Polatuzumab Vedotin Plus R-CHOP Being Explored in DLBCL Trial

Christopher R. Flowers, MD, MS

Professor of Hematology

and Medical Oncology

Director, Emory

Lymphoma Program

Emory University

School of Medicine

Atlanta, Georgia

The ongoing POLARIX clinical trial (NCT03274492) is investigating the novel investigational antibody—drug conjugate polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as a first-line therapy for patients with intermediate- or highrisk diffuse large B-cell lymphoma (DLBCL).1 The trial is currently open to enrollment in the United States and multiple global sites, with an estimated primary completion date of December 2019.

OncLive: What type of patients are included POLARIX trial and what are some key exclusion criteria?

How are participants randomized? Please describe the arms of the study.

Can you talk more about the study endpoints?

What prompted usage of polatuzumab vedotin in combination with R-CHP and R-CHOP?

What is the mechanism of action of polatuzumab vedotin?

How does polatuzumab vedotin interact with R-CHP?

How are the drugs administered to patients? At what doses and schedules?

In a recent edition of OncLive©, Christopher R. Flowers, MD, MS, a member of the POLARIX: GO39942 Steering Committee and principal investigator of the Emory University School of Medicine study site, shared insights about the trial’s goals and design.2 Following is the complete interview with Dr Flowers, with expanded commentary.Flowers: Patients diagnosed with CD20-positive diffuse DLBCL of any subtype with an Eastern Cooperative Oncology Group performance status of 0 to 2, cardiac ejection fraction of at least 50%, and intermediate- or high-risk (International Prognostic Index [IPI] score of 2-5) are eligible for the study. Full description of the eligibility criteria can be found in the study.Patients are randomized 1:1 into 2 groups: standard R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] given every 21 days for 6 cycles plus polatuzumab vedotin placebo, or R-CHP [rituximab, cyclophosphamide, doxorubicin, and prednisone] plus vincristine placebo and polatuzumab vedotin. Patients in both arms will also receive rituximab monotherapy in cycles 7 and 8.The investigators will assess the safety and efficacy of polatuzumab vedotin. The primary endpoint is investigator- assessed progression-free survival (PFS). Other endpoints include the rate of PET-negative complete response (CR) at the end of treatment, patient-reported outcomes, and potential biomarkers to predict improved outcomes and as a means for devising new therapeutic approaches in the future.Polatuzumab vedotin has been demonstrated to have encouraging efficacy when studied as monotherapy and in combination with anti-CD20 antibodies in the treatment of relapsed and refractory DLBCL, both by Palanca-Wessels and colleagues and Morschhauser and colleagues. Also, a doseescalation trial was conducted that revealed acceptable safety of polatuzumab in combination with R-CHP, and it established the dosing regimen for phase II trials [polatuzumab 1.8 mg/kg in combination with R-CHP].Polatuzumab vedotin is a CD79b-specific antibody conjugated to a microtubule disrupting agent, monomethyl auristatin E, with a stable linker. CD79b is a component of a B-cell receptor restricted to mature B cells, except plasma cells, that is expressed by many B-cell hematologic malignancies. Polatuzumab vedotin is the first CD79b-directed antibody drug conjugated to a potent cytotoxin that is selectively delivered to tumor cells. This combination delivers highly potent cytotoxins directly to tumor cells, which then absorb the cytotoxin.The standard of therapy for DLBCL is R-CHOP. RCHOP includes vincristine, unlike the studied arm which included polatuzumab vedotin with R-CHP in place of vincristine. Vincristine is a cytotoxic agent, and polatuzumab also works by delivering cytotoxin to tumor cells, but more selectively.Patients in the R-CHOP plus polatuzumab vedotin placebo group will receive placebo for polatuzumab vedotin, rituximab 375 mg/m² IV, cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV, and vincristine 1.4 mg/m² IV (maximum 2 mg/dose) on day 1, and prednisone 100 mg/day orally on days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m² IV will be administered as monotherapy in cycles 7 and 8.

What are the next steps in this research?

What clinical need is the PROLARIX trial seeking to address?

What earlier clinical trial results paved the way for this particular trial?

What are the safety and toxicity concerns with polatuzumab vedotin?

If successful, how would this drug change the standard of care?

Patients in the R-CHP plus vincristine placebo plus polatuzumab vedotin group will receive polatuzumab vedotin 1.8 mg/kg IV, placebo for vincristine IV, rituximab 375 mg/ m²) IV, cyclophosphamide 750 mg/m² IV, and doxorubicin 50 mg/m² IV on Day 1, and prednisone 100 mg/day orally on days 1-5 of every 21-day cycle for 6 cycles. Rituximab 375 mg/m² IV will be administered as monotherapy in Cycles 7 and 8.Since we are still in the enrollment stage of the trial, next steps are to complete enrollment, and await evaluation of primary endpoint by the statistical group. Then, we will be able to evaluate potential biomarkers to predict improved responses, outcomes, and means for devising new therapeutic approaches.Currently, patients receiving the first-line treatment for DLBCL, R-CHOP, are still at a 30% to 40% risk of relapse, and early relapse is a poor prognostic sign. PROLARIX focuses on patients with intermediate- to high-risk disease, defined by an IPI score of 2 to 5. PROLARIX is seeking to improve outcomes for these patients with IPI scores of 2 to 5 because these patients have greater risk of relapse and worse survival with standard R-CHOP therapy than does the general patient population with DLBCL.The phase II study included 65 patients (clinicaltrials. gov, NCT01992653), 40 of whom completed therapy with polatuzumab vedotin with R-CHP and showed promising results. At the end of treatment, 78% of patients had a complete response and 13% had a partial response.The phase II trial presented by Dr. Tilly showed that 58% of patients in the polatuzumab—R-CHP group experienced grade 3/4 adverse events, including 27% with neutropenia and 11% with febrile neutropenia. One patient experienced grade 5 atrial fibrillation. Serious adverse events, including febrile neutropenia, neutropenia, pneumonia, pulmonary embolism, and influenza A, occurred in 38% of patients. A particular safety concern for polatuzumab vedotin is peripheral neuropathy, because of the conjugated microtubule disrupting agent; it was found to occur in 40% of phase 2 trial patients. Instances of grade 2 or 3 peripheral neuropathy that occurred were during the fifth treatment cycle or later; this is why the POLARIX trial is limited to a maximum of 6 chemotherapy cycles.The idea behind the PROLARIX trial is to optimize the standard of care already available to further improve patient outcomes and reduce the risk of reccurrence. This treatment regimen will hopefully become the first-line treatment in DLBCL, as it improves the current R-CHOP standard by replacing vincristine with polatuzumab vedotin, a monoclonal antibody designed to selectively target tumor cells.

References

1. Forero-Torres A, Kolibaba KS, Lamy T, Jones S, Lee C, Sharma J. Polatuzumab vedotin combined with obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (G-CHP) for patients with previously untreated diffuse large B-cell lymphoma (DLBCL): preliminary results of a phase Ib/II dose-escalation study. Abstract presented at: 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, CA. bloodjournal.org/content/128/22/1856?sso checked=true.
2. Katz A. Novel antibody tested in first-line DLBCL therapy. Oncology Live website. onclive.com/publications/oncology-live/2018/vol- 19-no-2/novel-antibody-tested-in-firstline-dlbcl-therapy. Published January 25, 2018. Accessed April 25, 2018.