Most Biologics Have Good Tolerability in Clinical Settings

A study by Cristina Scavone, MS, and colleagues, published in Frontiers in Pharmacology, concludes that most biologic drugs used to treat cancer, rheumatoid arthritis (RA), and psoriatic arthritis (PA) in real-world clinical settings demonstrate good overall tolerability, with most identified adverse events (AEs) classified as not serious and expected for the respective drugs based on data from pivotal clinical trials. The study reports few cases of serious infections and no cases of malignancies among the 775 patients studied, and no new safety issues.

The prospective, 5-year observational study was carried out from April 2012 to December 2016 at 9 clinical centers in the Campania region of Italy in order to investigate the occurrence of AEs in patients who were treatment-naïve for the biologic drugs studied. The most commonly reported diagnoses were hematological malignancies (n = 155; 20%), followed by RA (n =130; 16.77%), colorectal cancer (n = 125; 16.13%), breast cancer (n = 88; 11.35%), and PA (n = 51; 6.58%).

The most commonly prescribed biologic drugs at the time of study enrollment were as follows:

• Rituximab (19.8%)
• Bevacizumab (12.00%)
• Infliximab (10.71%)
• Trastuzumab (8.90%)
• Adalimumab (8.52%)
• Cetuximab (8.13%)

No biosimilars were used in this population.

A total of 320 patients (41.29%) experienced at least 1 AE (mean, 4.2 AEs per patient), with no differences found between the sexes. Among the 1311 AEs that occurred in these 320 patients, 140 were classified as serious AEs (SAEs), defined as “any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or results in a congenital anomaly/birth defect, or clinically relevant conditions based on clinical judgments.” These SAEs included the development of anti-drug antibodies (ADAs), infections, malignancy, and cardiovascular and neurologic AEs.

SAEs were more commonly associated with:

• Bevacizumab (32 SAEs)
• Brentuximab (24 SAEs)
• Rituximab (20 SAEs)
• Trastuzumab (16 SAEs)
• Cetuximab (14 SAEs)

The study also reported the following:

• Fifty patients discontinued biologic treatment; most of these cases were reported for abatacept, bevacizumab, etanercept, and infliximab.
• A large number of patients taking cetuximab (68.25%), rituximab (52.60%), and trastuzumab (47.83%) experienced at least 1 AE.
• There was a statistically significant difference in AEs among women versus men taking adalimumab (35.90% versus 7.41%, P<.001) and etanercept (27.59% versus 10.00%, P=.023).
• Different incidences of AEs were reported for different therapeutic indications for the same biologic; for example, bevacizumab was associated with AEs in 58.6% of colorectal cancer patients, 20% of breast cancer patients, 40% of lung cancer patients, and 35.7% of patients with other solid tumors.
• The peak occurrence for all AEs was during the 91- to 180-day period after administration.

In conclusion, the authors point out that, although the preferred way to gain knowledge about drug safety is from randomized clinical trials (RCTs), strict inclusion criteria and ethical requirements for RCTs can exclude key populations such as the elderly, children, and pregnant women. Therefore, data from RCTs do not always predict AEs in real-world settings, and the authors suggest that real-world data should be considered complementary to data from traditional RCTs. “Considering that almost 40% of our patients had at least one comorbidity, in our opinion the occurrence of 140 serious AEs should not be considered an alarming figure,” they state. Rather, the number is the consequence of using biologic drugs in a widely varied population quite different from the population of patients enrolled in traditional RCTs.

Thus, it is important to continue to closely monitor the use of biologics in clinical practice to improve knowledge of their long-term safety and to better understand the role of ADAs on efficacy and safety of biologic drugs.