Ashling Wahner

Patients with blood cancer who were given Orca-T to prevent post-transplantation graft-versus-host disease (GVHD) tended to have better survival than those treated with post-transplant cyclophosphamide (PTCy), according to recent findings presented at the 2024 Transplantation & Cellular Therapy Meetings.

Of note, all patients had matched unrelated donors and were undergoing myeloablative conditioning (MAC), which delays an immune response to the donor cells.

Compared to traditional post-transplant cyclophosphamide (PTCy), Orca-T tends to result in better survival rates and lower rates of post-transplant complications.

The study, presented at the 2024 Transplantation & Cellular Therapy Meetings, found that Orca-T led to a 77% relapse-free survival rate and a 94% overall survival rate, compared to 62% and 77% respectively with PTCy.

These findings highlight the importance of identifying effective treatments to improve outcomes for patients undergoing stem cell transplantation, where over 40% face mortality within three years due to various complications.

Ongoing research, including the Orca Precision-T trial, aims to further evaluate Orca-T's effectiveness in different patient populations and refine its use in clinical practice.

The relapse-free survival (RFS; time patients lived without experiencing relapse) rate was 77% in the cohort of patients who received Orca-T vs 62% in the cohort of patients who received PTCy. Furthermore, the non-relapse mortality (NRM; post-transplant death without relapse or recurrent diseaes) rates with Orca-T and PTCy were 3% and 16%, respectively, and the overall survival (OS; percentage of patients who are still alive) rates were 94% and 77%, respectively.

“The positive impact [of Orca-T] on RFS, NRM and OS highlight the importance of identifying treatment approaches that may be beneficial across all key transplant outcomes in addition to the reduction of [chronic] GVHD,” Dr. Alexandra Gomez Arteaga, lead study author and an assistant professor of Medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine/New York-Presbyterian Hospital in New York, New York, stated in the presentation.

Although progress has been made in the treatment of patients with hematologic malignancies requiring allogeneic stem cell transplantation, over 40% of patients who receive allogeneic hematopoietic stem cell transplant (HSCT) die within the first three years of receiving this treatment, with most deaths caused by primary relapse (53%), infection (14%), GVHD (13%) and organ failure (13%). However, Orca-T cell therapy may improve clinical outcomes for these patients.

In the phase 3 BMT CTN 1703 trial, significantly higher GVHD-free RFS rates were observed with PTCy/mycophenolate mofetil/tacrolimus prophylaxis compared with standard prophylaxis in patients who received reduced-intensity conditioning.In the myeloablative setting, however, outcomes in the PTCy arm were not different than those with tacrolimus plus methotrexate. Despite these findings, the use of PTCy in the MAC setting has increased, and NRM and relapse risk continue to be drivers of PTCy progression.

This retrospective study compared historical outcomes with Orca-T vs PTCy in patients who received peripheral blood stem cell (PBSC) grafts and MAC. The Orca-T cohort (111 patients) used clinical data from a multicenter phase 1b trial of Orca-T plus single-agent tacrolimus, which had primary end points of the incidence and timing of primary graft failure and the incidence and timing of moderate to severe (grade 3/4) acute GVHD.

Patients were at least 18 years of age, with a median age of 49 years (range, 20-65). Primary diseases included acute leukemia in complete remission (CR; no detectable disease) or CR with incomplete hematologic recovery (CRi; acute myeloid leukemia [AML; 45.9%], acute lymphoblastic leukemia [ALL; 33.3%], and mixed phenotype [1.8%]), myelodysplastic syndrome (MDS; 15.3%), or chronic myeloid leukemia (CML; 3.6%) treated with Orca-T between 2019 and 2022.

Patients were required to have 8/8 matched related or unrelated donors, and 50.5% of patients had matched related donors. Forty-seven percent of patients were female, and patients had a hematopoietic cell transplantation–specific comorbidity index (HCT-CI; a scale used to predict prognosis) of up to 4 and a Karnofsky performance score (KPS) of at least 70, indicating that they can do most of their daily tasks independently. The median follow-up in this trial was 17 months.

Investigators found no difference in outcomes between matched unrelated donors and matched sibling donors with Orca-T in this trial.

Data from patients who underwent Orca-T treatment were compared to another cohort (83 patients), which consisted of data from a publicly available dataset from the Center for International Blood & Marrow Transplant Research (CIBMTR) database, which included 284 MUD transplantations with PTCy GVHD prophylaxis.

Patients were at least 18 years of age, with a median age of 52 years (range, 18-71). Primary diseases included ALL (26.5%), AML (49.4%), and MDS (24.1%). Forty-nine percent of patients were female, and all patients had 8/8 matched unrelated donors. The primary end point of this dataset was OS, and patients had a median follow-up of 12 months. The limitations to this CIBMTR dataset were that it included only matched unrelated donors, the treatment time frame was from 2011 to 2018, and the incidence of chronic GVHD (cGVHD) was not reported by grade, so investigators were unable to delineate the percentages of moderate and severe GVHD in this population.

The key outcomes assessed in this retrospective analysis were RFS, NRM and OS.

In the myeloid subgroup of the Orca-T cohort (48 patients), the median age was 54 years (range, 20-64) and the median follow-up was 15 months. Forty-eight percent of patients were female, and 58% had HLA-matched related donors. Additionally, 77.1% had ALL and 22.9% had MDS.

In the myeloid subgroup of the PTCy cohort (61 patients), the median age was 57 years (range, 20-71) and the median follow-up was 12 months. Forty-nine percent of patients were female, and 100% had HLA-matched unrelated donors. Additionally, 67.2% had ALL and 32.8% had MDS.

In the myeloid subgroups of the Orca-T and PTCy cohorts, the respective RFS rates were 86% and 63%, the respective NRM rates were 0% and 17%, and the respective OS rates were 100% and 76%.

Investigators found that older age was associated with higher NRM rates with PTCy but not with Orca-T. At 12 months, the NRM rates in patients with myeloid diseases who were younger than 55 years of age were 0% and 8.5% in the Orca-T and PTCy subgroups, respectively. These rates were 0% and 24%, respectively, in patients with myeloid diseases who were older than 55 years of age.

Limitations of this research include its retrospective, nonrandomized design. In the future, investigators plan to evaluate Orca-T vs PTCy in the MAC setting in contemporary homogenous patient populations that include 8/8 matched related and unrelated donors and comparable PBSC donor sources.

Long-term follow-up of this future research at two years and beyond will further demonstrate the differences in key clinical outcomes between treatment with Orca-T and PTCy, including relapse, GVHD, infections, organ toxicities, engraftment syndrome and length of hospitalization and hospital readmissions.

“Acknowledging the limitations of historical comparisons and retrospective analyses, Orca-T could potentially provide improved outcomes as compared with PTCy-based MAC with PBSC graft in patients with acute leukemia or MDS,” Gomez-Arteaga concluded.

The randomized phase 3 Orca Precision-T trial is currently enrolling patients across the United States with undifferentiated AML, ALL or mixed-phenotype acute leukemia who are in CR or CRi to their last line of therapy, as well as patients with high-risk, therapy-related MDS, including those with active disease at the time of transplant. Patients must be planned to undergo myeloablative allogeneic HSCT including one of the following MAC regimens: busulfan plus fludarabine and thiotepa, total body irradiation (TBI) plus etoposide, or TBI plus cyclophosphamide. Additionally, patients must be ages 18 to 65 and have an 8/8 matched related or unrelated donor, an HCT-CI of up to 4, a KPS of at least 70, and adequate organ function.

Patients will be randomly assigned to receive either Orca-T plus single-agent tacrolimus prophylaxis (87 patients) or standard unmanipulated allograft plus dual-agent tacrolimus and methotrexate prophylaxis (87 patients). cGVHD-­free survival will serve as the primary end point of the trial, and secondary end points will include GVHD-free RFS, moderate-to-severe cGVHD and RFS.

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Orca-T outperformed post-transplant cyclophosphamide when it came to relapse-free survival and overall survival in patients with blood cancer who underwent a stem cell transplantation from a matched unrelated donor. 

Orca-T Improves Post-Transplant Survival in Patients With Blood Cancers

Postsurgical Keytruda (pembrolizumab) tended to lengthen the time patients lived without relapse or complications from their cancer — a statistic known as “disease-free survival” (DFS) — compared to observation in patients with locally advanced urothelial carcinoma (bladder cancer), according to data from the phase 3 AMBASSADOR Alliance A031501 trial.

Keytruda showed promise in extending disease-free survival for patients with locally advanced urothelial carcinoma (bladder cancer) after surgery, compared to observation alone.

The positive effects of Keytruda were observed irrespective of the PD-L1 status, a pathway in cancer cells that Keytruda targets to enhance the immune system's ability to combat cancer.

While the trial met its main goal, the overall survival endpoint — which is the time patients live before death of any cause — did not show a significant difference, potentially influenced by patients in the observation group later receiving a checkpoint inhibitor.

The AMBASSADOR trial, which compared Keytruda to observation, closed early due to the FDA approval of adjuvant Opdivo for high-risk urothelial carcinoma in August 2021.

Keytruda demonstrated benefits across various patient subgroups, except for those with a primary tumor site in the upper tract, which requires further investigation.

Keytruda’s benefit was observed regardless of PD-L1 status, according to findings presented at the 

2024 ASCO Genitourinary Cancers Symposium

. PD-L1 is part of the PD-1 pathway found on cancer cells that Keytruda inhibits. In doing so, the immune system is better able to find and fight cancer.

At a median follow-up of 22.3 months, the median DFS with Keytruda in the intention-to-treat population was 29 months versus 14 months with.

However, at a median follow-up of 36.9 months, the median overall survival (OS; time patients live before death of any cause) was 50.9 months with Keytruda versus 55.8 months with observation.

“The trial met its efficacy end point and is a positive trial,” Dr. Andrea B. Apolo, of the National Institutes of Health in Bethesda, Maryland, stated in a presentation of the data. “The OS end point was not met at interim analysis. It may have been impacted by the high number of patients in the observation arm receiving a checkpoint inhibitor.”

Although the standard of care for patients with muscle-invasive urothelial carcinoma (MIUC) is radical surgery with or without postsurgical cisplatin-based chemotherapy, many patients are not eligible for cisplatin or have persistent muscle-invasive disease after neoadjuvant chemotherapy and surgery. Furthermore, cisplatin-based therapy in the adjuvant setting is not recommended for patients who have received neoadjuvant chemotherapy and is associated with side effects and administration difficulties post-radical surgery in patients not treated with neoadjuvant chemotherapy.

The AMBASSADOR trial assessed the PD-1 checkpoint inhibitor Keytruda versus observation in patients with high-risk MIUC, including cancers of the bladder, renal pelvis, urethra and ureter.Patients must have received radical surgery, including cystectomy, nephrectomy, nephroureterectomy or ureterectomy, more than four but no more than 16 weeks before trial initiation

AMBASSADOR closed early because of the August 2021 FDA approval of adjuvant Opdivo (nivolumab) for patients with high-risk urothelial carcinoma.

Patients in AMBASSADOR were randomly assigned to either Keytruda (354 patients) every three weeks for one year (18 cycles) or observation (348 patients).

DFS and OS served as the main areas assessed by researchers. Other areas of interest included DFS and OS by PD-L1 status and safety. Researchers also assessed DFS and OS by circulating tumor DNA (ctDNA) status; DFS and OS by immune gene signatures; DFS and OS by tumor molecular subtype; DFS and OS by T-cell receptor clonality; and quality of life.

A total of 131 and 126 OS events occurred in the Keytruda and observation arms, respectively. Patients in the Keytruda arm received a mean of 11 treatment cycles. All patients enrolled in the trial are currently not receiving study treatment.

All prespecified patient subgroups benefitted from Keytruda versus observation, except for those with a primary tumor site of the upper tract.

“The upper tract subgroup I think needs further investigation, and the magnitude of benefit is unclear,” Apolo noted.

In patients with PD-L1–positive disease, defined as those with a PD-L1 combined positive score (CPS) of at least 10%, the median DFS was 32.8 months with Keytruda versus 20.7 with placebo. In patients with PD-L­1–negative disease, the median DFS was 22.1 months with Keytruda vs 9.1 months with placebo. Regarding OS differences between prespecified patient subgroups, the HR in the subgroup whose primary site was in the upper tract was 1.45.

The median OS in patients with PD-L1–positive disease was not reached (meaning that researchers could not analyze this outcome because more than half of patients were alive) with Keytruda versus 56.1 months with observation. The median OS in patients with PD-L1–negative disease was 43.8 months with Keytruda versus 36.7 months with observation.

“PD-L1 positivity using the CPS was associated with a better prognosis but was not predictive for treatment efficacy,” Apolo emphasized. “PD-L1 status should not be used to select patients for treatment.”

Among the patients in the Keytruda arm who did not withdraw consent, 99 received alternative systemic therapy. Patients were permitted to report multiple alternative treatments. In the post-DFS setting, 82 patients received alternative systemic therapy, including a checkpoint inhibitor (19 patients), chemotherapy (38 patients), antibody-drug conjugates (ADCs; 45 patients), and other therapy (four patients). In the pre-DFS setting, 17 patients received alternative systemic therapy, including a checkpoint inhibitor (six patients), chemotherapy (four patients) and ADCs (three patients).

Among the patients in the observation arm who did not withdraw consent, 123 received alternative systemic therapy. In the post-DFS setting, 104 patients received alternative systemic therapy, including a checkpoint inhibitor (76 patients), chemotherapy (34 patients), ADCs (21 patients) and other therapy (three patients). In the pre-DFS setting, 19 patients received alternative systemic therapy, including a checkpoint inhibitor (18 patients), chemotherapy (six patients) and ADCs (one patient).

In the Keytruda arm, 48.4% of patients experienced side effects of grade 3 or higher, meaning that they were moderate to severe. In total, 38.6%, 4.9% and 4.9% of patients had grade 3 (moderate), 4 (severe) and 5 (fatal) side effects, respectively. Grade 3 and 4 blood-related side effects were observed in 5.5% and 0.9% of patients, respectively. Among the non-hematologic side effects observed, 37.7%, 4.6% and 4.9% were grade 3, 4 and 5, respectively.

Keytruda Side Effects: ‘If Something Doesn’t Feel Right … Call’

In the observation arm, 31.8% of patients experienced side effects of grade 3 or higher. In total, 23.3%, 3.8% and 4.7% of patients had grade 3, 4 and 5 side effects, respectively. Grade 3 blood-related side effects were observed in 2.6% of patients, and no grade 4/5 blood-related side effects were reported. Among the non-hematologic side effects observed, 22.7%, 3.8% and 4.7% were grade 3, 4 and 5, respectively.

Among the patients who received Keytruda, the most common treatment-related side effects were fatigue (any-grade, 47%; grade 3, 2%); itching (22%; 1%); diarrhea (21%; 3%); hypothyroidism (20%; 0%); maculo-papular rash (17%; 2%); increased creatine (15%; 1%); anorexia (15%; 1%); anemia (14%; 2%); increased lipase, which can indicate pancreatic issues (13%; 3%); difficulty breathing (11%; 0%); increased serum amylase, which can also indicate pancreatic issues (9%, 2%); hyperthyroidism (8%; 0%); and increased alanine aminotransferase (6%; 1%). Additionally, 1% of patients experienced grade 4 lipase increase.

“These results support adjuvant (Keytruda) as a new therapeutic option for patients MIUC at high risk of recurrence,” Apolo concluded.

Follow-up is ongoing for the final DFS/OS analysis of AMBASSADOR, as well as the ctDNA analyses and additional correlative analyses.

Postsurgical Keytruda improved disease-free survival — but not overall survival — in patients with locally advanced, muscle-invasive bladder cancer. 

Keytruda Improves Disease-Free Survival in Advanced Bladder Cancer

Patients with resectable mismatch repair–proficient and mismatch repair–deficient colorectal cancer treated with neoadjuvant (treatment given to shrink a tumor before the main treatment) botensilimab plus balstilimab had robust responses and prolonged circulating tumor DNA (ctDNA)/minimal residual disease (MRD) negativity.

Findings from the phase 2 NEST-1 trial were presented at the 

Of note, patients with mismatch repair–proficient colorectal cancer have a mismatch repair system that functions properly and helps to maintain DNA stability, whereas those with mismatch repair-deficient disease have cells with mutations in genes responsible for correcting mistakes that are made when DNA is copied in a cell.

 Patients with both resectable mismatch repair–proficient and mismatch repair–deficient colorectal cancer showed strong responses to neoadjuvant treatment with botensilimab plus balstilimab.

Extended circulating tumor DNA (ctDNA)/minimal residual disease (MRD) negativity:

 The treatment resulted in prolonged negativity of ctDNA/MRD, which are indicators of cancer presence. This suggests a positive impact on the disease.

 Mismatch repair–proficient colorectal cancer has a properly functioning system that helps maintain DNA stability, while mismatch repair-deficient cancer has mutations affecting this system. Knowing this helps tailor treatments.

A significant number of patients experienced pathologic responses, including tumor reduction. In some cases, the reduction was substantial, reaching at least 50% or even 90%, indicating positive outcomes.

 The neoadjuvant treatment was deemed safe, with no surgical delays or severe side effects. Analysis of tissue samples showed a robust immunogenic response, where immune cells penetrated cancer cells, providing insights into the pattern of immune responses.

ctDNA refers to small pieces of DNA that are released into a patient’s blood by tumor cells as they die, whereas MRD is a very small number of cancer cells in the body after treatment.

A total of 67% of patients with microsatellite-stable (when microsatellite DNA segments are not mutated in the disease) colorectal cancer (nine patients) experienced pathologic responses, defined as tumor reduction of at least 50%, and 100% of patients with microsatellite instability–high (cancer cells with many mutations within microsatellites) colorectal cancer (three patients) experienced major pathologic responses, defined as tumor reduction of at least 90%. In the microsatellite stable population, tumor reductions of 100% (complete response [disappearance of all signs of cancer from treatment]; two patients), 90% (one patient), 85% (one patient), 50% (two patients), 25% (one patient) and 10% (one patient) were observed. In the microsatellite instability–high population, tumor reductions of 100% (complete response; two patients) and 98% (one patient) were observed.

“Neoadjuvant botensilimab/balstilimab is a safe and active regimen in both (resectable mismatch repair–proficient)/microsatellite stable and (mismatch repair–deficient)/(microsatellite instability–high colorectal cancer),” lead study author Dr. Pashtoon Murtaza Kasi, of Weill Cornell Medicine and NewYork Presbyterian Hospital in New York, New York, and colleagues, wrote in a poster of the data.

The single-arm NEST-1 trial evaluated botensilimab plus balstilimab in the neoadjuvant setting in 12 patients with colon and rectal cancer who were eligible for surgery. All patients received one fixed dose of botensilimab plus two fixed doses of balstilimab at two weeks apart. Patients were permitted to proceed to surgery one week after completing the second dose of balstilimab. Less than 25% of patients were permitted to have mismatch repair–deficient/microsatellite instability–high disease.

Pre-treatment disease stages included stage 1 (one patient), stage 3A (one patient), stage 3B (five patients) and stage 3C (four patient). One patient had TXN0 disease, meaning the tumor could not be evaluated and there was no regional lymph node metastasis. Post-treatment disease stages included no tumor (four patients), stage 1 (three patients), stage 2A (two patients), stage 3A (one patient), stage 3B (one patient) and stage 3C (one patient

All patients enrolled in NEST-1 safely received botensilimab/balstilimab without surgical delay or increased risk of severe side effects. Six patients experienced no side effects. The remaining six patients experienced severe diarrhea; mild chills/fever; mild chills/headache and moderate fever; mild chills, headache, dizziness and severe fatigue; mild flu-like symptoms and mild fever; and mild fatigue, rash and headache.

Investigators assessed tissue immune microenvironment correlates on colon and rectal samples before and after immunotherapy. This analysis demonstrated a robust immunogenic pathologic response known as the “inside-out” phenomenon. Contrary to the pattern of response observed with neoadjuvant chemotherapy, targeted therapy and/or radiation, during the “inside-out” response, immune cells penetrate the cancer cells from layers deep within the body.

“Analyses show a significant increase and a diverse array of immune cells in more than one instance, shedding novel insights into the mechanism and pattern of immune responses,” the study authors noted in the poster.

Additionally, 100% of patients who were positive for ctDNA at screening (7 patients) cleared ctDNA. Furthermore, 100% of patients who were tested for ctDNA after surgery (11 patients) remained ctDNA/MRD negative for more than 30 cumulative blood draws.

“Clinical downstaging and deep pathological responses provide a framework for reduced reliance on surgery and/or adjuvant chemotherapy in future studies,” the study authors concluded in the poster.

Patients with resectable mismatch repair-proficient and -deficient colorectal cancer had robust responses to neoadjuvant botensilimab/balstilimab.

Neoadjuvant Botensilimab/Balstilimab Produces Early Responses in CRC

Tecartus was safe and effective in a real-world population of patients with high-risk, relapsed/refractory mantle cell lymphoma.

For patients with relapsed/refractory mantle cell lymphoma (MCL), regardless of the presence of high-risk features, Tecartus (brexucabtagene autoleucel) is safe and effective, according to findings from a subgroup analysis that were presented during the 2023 ASH Annual Meeting. These findings, which consisted of data from patients in the real-word setting and not on a clinical trial, were consistent with those observed in patients who received the agent in the pivotal phase 2 ZUMA-2 trial.

At a median follow-up of 12.3 months, the overall response rates (ORR; patients whose disease responded partially or completely to treatment) and complete response (CR; percentage of patients whose disease completely disappears) rates were consistent across patients in all observed high-risk subgroups. In the overall population, the ORR was 91%, with an 81% CR rate. In patients with TP53/17p deletions, no TP53/17p deletions, a Ki-67 proliferation index of at least 50%, a Ki-67 proliferation index of less than 50%, ZUMA-2 trial eligibility and ZUMA-2 trial ineligibility, the ORRs were 95%, 90%, 92%, 93%, 93% and 90%, respectively, and the CR rates were 84%, 81%, 83%, 84%, 79% and 84%, respectively.

“In this Center for International Blood and Marrow Transplant Research (CIBMTR) registry analysis, patients with high-risk features, including TP53 deletions and a high Ki-67 (proliferation index), did not have significant differences in efficacy outcomes compared with patients without these high-risk features,” lead study author Dr. Swetha Kambhampati, an assistant professor in the division of lymphoma, department of hematology and hematopoietic cell transplantation at City of Hope in Duarte, California, stated during a presentation of the data. “In the univariate analysis, patients without 

 deletions did have a numerically longer (median) overall survival (OS; time from treatment until death of any cayse) than those with TP53 deletions, but this wasn’t statistically significant.”

Of note, when the difference between two data points is not statistically significant, that means that researchers cannot definitively say that one treatment is better than the other.

Patients with relapsed/refractory MCL and high-risk features, such as TP53 mutations, TP53 deletions or a high Ki-67 proliferation index, have historically had limited treatment options. The CAR-T cell therapy, 

Tecartus, received FDA approval in 2020 

for adult patients with relapsed/refractory MCL based on findings from ZUMA-2.A three-year follow-up analysis of the study demonstrated comparable outcomes with Tecartus across prespecified high-risk subgroups.

This real-world analysis describes outcomes with Tecartus stratified by high-risk features, such as TP53 deletions, 17p deletions, Ki-67 proliferation index and ZUMA-2 trial eligibility.

Between 2020 and 2022, 499 adult patients who were receiving Tecartus for relapsed/refractory MCL across 85 centers in the United States were prospectively enrolled in the CIBMTR registry. Of these patients, 456 from 84 treatment centers were included in this real-world study. Forty-three patients were excluded because of a prior history of non-transplant cellular therapy (seven patients), a lack of efficacy and/or safety follow-up data (15 patients) or missing data (21 patients).

Of the evaluable patients, 42% had TP53 or 17p deletions (44 patients) and/or a Ki-67 proliferation index of at least 50% (146 patients). Furthermore, 183 patients had no TP53 or 17p deletions and 111 patients had a Ki-67 proliferation index of less than 50%. Moreover, 57% of patients would not have met the ZUMA-2 eligibility criteria, mostly because of the presence of comorbidities prior to Tecartus infusion.

In the overall population, the median age was 67 and 61% of patients were at least 65. Six percent of patients had an ECOG performance status (PS) of 2 or higher (they could not perform all daily tasks independently) prior to Tecartus infusion, 76% of patients had clinically significant comorbidities and 91%, 47% and 71% of patients had stage 3 to 4 disease at diagnosis, elevated lactate dehydrogenase (LDH) levels at diagnosis and were chemoresistant prior to Tecartus infusion, respectively. Patients had received a median of three prior lines of therapy, and 32%, 87% and 44% of patients had received prior hematopoietic cell transplantation (HCT), prior BTK inhibitors or any type of bridging therapy. Furthermore, 9% of patients received planned outpatient Tecartus infusion.

Compared with the overall population, the cohort of patients with TP53 or 17p deletions had fewer patients over the age of 65 (41%), a higher proportion of patients who were chemoresistant prior to Tecartus infusion (81%), and a lower proportion of patients who had received prior HCT (12%). Compared with the overall population, the cohort of patients with a Ki-67 proliferation index of at least 50% had lower proportions of patients with elevated LDH levels at diagnosis (41%), prior BTK inhibitor exposure (81%) and bridging therapy (37%). Compared with the overall population, the cohort of patients who would have been ineligible for enrollment in ZUMA-2 had higher proportions of patients with an ECOG PS of 2 or higher (10%), clinically significant comorbidities (87%) and chemoresistance prior to Tecartus infusion (76%), as well as a lower proportion of patients with prior exposure to BTK inhibitors (78%).

In the overall population, the median duration of response (DOR) was not reached. The estimated six- and 12-month DOR rates in patients who achieved a best response of CR were 83% and 69%, respectively. In all responders, these rates were 78% and 65%, respectively.

Among all 456 patients evaluable for survival, the median OS was not reached, and the estimated six- and 12-month OS rates were 86% and 75%, respectively. Among all 442 progression-free survival (PFS; the time a patient lives without their disease spreading or worsening)–evaluable patients, the median PFS was 19.3 months and the estimated six- and 12-month PFS rates were 75% and 61%, respectively. In comparison, the 12-month PFS and OS rates in the primary analysis of ZUMA-2 were 61% and 83%, respectively.

The six- and 12-month cumulative incidence rates of relapse or progressive disease (PD) were 19% and 30%, respectively, and the median time to relapse or PD among the 442 evaluable patients was 27.5 months.

Univariate analyses revealed no statistically significant differences in OS or PFS at any time point between any high-risk patient subgroups. In patients with TP53 or 17p deletions, the 12-month OS and PFS rates were 57% and 53%, respectively. In patients without TP53 or 17p deletions, the 12-month OS and PFS rates were 76% and 60%, respectively.

In patients with a Ki-67 proliferation index of at least 50%, the 12-month OS and PFS rates were 74% and 63%, respectively. In patients with a Ki-67 proliferation index of less than 50%, the 12-month OS and PFS rates were 76% and 57%, respectively.

In patients who would have been eligible for enrollment in ZUMA-2, the 12-month OS and PFS rates were 75% and 66%, respectively. In patients who would not have met the eligibility criteria for enrollment in ZUMA-2, the 12-month OS and PFS rates were 75% and 58%, respectively.

Safety outcomes with Tecartus did not vary significantly across high-risk subgroups. In the overall population, grade 3 or higher cytokine release syndrome (CRS; inflammatory markers known as cytokines rush into the blood), grade 3 or higher immune effector cell–associated neurotoxicity syndrome (ICANS), prolonged neutropenia, and prolonged thrombocytopenia were observed in 11%, 29%, 15% and 19% of patients, respectively. When adverse effects were stratified by patients with TP53 or 17p deletions, those with no TP53 or 17p deletions, those with a Ki-67 proliferation index of at least 50%, those with a Ki-67 proliferation index of less than 50%, those who met the ZUMA-2 eligibility criteria and those who did not meet the ZUMA-2 eligibility criteria, grade 3 or higher CRS was observed in 9%, 9%, 10%, 8%, 11% and 10% of patients, respectively; grade 3 or higher ICANS was observed in 37%, 30%, 23%, 28%, 27% and 31% of patients, respectively; prolonged neutropenia was observed in 25%, 13%, 14%, 12%, 15% and 16% of patients, respectively; and prolonged thrombocytopenia was observed in 28%, 16%, 20%, 19%, 23% and 14% of patients, respectively. Non-relapse mortality (NRM) rates were consistent across all subgroups, and the one-year NRM rate was 8%.

Upon multivariable adjustment, all safety outcomes were comparable between patients with a Ki-67 proliferation index of at least 50% and those with a Ki-67 proliferation index of less than 50%. The incidence of grade 3 or higher CRS, grade 3 or higher ICANS, infections, and NRM were comparable between patients with and without TP53 or 17p deletions.

Kambhampati noted in the presentation that limitations of this study include its short duration of follow-up and missing granular data regarding high-risk features, such as Mantle Cell Lymphoma International Prognostic Index score at diagnosis, complex karyotype, cytology and level of p53 expression, none of which were captured in the CIBMTR registry. Another limitation is the lack of information regarding TP53 mutations and aberrations, as the registry captured only TP53 deletion status.

These findings warrant further follow-up of the patients in this study with high-risk features.

“This is the largest real-world Tecartus study to date, and further supports the use of Tecartus across a diverse relapsed MCL population, including those with high-risk features, a patient population with limited treatment options and dire prognosis with standard therapies,” Kambhampati concluded.

Tecartus is safe and effective in real-world patients with relapsed/refractory mantle cell lymphoma, regardless of the presence of high-risk features.

Ashling Wahner

Orca-T Improves Post-Transplant Survival in Patients With Blood Cancers

Keytruda Improves Disease-Free Survival in Advanced Bladder Cancer

Neoadjuvant Botensilimab/Balstilimab Produces Early Responses in CRC

Tecartus Induces Responses in Real-World Population of High-Risk R/R MCL

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