Safety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study

doi:10.1016/S1470-2045(15)70128-2

The Lancet Oncology

Volume 16, Issue 6, June 2015, Pages 704-715

, , , , , , , , , , , , , , , , , , , …

https://doi.org/10.1016/S1470-2045(15)70128-2 Get rights and content

Summary

Background

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody–drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL).

Methods

In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1–2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m². Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549.

Findings

Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3–4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3–4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3–4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL.

Interpretation

Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL.

Funding

Genentech.

Introduction

Despite improvements in outcomes for B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukaemia (CLL), most patients experience disease recurrence or progression, and so novel treatments are urgently needed.¹

Antibody–drug conjugates directed against tumour-associated cell-surface antigens provide targeted drug delivery with the goal of improving potency while reducing non-specific cytotoxic effects. After regulatory approval of the CD30-directed antibody–drug conjugate brentuximab vedotin for the treatment of Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma, several antibody–drug conjugates targeting B-cell-specific surface antigens are under clinical investigation.¹

CD79B, a component of the B-cell receptor and expressed on mature B cells, is also expressed in most patients with NHL and CLL (Polson A, Genentech, South San Franciso, CA, USA, personal communication).2, 3, 4 Antibody–drug conjugates targeting CD79B have shown preclinical antitumour activity.5, 6 Polatuzumab vedotin (Genentech, South San Francisco, CA, USA) is an antibody–drug conjugate consisting of the microtubule-disrupting agent monomethyl auristatin E (MMAE) conjugated to an anti-CD79B monoclonal antibody by the protease-cleavable peptide linker maleimidocaproylvaline-citrulline-p-aminobenzoyloxycarbonyl.7, 8, 9 MMAE has a mode of action similar to that of vincristine, which is commonly used to treat NHL.

In this study, we aimed to identify the recommended phase 2 dose for polatuzumab vedotin and to investigate the safety, tolerability, pharmacokinetics, and preliminary antitumour activity of this drug in patients with NHL or CLL.

Section snippets

Study design and patients

We did a phase 1, multicentre, open-label study, using a 3 + 3 dose-escalation design to establish the maximum tolerated dose. Patients were enrolled from 13 centres in the USA, France, the Netherlands, and Canada. Eligible patients had NHL (including relapsed or refractory diffuse large B-cell lymphoma, indolent NHL, follicular lymphoma, marginal-zone lymphoma, small lymphocytic lymphoma, and mantle-cell lymphoma) or CLL, for whom no suitable therapy of curative intent or higher priority (ie,

Results

Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (appendix): 34 patients with NHL in dose-escalation cohorts, 18 patients with CLL in dose-escalation cohorts, 34 patients with NHL in the single-agent expansion cohorts at the recommended phase 2 dose, and nine patients to receive polatuzumab vedotin in combination with rituximab (figure 1). In total, 86 patients received single-agent polatuzumab vedotin (figure 1). Table 1 summarises patients' baseline and disease

Discussion

In this phase 1 study we established the recommended phase 2 dose for polatuzumab vedotin in NHL to be 2·4 mg/kg every 21 days. Grade 3–4 neutropenia and grade 1–2 adverse events associated with peripheral neuropathy were the main treatment-emergent toxic effects. Neutropenia was expected on the basis of preclinical toxicology observations (Lee D, Genentech, South San Franciso, CA, USA, personal communication) and clinical experience with brentuximab vedotin, which contains the same linker–MMAE

References (23)

D Dornan et al.
Therapeutic potential of an anti CD79b antibody drug conjugate, anti CD79b vc MMAE, for the treatment of non-Hodgkin lymphoma
Blood
(2009)
RL Bai et al.
Binding of dolastatin 10 to tubulin at a distinct site for peptide antimitotic agents near the exchangeable nucleotide and vinca alkaloid sites
J Biol Chem
(1990)
M Hallek et al.
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia; a report from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) updating the National Cancer Institute Working Group 1996 guidelines
Blood
(2008)
ED Jacobsen et al.
Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression
Blood
(2015)
YW Chu et al.
Antibody-drug conjugates for the treatment of B-cell non-Hodgkin's lymphoma and leukemia
Future Oncol
(2013)
E Cabezudo et al.
Quantitative analysis of CD79b, CD5 and CD19 in mature B-cell lymphoproliferative disorders
Haematologica
(1999)
G D'Arena et al.
Quantitative flow cytometry for the differential diagnosis of leukemic B- cell chronic lymphoproliferative disorders
Am J Hematol
(2000)
SH Olejniczak et al.
A quantitative exploration of surface antigen expression in common B-cell malignancies using flow cytometry
Immunol Invest
(2006)
AG Polson et al.
Antibody-drug conjugates for the treatment of non-Hodgkin's lymphoma: target and linker-drug selection
Cancer Res
(2009)
SO Doronina et al.
Development of potent monoclonal antibody auristatin conjugates for cancer therapy
Nat Biotechnol
(2003)

JA Francisco et al.

cAC10 vcMMAE, an anti CD30 monomethyl auristatin E conjugate with potent and selective antitumor activity

Blood

(2003)

Cited by (252)

Clinical pharmacology strategies to accelerate the development of polatuzumab vedotin and summary of key findings
2024, Advanced Drug Delivery Reviews
The favorable benefit–risk profile of polatuzumab vedotin, as demonstrated in a pivotal Phase Ib/II randomized study (GO29365; NCT02257567), coupled with the need for effective therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), prompted the need to accelerate polatuzumab vedotin development. An integrated, fit-for-purpose clinical pharmacology package was designed to support regulatory approval. To address key clinical pharmacology questions without dedicated clinical pharmacology studies, we leveraged non-clinical and clinical data for polatuzumab vedotin, published clinical data for brentuximab vedotin, a similar antibody–drug conjugate, and physiologically based pharmacokinetic and population pharmacokinetic modeling approaches. We review strategies and model-informed outcomes that contributed to regulatory approval of polatuzumab vedotin plus bendamustine and rituximab in R/R DLBCL. These strategies made polatuzumab vedotin available to patients earlier than previously possible; depending on the strength of available data and the regulatory/competitive environment, they may also prove useful in accelerating the development of other agents.
A paradox of choice: Sequencing therapy in relapsed/refractory diffuse large B-cell lymphoma
2024, Blood Reviews
The available treatments for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have experienced a dramatic change since 2017. Incremental advances in basic and translational science over several decades have led to innovations in immune-oncology. These innovations have culminated in eight separate approvals by the US Food and Drug Administration for the treatment of patients with R/R DLBCL over the last 10 years. High-dose therapy and autologous stem cell transplant (HDT-ASCT) remains the standard of care for transplant-eligible patients who relapse after an initial remission. For transplant-ineligible patients or for those who relapse following HDT-ASCT, multiple options exist. Monoclonal antibodies targeting CD19, antibody-drug conjugates, bispecific antibodies, immune effector cell products, and other agents with novel mechanisms of action are now available for patients with R/R DLBCL. There is increasing use of chimeric antigen receptor (CAR) T-cells as second-line therapy for patients with early relapse of DLBCL or those who are refractory to initial chemoimmunotherapy. The clinical benefits of these strategies vary and are influenced by patient and disease characteristics, as well as the type of prior therapy administered. Therefore, there are multiple clinical scenarios that clinicians might encounter when treating R/R DLBCL. An optimal sequence of drugs has not been established, and there is no evidence-based consensus on how to best order these agents. This abundance of choices introduces a paradox: proliferating treatment options are initially a boon to patients and providers, but as choices grow further they no longer liberate. Rather, more choices make the management of R/R DLBCL more challenging due to lack of direct comparisons among agents and a desire to maximize patient outcomes. Here, we provide a review of recently-approved second- and subsequent-line agents, summarize real-world data detailing the use of these medicines, and provide a framework for sequencing therapy in R/R DLBCL.
Second-line treatment of diffuse large B‐cell lymphoma: Evolution of options
2023, Seminars in Hematology
In the era of immunochemotherapy, approximately 60%-70% of diffuse large B-cell lymphoma (DLBCL) patients achieve remission with first-line rituximab-based chemoimmunotherapy. However, 30%-40% relapse after initial response to first-line therapy and, out of them, 20%-50% are refractory or experience early relapse. The second-line therapy algorithm for DLBCL has recently evolved, thanks to the recent approval of new therapeutic agents or their combinations. The new guidelines suggest a stratification of relapsed/refractory (R/R) DLBCL based on the time to relapse. For transplant-eligible patients, autologous stem cell transplant remains the preferred option when the patient relapses after 12 months from diagnosis, while anti-CD19 CART-cell therapy is the current preferred choice for high-risk DLBCL, defined as primary refractory or relapse ≤12 months. For transplant-ineligible or CAR T-cell therapy-ineligible patients, the therapeutic arsenal historically lacked effective options. However, new therapeutic options, including polatuzumab vedotin combined with bendamustine-rituximab and tafasitamab with lenalidomide, have been recently approved, and novel agents such as loncastuximab tesirine, selinexor, anti-CD19 CAR T-cell therapy, and bispecific antibodies have shown promising efficacy and manageable safety in this setting offering new hope to patients in this challenging scenario.
Antibody and immunotherapy in diffuse large B-cell lymphoma
2023, Seminars in Hematology
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and a heterogeneous B-cell disease. The majority of patients with newly diagnosed disease are cured with first-line combination immunochemotherapy treatment however, those who experience treatment failure have dismal outcomes. Antibody therapies and immunotherapy have provided the single most major advance in the treatment of DLBCL in the last 4 decades. Rituximab, the first immunotherapy, and a monoclonal antibody targeting CD20, improved DLBCL overall survival when added to chemotherapy 2 decades ago. Since then, the advent of further "naked" monoclonal antibodies that target malignant B-cells or stimulate the immune system to kill cancer, as well as antibody-drug conjugates and bispecific antibodies have all entered the DLBCL armamentarium; with 5 antibody therapy approvals in the last 6 years alone. Here we review the literature on antibodies and immunotherapies for DLBCL and the future directions involving this successful group of drugs.
Peripheral neuropathy associated with monomethyl auristatin E-based antibody-drug conjugates
2023, iScience
Since the successful approval of gemtuzumab ozogamicin, antibody-drug conjugates (ADCs) have emerged as a pivotal category of targeted therapies for cancer. Among these ADCs, the use of monomethyl auristatin E (MMAE) as a payload is prevalent in the development of ADC drugs, which has significantly improved overall therapeutic efficacy against various malignancies. However, increasing clinical observations have raised concerns regarding the potential nervous system toxicity associated with MMAE-based ADCs. Specifically, a higher incidence of peripheral neuropathy has been reported in ADCs incorporating MMAE as payloads. Considering the increasing global use of MMAE-based ADCs, it is imperative to provide an inclusive overview of diagnostic and management strategies for this adverse event. In this review, we examine current information and what future research directions are required to better understand and manage this type of clinical challenge.
Polatuzumab vedotin with infusional chemotherapy for untreated aggressive B-cell non-Hodgkin lymphomas
2023, Blood Advances
The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) regimen for large B-cell lymphomas, but it is unknown whether Pola can be safely incorporated into intensified regimens (eg, dose-adjusted [DA]–EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab]) typically used for the highest risk histologies. This was a single-center, open-label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R (vincristine omitted) in aggressive large B-cell lymphomas. The primary end point was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with prespecified suspension rules. Secondary and exploratory end points included efficacy and correlation with circulating tumor DNA (ctDNA) levels. We enrolled 18 patients on study, and with only 3 DLTs observed, the study met its primary end point for safety. There were 5 serious adverse events, including grade 3 febrile neutropenia (3, 17%), grade 3 colonic perforation in the setting of diverticulitis, and grade 5 sepsis/typhlitis. Among 17 evaluable patients, the best overall response rate was 100%, and the complete response rate was 76%. With a median follow-up of 12.9 months, 12-month event-free survival was 72%, and 12-month overall survival was 94%. No patient with undetectable ctDNA at the end of treatment has relapsed to date. Using Pola to replace vincristine in the DA-EPOCH-R regimen met its primary safety end point. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. This trial was registered at www.clinicaltrials.gov as #NCT04231877.

View all citing articles on Scopus

View full text

ArticlesSafety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and patients

Results

Discussion

Blood

J Biol Chem

Blood

Blood

Antibody-drug conjugates for the treatment of B-cell non-Hodgkin's lymphoma and leukemia

Future Oncol

Quantitative analysis of CD79b, CD5 and CD19 in mature B-cell lymphoproliferative disorders

Haematologica

Quantitative flow cytometry for the differential diagnosis of leukemic B- cell chronic lymphoproliferative disorders

Am J Hematol

A quantitative exploration of surface antigen expression in common B-cell malignancies using flow cytometry

Immunol Invest

Antibody-drug conjugates for the treatment of non-Hodgkin's lymphoma: target and linker-drug selection

Cancer Res

Development of potent monoclonal antibody auristatin conjugates for cancer therapy

Nat Biotechnol

cAC10 vcMMAE, an anti CD30 monomethyl auristatin E conjugate with potent and selective antitumor activity

Blood

Articles
Safety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study