Borderline Significant Cancer Risk With Fingolimod, Study Suggests

March 5, 2020

A 6136-patient comparative study of fingolimod, rituximab, and natalizumab suggested that the former was associated with a borderline‐significant increased risk of cancer compared to the general population.

Peter Alping, MD

A large comparative study of 3 high-efficacy disease-modifying therapies (DMTs) for multiple sclerosis (MS)—fingolimod, rituximab, and natalizumab—has suggested that the latter 2 treatments are not associated with an increased risk of cancer, and the former being linked to a borderline‐significant increased risk compared to the general population.

The study included 7477 first‐ever initiations of DMT treatment in 6136 patients with MS, age-matched to 37,80 non-MS general population individuals. When adjusting for baseline characteristics, the hazard rate (HR) of cancer with fingolimod was 1.53 (95% CI, 0.98—2.38) compared to the general population, and 1.68 (95% CI, 1.00–2.84) compared to rituximab.

The magnitude corresponds to a 50% increased risk compared to the general population’s rate of cancer. Importantly, there was no particular pattern of specific cancers between the assessed therapies nor was there a difference in risk when looking specifically at basal-cell carcinoma and cervical intraepithelial neoplasia grade 3 (CIN3).

The investigators, including Peter Alping, MD, of the department of clinical neuroscience, Karolinska Institutet, noted that “the pivotal trials for fingolimod and their long-term follow-up have given inconclusive reports of cancer risk, but taken together an increased risk of cancer cannot be excluded,” adding that those assessments “lacked comparisons to other highly effective MS DMTs, however, and did not include the full range of patients that are treated in clinical practice.”

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The FDA label for fingolimod includes lymphoma as a possible adverse effect based on data from pre-marketing clinical trials, and the EMA label further includes a warning for cutaneous cancers. Additionally, the FDA has issued a safety warning related to the halting of multiple sclerosis (MS) therapy with fingolimod, stating that the condition can become much worse when treatment is stopped in comparison to while it was being taken or when it was first started.

The nationwide register‐based cohort-linked data from the Swedish MS register to the Swedish Cancer Register and other national healthcare and census registers. Of the total numbers, 4187 were initiations of rituximab, 1620 of fingolimod, and 1670 of natalizumab. The primary outcome was time to first invasive cancer. In total, Alping and colleagues identified 78 invasive cancers among treated patients: 33 for rituximab (incidence rate [IR] per 10,000 person-years, 34.4; 95% CI, 23.7—48.3), 28 for fingolimod (IR, 44.0; 95% CI, 29.2–63.5), and 17 for natalizumab (IR, 26.0; 95% CI, 15.1–41.6). Comparatively, the general population IR was 31.0 (95% CI, 27.8–34.4).

When adjusting for demography, previous cancer, and comorbidities, the risk of invasive cancer was similar, or slightly lower, for natalizumab (HR, 1.01; 95% CI, 0.57—1.77) and rituximab (HR, 0.85; 95% CI, 0.54– 1.32), and the aforementioned fingolimod (HR, 1.53).

“Since rituximab for MS is used off-label, there is only limited data on its safety for this indication,” Alping and colleagues wrote. “However, our findings here are in line with those obtained from its use in rheumatoid arthritis, where a long-term (9.5 years) follow-up of the global clinical trials program found no evidence for an increased risk of cancer linked to ever use or accumulated exposure of rituximab.”

They also pointed out the contrast with the incidence rates 26.1 vs 0 per 10,000 person-years for ocrelizumab, another anti-CD20 drug that was recently approved for MS, and placebo, respectively. “Although it is well known that randomized controlled trials have limited ability to detect rare safety outcomes such as cancer,” they noted, in this rituximab cohort, there were 6 breast cancers, corresponding to an IR of 8.9 per 10,000 person-years (95% CI, 3.3—19.4).

“Collectively, cancer risks with the 2 studied biologics, natalizumab and rituximab, seem to be similar to the general population, while a possible modest increase in risk with fingolimod needs to be validated in studies with larger cohorts followed over longer periods of time,” Alping and colleagues concluded.

REFERENCE

Alping P, Askling J, Burman J, et al. Cancer Risk for Fingolimod, Natalizumab, and Rituximab in MS Patients. Ann Neurol. Published online February 13, 2020. doi: 10.1002/ana.25701