• Long-term data for Ocrevus indicate that the rate of malignancies is within the range observed in real-world registries.
• Data is limited for the use of Ocrevus in people with a history of malignancy.
• A history of malignancy is an exclusion criterion for clinical trials of Ocrevus due to the potential decreased immune surveillance associated with B-cell depletion.
• There are case reports in the published literature of people with multiple sclerosis and a history of malignancy who have been treated with Ocrevus.

DMT=disease-modifying therapy

MS=multiple sclerosis

PwMS=people with multiple sclerosis

PY=patient years

RRMS=relapsing-remitting multiple sclerosis

SPMS=secondary progressive multiple sclerosis

PPMS=primary progressive multiple sclerosis

Risk of malignancies with immunosuppressants

Given the potential impact of immunomodulators on tumor surveillance, malignancies are listed as an important potential risk in the risk management plan for most disease-modifying therapies approved for multiple sclerosis (MS), including Ocrevus.[1]

Malignancies in the clinical trials

In the pivotal Phase III clinical trials in MS, OPERA I and II, and ORATORIO, a higher incidence of malignancies, particularly a single cluster of female breast cancer, was observed in the Ocrevus treatment groups, compared with interferon beta-1a and placebo.[2,3]

Hauser et al. reported on a pooled safety analysis of PwMS in the Ocrevus all-exposure population over 11 years, which included all patients (n=6,155; 30,396 patient-years) who received >1 dose of Ocrevus during the controlled or open-label periods of 13 clinical trials of Ocrevus.[4] The incidence rates of malignancies across Ocrevus studies in MS were reported for the Ocrevus all exposure population as well as the comparators (IFN and placebo).

Over 11 years, the rates of all malignancies and female breast cancer in Ocrevus-treated patients remained stable over time and within the range reported in epidemiological data.[4]

Exclusion criteria in the clinical studies of Ocrevus

In the clinical trials of Ocrevus in MS, people with a history of malignancy were excluded.[5,6] The exclusion criteria included a history of malignancy, including solid tumours and haematological malignancies, with the exception of the following carcinomas, if they had been previously completely excised with documented, clear margins.[5,6]

• basal cell carcinoma,
• in situ squamous cell carcinoma of the skin, and
• in situ carcinoma of the cervix of the uterus.

Additional data from published literature

As of October 2024, a search of the published literature returned articles describing PwMS and a history of malignancy who received treatment with Ocrevus. There was only one report of a recurrence of malignancy in an individual treated with either Ocrevus or rituximab; the case report is not clear regarding the treatment received.[7] See Table 1 below.

Table 1. Published literature on PwMS and a history of malignancy treated with Ocrevus

Please note that this information is subject to the limitations inherent to the searched databases and cannot be considered exhaustive.

Roche systematically reviews the safety profile of Ocrevus based on the global collection of suspected adverse events from clinical trials and the post-marketing setting. The cumulative standardised incidence rates of all malignancies, including breast cancer, in patients treated with Ocrevus has remained within the range reported in real-world registries and the background rates expected in PwMS and the general population.[17]

The CONFIDENCE study is collecting data to be included in the global post-authorization safety studies, MANUSCRIPT and VERISMO.[18,19] MANUSCRIPT and VERISMO are multi-source, multicountry, noninterventional, longitudinal cohort studies on PwMS who are treated with Ocrevus. These trials will give better insight into the risk of malignancies in PwMS receiving Ocrevus. Patients are being followed for up to 10 years, or until censoring, loss to follow-up, or death.

The primary objective of the MANUSCRIPT study is to assess and characterize the long-term safety data, including rates of malignancies and serious infection, in PwMS over 18 years of age treated with Ocrevus.[20] The study is expected to include 5,000 patients treated with Ocrevus and 3,500 patients treated with other MS-approved disease-modifying therapies (DMTs). MANUSCRIPT will use secondary data from MS-specific registry sources (MS Documentation System 3D [Germany] and Big MS Data Group [a collaboration between the French, Danish, Italian, and Swedish national MS registries, and the international MSBase registry]).

The VERISMO study will determine and characterize the incidence and mortality rates of all malignancies, including breast cancer, in patients treated with Ocrevus in the US and Germany.[21] The study is expected to enroll 6,360 PwMS, over 18 years of age, including 4,000 patients exposed to Ocrevus and 2,360 patients exposed to other MS-approved DMTs. VERISMO will also include external comparators, including the international MSBase Registry, and the US Surveillance, Epidemiology, and End Results (SEER) Program.

1. The EU Risk Manangement Plan for Ocrevus. Available at https://www.ema.europa.eu/en/documents/rmp/ocrevus-epar-risk-management-plan_en.pdf. Accessed on February 7, 2025.
2. Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon Beta-1a in relapsing multiple sclerosis [supplementary appendix appears online]. N Engl J Med 376;376:221-234. https://www.ncbi.nlm.nih.gov/pubmed/28002679
3. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis [supplementary appendix appears online]. N Engl J Med 376;376:209-220. https://www.ncbi.nlm.nih.gov/pubmed/28002688
4. Hauser SL, Giovannoni G, Filippi M, et al. Safety of Ocrelizumab in Multiple Sclerosis: Up to 11 Years of Updated Analysis in Patients with Relapsing and Progressive Multiple Sclerosis. Presented at the 40th Congress of the European Committee for Treatment and Research in MS Meeting in Copenhagen, Denmark; September 18-20, 2024. ECTRIMS Poster #P300. https://ectrims.eu/ectrims2024/
5. Protocol for OPERA I and OPERA II studies: Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. August 19, 2017. Available at http://www.nejm.org/doi/suppl/10.1056/NEJMoa1601277/suppl_file/nejmoa1601277_protocol.pdf. Accessed on January 18, 2017.
6. Protocol for ORATORIO Study: Ocrelizumab versus placebo in primary progressive multiple sclerosis. January 19, 2017. Available at https://www.nejm.org/doi/suppl/10.1056/NEJMoa1606468/suppl_file/nejmoa1606468_protocol.pdf. Accessed on February 7, 2025.
7. Del Canto A, Garcia L, Aylwin E, et al. Real-world evidence of anti-CD20 monoclonal antibodies in chilean patients with multiple sclerosis. Mult Scler 2022;28:383-84. https://www.ncbi.nlm.nih.gov/pubmed/39757941
8. Patel H, Hutton G. A case of immune checkpoint inhibitor (ICI) use in multiple sclerosis. Neurology 2024;102 (17_supplement_1):https://doi.org/10.1212/WNL.0000000000205464
9. Pape K, Protopapa M, Schraad M, et al. Case Report: Balancing immune responses - multiple sclerosis disease exacerbation under BRAF/MEK treatment for malignant melanoma. Front Oncol 2023;13:1303141. https://www.ncbi.nlm.nih.gov/pubmed/38074649
10. Hoffmann F, Frohlich A, Schafer N, et al. Treatment of metastasized melanoma with combined checkpoint inhibition in a patient with highly active multiple sclerosis. J Dermatol 2020;47:e184-e185. https://doi.org/10.1111/1346-8138.15272
11. Ahsun S, Lekprasert P, Win K. n Interesting Case Of Primary Hypogonadism In A Patient With Multiple Sclerosis. 7:https://doi.org/10.1210/jendso/bvad114.1623
12. Sirito T, Tazza F, Inglese M, et al. Ocrelizumab treatment in newly diagnosed multiple sclerosis patients with previous Hodgkin’s lymphoma. Neuroimmunol 2022;2:100151.
13. Geils HM, Stribling IC, Katz JD, et al. ACAPELLA Real-World Experience with Ocrelizumab, Year Three Data. Presented at the Joint Americas and European Committee for Treatment & Research in Multiple Sclerosis in virtual; September 11-13, 2020. ACTRIMS-ECTRIMS Poster.
14. Greenawalt P, Fearey M, Stine S, et al. ACAPELLA: Real-World Experience with Ocrelizumab, 7-Year Data. Mult. Scler. J. 2024;30:(3S):648-649. journals.sagepub.com/home/msj
15. Rauer S, Hoshi MM, Pul R, et al. Ocrelizumab Treatment in Patients with Primary Progressive Multiple Sclerosis: Short-term Safety Results from a Compassionate Use Programme in Germany. Clin Neurol Neurosurg 2020;197:106142. https://www.ncbi.nlm.nih.gov/pubmed/32920498
16. Epstein S, Fong KT, De Jager PL, et al. Evaluation of ocrelizumab in older progressive multiple sclerosis patients. Mult Scler Relat Disord 2021;55:103171. https://www.ncbi.nlm.nih.gov/pubmed/34329872
17. Roche Internal Safety Report. (Accessed on 29.01.2025). .
18. Ziemessen T, Berthold H, Dirks P, et al. Integration of ocrelizumab safety data from the German study CONFIDENCE into the global post marketing safety studies MANUSCRIPT and VERISMO. Presented at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis in Berlin, Germany, Berlin; October 10-12, 2018. ECTRIMS Poster.
19. Dirks P, Zingler V, Leemhuis J, et al. Design of a non-interventional post-marketing study to assess the long-term safety and effectiveness of ocrelizumab in German real world multiple sclerosis cohorts - the CONFIDENCE study protocol. BMC Neurol 2020;20:95. https://www.ncbi.nlm.nih.gov/pubmed/32171264
20. Wormser D, Butzkueven H, Hiller J, et al. MANUSCRIPT: Long-Term Surveillance of Ocrelizumab-Treated Patients with Multiple Sclerosis. Presented at the European Academy of Neurology in Oslo, Norway; June 29 - July 2, 2019. EAN Poster #EPO3217.
21. Wormser D, Evershed J, Ferreira G, et al. VERISMO: A Post-Marketing Safety Study to Determine the Incidence of All Malignancies and Breast Cancer in Patients With Multiple Sclerosis Treated With Ocrelizumab. Presented at the Annual Meeting of the American Academy of Neurology in Philadelphia, PA, Philadelphia; May 4-10, 2019. AAN Poster #p4.2-043.