Drug Interactions between durvalumab and moxifloxacin / triamcinolone

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

MONITOR: Although immune checkpoint inhibitors (ICI) such as programmed cell death-1 (PD-1), programmed death ligand-1 inhibitors (PD-L1), and anti-CTLA-4 monoclonal antibodies may be indicated for use in combination in with other immunosuppressive agents, their pharmacodynamic effects and efficacy may be affected by corticosteroids and immunosuppressants. The mechanism of this interaction is related to the immunosuppressive effects of corticosteroids and other immunosuppressants, particularly their inhibition of T-cell activation, which may reduce the efficacy of immune checkpoint inhibitors that rely on a strong immune response to target tumor cells. Additionally, immune-related adverse events (irAEs) from ICIs may indicate a stronger immune response and improved tumor outcomes and treating them with immunosuppressive agents could therefore reduce immune activity and the efficacy of ICIs. For instance, data from the Dutch Melanoma Treatment Registry (DTMR) showed that patients with advanced melanoma who experienced severe ICI toxicity had a longer median overall survival (OS) (23 months vs. 15 months), but those needing anti-TNF therapy for steroid-refractory toxicity had worse outcomes (17 months vs. 27 months with steroids alone). In a study of patients with advanced NSCLC (n=640), oral or intravenous corticosteroid use (>/= 10 mg prednisone equivalent per day) at the time of or within 30 days of starting PD-1/PD-L1 blockade with either pembrolizumab, nivolumab, atezolizumab, or durvalumab (n=90) was associated with decreased response and overall poorer outcomes, compared to those who received and discontinued corticosteroid treatment prior to commencing PD-1/PD-L1 therapy. Further, an international multicenter cohort study in melanoma patients who developed irAEs with ICI therapy found that higher peak doses of corticosteroids, but not cumulative doses, were associated with worse survival, though the impact of second-line immunosuppressants remains unclear. A prospective observational study using data from a German multicenter skin cancer registry (ADOREG) evaluated patients with unresectable advanced melanoma who received immunosuppressive therapy (IST) (e.g., methylprednisolone, prednisolone, dexamethasone, infliximab, interferon, methotrexate) within 60 days before or within 30 days after the start of an ICI. The initiation of IST before, but not after the start of ICI, was associated with worse progression free survival in patients without brain metastasis, and worse OS in patients with brain metastasis. However, based on available literature, it is difficult to determine whether these effects are due to corticosteroid and/or immunosuppressant use or if they reflect subgroups of patients in studies with poorer prognoses.

MANAGEMENT: Caution and closer monitoring for reduced efficacy of immune checkpoint inhibitors (ICI) is advised if corticosteroids and/or other immunosuppressants are used concurrently. Based on available literature, the use of immunosuppressants and/or systemic corticosteroids (>=10 mg prednisone equivalent/day) should be avoided at the time of, or within 30 to 60 days of starting therapy with an ICI if clinically possible. Corticosteroids and/or immunosuppressants can generally be safely used for the treatment of immune-mediated reactions after starting an ICI. Some manufacturers advise that corticosteroids may be used as premedication when the ICI is used in combination with chemotherapy, as antiemetic prophylaxis, and/or to alleviate chemotherapy-related adverse effects. Individual product labeling for the ICI in question should be consulted for specific recommendations.

MONITOR: Use of systemic antibiotics during or close to therapy with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 monoclonal antibodies and/or inhibitors of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) may result in reduced clinical efficacy of the ICI. The exact mechanism of this interaction has not been fully characterized, but may be related to alterations in the gut microbiota by the systemic antibiotic, potentially resulting in immune dysregulation and a decreased response to the ICI. A meta-analysis of 6 studies involving nivolumab for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) found that the median progression-free survival (PFS) and overall survival (OS) were reduced by 1.6 months and 8.8 months, respectively, in patients who were exposed to systemic antibiotics before, during, or after nivolumab therapy. Similarly, a single-site retrospective review of patients (n=291) with advanced cancer (melanoma, NSCLC, or renal cell carcinoma) treated with ICI(s) also revealed poorer clinical outcomes associated with the receipt of systemic antibiotics. This study divided patients into 3 groups: no antibiotics, single course of antibiotics, or cumulative courses of antibiotics (i.e., administration of concurrent or successive antibiotics for >7 days) during the 2 weeks prior to and 6 weeks after ICI treatment. The median PFS (6.3 months vs. 3.7 months vs. 2.8 months, respectively) and median OS (21.7 months vs. 17.7 months vs. 6.3 months, respectively) decreased as the antibiotic use increased, though the difference between no antibiotic use and cumulative courses of antibiotics was the only difference determined to be clinically significant. Additionally, a different retrospective analysis of patients (n=635) with advanced cancer treated with ICIs found that antibiotic use was associated with significantly shorter median OS (8 months vs. 23 months), median PFS (4 months vs. 7 months), as well as a reduction in tumor response (57% vs. 71%) when compared to patients who did not receive antibiotics. In contrast, a retrospective study of patients (n=302) with stage IV NSCLC treated with first-line chemo-immunotherapy combinations (i.e., ICI and cytotoxic chemotherapy) had similar OS, PFS, and objective response rate between those who did and did not receive antibiotics during the 30 days prior to initiating an ICI. The receipt of concurrent systemic antibiotics in this patient population was likewise not associated with changes in OS nor PFS.

MANAGEMENT: Until more information is available, caution and clinical monitoring for reduced efficacy of immune checkpoint inhibitors (ICIs) are advised if systemic antibiotics are indicated prior to, concurrently with, or after an ICI. Antibiotic use should be limited to clinically appropriate indications and durations. Clinicians should consult relevant literature, local and national treatment guidelines, and package labeling for further guidance.