CIBMTR registry demonstrated similar real-world efficacy with tisagenlecleucel, as well as a more favorable safety profile compared with the data from the JULIET trial. During the 2021 ASH Annual Meeting and Exposition, longer-term real-world data were reported for a larger group of patients with DLBCL and HGBL, including those not meeting eligibility criteria for the JULIET trial.

The non-interventional, prospective, longitudinal study utilized the CIBMTR database to evaluate patients treated in the United States, Israel, and Canada who were infused with tisagenlecleucel and had at least 6 months of follow-up unless they died earlier.

Efficacy outcomes for assessment included ORR, CR/PR rates, progression-free survival (PFS), duration of response (DOR), and overall survival. Safety outcomes for assessment included cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).

The overall infused patient population (n = 682) comprised an efficacy set (n = 613) and a safety set (n = 625). The efficacy set consisted of JULIET-eligible patients (n = 200) and JULIET-ineligible patients (n = 413), as did the safety set (n = 202 and n = 423, respectively).

Reasons for JULIET ineligibility in the infused set included age less than 18 years (n = 1; 0.1%), ECOG performance status (PS) of 2 or higher (n = 137; 20.1%), ineligible disease histology (n = 38; 5.6%), radiographic CR at infusion (n = 55; 8.1%), less than 2 prior lines of therapy (n = 109; 16%), prior allogeneic hematopoietic stem cell transplant (allo-HSCT; n = 18; 2.6%), and comorbidities (n = 372; 54.5%). This translated to a total of 462 JULIET-ineligible patients (67.7%).

The median follow-up in all patients was 16.3 months (range, 6-34.7).

In the infused set, patients were a median age of 66.5 years (range, 14-91) at infusion, with the majority of patients (n = 377; 55.3%) being at least 65 years of age and 17.6% (n = 120) being at least 75 years of age. Most patients (n = 400; 58.7%) were male.

Most patients (n = 366; 53.7%) had relapsed disease while 38.3% (n = 261) had primary refractory disease. Patients had a median of 3 prior therapies (range, 0-11). Most patients (n = 545; 79.9%) had an ECOG PS of 0 or 1.

The majority of patients (n = 554; 81.2%) had DLBCL; 12.9% (n = 88) had HGBL, 11.4% (n = 78) of which was double- or triple-hit lymphoma, and 27.9% (n = 190) had transformed lymphoma, 3.8% (n = 26) of which was transformed from chronic lymphocytic leukemia. Regarding prior HSCT, 25.8% (n = 176) of patients had prior autologous HSCT, 1.6% (n = 11) had prior allo-HSCT, and 0.4% (n = 3) had both.

Moreover, most baseline patient demographics except for ECOG PS were similar between JULIET-eligible and JULIET-ineligible subgroups, Landsburg explained.

Additional results showed that the median time from receipt of leukapheresis product at the manufacturing site to shipment was 26 days (range, 24-32) in all patients, 26 days (range, 25-

31) in JULIET-eligible patients, and 26 days (range, 24-32) in JULIET-ineligible patients. The rate of PR to CR conversion was 2%, 3%, and 1.5%, respectively.

By JULIET eligibility, the median PFS was 3.9 months (95% CI, 3.16-5.13) in JULIET-eligible patients, 3.9 months (95% CI, 3.29-4.93) in JULIET-ineligible patients, and 3.9 months (95% CI, 3.36-4.80) in all patients. By BOR, the median PFS was not evaluable (NE; 95% CI, 14.84-NE) with CRs (n = 260), 5.1 months (95% CI, 3.62-7.4) with PRs (n = 92), and 14.8 months (95% CI, 9.34-NE) with CR/PRs (n = 352).

The 12-month PFS rates were similar between JULIET-ineligible patients and the efficacy set, both reflecting similar rates as observed in the JULIET trial at 34.6%.

By JULIET eligibility, the median DOR was 10.9 months (95% CI, 4.44-NE) in JULIET-eligible patients, NE (95% CI, 7.14-NE) in JULIET-ineligible patients, and NE (95% CI, 7.2-NE) in all patients. By BOR, the median DOR was NE (95% CI, NE-NE) with CRs, 3.1 months (95% CI, 2.37-4.87) with PRs, and NE (95% CI, 7.2-NE) with CR/PRs.

“The 12-month DOR of 54% was similar between JULIET eligible- and -ineligible patients and was numerically lower than that seen in JULIET at 63%; however, it is worth noting the much narrower confidence interval in our cohort as expected from a larger patient sample size,” Landsburg said.

Regarding safety, any-grade CRS per American Society for Transplantation and Cellular Therapy (ASTCT) grading was observed in 51.8% of patients; 8% of patients had grade 3 or greater CRS, and 0.5% of patients had grade 5 CRS. Therapy for CRS was provided to 60.5% of patients overall; treatment interventions included tocilizumab (Actemra; 44.1%), corticosteroids (15.4%), siltuximab (Sylvant; 0.9%), and others (17.9%). The median time to onset of CRS was 4 days (range, 1-30), and the median time to resolution of CRS was 5 days (range, NE-NE).

“The rate of use of therapy was higher in the JULIET-ineligible subgroup. This may be because these patients were less fit and their clinicians felt they would not tolerate ongoing CRS or higher-grade CRS well and chose to use therapy to treat this,” Landsburg said.

Notably, the rates of grade 3 or higher CRS were lower in the CIBMTR population compared with the JULIET trial population at 8% vs 13.5%, respectively.

Tocilizumab was provided to 44.1% of patients with any-grade CRS; the maximum CRS grade tocilizumab was used in included grade 1 (39.9%), grade 2 (34.3%), grade 3 (12.6%), grade 4 (5.6%) and grade 5 (2.1%).

“While 44% of patients received tocilizumab for CRS, 74% of those patients received it for grade 1 or 2 CRS. In the JULIET study, tocilizumab was only recommended for grade 3 or 4 CRS. It is very possible that earlier use of tocilizumab prevented the onset of higher-grade CRS in this patient population,” Landsburg said.

Regarding ICANS, any-grade ICANS was observed in 19.8% of all patients; 7.7% of patients had grade 3 or higher ICANS and 0.8% of patients had grade 5 ICANS. Corticosteroids were provided to 58.9% of patients. The median time to onset of ICANS was 6 days (range, 1-33), and the median time to resolution of ICANS was 9 days (range, 6-11).

Notably, the rates of grade 3 or higher ICANS were lower in the CIBMTR population compared with the JULIET trial population at 7.7% vs 12.6%, respectively.

“Approximately two-thirds of patients in this analysis were deemed JULIET ineligible, suggesting that patients with relapsed/refractory aggressive lymphomas may benefit from commercial tisagenlecleucel even if they would not have met criteria for the JULIET study,” Landsburg concluded.

1. Landsburg DJ, Frigault MJ, Hu ZH, et al. Real-world efficacy and safety outcomes for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin’s lymphoma (aBNHL) treated with commercial tisagenlecleucel: update from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. Presented at 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 429.

2. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. News release. FDA. May 1, 2018. Accessed December 12, 2021. https://bit.ly/3E0sxg5

3. Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. 

 2021;22(10):1403-1415. doi:10.1016/S1470-2045(21)00375-2

Real-world data on tisagenlecleucel in patients with relapsed/refractory B-cell lymphoma was consistent with the phase 2 JULIET trial, demonstrating favorable efficacy and safety. 

Real-World Study of Tisagenlecleucel in R/R B-Cell Non-Hodgkin Lymphomas Shows Efficacy, Safety

The combination of obinutuzumab (Gazyva) and venetoclax (Venclexta; GVe), as well as GVe plus ibrutinib (Imbruvica; GIVe) demonstrated superior rates of undetectable minimal residual disease (uMRD) compared to chemoimmunotherapy in fit patients with chronic lymphocytic leukemia (CLL), according to data presented during the 2021 Annual ASH Meeting and Exposition.

In the phase 3 GAIA (CLL13) trial (NCT02950051), at 15 months the rate of uMRD (< 10-4) was 86.5% (97.5% CI, 80.6%-91.1%) with GVe compared with 52% (97.5% CI, 44.4%-59.5%) with chemoimmunotherapy (

 < .0001). The rate of uMRD was 92.2% (97.5% CI, 87.3%-95.7%) with GIVe vs 52% with chemoimmunotherapy (

The combination of rituximab (Rituxan) and venetoclax (RVe) was not found to induce statistically significantly higher rates of uMRD compared with chemoimmunotherapy, at 57% (97.5% CI, 49.5%-64.2%) vs 52%, respectively (

Venetoclax-based, time-limited therapies have demonstrated high efficacy in unfit patients with CLL. Findings from the phase 3 CLL14 trial (NCT02242942) demonstrated that the median progression-free survival (PFS) was not reached with the combination of venetoclax and obinutuzumab vs 36.4 months with chlorambucil and obinutuzumab (HR, 0.33; 95% CI, 0.25-0.45; 

 < .0001).2 The 4-year PFS rates were 74% vs 35.4%, respectively.

In the phase 3 CLL10 trial (NCT00769522), the chemoimmunotherapy combination of fludarabine, cyclophosphamide, and rituximab (FCR) demonstrated improved PFS in older and younger patients compared with bendamustine/rituximab (BR).3 The median PFS was 57.6 months with FCR in patients 65 years of age or younger and 57.9 months with FCR in patients older than 65 years of age compared with 38.2 months with BR in patients 65 years of age or younger and 48.5 months with BR in patients older than 65 years of age.

“The first co-primary end point of uMRD rate in peripheral blood at month 15 was met by this study, showing a highly significantly superior uMRD rate with GVe in fit patients, confirming or even exceeding the results of the CLL14 trial in unfit patients. The triplet combination achieved even higher rates of uMRD,” said lead study author Barbara Eichhorst, MD, an associate professor and attending physician at the University Hospital Cologne in Cologne, Germany, during a presentation of the data.

The GAIA trial aimed to determine whether venetoclax-based, time-limited, frontline combinations were superior to chemoimmunotherapy.

Fit patients with CLL whose Cumulative Incidence Rating Scale (CIRS) score was 6 or less and had normal creatinine clearance were eligible to enroll on the study. Patients must not have harbored 

 mutations or 17p deletions by central screening.

Overall, 926 patients were randomized to 1 of 4 arms: chemoimmunotherapy (FCR, n = 150; BR, n = 79 or BR; total, n = 229), RVe (n = 237), GVe (n = 229), or GIVe (n = 231). Chemoimmunotherapy was given based on age with patients 65 years or younger receiving FCR and patients older than 65 receiving BR.

Patients were stratified by age, disease stage, and region.

The co-primary end points of the study were uMRD at 15 months in the GVe vs chemoimmunotherapy arms and PFS in the GIVe vs chemoimmunotherapy arms. However, the PFS interim analysis was postponed because of a low number of events; the results are expected in quarter 1 of 2022.

uMRD was defined as less than 10-4 in the peripheral blood and was assessed by 4-colour-flow.

All treatment regimens were given in 28-day interval cycles. Notably, patients randomized to the GIVe regimen were eligible to continue ibrutinib for up to 36 cycles if they had detectable MRD.

Patients in the intention-to-treat (ITT) cohort (n = 926) were a median age of 61 years (range, 27-84). The median CIRS score was 2 (range, 0-7), and the median creatinine clearance by the Cockcroft-Gault equation was 85.7 mL/min (range, 39.5-268.3). Binet stages ranged from stage A (n = 246; 26.6%), stage B (n = 350; 37.8%), and stage C (n = 330; 35.6%).

Risk factors in the overall ITT population included deletion 11q (n = 162; 17.5%), trisomy 12 (n = 150; 16.2%), and deletion 13q (n = 413; 44.6%). Moreover, 21.7% of patients (n = 201) did not have any cytogenetic abnormalities. Most patients (n = 518; 56%) had unmutated 

; 41.1% (n = 380) of patients had mutated 

At a median follow-up of 27.9 months (range 0-49), 81.5% (n = 176) of patients who received chemoimmunotherapy completed at least 12 cycles of treatment vs 92.4% (n = 219) of patients who received RVe, 93.9% (n = 214) of patients who received GVe, and 85.3% (n = 197) of patients who received GIVe. Reasons for treatment discontinuation included adverse effects (AEs) or intercurrent illness, progressive disease, and other reasons. Dose intensity reductions were required in 14.8% (n = 32), 19.3% (n = 44), 21.5% (n = 47), and 36.5% (n = 81) of patients, respectively.

Overall, 19% of patients (n = 35) completed at least 12 cycles of treatment, 72% (n = 135) completed 13 to 15 cycles of treatment with ibrutinib alone, and 10% (n = 18) completed 16 to 36 cycles of treatment with ibrutinib alone.

In the ibrutinib-containing arm, early treatment discontinuations may have been caused by more than 1 reason and 9 patients were not evaluable for dose modification because of unclean data.

Additional results compared uMRD rates in the peripheral blood vs bone marrow at 15 months. Respectively, the rates were 52% vs 37.1% in the chemoimmunotherapy arm, 57% vs 43% in the RVe arm, 86.5% vs 72.5% in the GVe arm, and 92.2 vs 77.9% in the GIVe arm.

Per International Workshop on CLL criteria, complete remissions with incomplete bone marrow recovery (CRis) were observed in 61.9% of patients who received GIVe, 56.8% of patients who received GVe, 49.4% of patients who received RVe, and 31% of patients who received chemoimmunotherapy. Clinical CRis were observed in 10%, 10.5%, 11.4%, and 30.1% of patients, respectively. Partial responses (PRs) were observed in 22.5%, 28.8%, 32.5%, and 19.7% of patients, respectively.

Best responses until month 15 included CRis in 62.3% of patients with GIVe, 56.8% of patients with GVe, 49.4% of patients with RVe, and 39.3% in patients with chemoimmunotherapy. Clinical CRis were reported in 30.7%, 35.4%, 41.8%, and 42.8% of patients, respectively. PRs were reported in 6.5%, 6.1%, 7.2%, and 10% of patients, respectively.

Regarding safety, any-grade AEs were reported in 98.7% of patients who received GIVe, 98.7% of patients who received GVe, 96.6% of patients who received RVe, and 98.6% of patients who received chemoimmunotherapy. Maximum grade 3 AEs were observed in 46.3%, 49.6%, 46.8%, and 37.5% of patients, respectively. Maximum grade 4 AEs were observed in 32%, 32.5%, 21.5%, and 38.9% of patients, respectively. Maximum grade 5 AEs were observed in 3.9%, 2.6%, 3%, and 2.3% of patients, respectively.

The most common grade 3 or higher AEs included anemia, neutropenia, thrombocytopenia, febrile neutropenia, infections, tumor lysis syndrome (TLS), bleeding events, and atrial fibrillation. Of these, febrile neutropenia was reported in 7.8% of patients with GIVe, 3.1% of patients with GVe, 4.2% of patients with RVe, and 11.1% of patients with chemoimmunotherapy. Infections were reported in 22.1%, 14%, 11.4%, and 19.9% of patients, respectively. TLS was reported in 6.5%, 8.8%, 10.1%, and 4.2% of patients, respectively.

Twelve patients developed grade 5 AEs during therapy until day 84 after end of treatment; these included infections other than COVID-19 (n = 4), COVID-19 (n = 2), and secondary neoplasia (n = 4). Fifteen patients developed grade 5 AEs after 84 days following end of treatment; these included pneumonia (n = 2), Richter transformation (RT; n = 3), and secondary neoplasia. Other grade 5 AEs included suicide, RT, toxic leukoencephalopathy, cardiac arrest, and respiratory failure.

“Although there were some severe BTK-associated AEs, the AE profiles did not otherwise show significant differences between arms,” concluded Eichhorst.

Eichhorst B, Niemann CU, Kater AP, et al. A randomized phase III study of venetoclax-based time-limited combination treatments (RVE, GVE, GIVE) vs standard chemoimmunotherapy (CIT: FCR/BR) in frontline chronic lymphocytic leukemia of fit patients: first co-primary endpoint analysis of the international intergroup GAIA (CLL13) trial. Presented at 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 71.

Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. 

. 2020; 21(9):1188-1200. doi:10.1016/S1470-2045(20)30443-5

Kutsch N, Bahlo J, Robrecht S, et al. Long-term follow-up data and health-related quality of life in frontline therapy of fit patients treated with FCR versus BR (CLL10 trial of the GCLLSG). 

 2020;4(1):e336. doi:10.1097/HS9. 0000000000000336

Looking at frontline venetoclax based combinations shows promise for fit patients with CLL. 