Faculty Bibliography

Objective: Genitourinary syndrome of menopause (GMS), comprising vulvovaginal atrophy (VVA), impacts the health and quality of life of postmenopausal women. Genital symptoms of VVA include vaginal dryness as a most bothersome symptom (MBS) which over time leads to sexual dysfunction and emotional distress and remains a condition of unmet need. The objective of the study was to evaluate the safety and efficacy of ospemifene, an oral, selective estrogen receptor modulator and nonhormonal option, for the treatment of vaginal dryness as the MBS of postmenopausal women with VVA.
Design(s): This Phase 3, multicenter, randomized, double-blind, placebo-controlled study assessed the efficacy and safety of ospemifene in menopausal women with vaginal dryness as MBS of VVA. Eligible subjects were postmenopausal, age 40-80 with moderate to severe vaginal dryness as a self-reported MBS of VVA. Subjects were randomized dryness) and female sexual function index (FSFI).
Result(s): 631 subjects were enrolled into the study and included in the intention-to-treat (ITT) population (ospemifene=316; placebo=315). The differences between treatment groups in change from baseline to Week 12 for each of the co-primary efficacy endpoints were statistically significant (p < 0.0001). These differences between treatment groups for co-primary endpoints were change from baseline at Week 4, 8, and 12 were the response variable. Other endpoints evaluated included vaginal pain associated with sexual activity, percentage of responders (a composite of increase from baseline of >= 10 in maturation value, decrease of >= 0.5 in vaginal pH, and decrease of >= 1 in categorical score for severity of MBS of vaginal dryness) and female sexual function index (FSFI).
Result(s): 631 subjects were enrolled into the study and included in the intention-to-treat (ITT) population (ospemifene=316; placebo=315). The differences between treatment groups in change from baseline to Week 12 for each of the co-primary efficacy endpoints were statistically significant (p < 0.0001). These differences between treatment groups for co-primary endpoints were observed as early as Week 4 and continued through Weeks 8 and 12. The severity of vaginal pain associated with sexual activity, among the other VVA symptoms assessed, also showed a significantly greater reduction from baseline in the ospemifene group compared to placebo by week 12. The percentage of responders significantly increased in the ospemifene group compared to placebo at weeks 4 and continued through weeks 8 and 12 with a statistically significant increase in the FSFI score in the ospemifene group at week 12. In the safety population, overall treatment-emergent AEs (TEAE) were reported within Week 12 for 35.3% of subjects in the ospemifene group and 33.3% of subjects in the placebo group. There were no TEAEs of deep vein thrombosis or breast cancer, and no deaths. Consistent with previous trials, subjects with intact uteri showed a slight mean endometrial thickening with ospemifene treatment; a mean increase of 0.63 mm in the ospemifene group compared to a mean decrease of 0.23 mm in the placebo group. No cases of endometrial hyperplasia or carcinoma were observed.
Conclusion(s): The results of this double-blind, randomized, placebo-controlled Phase 3 trial support that ospemifene 60 mg daily may be efficacious and safe in the treatment of moderate or severe vaginal dryness as the MBS of VVA. Ospemifene demonstrated statistically significant superiority over placebo for all co-primary efficacy endpoints by Week 12. The effectiveness of ospemifene was evident at week 4 and maintained through the study at Weeks 8 and 12. Endometrial findings at 12 weeks showed slight increase in endometrial thickness and no cases of hyperplasia or carcinoma

Background: TAK-788 (AP32788) is an investigational tyrosine kinase inhibitor (TKI) with potent, selective preclinical activity against activating EGFR and HER2 mutations, including exon 20 insertions. We report early results of a phase 1/2 first-in-human, open-label, multicenter study of TAK-788 (NCT02716116). Method: Patients with advanced non-small cell lung cancer (NSCLC) refractory to standard therapy received daily oral doses (5-120 mg) of TAK-788 in the ongoing dose-escalation phase (3+3 design). Preliminary antitumor activity (by RECIST v1.1), safety, and PK are reported for patients who received >=1 dose. Result: As of 8-Sep-2017, 34 patients (median age, 60 y; female, 65%; >=2 prior anticancer therapies, 88%; Table) were treated with TAK-788; 10 remain on treatment at data cutoff. AUC0-24,ss increased in a dose-proportional manner over the dose range evaluated; the effective t1/2 was ~16 (range 6-28) h. The most common treatment-emergent AEs (TEAEs; >=20%) were diarrhea (47%), nausea (26%), and fatigue (21%). Grade >=3 TEAEs in >=2 patients (excluding disease progression) were dyspnea (n=3, 9%) and anemia, asthenia, dehydration, lung infection, pleural effusion, pneumonia, and pneumonitis (n=2 each, 6%). Two DLTs, both pneumonitis, were reported (80 mg, grade 3; 120 mg, grade 5). Of 14 evaluable patients, 3 had PR (80 mg, n=2, both confirmed; 120 mg, single PR awaiting confirmation), 6 had SD (40 mg, n=3; 80 mg, n=2; 120 mg, n=1), and 5 had PD as best response (40 mg, n=3; 80 mg, n=1; 120 mg, n=1). All patients with PR had EGFR exon 20 insertions. Conclusion: TAK-788 exhibits antitumor activity in patients with EGFR exon 20 insertions with an AE profile consistent with other EGFR TKIs. Phase 2 will begin after determination of the RP2D, with 4 molecularly defined cohorts in NSCLC. Updated data will be presented, including the recommended phase 2 dose (RP2D). [Figure presented] Keywords: EGFR exon 20 mutation, EGFR tyrosine kinase inhibitor, HER2 mutation

Categories help us make predictions, or inductions, about new objects. However, we cannot always be certain that a novel object belongs to the category we are using to make predictions. In such cases, people should use multiple categories to make inductions. Past research finds that people often use only the most likely category to make inductions, even if it is not certain. In two experiments, subjects read stories and answered questions about items whose categorization was uncertain. In Experiment 1, the less likely category was either emotionally neutral or dangerous (emotionally charged or likely to pose a threat). Subjects used multiple categories in induction when one of the categories was dangerous but not when they were all neutral. In Experiment 2, the most likely category was dangerous. Here, people used multiple categories, but there was also an effect of avoidance, in which people denied that dangerous categories were the most likely. The attention-grabbing power of dangerous categories may be balanced by a higher-level strategy to reject them.