Safety and efficacy of tisagenlecleucel (tisa-cel) plus pembrolizumab (pembro) in patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL): Updated analysis of the phase 1b PORTIA study.
Bibliographic record
Abstract
e19537 Background: Tisa-cel showed durable responses and manageable safety in pts with r/r DLBCL in the phase 2 JULIET trial. High baseline programmed cell death 1 (PD-1) expression associated with higher probability of no response (Schuster et al. NEJM 2019). Here we report an updated analysis of PORTIA, a phase 1b, multicenter, open-label study of tisa-cel plus pembro in pts with r/r DLBCL. Methods: Eligible pts (≥18 y) had r/r DLBCL after ≥2 lines of therapy and relapsed after or were not candidates for autologous stem cell transplant (autoSCT). Patients received a single tisa-cel infusion on Day 1 and were enrolled in 1 of 3 cohorts that initiated pembro (200 mg q 21 days, for up to 6 doses) on either Days +15, +8, or –1. Primary endpoints were incidence of dose-limiting toxicities (DLTs) and overall response rate (ORR; complete response [CR] and partial response [PR]). Secondary endpoints included duration of response, progression-free survival, overall survival, safety, and cellular kinetics. Results: As of November 9, 2020, 15 pts were enrolled and 12 received tisa-cel (n = 4 pts for each Days +15, +8, and –1 cohorts; median follow-up, 4 mo). At study entry, the median age among treated pts was 62 y (range, 35-79), 100% had an International Prognostic Index score ≥2, 67% had ≥3 prior lines of therapy, 58% had stage IV disease, 58% had lactate dehydrogenase > ULN, and 42% had prior autoSCT. All 12 pts had ≥1 AE. Grade ≥3 AEs suspected to be related to tisa-cel and/or pembro were neutropenia (n = 4); neutrophil count decreased (n = 3); febrile neutropenia, lymphocyte count decreased, malnutrition (each n = 2); anemia, leukopenia, diarrhea, white blood count decreased, liver function tests increased, thrombocytopenia, hepatitis, and cytokine release syndrome (CRS; each n = 1). No neurotoxicity or DLTs were observed. Among the Day +15, +8, and –1 cohorts (each n = 4), the ORR was 50% (2/4; CR n = 0, PR n = 2), 25% (1/4; CR n = 1, PR n = 0), and 25% (1/4; CR n = 1, PR n = 0; longer follow-up is needed for n = 2 pts), respectively. Tisa-cel exposure and peak expansion were consistent with JULIET, with a trend toward delayed expansion in the Day –1 cohort (n = 4). There was no sign of secondary expansion following pembro administration regardless of the number of doses. Compared with JULIET, lower CRS severity and frequency and lower cytokine profiles were observed for all 3 cohorts. Conclusions: The combination of tisa-cel plus pembro was feasible and showed manageable safety. The lack of improved efficacy in PORTIA with the addition of pembro compared with tisa-cel alone may be related to more pts with ≥3 prior lines of therapy (67% vs 51%, respectively), and/or pts with more advanced disease in PORTIA. Additional studies with larger patient cohorts are needed to determine the value of adding PD-1 inhibitors to CAR-T cell therapy in pts with r/r DLBCL. Clinical trial information: NCT03630159.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".