Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation

Aim: The selective BRAF and MEK inhibitors (BRAFi+MEKi) have substantially improved the survival of melanoma patients with BRAF V600 mutations. However, BRAFi+MEKi can also cause severe or fatal outcomes. We aimed to identify and compare serious adverse events (sAEs) that are significantly associated with BRAFi+MEKi. Methods: In this pharmacovigilance study, we reviewed FDA Adverse Event Reporting System (FAERS) data in order to detect sAE reporting in patients treated with the combination therapies vemurafenib+cobimetinib (V+C), dabrafenib+trametinib (D+T) and encorafenib+binimetinib (E+B). We evaluated the disproportionate reporting of BRAFi+MEKi-associated sAEs. Significant associations were further analyzed to identify combination-specific safety signals among BRAFi+MEKi. Results: From January 2018 through June 2019, we identified 11,721 sAE reports in patients receiving BRAFi+MEKi. Comparison of BRAFi+MEKi combinations demonstrates that skin toxicities, including Stevens–Johnson syndrome, were disproportionally reported using V+C, with an age-adjusted reporting odds ratio (adj. ROR) of 3.4 (95%CI, 2.9–4.0), whereas fever was most significantly associated with D+T treatment with an adj. ROR of 1.9 (95%CI, 1.5–2.4). Significant associations using E+B treatment include peripheral neuropathies (adj. ROR 2.7; 95%CI, 1.2–6.1) and renal disorders (adj. ROR 4.1; 95%CI, 1.3–12.5). Notably, we found an increase in the proportion of Guillain–Barré syndrome reports (adj. ROR 8.5; 95%CI, 2.1–35.0) in patients administered E+B. Conclusion: BRAFi+MEKi combinations share a similar safety profile attributed to class effects, yet concomitantly, these combinations display distinctive effects that can dramatically impact patients’ health. Owing to the limitations of pharmacovigilance studies, some findings warrant further validation. However, the possibility of an increased risk for these events should be considered in patient care

Ocular Adverse Events Induced by Immune Checkpoint Inhibitors: A Comprehensive Pharmacovigilance Analysis

PURPOSE Characterize ocular adverse events (oAEs) caused by immune checkpoint inhibitors (ICIs). METHODS Retrospective analysis of 41,674 cancer patients in the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database receiving anti-PD-1/PD-L1, anti-CTLA-4, or anti-PD-1+ anti-CTLA-4 combination. Reporting odds ratio (ROR) was used to approximate oAE rate across regimens and indications. RESULTS The most common indications were lung cancer (27.3%) and melanoma (22.7%); 76.3% received anti-PD-1/PD-L1 monotherapy. 1,268 patients (3.0%) reported oAEs, namely vision disorders (30.8%), uveitis (15.1%), and retinal, lacrimal, and optic nerve disorders (10.7%, 9.0%, 8.4%). Melanoma showed the highest proportion of uveitis (117/9,471 cases; 1.2%). Addition of anti-CTLA-4 to anti-PD-1 increased the ROR of uveitis from 4.77 (95% CI 3.83-5.94) to 17.1 (95% CI 12.9-22.7). Among anti-PD-1/PD-L1 cases, uveitis was differentially reported in melanoma (ROR 14.7, 95% CI 10.7-20.2) compared with lung cancer (ROR 2.67, 95% CI 1.68-4.23). CONCLUSION ICI-induced oAEs are rare, and uveitis is significantly associated with melanoma and anti-PD-1+ anti-CTLA-4 combination

Failures to highlight the binding site of proteins.

<p>Displayed are EXPOSITE predictions of four proteins (A) 1igj, (B) 3gch, (C) 3mth, (D) and 2tmn, from the PLD database. The predicted and observed binding sites are indicated by green stars and red ligands respectively. In orange, cyan, and green, are residues displaying large changes of accessibility in normal modes, and in blue, are residues which display little or no change of exposure. Note that EXPOSITE failed to predict the binding site in these cases due to multiple backbone breaks resulting in unusual modes (i.e. 3mth, 3gch), and to odd shaped protein structure (i.e. 1igj). The figure was prepared using Pymol.</p

Accessible surface changes in normal modes.

<p>Upon distortion along a normal mode, different pockets experience different changes of accessible surface. In the shown example, the accessible surface of pockets 1 and 2 does not significantly change. However, the accessible surface of pocket 3 significantly changes to a larger extent than pocket 4. The solvent accessible surface is represented as red squares.</p

Percent success rate of predictions.

<p>Percent success rate of predictions.</p