"Treatment with liso-cel resulted in high response rates and durable complete responses in a patient population considered to be high risk.”
Lisocabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T-cell agent, induced high response rates with durable complete responses (CRS) in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma who had poor prognostic features and were transplant ineligible. The findings were from the phase 2 PILOT trial (NCT03483103), which were presented during the 2020 European Hematology Association Annual Congress.1
Results showed an overall response rate (ORR) of 89% (n = 24; 95% CI, 71%-98%), with all patients achieving an early objective response by day 30. The CR rate was 56% (n = 15), and 10 of 12 patients who had a CR with at least 1 follow-up assessment remained in a CR. Partial responses (PRs) were observed in 33% (n = 9) of patients, and 2 patients had PRs that could be converted into a CR. Furthermore, Kaplan-Meier–estimated probability of continued response was 63% (95% CI, 37%-81%) at 3 months and 53% (95% CI, 25%-75%) at 6 months.
“The ongoing phase 2 PILOT study is the first to assess safety and efficacy of CAR T cells as second-line therapy in patients with aggressive B-cell lymphoma who are considered poor candidates for transplantation based on frailty, comorbidities, and who had poor prognostic features,” study co-author Nilanjan Ghosh, MD, PhD, director of the Lymphoma Program at Levine Cancer Institute, Atrium Health said in a presentation during the meeting. “Treatment with liso-cel resulted in high response rates and durable CRs in a patient population considered to be high risk.”
Patients who have aggressive relapsed/refractory large B-cell lymphoma following frontline chemoimmunotherapy can potentially achieve cure if they respond to salvage chemotherapy and are eligible to undergo autologous stem cell transplantation. Unfortunately, only a small percentage of patients are able to successfully complete that treatment because of poor prognostic features that render the disease resistant to chemotherapy or comorbidities that could reduce their tolerance of a high-intensity therapeutic approach.
Furthermore, no standard of care exists for patients who are transplant ineligible or who unable to receive high-dose chemotherapy, according to Ghosh, revealing a patient population with a significant unmet need.
“We know from previously reported studies that CAR T-cell therapy has shown durable responses in patients with third- or later-line relapsed/refractory large B-cell lymphoma,” said Ghosh. “This provided the rationale to explore the efficacy and safety of liso-cel in patients with second-line relapsed/refractory large B-cell lymphoma who are poor candidates for transplant.”
In the open-label phase 2 trial, patients underwent leukapheresis after which bridging therapy was permitted, but PET-positive disease was reconfirmed prior to lymphodepletion followed by liso-cel. Patients with diffuse large-cell lymphoma (DLBCL), high-grade B-cell lymphoma, or follicular lymphoma grade 3B were eligible for enrollment. Additionally, patients should have undergone 1 prior line of therapy consisting of an anthracycline and a CD20-targeted agent. Patients must have been deemed to be ineligible for high-dose chemotherapy followed by transplant per the investigators, and patients needed to meet at least 1 or more of the transplant noneligible (TNE) criteria. Secondary central nervous system (CNS) involvement was permitted.
The primary end point of the trial was ORR, and key secondary end points included adverse effects (AEs), CR rate, duration of response, progression-free survival, event-free survival, overall survival, pharmacokinetics, laboratory abnormalities, and health-related quality of life.
The TNE criteria were created based on published literature, treatment guidelines, and expert opinions, according to Ghosh. These criteria included age of 70 years or older, an ECOG performance status of 2, along with various organ function criteria, such as impaired pulmonary function with a diffusing capacity of the lungs for carbon monoxide of 60% or lower adjusted for hemoglobin concentration; impaired cardiac function with left ventricular fraction of at least 40% to less than 50%; impaired renal function with creatinine clearance of greater than 30 and less than 60 mL/min, and impaired hepatic function with aspartate and alanine aminotransferase levels of greater than 2 and 5 or lower x the upper limit of normal. To be eligible for enrollment, patients needed to meet at least 1 of the TNE criteria.
The most common TNE criteria for patients on the trial was age of 70 years or older (76%), followed by an ECOG performance status of 2 (31%), creatinine clearance of greater than 30 and less than 60 mL/min (28%), and 62% of patients met 2 or more TNE criteria.
“Another measure for comorbidities is the hematopoietic stem cell transplantation comorbidities index score (HCT-CI score), which can predict non-relapse mortality after transplantation. It has been shown in past studies that subjects who have a score of 3 or above have a higher risk of non-relapse mortality,” said Ghosh. “In our study, the median HCT-CI score was 3 with 52% of patients having a score of 3 or above, which again indicates a high-risk population.”
With regard to prognostic factors, 52% (n = 52) of patients had primary refractory disease, 31% (n = 9) had double-/triple-hit lymphoma, and 21% (n = 6) of patients had relapsed within 1 year. Moreover, 79% of patients had 1 or more poor prognostic factors, said Ghosh.
At baseline, the median age of study participants was 72 years and 62% (n = 18) were male; notably, 86% (n = 25) were 65 years and older. Forty-eight percent (n = 14) of patients had DLBCL not otherwise specified NOS, 17% (n = 5) had DLBCL transformed from follicular lymphoma, 31% (n = 9) had high-grade B-cell lymphoma, and 3% (n = 1) had follicular lymphoma grade 3B disease. Bulky disease shown by sum of the product of perpendicular diameters of at least 50 cm2 was noted in 37% (n = 10) of patients. The study protocol allowed for outpatient monitoring and this was done in 41% (n = 12) of patients.
Regarding safety, liso-cel was found to have an acceptable toxicity profile. Any-grade treatment-emergent AEs (TEAEs) were reported in 86% (n = 25) of patients; 69% (n = 20) were grade 3/4 in severity, and 3% (n = 1) were grade 5.
The TEAEs observed in ≥15% of patients included fatigue (34.5%, any grade), neutropenia (34.5%, any grade; 34.5%, grade 3/4), anemia (28%, any grade; 10%, grade 3/4), leukopenia (24%, any grade; 21%, grade 3/4); cytokine release syndrome (CRS; 21%, any grade), lymphopenia (21%, any grade; 21%, grade 3/4), thrombocytopenia (21%, any grade; 17%, grade 3/4); cough (17%, any grade), hypotension (17%, any grade), and nausea (17%, any grade; 3%, grade 3/4).
AEs of special interest included CRS, which was only observed in 21% (n = 6) of patients and were grade 1/2. The time to onset of the first CRS event was a median of 5 days and the time to resolution of the first CRS event was a median 2.5 days. Neurotoxicity was also noted as an AE of special interest, with grade 1/2 events occurring in 3% (n = 1) of patients, and grade 3 events presenting in 7% (n = 2) of patients. The time to onset of the first neurotoxic event was a median of 8 days and the time to resolution of the first neurotoxic event was a median of 4 days. Tocilizumab (Actemra) and corticosteroids were administered in 10% (n = 3) of patients with CRS and in 7% (n = 2) of patients with neurotoxicity.
“These data support further evaluation of liso-cel in the second-line setting for high-risk patients with aggressive relapsed/refractory large B-cell lymphoma who are poor candidates for stem cell transplant,” Ghosh concluded.
In December 2019, Bristol-Myers Squibb (BMS), the manufacturer of liso-cel, submitted a biologics license application (BLA) to the FDA seeking approval of the anti-CD19 CAR T-cell therapy for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after at least 2 prior therapies, based on data from the phase 1 TRANSCEND NHL 001 trial. In that study, liso-cel inducted an ORR of 73% and a CR rate of 53%, with the time to first CR or PR occurring at a median of 1 month.2
Earlier this month, May 2020, the FDA made the decision to add 3 months to the review period of the BLA of the drug for the treatment of these patients. The extension will allow the agency to review additional data provided by BMS.3
1. Ghosh N, Sehgal A, Hildebrandt GC, et al. Lisocabtagene maraleucel for treatment of second-line transplant noneligible relapsed/refractory aggressive large B-cell non-Hodgkin lymphoma: updated results from the PILOT study. Presented at: 2020 European Hematology Association Annual Congress; June 11-14, 2020; Virtual. Accessed June 11, 2020.
2. Abramson JS, Palomba ML, Gordon LI, et al. Pivotal safety and efficacy results from Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas. Blood. 2019;134(suppl 1):241. doi:10.1182/blood-2019-127508
3. Bristol Myers Squibb provides update on biologics license application (BLA) for lisocabtagene maraleucel (liso-cel). News release. May 6, 2020. Accessed June 12, 2020. bit.ly/2W7HGcr.