A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: Checkpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC. METHODS: The 516-003 trial (NCT03606174) is an open-label, multicohort phase 2 study evaluating sitravatinib plus nivolumab in patients with advanced/metastatic UC enrolled in eight cohorts depending on prior treatment with CPI, platinum-based chemotherapy (PBC), or antibody-drug conjugate (ADC). Overall, 244 patients were enrolled and treated with sitravatinib plus nivolumab (median follow-up 14.1-38.2 mo). Sitravatinib (free-base capsules 120 mg once daily [QD] or malate capsule 100 mg QD) plus nivolumab (240 mg every 2 wk/480 mg every 4 wk intravenously). KEY FINDINGS AND LIMITATIONS: The primary endpoint was objective response rate (ORR; RECIST v1.1). The secondary endpoints included progression-free survival (PFS) and safety. The Predictive probability design and confidence interval methods were used. Among patients previously treated with PBC, ORR, and median PFS were 32.1% and 3.9 mo in CPI-naïve patients (n = 53), 14.9% and 3.9 mo in CPI-refractory patients (n = 67), and 5.4% and 3.7 mo in CPI- and ADC-refractory patients (n = 56), respectively. Across all cohorts, grade 3 treatment-related adverse events (TRAEs) occurred in 51.2% patients and grade 4 in 3.3%, with one treatment-related death (cardiac failure). Immune-related adverse events occurred in 50.4% patients. TRAEs led to sitravatinib/nivolumab discontinuation in 6.1% patients. CONCLUSIONS AND CLINICAL IMPLICATIONS: Sitravatinib plus nivolumab demonstrated a manageable safety profile but did not result in clinically meaningful ORRs in patients with advanced/metastatic UC in the eight cohorts studied. PATIENT SUMMARY: In this study, the combination of two anticancer drugs, sitravatinib and nivolumab, resulted in manageable side effects but no meaningful responses in patients with bladder cancer.

Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma.

Immune checkpoint inhibitors, such as nivolumab, a programmed death receptor-1 (PD-1) inhibitor, have dramatically improved the treatment of advanced melanomas. Chemosaturation with percutaneous hepatic perfusion (PHP) delivers chemotherapy in high doses directly to the liver and is a potentially effective treatment modality in metastatic uveal melanoma with liver metastases. Its safety and effectiveness have not been studied in patients also receiving immunotherapy. A 46-year-old male with a history of uveal melanoma of the right eye was found to have liver metastases. He was treated with PHP using high-dose melphalan for 6 months with a partial response followed by progression. Two months after his last PHP treatment, the patient was started on nivolumab. After two doses of nivolumab, the patient developed severe hepatitis that progressed to fulminant hepatic failure and death despite treatment with high-dose corticosteroids and mycophenolate mofetil. Nivolumab and other immune checkpoint inhibitors have been effective in treating advanced melanoma and extending life. However, there are serious immune adverse events that can occur. While hepatitis after taking nivolumab has been documented, fulminant hepatic failure is rare. We believe that prior PHP treatment contributed to the severity of the hepatitis and, ultimately, fulminant hepatic failure. To our knowledge, this is the only case of fulminant hepatic failure secondary to a checkpoint inhibitor with preceding PHP. Specific precautions should be made in patients who have been exposed to PHP in the past, and further studies should be done to assess the safety of using checkpoint inhibitors after PHP.

Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma.

BACKGROUND: There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC. METHODS: A retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/metastatic ACC. RESULTS: Eight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21-49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2-9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression-free survival was 5.5 months (95% CI 1.8-not reached) and median duration of therapy was 8.5 months (range 2-22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events. CONCLUSIONS: In our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response.

An interprofessionally developed geriatric oncology curriculum for hematology-oncology fellows.

OBJECTIVE: Because the cancer population is aging, interprofessional education incorporating geriatric principles is essential to providing adequate training for oncology fellows. We report the targeted needs assessment, content, and evaluation tools for our geriatric oncology curriculum at MD Anderson Cancer Center. METHODS: A team comprising a geriatrician, a medical oncologist, an oncology PharmD, an oncology advanced nurse practitioner, and two oncology chief fellows developed the geriatric oncology curriculum. First, a general needs assessment was conducted by reviewing the literature and medical societies' publications and by consulting experts. A targeted needs assessment was then conducted by reviewing the fellows' evaluations of the geriatric oncology rotation and by interviewing fellows and recently graduated oncology faculty. RESULTS: Geriatric assessment, pharmacology, and psychosocial knowledge skills were the three identified areas of educational need. Curriculum objectives and an evaluation checklist were developed to evaluate learners in the three identified areas. The checklist content was validated by consulting experts in the field. Online materials, including a curriculum, a geriatric pharmacology job aid, and pharmacology cases, were also developed and delivered as part of the curriculum. CONCLUSION: An interprofessional team approach was a successful method for identifying areas of learners' educational needs, which in turn helped us develop an integrated geriatric oncology curriculum. The curriculum is currently being piloted and evaluated.

Treatment decisions in a man with Hodgkin lymphoma and Guillian-Barré syndrome: a case report.

INTRODUCTION: Guillain-Barre syndrome, or acute inflammatory demyelinating polyneuropathy, has been described in the presence of malignancies such as lymphoma. Guillain-Barre syndrome/acute inflammatory demyelinating polyneuropathy causes paresthesias and weakness, which can make the treatment of lymphoma with chemotherapy challenging. Given the rarity of this co-presentation it is not known if the effects of Guillain-Barre syndrome should be considered when selecting a treatment regimen for Hodgkin lymphoma. To the best of our knowledge, the impact of these treatment modifications has not been previously reported. CASE PRESENTATION: We report the case of a 37-year-old Caucasian man with a diagnosis of stage IIB classical Hodgkin lymphoma with concomitant Guillain-Barre syndrome. Our patient originally presented with an enlarged cervical lymph node and quickly developed distal paresthesia and progressive weakness of all four extremities. He was diagnosed with Hodgkin's lymphoma and initiated on treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine. Doses of bleomycin and vinblastine were held or dose-reduced throughout his initial treatment course due to underlying neuropathy and dyspnea. He continued to have persistent disease after five cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine and went on to receive salvage treatments including more chemotherapy, radiation, autologous stem cell transplant and is currently preparing for an allogeneic stem cell transplant. CONCLUSIONS: Paraneoplastic syndromes such as Guillain-Barre syndrome/acute inflammatory demyelinating polyneuropathy can make the treatment of patients with Hodgkin lymphoma more challenging and can interfere with delivering full-dose chemotherapy. Further case series are needed to evaluate the effect that paraneoplastic syndromes, or adjustments made in therapy due to these syndromes, negatively affect the prognosis of patients with Hodgkin lymphoma.

Case of vemurafenib-induced Sweet's syndrome.

Vemurafenib is a targeted therapy that has become standard treatment for patients with advanced melanoma with a V600E BRAF mutation. It has been associated with frequent skin toxicity, including photosensitivity, rash and squamous cell carcinomas. We present an 83-year-old woman with an advanced V600E BRAF-mutant melanoma who developed a severe skin rash and fatigue after taking vemurafenib. The dose was reduced from 960 to 720 to 480 mg twice a day; however, she was subsequently admitted to the hospital with fever, chills, fatigue, confusion and a diffuse skin eruption. She then developed hypoxia and acute renal failure that required hemodialysis. A biopsy of her skin lesions revealed a neutrophilic dermatitis with papillary dermal edema, consistent with Sweet's syndrome. Her symptoms resolved upon discontinuation of vemurafenib and treatment with prednisone. This constellation of symptoms and clinical course are consistent with drug-induced Sweet's syndrome caused by vemurafenib.

Influence of medical comorbidities on the presentation and outcomes of stage I-III non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer presentation, treatment, and outcomes vary widely according to socioeconomic factors and other patient characteristics. To determine whether medical comorbidities account for these observations, we incorporated a validated medical comorbidity index into an analysis of patients diagnosed with stage I to III NSCLC. PATIENTS AND METHODS: We performed a retrospective analysis of consecutive patients diagnosed with stage I to III NSCLC. Demographic, tumor, and comorbidity data were obtained from hospital tumor registries and individual patient records. The association between variables was assessed using multivariate logistic regression and survival analysis. RESULTS: A total of 454 patients met criteria for analysis. The median age was 65 years, and 51% were men. Individuals with a higher Charlson Comorbidity Index (CCI) were significantly more likely to present with early stage (stage I-II) NSCLC than were patients with lower CCI (odds ratio, 1.72; 95% confidence interval, 1.14-2.63; P = .01), although this association lost statistical significance (P = .21) in a multivariate model. In multivariate logistic regression, overall survival remained associated with all variables: age, sex, race, insurance type, stage, histology, and CCI (P = .0007). The CCI was associated with survival for patients with early stage (P = .02) and locally advanced (P = .02) disease. CONCLUSION: In this cohort of patients with stage I to III NSCLC, increasing comorbidity burden had a nonsignificant association with diagnosis at earlier disease stage. Although comorbidity burden was significantly associated with outcome for early stage and locally advanced disease, it did not account for survival differences based on multiple other patient and disease characteristics.

Rare Though Not Mutually Exclusive: A Report of Three Cases of Concomitant KRAS and BRAF Mutation and a Review of the Literature.

KRAS mutations occur frequently in colorectal cancers (CRC) and predict lack of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. CRC BRAF mutations, most commonly at V600E, occur less than 10% of the time, and occur usually in KRAS wild-type tumors, and more frequently in microsatellite instable tumors. Concomitant KRAS and BRAF mutant CRCs are rare (occurring in 0.001%); BRAF mutations should not be routinely tested in patients with KRAS mutant tumors, unless the patients is participating in a clinical trial enriching for the presence of a KRAS or BRAF tumor. Clinical trials treating patients with either KRAS or BRAF mutant tumors should address eligibility of patients with concomitant KRAS and BRAF mutations.

Socioeconomic disparities in lung cancer treatment and outcomes persist within a single academic medical center.

BACKGROUND: Socioeconomic disparities in treatment and outcomes of non-small-cell lung cancer (NSCLC) are well established. To explore whether these differences are secondary to individual or institutional characteristics, we examined treatment selection and outcome in a diverse population treated at a single medical center. PATIENTS AND METHODS: We performed a retrospective analysis of consecutive patients diagnosed with NSCLC stages I-III from 2000 to 2005 at the University of Texas Southwestern Medical Center. Treatment selection was dichotomized as 'standard' (surgery for stage I-II; surgery and/or radiation therapy for stage III) or 'other.' Associations between patient characteristics (including socioeconomic status) and treatment selection were examined using logistic regression; associations between characteristics and overall survival were examined using Cox regression models and Kaplan-Meier survival analysis. RESULTS: A total of 450 patients were included. Twenty-eight percent of patients had private insurance, 43% had Medicare, and 29% had an indigent care plan. The likelihood of receiving 'standard' therapy was significantly associated with insurance type (indigent plan versus private insurance odds ratio [OR] 0.13, 95% confidence interval [CI] 0.04, 0.43 for stage I-II; OR 0.38, 95% CI 0.14, 1.00 for stage III). For patients with stage I-II NSCLC, survival was associated with age, sex, insurance type (indigent plan versus private insurance hazard ratio for death 1.98; 95% CI 1.16, 3.37), stage, and treatment selection. In stage III NSCLC, survival was associated with treatment selection. CONCLUSION: Within a single academic medical center, socioeconomically disadvantaged patients with stage I-III NSCLC are less likely to receive 'standard' therapy. Socioeconomically disadvantaged patients with stage I-II NSCLC have inferior survival independent of therapy.

How have we diagnosed early-stage lung cancer without radiographic screening? A contemporary single-center experience.

BACKGROUND: The National Lung Screening Trial (NLST), which demonstrated a reduction in lung cancer mortality, may result in widespread computed tomography (CT)-based screening of select populations. How early-stage lung cancer has been diagnosed without screening, and what proportion of these cases would be captured by a screening program modeled on the NLST, is not currently known. We therefore evaluated current patterns of early-stage lung cancer presentation. METHODOLOGY/PRINCIPAL FINDINGS: We performed a single-institution retrospective analysis of patients diagnosed with stage I-II non-small cell lung cancer (NSCLC) from 2000-2009. Associations between patient and imaging characteristics were assessed using univariate and multivariate analyses. A total of 412 patients met criteria for analysis. Among those with available reason for initial imaging, the reason was symptoms in 51%, follow-up of other conditions in 43%, and screening in 6%. Reason for imaging was associated with race (P<0.001), insurance type (P=0.005), and disease stage (P<0.001). Type of initial imaging was associated with reason for imaging (P<0.001), year (chest x-ray 67% in 2000-2004 vs. 49% in 2005-2009; P<0.001), and disease stage (P = 0.005). Among patients with available quantified smoking history, 48% were age 55-74 years and smoked 30-plus pack-years, therefore meeting NLST entry criteria. CONCLUSIONS/SIGNIFICANCE: Symptoms remain a dominant but declining reason for detection of early-stage NSCLC. The proportion of cases detected initially by CT scan without antecedent chest x-ray has increased considerably. Because as few as half of cases meet NLST eligibility criteria, clinicians should remain aware of the diverse circumstances of early-stage lung cancer presentation to expedite therapy.

A Primer on the Current State-of-the-Science Neoadjuvant and Adjuvant Therapy for Patients with Locally Advanced Rectal Adenocarcinomas.

Patients with rectal cancers, due to the unique location of the tumor, have a recurrence pattern distinct from colon cancers. Advances in adjuvant therapy over the last three decades have played an important role in improving patient outcomes. This article serves to review the clinical studies that lay the basis for our current standard-of-care treatment of patients with locally advanced rectal cancer, as well as touch upon future ongoing experimental clinical trials of adjuvant chemoradiation therapy.

Lung cancer diagnostic and treatment intervals in the United States: a health care disparity?

INTRODUCTION: Lung cancer diagnostic and treatment delays have been described for several patient populations. However, few studies have analyzed these intervals among patients treated in contemporary health care systems in the United States. We therefore studied the timing of lung cancer diagnosis and treatment at a U.S. medical center providing care to a diverse patient population within two different hospital systems. METHODS: We performed a retrospective analysis of consecutive patients diagnosed with non-small cell lung cancer stage I to III from 2000 to 2005 at public and private hospitals affiliated with the University of Texas Southwestern Medical Center. We recorded patient and disease characteristics; dates of initial radiograph suspicious for lung cancer, diagnosis, and treatment; and overall survival. Associations between these factors were assessed using univariate analysis, multivariate logistic regression, and Kaplan-Meier survival analysis. RESULTS: A total of 482 patients met criteria for analysis. In univariate analyses, the image-treatment interval was significantly associated with race, age, income, insurance type, and hospital type (76 days for public versus 45 days for private; p < 0.0001). In multivariate analysis, only hospital type remained significantly associated with the image-treatment interval; patients in the private hospital setting were more likely to receive timely treatment (hazard ratio 1.85; 95% confidence interval, 1.37-2.50; p < 0.001). In univariate analysis, the image-treatment interval was not associated with disease stage (p = 0.27) or with survival (p = 0.42). CONCLUSION: Intervals between suspicion, diagnosis, and treatment of lung cancer vary widely among patients. Health care system factors, such as hospital type, largely account for these discrepancies. In this study, these intervals do not appear to be associated with clinical outcomes.