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Home , Obinutuzumab, Polatuzumab vedotin

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Obinutuzumab for the treatment of non-Hodgkin lymphomas

AUTHORS Juana Hernandez, Tina Nielsen, Christian Klein, Michael Wenger Complement-dependent cytotoxicity + Lipid raft

Rituximab AFFILIATION Direct F. Hoffmann-La Roche Ltd, cell death + Grenzacherstrasse 124, CH-4070, Basel, Switzerland -dependent cellular cytotoxicity +

B cell

Natural Hoffmann-La Roche Ltd sweats, weight loss and general killer cell CD20 (Roche) has a rich history of lack of energy. The disease is Fresearch and development typically characterised by a series of antibody therapies to treat of relapses and retreatment. cancers (malignancies) that Often, with each relapse, the affect B cells (a type of white disease becomes increasingly blood cell), including non- resistant to chemotherapy2. Antibody-dependent Hodgkin lymphoma and chronic Chronic lymphocytic phagocytosis + lymphocytic leukaemia. While leukaemia is the most common

dependent on the type of cancer type of adult leukaemia in the + = has a greater e ect than obinutuzumab Macrophage and the stage when the cancer Western world. Most patients + = obinutuzumab has a greater e ect than rituximab is diagnosed, the outcomes for are diagnosed when a high Figure 1: Differences in the proposed mechanisms of action of rituximab and patients with B-cell malignancies number of blood lymphocytes obinutuzumab. Rituximab is a type I antibody that functions by the stabilisation of CD20 are generally poor and require are found after a patient has a on lipid rafts, resulting in strong complement-dependent cytotoxicity. Obinutuzumab is a glycoengineered type II antibody that leaves CD20 distributed across the surface of the further improvement. full blood count for an unrelated and has much lower complement-dependent cytotoxicity, but greater antibody- reason. In common with follicular dependent cellular cytotoxicity, antibody-dependent phagocytosis and direct cell death. INDOLENT NON-HODGKIN lymphoma, chronic lymphocytic LYMPHOMA AND CHRONIC leukaemia is slow to progress. LYMPHOCYTIC LEUKAEMIA Many patients do not have IMMUNOTHERAPIES Idec, was the first anti- Non-Hodgkin lymphomas can be symptoms for years, but if the FOR NON-HODGKIN CD20 to classified according to the speed treating physician notices a LYMPHOMA AND CHRONIC be approved for the treatment at which they progress. Those sharp increase in the number of LYMPHOCYTIC LEUKAEMIA of non-Hodgkin lymphomas. It that grow and spread slowly are lymphocytes and a drop in the Immunotherapies are often works by specifically targeting described as ‘indolent’, one of the number of red blood cells, they described as ‘biological’ or the CD20 protein and kills B most common types of which is may begin treatment. ‘targeted’ therapies that cells in three different ways: . About one- These chronic diseases stimulate the body's immune 1) antibody-dependent cellular fifth of new cases of non-Hodgkin contrast with the aggressive system to act against cancer cytotoxicity –‘effector’ immune lymphoma are diagnosed as non-Hodgkin lymphoma subtype, cells. In the search for an cells such as natural killer follicular lymphoma1. Follicular diffuse large B-cell lymphoma, immunotherapy for B-cell cells and macrophages are lymphoma usually appears as which can be fatal within weeks or malignancies, the membrane recruited to kill the B cells, painless, slowly growing lymph months of diagnosis if not treated. protein CD20 was considered a including the cancerous B cells; nodes. In the early stages of Diffuse large B-cell lymphoma prime target. CD20 is found on 2) complement-dependent disease there are typically no and treatment advances for the surface of all normal B cells cytotoxicity – the proteins of symptoms, but at advanced diffuse large B-cell lymphoma and on 95% of cancerous B cells. the 'complement' system are stages the patient may experience are described further in this issue Rituximab, developed in recruited, which damage the symptoms such as fever, night of Nature Outlook: Lymphoma. partnership by Roche and B-cell membrane leading to cell

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death; and 3) direct cell death some patients do not respond which is a type I antibody. These were similar, although the number – as rituximab binds to the B to initial rituximab treatment, or classifications are based on the of patients experiencing side cell through the CD20 receptor, their disease continues to get way the bind to CD20. effects, including reactions during the signal causes the B cell to worse while receiving rituximab5. When rituximab binds to CD20, it or following drug infusions, and die3. These mechanisms are Furthermore, while patients reorganises the CD20 molecules a decrease in some blood cell shown in more detail in Figure 1. with indolent diseases survive on the cancerous B cells into lipid counts (neutrophils), was higher in Rituximab in combination with for a comparatively long time, rafts, which indirectly triggers cell those treated with obinutuzumab was found to on average between six and ten death by a mechanism known as compared with rituximab. be effective at destroying both years with treatment, they usually complement-dependent cytotox- A phase III study, called the cancerous and healthy B cells; cannot be cured if they present icity (Fig. 1). In contrast, the type GADOLIN trial, looked at the when the rituximab treatment is in the clinic in the advanced II antibody, obinutuzumab, is not risk of disease worsening or completed, the body replaces the stages of disease. Also, at some as effective at inducing comple- death in patients with indolent normal B cells. stage their disease may become ment-dependent cytotoxicity non-Hodgkin lymphoma who did In 1997, rituximab received more aggressive. Consequently, but is much more effective than not respond to, or who relapsed approval for use by the Roche has continued to develop rituximab at inducing direct during or within 6 months after United States Food and Drug new treatments to improve cell death. This direct action of a previous rituximab treatment Administration (US FDA) for upon rituximab for these patient obinutuzumab on B-cell death, regimen. These patients received the treatment of patients with populations. together with its effective either obinutuzumab plus relapsed low-grade non-Hodgkin induction of antibody dependent chemotherapy () lymphomas. It was the first OBINUTUZUMAB, cellular cytotoxicity and anti- or bendamustine only. Patients therapeutic antibody to be A HUMANISED, body-dependent phagocytosis, who received the obinutuzumab approved for chronic lymphocytic GLYCOENGINEERED, TYPE II, may represent an important ad- regimen were 43% less likely to leukaemia and non-Hodgkin MONOCLONAL ANTIBODY vantage, as it has the potential to experience disease worsening or lymphoma. Compared with the Roche wanted to create an reduce the risk of drug resistance death than those who received previously available chemotherapy antibody that would overcome seen with rituximab. chemotherapy only. This trial treatments, rituximab improved some of the limitations also showed that 75% of patients the survival outlook for these of rituximab and be more CLINICAL TRIALS OF in the group who received patients. One study showed effective than rituximab at OBINUTUZUMAB obinutuzumab survived to the that after a median observation treating B-cell malignancies. The superior effects of end of the study, compared period of 18 months, patients Roche used a process known obinutuzumab seen in the with only 65% of the patients with advanced stage follicular as glycoengineering to design laboratory have been confirmed receiving chemotherapy alone; lymphoma who received obinutuzumab. Glycoengineering in clinical trials and, in 2013, the this represented a 33% lower risk rituximab in combination with involves controlling the type drug was the first drug to be of death in the group of patients chemotherapy were significantly of sugar molecules in the Fc awarded Breakthrough Therapy who received obinutuzumab less likely to experience treatment region of the antibody. The Fc Designation by the US FDA. (Fig. 2)⁸. The side effects failure than patients who received region of the antibody recruits Obinutuzumab was compared experienced by patients in the chemotherapy alone4. immune cells to kill the target with rituximab in stage 2 of the GADOLIN study were similar cell, which is bound by the CLL11 of patients with for both treatment groups. The THE UNMET MEDICAL antibody. Laboratory testing chronic lymphocytic leukaemia findings from GADOLIN led to the NEED FOR FOLLICULAR of obinutuzumab showed that and other co-existing conditions; US approval of obinutuzumab in LYMPHOMA AND CHRONIC compared with rituximab, the both groups also received combination with bendamustine LYMPHOCYTIC LEUKAEMIA Fc region of obinutuzumab is chemotherapy7. The chemotherapy, followed by Although rituximab helps more effective at recruiting use of obinutuzumab in the CLL11 obinutuzumab alone, as a new many patients with non- effector immune cells (antibody- trial led to a 51% decrease in the treatment regimen for patients Hodgkin lymphoma and chronic dependent cellular cytotoxicity risk of disease worsening or death with follicular lymphoma lymphocytic leukaemia, and and phagocytosis) and thus compared with rituximab. The who relapse after rituximab was a major step forward in better at triggering the death trial also showed that patients treatment, or who do not respond the treatment of the disease, it of cancerous cells (Fig. 1). who received obinutuzumab to rituximab. Shortly after, has some limitations. The level Obinutuzumab was the first survived for longer than those obinutuzumab in combination and duration of the response to medicinal product using who received rituximab; the risk with bendamustine was approved rituximab may decrease over glycoengineering technology to of death was 24% lower in the in the EU for patients with time. Eventually, the majority be approved in the US and the obinutuzumab group compared follicular lymphoma who do not of patients receiving rituximab European Union (EU)6. with the rituximab group (Fig. 2). respond to rituximab or who relapse and some even develop Obinutuzumab is a type II The side effect profiles of relapse within six months of resistance to the drug. In addition, antibody, unlike rituximab, rituximab and obinutuzumab rituximab treatment.

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GALLIUM study (41.1 months median observation time) in the US, EU and many other An ongoing study (CLL14) Obinutuzumab plus chemotherapy (n=601) countries, of obinutuzumab in of patients with previously 120 (20%) 41 patients combination with chemotherapy untreated chronic lymphocytic FEWER progressed PATIENTS or died for the treatment of patients with leukaemia is comparing the experienced disease Rituximab plus chemotherapy (n=601) worsening or died previously untreated advanced efficacy of obinutuzumab in with the obinutuzumab-based 161 (27%) regimen patients follicular lymphoma. combination with the drugs p=0.0016 progressed or died Disappointingly, the results of or chlorambucil. the GOYA trial of obinutuzumab Roche is dedicated to improving CLL11 study (59.4 months median observation time) in patients with the aggressive the lives of patients with non- Obinutuzumab plus chemotherapy (n=333) form of non-Hodgkin lymphoma, Hodgkin lymphoma and chronic 244 (73.3 %) 48 patients diffuse large B-cell lymphoma, FEWER progressed lymphocytic leukaemia. A PATIENTS or died experienced disease revealed that outcomes with number of additional approaches worsening or died Rituximab plus chemotherapy (n=330) with the obinutuzumab were not better to the treatment of B-cell obinutuzumab-based 292 (88.5%) regimen patients p<0.001 progressed than with rituximab when malignancies are in the pipeline, or died combined with chemotherapy10. including the bispecific 11 GADOLIN study (31.8 months median observation time) Diffuse large B-cell lymphoma is antibodies, mosunetuzumab 12 Obinutuzumab plus chemotherapy (n=204) the most common type of non- and CD20-TCB . Our aim is to 115 (56.4 %) Hodgkin lymphoma making up optimise the use of available 31 patients FEWER progressed about 30% of all lymphomas. It treatments while continuing to PATIENTS or died experienced disease worsening or died $hemotherapy (n=209) is typically fatal if left untreated search for new, more effective with the obinutuzumab-based 146 (69.9%) and so more effective drugs treatments for these life-limiting regimen patients p<0.001 progressed for patients with diffuse large diseases. or died B-cell lymphoma are desperately GOYA study (29 months median observation time) needed. The search for such Obinutuzumab plus chemotherapy (n=706) treatments by Roche has 201 (29 %) 14* patients uncovered a new antibody-drug ACKNOWLEDGEMENT FEWER progressed PATIENTS or died conjugate, , Third-party medical writing experienced disease worsening or died Rituximab plus chemotherapy (n=712) with the described in this edition of assistance, under the direction obinutuzumab-based 215 (30%) regimen patients Nature Outlook: Lymphoma. of the authors, was provided progressed or died by Angela Rogers of Gardiner- = approximately 10 patients FUTURE DIRECTIONS Caldwell Communications, and *not statistically signi cant Roche continues to look at ways was funded by F. Hoffmann-La Figure 2: Reduction in the risk of disease worsening and death in four key clinical trials of advancing the treatment Roche Ltd. of obinutuzumab. The GALLIUM trial compared obinutuzumab plus chemotherapy of lymphomas. One approach combinations with rituximab plus chemotherapy in patients with previously untreated is to combine obinutuzumab follicular lymphoma9. The CLL11 trial compared obinutuzumab plus chemotherapy (chlorambucil), with rituximab plus chlorambucil in patients with chronic lymphocytic with different drugs, including REFERENCES leukaemia. GADOLIN compared obinutuzumab plus chemotherapy (bendamustine) chemotherapy-free treatment 1. The Non-Hodgkin’s Lymphoma with bendamustine alone in patients with indolent non-Hodgkin lymphoma who did not Classification Project. Blood 89, options. A programme of 3909–3918 (1997). respond to rituximab8. GOYA compared obinutuzumab plus chemotherapy combinations early phase clinical studies, 2. Montoto, S. et al. Ann. Oncol. 13, with rituximab plus chemotherapy in patients with previously untreated advanced-stage 523–530 (2002). diffuse large B-cell lymphoma10. known as InHarmony, is testing 3. Freeman, C. L. & Sehn, L. H. Br. J. obinutuzumab combinations Haematol. 182, 29–45 (2018). with various different drugs 4. Hiddemann, W. et al. Blood 106, Roche also investigated the lower in patients who received that have different mechanisms 3725–3732 (2005). use of obinutuzumab for indolent obinutuzumab compared with of action in different groups 5. Cartron, G., Trappe, R. U. Clin. Cancer Res. 17, 19–30 (2011). 9 non-Hodgkin lymphoma patients those who received rituximab . of patients with lymphoma 6. Mössner, S. et al. Blood 115, who have not previously received Obinutuzumab was more effective (either those receiving their first 4393–4402 (2010). treatment. The GALLIUM than rituximab but the group treatment or those who have 7. Goede, V. et al. N. Eng. J. Med. 370, 1101-1110 (2014). clinical trial assessed the receiving obinutuzumab had a relapsed following treatment). 8. Cheson, B. et al. J. Clin. Oncol. 36, efficacy of obinutuzumab plus different profile of side effects. Such combinations include 2259–2266 (2018). chemotherapy compared with Importantly, the improvement an immunomodulatory agent 9. Hiddemann, W. et al. J. Clin. Oncol. 36, 2395–2404 (2018). rituximab plus chemotherapy in patient quality of life was (), a checkpoint 10. Vitolo, U. et al. J. Clin. Oncol. 35, in patients with previously similar with obinutuzumab and inhibitor (), a 3529–3537 (2017). untreated follicular lymphoma. rituximab, despite the different Bcl2 inhibitor (venetoclax) or 11. Sun, L. L. et al. Sci. Transl. Med. 7, 287ra70 (2015). In this trial, the risk of disease side effects9. The outcomes of the an antibody-drug conjugate 12. Bacac, M. et al. Clin. Cancer Res. 24, worsening or death was 32% GALLIUM trial led to the approval, (polatuzumab vedotin). 4785-4797 (2018).

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