Have side effects of immunotherapies been underestimated in initial studies?

Oncology & Hematology
By Dr. Sophie Christoph

New research results on Immune-Related Adverse Events  (irAEs) of checkpoint inhibitors provided discussion material at the "Palliative and Supportive Care in Oncology Symposium" on November 16-17, 2018 in San Diego.

From the Palliative and Supportive Care in Oncology Symposium that has just taken place, we have selected a topic that should be interesting not only for oncologists who work with the active ingredients. Data presented during the meeting from nearly 2,800 patients suggest that side effects under immune checkpoint blockade may be more frequent than first studies that led to the approval of the drugs reported (Source 1).

Immunotherapies prolong survival in some patients, but their use is not without risk. "We have only been using these therapies for a few years, so the new analysis provides more information on the prevalence of such side effects when used more widely," says Dr. Joe Rotella, Medical Director of the American Academy of Hospice and Palliative Medicine (AAHPM).

First comprehensive consideration of outcomes for mostly insured patients

The researchers reviewed a very large database of insurance claims that collects clinical data from over 150 million people in the US. The investigators selected patients with non-small cell lung cancer (NSCLC) who had been treated with the PD-1 or PD-L1 inhibitors nivolumab (71.4%), pembrolizumab (25%) or atezolizumab (3.6%) between 2015 and 2017. Just over half of these patients were pre-treated with conventional chemotherapy.

"Our study is probably the first to investigate side effects using claims, which provides a much broader, population-based perspective on outcomes than a single study," explains lead author Dr. Elizabeth Jane Cathcart-Rake. "It is important to understand the full scope of the side effects of tumor therapies and patients and physicians should be aware that new therapies take a while to fully assess them."

Of course, this does not only apply to immunotherapies. Dr. Cathcart-Rake cites as another example of the initial study results for aromatase inhibitors for the treatment of breast cancer, in which 8% of patients reported joint pain. Current study results, which include patient surveys and more comprehensive analyses over the past 20 years, show that about 50% of patients with aromatase inhibitors report joint pain.

A frequency of immune-mediated side effects in large patient populations

Although checkpoint inhibitors are predominantly better tolerated than conventional chemotherapies, irAEs can be very variable and potentially severe. It is estimated that up to 70% of patients with PD-1 or PD-L1 antibodies are affected by such antibodies (all severity levels) (Sources 2, 3), with the figures diverging widely between different studies.

Thus, the new analysis found the following rates for the most frequent irAEs (Source 1):

Further evaluations of this data are still in progress. The researchers are trying to gain a better understanding of the differences between the toxicities reported in studies and those observed in larger populations. The chronological classification of autoimmune side effects is also traceable from the insurance databases and would be of interest. The better it is known when the probability for certain irAEs is particularly high, the faster practitioners could possibly intervene.

Sources:
Side Effects From Certain Immunotherapies May Be Higher Than Initially Reported. ASCO (2018). Available at: https://www.asco.org/about-asco/press-center/news-releases/side-effects-certain-immunotherapies-may-be-higher-initially. (Accessed: 17th November 2018)
2. Brahmer, J. R. et al. Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer. New England Journal of Medicine 366, 2455-2465 (2012).
3. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. J. Med. 366, 2443-2454 (2012).

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