MATCHING-ADJUSTED INDIRECT COMPARISON OF PIRTOBRUTINIB VS VENETOCLAX CONTINUOUS MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY CLL PREVIOUSLY TREATED WITH A COVALENT BTK INHIBITOR
Objectives: Venetoclax-based therapy is a standard option for pts with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) previously treated with a covalent BTK inhibitor (cBTKi). Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi designed to overcome the pharmacologic lim...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | Hematology, Transfusion and Cell Therapy |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2531137923005370 |
| _version_ | 1797655046963331072 |
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| author | O Al-Sawaf M Jen LM Hess J Zhang B Goebel JM Pagel TA Eyre LYCGN Presenter |
| author_facet | O Al-Sawaf M Jen LM Hess J Zhang B Goebel JM Pagel TA Eyre LYCGN Presenter |
| author_sort | O Al-Sawaf |
| collection | DOAJ |
| description | Objectives: Venetoclax-based therapy is a standard option for pts with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) previously treated with a covalent BTK inhibitor (cBTKi). Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi designed to overcome the pharmacologic limitations of cBTKi and restore BTK inhibition. Pirtobrutinib has demonstrated marked efficacy and a favorable safety profile. This unanchored MAIC was designed to estimate the treatment effect of pirtobrutinib (BRUIN, NCT03740529) vs venetoclax continuous monotherapy (NCT02141282) in pts with R/R CLL previously treated with a cBTKi. Materials and methods: Data from pts with R/R CLL previously treated with at least 1 cBTKi and without prior venetoclax exposure who received pirtobrutinib were analyzed (n = 146). Only 1 prospective trial of venetoclax (administered as a continuous monotherapy) for pts previously treated with a cBTKi (n = 91) was identified. Progression-free survival (PFS), overall survival (OS), investigator-assessed overall response rate (ORR), and grade≥3 treatment-emergent adverse events (TEAEs) regardless of attribution were evaluated. Pt-level data from the pirtobrutinib cohort were re-weighted to match the venetoclax cohort using method of moments approach, adjusting for well-established prognostic factors reported in both studies (age, IGHV mutation status, TP53 aberrancy, del(17p), del(11q); number of prior lines of therapy, and reason for prior cBTKi discontinuation). KaplanMeier PFS and OS curves from the venetoclax trial were digitized (using WebPlotDigitizer) for time-to-event analyses. Fishers exact test was used to compare proportional outcomes (ORR, TEAEs); time-to-event outcomes (PFS, OS) were compared using Cox regression model and log-rank test. Results: The median age in pirtobrutinib and venetoclax cohorts was 66.5 and 66.0 years; all other prognostic factors were well matched in both cohorts. Median follow-up was 21.3 months and 14 months for the pirtobrutinib and venetoclax cohorts, respectively. PFS and OS were comparable with no significant differences noted for pirtobrutinib versus venetoclax (both p > 0.05). ORR was 80% for pirtobrutinib (inclusive of PR-L) vs 65% for venetoclax (p = 0.01). Grade ≥3 TEAEs reported in both trials indicated that febrile neutropenia, neutropenia, anemia, and thrombocytopenia were significantly lower for pirtobrutinib vs venetoclax in adjusted analyses (all p < 0.01). No differences were observed for pneumonia (p = 0.06) or for discontinuation due to TEAEs (3% vs 7%, p = 0.32) in adjusted analyses. Unadjusted results were consistent with the adjusted analyses. Conclusions and discussion: The efficacy of pirtobrutinib was comparable to continuously administered venetoclax monotherapy in pts with R/R CLL previously treated with a cBTKi. Pirtobrutinib was associated with improved ORR and favorable overall safety profile for most TEAEs vs venetoclax. This study raises questions regarding optimal treatment sequencing of pirtobrutinib and venetoclax in cBTKi-treated CLL, but the lack of prospective direct comparisons and limited long-term follow-up preclude definitive conclusions. Randomized Phase 3 studies of pirtobrutinib in pts with CLL are ongoing. Previously presented at EHA 2023. |
| first_indexed | 2024-03-11T17:08:28Z |
| format | Article |
| id | doaj.art-7d318f13915c476ba6fcf0221626f667 |
| institution | Directory Open Access Journal |
| issn | 2531-1379 |
| language | English |
| last_indexed | 2024-03-11T17:08:28Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Hematology, Transfusion and Cell Therapy |
| spelling | doaj.art-7d318f13915c476ba6fcf0221626f6672023-10-20T06:41:23ZengElsevierHematology, Transfusion and Cell Therapy2531-13792023-10-0145S162MATCHING-ADJUSTED INDIRECT COMPARISON OF PIRTOBRUTINIB VS VENETOCLAX CONTINUOUS MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY CLL PREVIOUSLY TREATED WITH A COVALENT BTK INHIBITORO Al-Sawaf0M Jen1LM Hess2J Zhang3B Goebel4JM Pagel5TA Eyre6LYCGN Presenter7University Hospital, Cologne, GermanyEli Lilly and Company, Indianapolis, United StatesEli Lilly and Company, Indianapolis, United StatesTechData Services LLC, United StatesEli Lilly and Company, Indianapolis, United StatesSwedish Cancer Institute, United StatesChurchill Cancer Center, Oxford University Hospitals NHS Foundation Trust, Oxford, United KingdomEli Lilly and Company, BrazilObjectives: Venetoclax-based therapy is a standard option for pts with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) previously treated with a covalent BTK inhibitor (cBTKi). Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi designed to overcome the pharmacologic limitations of cBTKi and restore BTK inhibition. Pirtobrutinib has demonstrated marked efficacy and a favorable safety profile. This unanchored MAIC was designed to estimate the treatment effect of pirtobrutinib (BRUIN, NCT03740529) vs venetoclax continuous monotherapy (NCT02141282) in pts with R/R CLL previously treated with a cBTKi. Materials and methods: Data from pts with R/R CLL previously treated with at least 1 cBTKi and without prior venetoclax exposure who received pirtobrutinib were analyzed (n = 146). Only 1 prospective trial of venetoclax (administered as a continuous monotherapy) for pts previously treated with a cBTKi (n = 91) was identified. Progression-free survival (PFS), overall survival (OS), investigator-assessed overall response rate (ORR), and grade≥3 treatment-emergent adverse events (TEAEs) regardless of attribution were evaluated. Pt-level data from the pirtobrutinib cohort were re-weighted to match the venetoclax cohort using method of moments approach, adjusting for well-established prognostic factors reported in both studies (age, IGHV mutation status, TP53 aberrancy, del(17p), del(11q); number of prior lines of therapy, and reason for prior cBTKi discontinuation). KaplanMeier PFS and OS curves from the venetoclax trial were digitized (using WebPlotDigitizer) for time-to-event analyses. Fishers exact test was used to compare proportional outcomes (ORR, TEAEs); time-to-event outcomes (PFS, OS) were compared using Cox regression model and log-rank test. Results: The median age in pirtobrutinib and venetoclax cohorts was 66.5 and 66.0 years; all other prognostic factors were well matched in both cohorts. Median follow-up was 21.3 months and 14 months for the pirtobrutinib and venetoclax cohorts, respectively. PFS and OS were comparable with no significant differences noted for pirtobrutinib versus venetoclax (both p > 0.05). ORR was 80% for pirtobrutinib (inclusive of PR-L) vs 65% for venetoclax (p = 0.01). Grade ≥3 TEAEs reported in both trials indicated that febrile neutropenia, neutropenia, anemia, and thrombocytopenia were significantly lower for pirtobrutinib vs venetoclax in adjusted analyses (all p < 0.01). No differences were observed for pneumonia (p = 0.06) or for discontinuation due to TEAEs (3% vs 7%, p = 0.32) in adjusted analyses. Unadjusted results were consistent with the adjusted analyses. Conclusions and discussion: The efficacy of pirtobrutinib was comparable to continuously administered venetoclax monotherapy in pts with R/R CLL previously treated with a cBTKi. Pirtobrutinib was associated with improved ORR and favorable overall safety profile for most TEAEs vs venetoclax. This study raises questions regarding optimal treatment sequencing of pirtobrutinib and venetoclax in cBTKi-treated CLL, but the lack of prospective direct comparisons and limited long-term follow-up preclude definitive conclusions. Randomized Phase 3 studies of pirtobrutinib in pts with CLL are ongoing. Previously presented at EHA 2023.http://www.sciencedirect.com/science/article/pii/S2531137923005370 |
| spellingShingle | O Al-Sawaf M Jen LM Hess J Zhang B Goebel JM Pagel TA Eyre LYCGN Presenter MATCHING-ADJUSTED INDIRECT COMPARISON OF PIRTOBRUTINIB VS VENETOCLAX CONTINUOUS MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY CLL PREVIOUSLY TREATED WITH A COVALENT BTK INHIBITOR Hematology, Transfusion and Cell Therapy |
| title | MATCHING-ADJUSTED INDIRECT COMPARISON OF PIRTOBRUTINIB VS VENETOCLAX CONTINUOUS MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY CLL PREVIOUSLY TREATED WITH A COVALENT BTK INHIBITOR |
| title_full | MATCHING-ADJUSTED INDIRECT COMPARISON OF PIRTOBRUTINIB VS VENETOCLAX CONTINUOUS MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY CLL PREVIOUSLY TREATED WITH A COVALENT BTK INHIBITOR |
| title_fullStr | MATCHING-ADJUSTED INDIRECT COMPARISON OF PIRTOBRUTINIB VS VENETOCLAX CONTINUOUS MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY CLL PREVIOUSLY TREATED WITH A COVALENT BTK INHIBITOR |
| title_full_unstemmed | MATCHING-ADJUSTED INDIRECT COMPARISON OF PIRTOBRUTINIB VS VENETOCLAX CONTINUOUS MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY CLL PREVIOUSLY TREATED WITH A COVALENT BTK INHIBITOR |
| title_short | MATCHING-ADJUSTED INDIRECT COMPARISON OF PIRTOBRUTINIB VS VENETOCLAX CONTINUOUS MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY CLL PREVIOUSLY TREATED WITH A COVALENT BTK INHIBITOR |
| title_sort | matching adjusted indirect comparison of pirtobrutinib vs venetoclax continuous monotherapy in patients with relapsed refractory cll previously treated with a covalent btk inhibitor |
| url | http://www.sciencedirect.com/science/article/pii/S2531137923005370 |
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