Transforming approaches to treating TRK fusion cancer: historical comparison of larotrectinib and histology-specific therapies.

OBJECTIVE: The results from basket trials utilized to gain regulatory approval of tumor-agnostic therapies can be difficult to interpret without the context of a comparator arm. We describe the role and efficacy of histology-based treatments to provide a historical comparison with larotrectinib. METHODS: A systematic literature review (SLR) was conducted on the clinical outcomes of current histology-based standard of care treatments used in non-small cell lung cancer, colorectal cancer, thyroid cancer, gliomas, soft tissue sarcoma, salivary gland cancer, and infantile fibrosarcoma (7 of the 21 tumor histologies in the larotrectinib trials). The review focused on advanced stage/metastatic disease to make a historical comparison with larotrectinib. RESULTS: Larotrectinib provides positive outcomes in both adult and pediatric patients with advanced or metastatic solid tumors known to harbor NTRK gene fusions across a wide range of tumor types. Although the numbers of patients per tumor type are limited, the results of this historical comparison demonstrated that larotrectinib is an efficacious treatment option when naïvely indirectly compared with historical treatments across all 7 reviewed tumor types, especially in comparison to later lines of therapy. CONCLUSIONS: Utilizing larotrectinib as a case example across these types of historical comparisons shows that larotrectinib provides positive efficacy outcomes in TRK fusion cancer across tumor histologies known to harbor NTRK gene fusions that may be preferable to historical treatments.

Effect of Concomitant pH-Elevating Medications with Pazopanib on Progression-Free Survival and Overall Survival in Patients with Metastatic Renal Cell Carcinoma.

BACKGROUND: Pazopanib is an oral tyrosine-kinase inhibitor that is approved by the U.S. Food and Drug Administration for treatment of metastatic renal cell carcinoma (mRCC). Pharmacokinetic data have shown that concomitant administration of pazopanib and esomeprazole, a proton pump inhibitor (PPI), leads to decreased area under the curve and thus decreased exposure of pazopanib by 40%. Despite the pharmacokinetic data published to date, the clinical significance and impact on patient outcomes resulting from decreased pazopanib exposure remains unknown. MATERIALS AND METHODS: In this retrospective, observational, cohort study, 90 patients with mRCC who either received pazopanib in combination with a PPI or histamine 2 receptor antagonist (H2RA; concurrent PPI/H2RA group) or who did not take concurrent pH-elevating medications (no PPI/H2RA group) were compared to determine if there was an impact on progression-free survival (PFS), the primary endpoint, and secondary endpoints, overall survival (OS) and safety. RESULTS: The differences between the PFS of 9.0 months and OS of 28.0 months for the concomitant PPI/H2RA group versus 11.0 months and 30.1 months, respectively, for the no PPI/H2RA group were not statistically significant. Rates of adverse events were similar between the concomitant PPI/H2RA and no PPI/H2RA groups. CONCLUSION: Concomitant PPI or H2RA usage was not shown to be associated with a reduction in PFS or OS for patients receiving pazopanib for mRCC, with a similar toxicity profile in each group. Based on the results of this retrospective cohort study and the palliative nature of the treatment of patients with mRCC, clinicians should consider allowing patients to remain on concomitant pazopanib and acid-reducing therapy. IMPLICATIONS FOR PRACTICE: Pazopanib is a preferred category-one first-line treatment for predominant clear cell metastatic renal cell carcinoma (mRCC). However, because of an aging demographic, coupled with patients with mRCC presenting with multiple comorbidities, including symptomatic dyspepsia or gastroesophageal reflux disease, patients are commonly required to take pazopanib concomitantly with a proton pump inhibitor (PPI) or a histamine 2 receptor antagonist (H2RA). Despite earlier pharmacokinetic reports suggesting that an alkaline pH may result in poorer absorption, this institutional retrospective study found no effect on clinical outcomes. These data suggest that concurrent treatment of mRCC with pazopanib and a PPI or H2RA may be safe in everyday practice.

Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction.

BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced malignancies. Patients with baseline organ dysfunction are largely excluded from clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or effective in this setting. Further, these patients are often not candidates for other anti-cancer therapies, highlighting their need for active treatment options. METHODS: We performed a retrospective analysis of patients from multiple centers with advanced solid tumors and baseline organ dysfunction who received anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular ejection fraction ≤45 %), renal (creatinine ≥2 mg/dL or GFR ≤30 ml/min) or hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin ≥3x ULN). We assessed change in organ dysfunction, immune related adverse events (irAEs), response rate, progression free survival (PFS) and overall survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4). Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective response or stable disease) at data collection (48 %). Eleven patients had primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial responses (15 %), and one had a complete response (4 %). Overall, median PFS was 168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable irAEs and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.

Community and social participation among adults with mobility impairments: A mixed methods study.

BACKGROUND: Community and social participation is a complex phenomenon that is influenced by personal and environmental factors and is linked to a good quality of life and well-being. Individuals with mobility impairments are at risk of experiencing limitations in participating in community activities due to a wide range of factors. OBJECTIVE: To understand community participation as defined by adults with mobility impairments and to examine relationships among factors that influence community participation. METHODS: A mixed-methods study design was used. In-depth interviews of 13 adults with mobility impairments were conducted and themes related to community participation were identified. Data from the Americans' Changing Lives Survey were used to construct variables that mimic the themes from the qualitative phase and structural equation modeling was used to examine the relationships among those variables including community participation. RESULTS: Individuals with mobility impairments identified health and function, neighborhood factors and self-efficacy as possible factors influencing participation in community activities. Findings from the SEM suggest a strong causal pathway between health and function and community and social participation. Neighborhood factors and health and function had a significant impact on self-efficacy, and a possible indirect effect through self-efficacy on community and social participation. CONCLUSIONS: Our study provides new empirical evidence that health and function have a significant impact on community and social participation. Our quantitative findings did not support the direct influence of neighborhood factors in community and social participation, yet these factors may have an indirect role by influencing the self-efficacy of individuals with mobility impairments.

Emerging targeted therapies for melanoma.

INTRODUCTION: Melanoma is an aggressive cutaneous malignancy associated with poor response to traditional therapies. Recent regulatory approval for immune checkpoint inhibitors and agents targeting mutated BRAF has led to a tremendous expansion of effective treatment options for patients with advanced melanoma. Unfortunately, primary or acquired resistance develops in most patients, highlighting the need for additional therapies. Numerous genetic and other molecular features of this disease may provide effective targets for therapy development. AREAS COVERED: This article reviews available melanoma treatments, including immune and molecularly-targeted therapies. We then discuss agents in development, with a focus on targeted (rather than immune) therapies. In particular, we discuss agents that block mitogen-activated protein kinase (MAPK) signaling, as well as other emerging approaches such as antibody-drug conjugates, cell-cycle targeting, and novel genetically-informed clinical trials. EXPERT OPINION: Despite the incredible advances in melanoma therapeutics over the last several years, a clear need to develop more effective therapies remains. Molecularly-targeted therapy approaches will likely remain a cornerstone of melanoma treatment in parallel to immune therapy strategies.