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Polatuzumab Vedotin plus Venetoclax with Rituximab in relapsed / refractory diffuse large B-cell lymphoma


Polatuzumab vedotin ( Polivy ) combined with Rituximab ( MabThera ) has demonstrated activity and tolerability in a phase II trial of patients with relapsed / refractory ( R/R ) diffuse large B-cell lymphoma ( DLBCL ) ( Morschhauser et al. Lancet 2019 ).
The pro-survival MCL-1 protein has been identified as a mechanism of resistance to Venetoclax ( Venclyxto ), a potent inhibitor of BCL-2, in non-Hodgkin lymphoma cell lines.
Preclinical studies have demonstrated that concurrent treatment with Polatuzumab vedotin promotes MCL-1 degradation and enhances anti-tumor efficacy in vivo, thus providing a strong rationale for the combination with Venetoclax ( Amin et al. AACR 2020 ).
Researchers sought to determine whether the combination of Pola-Ven-R might further enhance anti-tumor response.

Researchers have presented the primary efficacy and safety analysis from a phase Ib/II study of Pola-Ven-R in patients with R/R DLBCL ( GO29833 ).

GO29833 is an open-label, multicenter study of patients with R/R DLBCL who had received greater than or equal to 1 prior anti-CD20 chemo-immunotherapy regimen.
The recommended phase II dose ( RP2D ) combination for Pola-Ven-R was initially defined in a 3+3 dose escalation phase and was then expanded into phase II.
Patients in the expansion cohort received induction therapy with six 21-day cycles of: intravenous ( IV ) Polatuzumab vedotin 1.8 mg/kg ( Cycle [ C ] 1–6: Day [ D ] 1 ), Venetoclax 800 mg by mouth daily and Rituximab 375mg/m2 IV ( C1–6: D1 ).
Responders received consolidation therapy for 8 months ( Venetoclax 800 mg daily and Rituximab 375 mg/m2 on D1 every 2 months ).
The primary safety objectives were to determine the RP2D for Polatuzumab vedotin and Venetoclax when given in combination with Rituximab and to evaluate the safety and tolerability of the Pola-Ven-R combination.
The primary efficacy endpoint was complete response ( CR ) at end of induction ( EOI ), as determined by the Independent Review Committee ( IRC ) based on positron emission tomography-computed tomography ( PET-CT ) scans using modified Lugano 2014 response criteria.
Secondary objectives included CR-rate at EOI and best overall response ( BOR ) determined by the investigator.
Exploratory objectives included investigator-assessed progression-free survival ( PFS ) and overall survival ( OS ).

At the primary analysis ( January 30, 2020 ), 57 patients from the phase Ib/II populations were enrolled and received at least one study drug; the median duration of follow-up was 7.0 ( range 0.2–30.4 ) months.

Baseline characteristics of the safety-evaluable patients were: median age, 65 years; male, 49%; Ann Arbor Stage III–IV, 84%; International Prognostic Index ( IPI ) greater than or equal to 3, 54%; median prior lines of therapy, 3; refractory to last line, 83%; primary refractory, 65%.

Dose limiting toxicity was not observed in phase I and the maximum dose level was chosen as RP2D.

All except two patients experienced at least one adverse event, 21 ( 37% ) had a serious adverse effect, and 45 ( 79% ) had a grade 3-4 adverse reactions.
The most common grade 3-4 adverse effects were neutropenia ( 30 pts, 53% ), infections ( 9 pts, 16% ), and anemia ( 6 pts, 11% ).

Adverse effects leading to dose reduction or interruption of any drug occurred in 10 ( 18% ) and 35 ( 61% ) patients, respectively; the majority of dose modifications were changes to Venetoclax dosing.

Seven ( 12% ) patients had an adverse effects that led to the discontinuation of any study drug ( Polatuzumab vedotin [ n=5 ]; Venetoclax [ n=7 ]; Rituximab [ n=6 ] ).

One grade 5 adverse reaction was reported ( pneumonia ); however, it was not considered related to study treatment as the patient had received new anti-lymphoma therapy following disease progression.
In the primary efficacy-evaluable population ( n=48 ), the IRC-assessed modified Lugano CR rate at EOI was 29%.
The investigator-assessed CR rate at EOI and best overall response were 31% and 65%, respectively, with a median duration of response of 5.8 months ( 95% confidence interval [ CI ]: 3.4–6.7 ).

The median progression-free survival and overall survival were 4.4 months ( 95% CI: 3.0–7.1 ) and 11.0 months ( 95% CI: 6.7 – not-evaluable ), respectively.

In conclusion, the study of the novel triplet combination, Pola-Ven-R, has demonstrated a safety profile consistent with the known profiles of the individual drugs.
This first report of the full efficacy population has shown promising activity in a heavily pre-treated and refractory population of patients with R/R DLBCL. ( Xagena )

Source: American Society of Hematology ( ASH ) Virtual Meeting, 2020

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