Characterization and Management of Treatment-emergent Hepatic Toxicity in Patients with Advanced Renal Cell Carcinoma Receiving First-line Pembrolizumab plus Axitinib. Results from the KEYNOTE-426 Trial.

BACKGROUND: Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed. OBJECTIVE: To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib. DESIGN, SETTING, AND PARTICIPANTS: Patients enrolled in KEYNOTE-426 were included in this study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s). RESULTS AND LIMITATIONS: The HEAS comprised 189/429 (44%) pembrolizumab-axitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to <3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT <3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred. CONCLUSIONS: A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment. PATIENT SUMMARY: Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management.

Board certification in obstetrics and gynecology: associations with physicians' demographics and performances during medical school.

OBJECTIVE: This study was undertaken to investigate the relationship of demographics, medical school performance, and licensing examination scores to board certification. STUDY DESIGN: A longitudinal follow-up study of graduates of Jefferson Medical College between 1968 and 1994 identified in the AMA Physicians' Professional Data (AMA-PPD) file as practicing obstetrics and gynecology in 2003. Demographics, grades, and licensing examination scores had been collected prospectively. Board certification status was obtained from the AMA-PPD in 2003. Bivariate differences were evaluated with t tests. Logistic regression was used to evaluate multivariate relationships to board certification status. RESULTS: Of 310 physicians in obstetrics and gynecology, 291 (94%) were board certified. Those without certification were more likely to be underrepresented minorities, to have been older in medical school, and to have weaker academic records. Logistic regression indicated that scores on step 2 of the United States Medical Licensing Examination were the single most important predictor of achieving board certification. Those with scores of 200 or higher were 7 times more likely to achieve certification than those below 200. CONCLUSION: Age, gender, and minority status are not independent predictors of achieving board certification. A low score on United States Medical Licensing Examination step 2 is a risk factor for not achieving certification.

Do global rating forms enable program directors to assess the ACGME competencies?

PURPOSE: In 1999 the Accreditation Council for Graduate Medical Education (ACGME) mandated that GME programs require their residents to be proficient in six general competencies. The purpose of this study was to ascertain whether an existing global rating form could be modified to assess these competencies. METHOD: A rating form covering 23 skills described in the ACGME competencies was developed. The directors of 92 specialty and subspecialty programs at Thomas Jefferson University Hospital and the Albert Einstein Medical Center in Philadelphia were asked to rate residents at the end of the 2001-02 and 2002-03 academic years. RESULTS: Ratings for 1,295 of 1,367 (95%) residents were available. Residents were awarded the highest mean ratings on items tied to professionalism, compassion, and empathy. The lowest mean ratings were assigned for items related to consideration of costs in care and management of resources. Factor analysis indicated that the program directors viewed overall competence in two dimensions of medical knowledge and interpersonal skills. This factor structure was stable for groups of specialties, and residents' gender and training level. Mean ratings in each dimension were progressively higher for residents at advanced levels of training. CONCLUSION: Global rating forms, the tool that program directors use most frequently to document residents' competence, may not be adequate to assess the six general competencies. The results are consistent with earlier published research indicating that physicians view competence in just two broad dimensions, which questions the premise of the six ACGME competencies. Further research is needed to validate and measure six distinct dimensions of clinical competence.