Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial

In patients with chronic lymphocytic leukemia, Richter transformation (RT) reflects the development of an aggressive lymphoma that is associated with poor response to chemotherapy and short survival. We initiated an international, investigator-initiated, prospective, open-label phase 2 study in whic...

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Veröffentlicht in:Nature medicine 2024, Vol.30 (1), p.240-248
Hauptverfasser: Al-Sawaf, Othman, Ligtvoet, Rudy, Robrecht, Sandra, Stumpf, Janina, Fink, Anna-Maria, Tausch, Eugen, Schneider, Christof, Boettcher, Sebastian, Mikusko, Martin, Ritgen, Matthias, Schetelig, Johannes, von Tresckow, Julia, Vehling-Kaiser, Ursula, Gaska, Tobias, Wendtner, Clemens Martin, Chapuy, Bjoern, Fischer, Kirsten, Kreuzer, Karl-Anton, Stilgenbauer, Stephan, Staber, Philipp, Niemann, Carsten, Hallek, Michael, Eichhorst, Barbara
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container_title Nature medicine
container_volume 30
creator Al-Sawaf, Othman
Ligtvoet, Rudy
Robrecht, Sandra
Stumpf, Janina
Fink, Anna-Maria
Tausch, Eugen
Schneider, Christof
Boettcher, Sebastian
Mikusko, Martin
Ritgen, Matthias
Schetelig, Johannes
von Tresckow, Julia
Vehling-Kaiser, Ursula
Gaska, Tobias
Wendtner, Clemens Martin
Chapuy, Bjoern
Fischer, Kirsten
Kreuzer, Karl-Anton
Stilgenbauer, Stephan
Staber, Philipp
Niemann, Carsten
Hallek, Michael
Eichhorst, Barbara
description In patients with chronic lymphocytic leukemia, Richter transformation (RT) reflects the development of an aggressive lymphoma that is associated with poor response to chemotherapy and short survival. We initiated an international, investigator-initiated, prospective, open-label phase 2 study in which patients with RT received a combination of the PD-1 inhibitor tislelizumab plus the BTK inhibitor zanubrutinib for 12 cycles. Patients responding to treatment underwent maintenance treatment with both agents. The primary end point was overall response rate after six cycles. Of 59 enrolled patients, 48 patients received at least two cycles of treatment and comprised the analysis population according to the study protocol. The median observation time was 13.9 months, the median age was 67 (range 45–82) years. Ten patients (20.8%) had received previous RT-directed therapy. In total, 28 out of 48 patients responded to induction therapy with an overall response rate of 58.3% (95% confidence interval (CI) 43.2–72.4), including 9 (18.8%) complete reponse and 19 (39.6%) partial response, meeting the study’s primary end point by rejecting the predefined null hypothesis of 40% ( P  = 0.008). Secondary end points included duration of response, progression-free survival and overall survival. The median duration of response was not reached, the median progression-free survival was 10.0 months (95% CI 3.8–16.3). Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4–91.0). The most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) and hematological toxicities (11.4%). These data suggest that combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. ClinicalTrials.gov Identifier: NCT04271956 . In a large single-arm phase 2 trial, the anti-PD-1 inhibitor tislelizumab combined with the next-generation BTK inhibitor zanubrutinib had an overall response rate of 58.3% and was well tolerated in patients with Richter’s transformation.
doi_str_mv 10.1038/s41591-023-02722-9
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We initiated an international, investigator-initiated, prospective, open-label phase 2 study in which patients with RT received a combination of the PD-1 inhibitor tislelizumab plus the BTK inhibitor zanubrutinib for 12 cycles. Patients responding to treatment underwent maintenance treatment with both agents. The primary end point was overall response rate after six cycles. Of 59 enrolled patients, 48 patients received at least two cycles of treatment and comprised the analysis population according to the study protocol. The median observation time was 13.9 months, the median age was 67 (range 45–82) years. Ten patients (20.8%) had received previous RT-directed therapy. In total, 28 out of 48 patients responded to induction therapy with an overall response rate of 58.3% (95% confidence interval (CI) 43.2–72.4), including 9 (18.8%) complete reponse and 19 (39.6%) partial response, meeting the study’s primary end point by rejecting the predefined null hypothesis of 40% ( P  = 0.008). Secondary end points included duration of response, progression-free survival and overall survival. The median duration of response was not reached, the median progression-free survival was 10.0 months (95% CI 3.8–16.3). Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4–91.0). The most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) and hematological toxicities (11.4%). These data suggest that combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. ClinicalTrials.gov Identifier: NCT04271956 . 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Secondary end points included duration of response, progression-free survival and overall survival. The median duration of response was not reached, the median progression-free survival was 10.0 months (95% CI 3.8–16.3). Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4–91.0). The most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) and hematological toxicities (11.4%). These data suggest that combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. ClinicalTrials.gov Identifier: NCT04271956 . 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We initiated an international, investigator-initiated, prospective, open-label phase 2 study in which patients with RT received a combination of the PD-1 inhibitor tislelizumab plus the BTK inhibitor zanubrutinib for 12 cycles. Patients responding to treatment underwent maintenance treatment with both agents. The primary end point was overall response rate after six cycles. Of 59 enrolled patients, 48 patients received at least two cycles of treatment and comprised the analysis population according to the study protocol. The median observation time was 13.9 months, the median age was 67 (range 45–82) years. Ten patients (20.8%) had received previous RT-directed therapy. In total, 28 out of 48 patients responded to induction therapy with an overall response rate of 58.3% (95% confidence interval (CI) 43.2–72.4), including 9 (18.8%) complete reponse and 19 (39.6%) partial response, meeting the study’s primary end point by rejecting the predefined null hypothesis of 40% ( P  = 0.008). Secondary end points included duration of response, progression-free survival and overall survival. The median duration of response was not reached, the median progression-free survival was 10.0 months (95% CI 3.8–16.3). Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4–91.0). The most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) and hematological toxicities (11.4%). These data suggest that combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. ClinicalTrials.gov Identifier: NCT04271956 . In a large single-arm phase 2 trial, the anti-PD-1 inhibitor tislelizumab combined with the next-generation BTK inhibitor zanubrutinib had an overall response rate of 58.3% and was well tolerated in patients with Richter’s transformation.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>38071379</pmid><doi>10.1038/s41591-023-02722-9</doi><tpages>9</tpages><orcidid>https://orcid.org/0009-0006-6169-9152</orcidid><orcidid>https://orcid.org/0000-0001-9880-5242</orcidid><orcidid>https://orcid.org/0000-0001-6546-0911</orcidid><orcidid>https://orcid.org/0000-0001-9895-0570</orcidid><orcidid>https://orcid.org/0000-0002-6830-9296</orcidid><orcidid>https://orcid.org/0000-0001-6729-7708</orcidid><orcidid>https://orcid.org/0000-0002-2780-2981</orcidid><oa>free_for_read</oa></addata></record>
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1546-170X
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subjects 692/699/67/1059
692/699/67/1059/2325
692/699/67/1990/283/1895
692/699/67/1990/291/1621/1915
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Biomedical and Life Sciences
Biomedicine
Cancer Research
Chemotherapy
Chronic lymphocytic leukemia
Confidence intervals
Gastrointestinal diseases
Humans
Induction therapy
Infectious Diseases
Inhibitors
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
Lymphatic leukemia
Lymphoma
Metabolic Diseases
Middle Aged
Molecular Medicine
Neurosciences
PD-1 protein
Piperidines
Population studies
Prospective Studies
Pyrazoles
Pyrimidines
Response rates
Survival
Transformations
title Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial
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