Novel Antibody Tested in First-Line DLBCL Therapy

Christopher R. Flowers, MD, MS

Investigators are studying the value of polatuzumab vedotin (RG7596) in patients with intermediate- or high-risk diffuse large B-cell lymphoma (DLBCL). Polatuzumab vedotin is a CD79b-specific antibody conjugated to a microtubule disrupting agent, monomethyl auristatin E (MMAE), with a stable linker. The novel antibody—drug conjugate is being combined with R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) as a first-line treatment in the phase III, randomized, multicenter POLARIX clinical trial (NCT03274492) (Figure).

Figure. Polatuzumab Vedotin in DLBCL (Click to enlarge image)

This combination is being compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), which is the current first-line standard of care for patients with DLBCL. Although many patients with DLBCL treated with R-CHOP are cured, “following standard R-CHOP, 30% to 40% of patients with DLBCL relapse, [and] patients who experience early relapse have a poor prognosis. The trial aims to address these problems by evaluating a new approach for firstline treatment of DLBCL that may improve upon [outcomes with] R-CHOP,” said Christopher R. Flowers, MD, MS, professor of hematology and medical oncology at Emory University School of Medicine in Atlanta, Georgia. He also is director of the Emory Lymphoma Program and scientific director of Winship Research Informatics Shared Resource at Emory University’s Winship Cancer Institute. Flowers is the principal investigator for POLARIX at Emory and a member of the trial’s international steering committee.

The study will enroll patients with any subtype of CD20-positive DLBCL with an ECOG performance status of 0 to 2, a cardiac ejection fraction of at least 50%, and intermediate- to high-risk disease (International Prognostic Index [IPI]score, 2-5). Patients with an IPI score of 2 to 5 havea a greater risk of relapse and worse survival with standard R-CHOP than the general group of patients with DLBCL. Participants cannot have had prior treatment for DLBCL. The investigators will assess the safety and efficacy of polatuzumab vedotin using investigator-assessed progression-free survival as the primary endpoint. They also will evaluate potential biomarkers to predict improved outcomes and as a means for devising new therapeutic approaches in the future, according to Flowers.

Polatuzumab vedotin consists of a CD79bspecific monoclonal antibody conjugated to a potent cytotoxin that is selectively delivered to tumor cells.¹ This combination delivers highly potent cytotoxins directly to tumor cells, which then absorb the cytotoxin.²

Previous trials of the drug yielded favorable results. A dose escalation trial showed an acceptable safety profile and established a recommended phase II dose of polatuzumab vedotin of 1.8 mg/kg in combination with R-CHP.³

Updated results from the same trial showed promising responses in patients with DLBCL and follicular lymphoma (FL). The study enrolled 65 patients, and 64 patients received more than 1 dose of polatuzumab vedotin. “Forty-five patients with DLBCL completed therapy with polatuzumab vedotin with R-CHP, including 40 in the phase II portion of the trial,” Flowers said. At the end of treatment in the phase II portion of the study, 78% of patients had a CR, and 13% had a partial response, according to Flowers.

Grade 3/4 adverse events (AEs) occurred in 58% of patients, including neutropenia (27%) and febrile neutropenia (11%). One patient experienced grade 5 atrial fibrillation. Serious AEs were reported in 17 patients (38%), including 3 instances of febrile neutropenia, and 2 each of neutropenia, pneumonia, pulmonary embolism, and influenza A.⁴

“An adverse event of particular interest was peripheral neuropathy, given that MMAE is a microtubule disrupting agent,” Flowers said. Peripheral neuropathy occurred in 18 patients, including 12 instances that were grade 1; 4, grade 2; and 2, grade 3. All instances of grade 2/3 peripheral neuropathy that could be attributed to polatuzumab vedotin occurred at the fifth cycle of treatment or later.⁴ For this reason, Flowers said, the POLARIX trial is limited to 6 cycles of chemoimmunotherapy with or without polatuzumab vedotin.

Polatuzumab vedotin is being developed by Hoffmann-La Roche, based in Basel, Switzerland.

References

1. Product development portfolio. Hoffmann-La Roche website. roche.com/research_and_development/who_we_are_how_ we_work/pipeline.htm. Updated October 23, 2017. Accessed December 28, 2017.
2. Polatuzumab vedotin (RG7596). Genentech website. biooncology. com/pipeline-molecules/polatuzumab-vedotin.html. Published 2017. Accessed December 28, 2017.
3. 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.
4. Tilly H, Sharman J, Bartlett N, et al. POLA-R-CHP: polatuzumab vedotin combined with rituximab, cyclophosphamide, doxorubicin, prednisone for patients with previously untreated diffuse large B-cell lymphoma. Presented at: 22nd Annual Congress of EHA; June 22-25, 2017; Madrid, Spain. Abstract S106. https:// learningcenter.ehaweb.org/eha/2017/22nd/181393/herv.tilly. pola-r-chp.polatuzumab.vedotin.combined.with.rituximab.html.