Pre-existing antibodies linked to benefit, risks of anti-PD-1 therapy for lung cancer

Preexisting antibodies in patients with non-small cell lung cancer treated with nivolumab or pembrolizumab appeared associated with both clinical benefit and the development of immune-related adverse events , according to a study published in JAMA Oncology.

“Nivolumab [Opdivo, Bristol-Myers Squibb] and pembrolizumab [Keytruda, Merck] monotherapy have become the new treatment of choice for advanced NSCLC instead of standard chemotherapy,” Yukihiro Toi, MD, of the department of pulmonary medicine at Sendai Kousei Hospital in Japan, and colleagues wrote. “However, T-cell activation may cause immune-related adverse events (irAEs) that are not triggered by conventional cytotoxic anticancer agents, including skin reactions, thyroid dysfunction, pneumonitis and hepatitis. These may require systemic immunosuppression or treatment termination.”
a retrospective medical records analysis, Toi and colleagues assessed treatment efficacy, irAEs and factors that may be associated with irAEs among 137 patients (men, n =105; median age, 68 years; range, 36-88) with advanced NSCLC treated with nivolumab (3 mg/kg every 2 weeks; n = 99) or pembrolizumab (200 mg every 2 weeks; n = 38) at Sendai Kousei Hospital between 2016 and 2018.

The cohort included 51 patients (37%) diagnosed with squamous cell carcinoma, and 86 (63%) diagnosed with nonsquamous NSCLC. Almost all of the study participants (n = 134) had an ECOG performance status of 0 or 1. Sixteen (12%) harbored mutations in epidermal growth factor receptor, and 18 (13%) were chemotherapy naive.

One-fifth of patients (n = 27) had abundant PD-L1 expression (tumor proportion score of 50% or higher), whereas 30 (22%) had low levels of PD-L1 expression, 15 (11%) had no expression and the remaining 65 (47%) had unknown expression.

Researchers tested blood samples taken at screening for preexisting rheumatoid factor, antinuclear antibody, antithyroglobulin and antithyroid peroxidase.

The primary outcome and measures included preexisting antibodies and autoimmune markers, PFS and irAEs.

Follow-up continued until death, loss of contact or withdrawal of consent.

Results showed that patients with any preexisting antibodies had median PFS of 6.5 months (95% CI, 4.4-12.9), compared with 3.5 months (95% CI, 2.4-4.1) among patients without antibodies (HR for disease progression or death = 0.53; 95% CI, 0.36-0.79).

Patients with preexisting rheumatoid factor had PFS of 10.1 months (95% CI, 4.4-15.2) vs. 3.7 months (95% CI, 3.2-5.4) among those without (HR for disease progression or death = 0.61; 95% CI, 0.38-0.79).

Researchers observed no significant differences in PFS between patients with or without antinuclear or antithyroid antibodies.

Patients with any preexisting antibodies had a significantly higher overall response rate (41% vs. 18%; P = .006) and disease control rate (81% vs. 54%; P = .001) than those without antibodies, as well as more frequent irAEs (60% vs. 32%; P = .002).
Among the 66 patients who developed irAEs, 42 (64%) had skin reactions, 14 (21%) had pneumonia, 15 (23%) had hypothyroidism, one (2%) had hyperthyroidism, six (9%) had hepatitis, five (8%) had myositis/peripheral neuropathy and two (3%) had diarrhea.

ORR (52% vs. 13%) and disease control rate (92% vs. 49%; P < .001 for both) were higher among patients who experienced an irAE. Further, these patients experienced longer median PFS (10.3 months vs. 3.4 months; HR = 0.45; 95% CI, 0.3-0.68) and OS (not reached vs. 11.4 months; HR = 0.42; 95% CI, 0.24-0.71).

On multivariate analysis, the researchers found an independent association between the examined preexisting antibodies and irAEs (OR = 3.25; 95% CI, 1.59-6.65).

Patients who developed irAEs more frequently had preexisting antibodies (60% vs. 32%; P = .002) and rheumatoid factor (68% vs. 40%; P = .006).

Researchers observed a higher prevalence of skin reactions among patients with vs. without preexisting rheumatoid factor (47% vs. 24%; P = .02), and more frequent thyroid dysfunction among those with preexisting antibodies (20% vs. 1%; P < .001).

“The presented study showed that ORR, disease control rate and PFS were significantly better following nivolumab or pembrolizumab monotherapy among patients with any of the preexisting antibodies examined than those without,” the researchers wrote. “Moreover, the existence of any of those preexisting antibodies was significantly and independently associated with irAEs. Although larger retrospective and prospective surveys may further illuminate the risks of immunotherapy in patients with subclinical disease and preexisting autoimmune markers, our study adds to the growing evidence supporting the use of immunotherapy in such patients, although close monitoring for adverse events is recommended.” – by Jennifer Byrne

Disclosure s : Toi reports lecture fees from Bristol-Myers Squibb, Merck and Ono Pharmaceutical. Please see the study for all other authors’ relevant financial disclosures.

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