2 Minute Medicine Rewind February 20, 2017

Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer

First line treatment for patients with advanced, non-small cell lung cancers that overexpress epidermal growth factor receptor (EGFR) is a tyrosine kinase inhibitor to that receptor(EGFR-TKI). However, a common T790M mutation has been identified that reduces TKI binding, reduces drug efficacy and leads to cancer progression and recurrence in up to 60% of patients. Osimertinib is an irreversible TKI selective for both EGFR-TKI sensitizing and T790M resistance mutations,  In this international phase 3, randomized control trial, 419 non-small cell lung cancer patients who have a T790M mutation and disease progression after EGFR-TKI therapy were randomized in a 2:1 ratio to receive oral osimertinib daily or IV platinum-pemetrexed every 3 weeks for 6 cycles along with maintenance pemetrexed. The primary outcome of median progression-free survival was significantly longer with osimertinib (10.1 months vs. 4.4 months, HR 0.30, 95% CI: 0.23 to 0.41, p < 0.001). This was also true among the 144 patients who had central nervous system metastases (8.5 months vs. 4.2 months, HR 0.32, 95% CI: 0.21 to 0.49). Patients who received osimertinib experienced more diarrhea, rash, and dry skin, but less myelotoxicity. In conclusion, osimertinib was superior in efficacy to conventional cytotoxic chemotherapy and is a promising option for patients with disease progression from a T790M EGFR mutation.

Risk of heart failure after community acquired pneumonia

Community acquired pneumonia is the seventh leading cause of death in the U.S. and carries associated long term risks, such as increase in long term mortality rates after incident hospitalization. In this prospective cohort study, investigators followed 4988 patients who had community acquired pneumonia between 2000 and 2002 as well as 23,060 population controls without pneumonia in order to determine the disease’s attributable risk on heart failure incidence. Patients were from six hospitals and seven emergency departments in Edmonton, Alberta, Canada. Primary outcome measure was incident heart failure, defined as any heart failure-related hospital admission or emergency department visit after the initial pneumonia event. Over a median of 9.9 years, this occurred in significantly more pneumonia patients (11.9% compared to 7.4% of controls, adjusted HR 1.61, 95% CI: 1.44 to 1.81, p < 0.001). They were also more likely to suffer heart failure within 90 days of discharge (1.4% vs. 0.6%, 1.52, 1.08 to 2.13, p = 0.015) and at one year (3.3% vs. 1.4%, 1.86, 1.50 to 2.32, p < 0.001). Notably, while younger adults (65 years or less) had the lowest absolute increase in heart failure incidence, their relative risk for developing heart failure more than tripled. Authors conclude that community acquired pneumonia increases future risk for heart failure. Post-discharge plans for cardiovascular disease screening and prevention strategies should be considered.

Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy

Sirukumab is a human monoclonal antibody under development that targets IL-6, a cytokine that plays a role in the articular and extra-articular manifestations of rheumatoid arthritis. Researchers conducted this phase 3, randomized, double-blind study across centers in 20 countries in order to evaluate the safety and efficacy of sirukumab as compared to placebo in patients with rheumatoid arthritis refractory to previous anti-TNF medication. 878 adult patients were randomized to placebo every 2 weeks, 50 mg sirukumab every 4 weeks, or 100 mg sirukumab every 2 weeks for a maximum length of 52 weeks. At week 18, placebo patients who had minimal (<20%) improvement in swollen and tender joint counts were reassigned to one of the two sirukumab groups, with the remainder of placebo patients following suit at week 24. Primary outcome was a 20% or greater improvement according to American College of Rheumatology criteria score (ACR20) at week 16. Results showed a significantly greater ACR20 improvement for sirukumab patients (40% of the 50 mg group and 45% of the 100 mg group vs. only 24% of placebo). Between-group differences compared to placebo were significant for both (0.16 for 50 mg, 95% CI: 0.09 to 0.23; 0.21 for 100 mg, 0.14 to 0.29, p < 0.0001). Adverse event incidence, namely erythema at the injection sites,was similar across groups. Researchers conclude that both dosing schedules of sirukumab were not only superior in efficacy over placebo, but also well-tolerated in these anti-TNF-refractory rheumatoid arthritis patients.

Daptomycin for complicated pediatric skin infections

With methicillin-resistant Staphylococcus aureus (MRSA) on the rise both in the healthcare environment and in the community, resistance and toxicity associated with first line antibiotics is concerning. Daptomycin is approved for use in adults and undergoing review by the FDA for children. This was a multicenter, evaluator-blinded randomized control trial investigating daptomycin safety and efficacy in hospitalized patients 1-17 years old who had complicated skin and skin structure infections (cSSSI) caused by Gram-positive organisms. 35% had confirmed MRSA. Patients were randomized in a 2:1 ratio to IV daptomycin once daily (n = 257) or standard of care treatment, primarily vancomycin or clindamycin (n = 132). The study found no significant difference between groups for adverse events (14% of daptomycin and 17% of control). The most common of these included diarrhea (7% daptomycin vs. 5% control) and increased creatinine phosphokinase (6% vs. 5%). There was no difference between groups for complete or partial resolution of cSSSI symptoms 7-14 days after therapy (91%). This study shows that daptomycin has comparable safety and efficacy to standard antibiotics and can be a suitable alternative for pediatric patients with MRSA or other Gram-positive skin infections.

Effect of 2 years of treatment with sublingual grass pollen immunotherapy on nasal response to allergen challenge at 3 years among patients with moderate to severe seasonal allergic rhinitis

Current guidelines recommend continuous sublingual or subcutaneous immunotherapy for 3 years for seasonal allergic rhinitis, after which patients usually experience at least 2 years of symptom improvement. However, this can prove expensive and inconvenient. This was a randomized, double-blind control trial to investigate whether a two-year period of sublingual therapy would provide nasal symptom improvement to allergen challenge at 3-year follow up. 106 adult patients with moderate to severe seasonal allergic rhinitis were randomized in a 1:1:1 ratio to sublingual daily tablets containing15 µg of major allergen Phleum p 5, subcutaneous monthly injections containing 20 µg Pleum p 5 as a positive control, or double-placebo. The primary end point was difference in total nasal symptom scores (TNSS, 0 best to 12 worst) between sublingual patients and placebo after an allergen challenge at year 3. Pretreatment allergen challenge produced a mean TNSS score of 6.36 for sublingual patients (95% CI: 5.76 to 6.96) and 6.06 for placebo patients (5.23 to 6.88). At year 3, scores were 4.73 (95% CI: 3.97 to 5.48) and 4.81 (3.97 to 5.65), respectively. The between group difference was -0.18 and nonsignificant (95% CI: -1.25 to 0.90, p = 0.75). Based on this information, researchers indicate that a shorter period of sublingual immunotherapy is not sufficient in generating long-term relief. Clinicians are advised to continue following the established 3 year treatment regimen.

Image: PD

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