Diffuse large B-cell lymphoma (DLBCL), the most common type of an aggressive form of non-Hodgkin lymphoma (NHL) in the United States and worldwide, is often treated with a  combination of chemotherapy and the monoclonal antibody rituximab (Rituxan®; Genentech/Roche), with or without radiation therapy.

While effective, up to 40% of patients receiving the standard R-CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone), plus rituximab for the treatment of DLBCL have refractory disease or relapse.

Polatuzumab vedotin-piiq (Polivy™) Packaging
Polatuzumab vedotin-piiq (Polivy™) Packaging

In a double-blind, placebo-controlled, international phase 3 clinical trial (POLARIX; NCT03274492) in patients with previously untreated intermediate-risk or high-risk DLBCL, researchers modified the standard regimen by replacing vincristine with polatuzumab vedotin (Polivy®; Genentech/Roche), an antibody-drug conjugate (ADC) targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. The study was funded by Genentech and Roche.

Results of the study were presented in December 2021 as a late-breaking abstract at the 2021 annual meeting of the American Society of Hematology (ASH) and simultaneously published in the New England Journal of Medicine.[1]

Participating patients were 18 to 80 years of age and were randomly assigned in a 1:1 ratio to receive six cycles of either the modified pola-R-CHP regimen or the standard R-CHOP regimen, plus two cycles of rituximab alone. The primary endpoint was investigator-assessed progression-free survival while the secondary endpoints included overall survival and safety.

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Overall, 879 patients were randomized. Of these patients, 440 were assigned to the modified pola-R-CHP treatment group and 439 received the standard R-CHOP treatment.

After a median follow-up of 28.2 months, the percentage of patients surviving without disease progression was significantly higher in the group of patients receiving the modified pola-R-CHP treatment than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P=0.02).

The study results demonstrated that at 2 years overall survival did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P=0.75).

The researchers also note that the safety profile of the two regimens was similar in the two groups.

Adverse events
The study authors noted that adverse events included rates of Grade 3-4 adverse events (AEs; 57.7% versus 57.5%), serious AEs (34.0% versus 30.6%), Grade 5 AEs (3.0% versus 2.3%), and AEs leading to dose reduction (9.2% versus 13.0%).

One known adverse event expected in patients being treated with an antibody-drug conjugate containing monomethyl auristatin E (MMAE; vedotin) a synthetic antineoplastic agent which forms the cytotoxic payload of the ADC, included the occurrence of peripheral neuropathy, which often causes weakness, numbness, and pain, usually in the hands and feet. The occurrence of peripheral neuropathy in patients with DLBCL treated with single-agent polatuzumab vedotin, as well as polatuzumab vedotin in combination with other agents, has been described in previous studies.[2][3][4] In this trial, the incidence of peripheral neuropathy was, in the majority of cases of grade 1.

Interestingly, the researchers noted that the incidence and severity of peripheral neuropathy in this study were similar to those observed in the ECHELON-2 study, in which brentuximab vedotin (Adcetris®; Seattle Genetics), another ADC, in combination with CHP (cyclophosphamide, doxorubicin, and prednisone), was compared with CHOP in patients with T-cell lymphoma. [5]

Although the study authors observed a higher incidence of febrile neutropenia, which includes the occurrence of fever during a period of significant neutropenia, among patients who received the modified pola-R-CHP treatment compared to patients who received R-CHOP (14.3% vs. 8.0%), they also noted that this finding did not translate into a higher overall incidence of infection, treatment discontinuation or treatment, or dose reductions. They confirmed that the occurrence of febrile neutropenia was similar to the percentages reported in other R-CHOP studies, including one study in which obinutuzumab, a glycoengineered, type II, anti-CD20 monoclonal antibody, replaced rituximab in patients with previously untreated advanced-stage DLBCL [6] and another, double-blind, phase III study which evaluated ibrutinib and rituximab plus CHOP in untreated non-germinal center B-cell DLBCL. [7]

When comparing all the available data, the researchers concluded that among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP.

The study data is expected to form the basis of ongoing marketing applications to global health authorities designed to broaden the treatment options in areas of unmet medical need. In addition, ongoing studies investigating combinations of polatuzumab vedotin with the CD20xCD3 T-cell engaging bispecific antibodies mosunetuzumab and glofitamab, with venetoclax (Venclexta®; AbbVie and Genentech), and with Rituxan in combination with gemcitabine and oxaliplatin in the Phase 3 POLARGO study.

Clinical trial
A Study Comparing the Efficacy and Safety of Polatuzumab Vedotin With Rituximab-Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) Versus Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Participants With Diffuse Large B-Cell Lymphoma (POLARIX) – NCT03274492
A Study of Escalating Doses of Polatuzumab Vedotin in Participants With Relapsed or Refractory B-Cell Non-Hodgkins Lymphoma and Chronic Lymphocytic Leukemia and Polatuzumab Vedotin in Combination With Rituximab in Participants With Relapsed or Refractory B-Cell Non-Hodgkins Lymphoma – NCT01290549
ECHELON-2: A Comparison of Brentuximab Vedotin and CHP With Standard-of-care CHOP in the Treatment of Patients With CD30-positive Mature T-cell Lymphomas (ECHELON-2) – NCT01777152.
A Study to Evaluate the Safety and Efficacy of Polatuzumab Vedotin in Combination With Rituximab, Gemcitabine and Oxaliplatin Compared to Rituximab, Gemcitabine and Oxaliplatin Alone in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (POLARGO) – NCT04182204

Highlights of Prescribing Information
Rituximab (Rituxan®; Genentech/Roche)(Prescribing Information)
Polatuzumab vedotin (Polivy®; Genentech/Roche)(Prescribing Information)
Brentuximab vedotin (Adcetris®; Seattle Genetics)(Prescribing Information)
Venetoclax (Venclexta®>; AbbVie and Genentech)(Prescribing Information)

Reference
[1] Tilly H, Morschhauser F, Sehn LH, Friedberg JW, Trněný M, Sharman JP, Herbaux C, Burke JM, Matasar M, Rai S, Izutsu K, Mehta-Shah N, Oberic L, Chauchet A, Jurczak W, Song Y, Greil R, Mykhalska L, Bergua-Burgués JM, Cheung MC, Pinto A, Shin HJ, Hapgood G, Munhoz E, Abrisqueta P, Gau JP, Hirata J, Jiang Y, Yan M, Lee C, Flowers CR, Salles G. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022 Jan 27;386(4):351-363. doi: 10.1056/NEJMoa2115304. Epub 2021 Dec 14. PMID: 34904799.
[2] Palanca-Wessels MC, Czuczman M, Salles G, Assouline S, Sehn LH, Flinn I, Patel MR, Sangha R, Hagenbeek A, Advani R, Tilly H, Casasnovas O, Press OW, Yalamanchili S, Kahn R, Dere RC, Lu D, Jones S, Jones C, Chu YW, Morschhauser F. 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. Lancet Oncol. 2015 Jun;16(6):704-15. doi: 10.1016/S1470-2045(15)70128-2. Epub 2015 Apr 27. PMID: 25925619.
[3] Morschhauser F, Flinn IW, Advani R, Sehn LH, Diefenbach C, Kolibaba K, Press OW, Salles G, Tilly H, Chen AI, Assouline S, Cheson BD, Dreyling M, Hagenbeek A, Zinzani PL, Jones S, Cheng J, Lu D, Penuel E, Hirata J, Wenger M, Chu YW, Sharman J. Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS). Lancet Haematol. 2019 May;6(5):e254-e265. doi: 10.1016/S2352-3026(19)30026-2. Epub 2019 Mar 29. PMID: 30935953.
[4] Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M, Assouline S, Kim TM, Kim WS, Ozcan M, Hirata J, Penuel E, Paulson JN, Cheng J, Ku G, Matasar MJ. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020 Jan 10;38(2):155-165. doi: 10.1200/JCO.19.00172. Epub 2019 Nov 6. PMID: 31693429; PMCID: PMC7032881.
[5] Horwitz S, O’Connor OA, Pro B, Illidge T, Fanale M, Advani R, Bartlett NL, Christensen JH, Morschhauser F, Domingo-Domenech E, Rossi G, Kim WS, Feldman T, Lennard A, Belada D, Illés Á, Tobinai K, Tsukasaki K, Yeh SP, Shustov A, Hüttmann A, Savage KJ, Yuen S, Iyer S, Zinzani PL, Hua Z, Little M, Rao S, Woolery J, Manley T, Trümper L; ECHELON-2 Study Group. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019 Jan 19;393(10168):229-240. doi: 10.1016/S0140-6736(18)32984-2. Epub 2018 Dec 4. Erratum in: Lancet. 2019 Jan 19;393(10168):228. PMID: 30522922; PMCID: PMC6436818.
[6] Vitolo U, Trněný M, Belada D, Burke JM, Carella AM, Chua N, Abrisqueta P, Demeter J, Flinn I, Hong X, Kim WS, Pinto A, Shi YK, Tatsumi Y, Oestergaard MZ, Wenger M, Fingerle-Rowson G, Catalani O, Nielsen T, Martelli M, Sehn LH. Obinutuzumab or Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Previously Untreated Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2017 Nov 1;35(31):3529-3537. doi: 10.1200/JCO.2017.73.3402. Epub 2017 Aug 10. PMID: 28796588.
[7] Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, Patti C, Belada D, Samoilova O, Suh C, Leppä S, Rai S, Turgut M, Jurczak W, Cheung MC, Gurion R, Yeh SP, Lopez-Hernandez A, Dührsen U, Thieblemont C, Chiattone CS, Balasubramanian S, Carey J, Liu G, Shreeve SM, Sun S, Zhuang SH, Vermeulen J, Staudt LM, Wilson W; PHOENIX investigators. Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2019 May 20;37(15):1285-1295. doi: 10.1200/JCO.18.02403. Epub 2019 Mar 22. PMID: 30901302; PMCID: PMC6553835.

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