Efficacy of a Dual-Epitope Dendritic Cell Vaccine as Part of Combined Immunotherapy for HER2-Expressing Breast Tumors.

Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.

Lymphangitic Melanomatosis: Case Report of Intralymphatic Spread of Melanoma in a 66-year-old Man.

ABSTRACT: Melanoma with lymphatic invasion has been associated with increased risk of metastasis, but the mechanisms and clinical implications are poorly understood. Although current reports have documented angiotropic spread of melanoma and suggest lymphatic spread of melanoma to increase the likelihood of metastasis, to our knowledge, lymphangitic metastatic melanoma resembling cutaneous carcinomatosis or presenting with facial hyperpigmentation has not been described. In this case report, we describe extensive cutaneous intralymphatic spread of melanoma, or lymphangitic melanomatosis, producing macular skin pigmentation in a 66-year-old man.

Brief Report: Improving Fellow Performance of the Pharmacology Section of the American Society of Clinical Oncology In-Training Exam.

Though the electronic medical record has streamlined the process for ordering chemotherapy and reduced medical error, it has come at the cost of potentially hindering medical oncology fellows' acquisition of basic principles of chemotherapy administration. Recognizing the need for improving fellow knowledge and comfort level in chemotherapy prescription, we created an anticancer therapeutics curriculum for fellows at the University of North Carolina (UNC). The curriculum, which was comprised of a self-assessment, review session, and chemotherapy writing workshop, was offered voluntarily to all UNC fellows planning to take the medical oncology boards. We distributed a pre-intervention and post-intervention survey. In total, 11 of 18 fellows participated. After our interventions, there were statistically significant improvements in comfortability with calculating a dose of chemotherapy (p = 0.002), writing orders (p = 0.004), and taking the American Society of Clinical Oncology (ASCO) In-Training Exam (ITE) (p = 0.002). Furthermore, we saw a 4% overall improvement in pharmacology subset scores on the ITE compared to the prior year. Overall, our study suggested that the addition of a chemotherapy competency curriculum led to improved outcomes on the ASCO ITE, improved comfortability in chemotherapy administration, and hopefully improved patient care.

Seeking Racial Equity in Hematology and Oncology: a Fellow-Led Educational Series to Promote Reflection and Action.

The USA is experiencing a reckoning with racial injustice and graduate medical education programs are seeking ways to address this important topic in training. Fellows in hematology/oncology at the University of North Carolina recognized this important gap and adapted a curriculum for medical residents on racial equity to a subspecialty audience. Aims were (1) to improve knowledge and awareness about implicit bias and systemic racism and (2) introduce methods to address racial inequities. We used lived experiences and collated materials from scientific literature and lay media to illustrate key points. The course explored the effects of implicit bias on individual, clinical, and health system levels, anchored in Kahneman's two-system theory. Videos, journal articles, and group discussion were employed to appeal to many learning styles. A post-curriculum survey assessed perceptions of racial inequality in medicine and the series' effects using a Likert scale. Twenty-nine participants completed the survey (12 fellows), 71% reported improved awareness of racial inequities, and 61% reported improved comfort level in addressing racial inequities. All participants recognized at least "some" racial inequity in medicine, and over 75% of participants indicated interest in further sessions. Formulation of an educational curriculum by fellows and delivered in a division-wide setting was feasible and well received by participants, filling a key educational gap. We encourage other institutions to take similar steps to highlight issues of systemic racism and move our field in the right direction.

The clinical significance of adenomatous polyposis coli (APC) and catenin Beta 1 (CTNNB1) genetic aberrations in patients with melanoma.

BACKGROUND: Melanoma-intrinsic activated ß-catenin pathway, the product of the catenin beta 1 (CTNNB1) gene, has been associated with low/absent tumor-infiltrating lymphocytes, accelerated tumor growth, metastases development, and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. Little is known about the association between the adenomatous polyposis coli (APC) and CTNNB1 gene mutations in stage IV melanoma with immunotherapy response and overall survival (OS). METHODS: We examined the prognostic significance of somatic APC/CTNNB1 mutations in the Cancer Genome Atlas Project for Skin Cutaneous Melanoma (TCGA-SKCM) database. We assessed APC/CTNNB1 mutations as predictors of response to immunotherapies in a clinicopathologically annotated metastatic patient cohort from three US melanoma centers. RESULTS: In the TCGA-SKCM patient cohort (n = 434) presence of a somatic APC/CTNNB1 mutation was associated with a worse outcome only in stage IV melanoma (n = 82, median OS of APC/CTNNB1 mutants vs. wild-type was 8.15 vs. 22.8 months; log-rank hazard ratio 4.20, p = 0.011). APC/CTNNB1 mutation did not significantly affect lymphocyte distribution and density. In the 3-melanoma institution cohort, tumor tissues underwent targeted panel sequencing using two standards of care assays. We identified 55 patients with stage IV melanoma and APC/CTNNB1 genetic aberrations (mut) and 169 patients without (wt). At a median follow-up of more than 25 months for both groups, mut compared with wt patients had slightly more frequent (44% vs. 39%) and earlier (66% vs. 45% within six months from original diagnosis of stage IV melanoma) development of brain metastases. Nevertheless, time-to-development of brain metastases was not significantly different between the two groups. Fortunately, mut patients had similar clinical benefits from PD-1 inhibitor-based treatments compared to wt patients (median OS 26.1 months vs. 29.9 months, respectively, log-rank p = 0.23). Less frequent mutations in the NF1, RAC1, and PTEN genes were seen in the mut compared with wt patients from the 3-melanoma institution cohort. Analysis of brain melanoma tumor tissues from a separate craniotomy patient cohort (n = 55) showed that melanoma-specific, activated ß-catenin (i.e., nuclear localization) was infrequent (n = 3, 6%) and not prognostic in established brain metastases. CONCLUSIONS: APC/CTNNB1 mutations are associated with a worse outcome in stage IV melanoma and early brain metastases independent of tumor-infiltrating lymphocyte density. However, PD1 inhibitor-based treatments provide comparable benefits to both mut and wt patients with stage IV melanoma.

A hybrid model of acute unscheduled cancer care provided by a hospital-based acute care clinic and the emergency department: a descriptive study.

PURPOSE: Patients with cancer often experience medical events that require immediate evaluation. These evaluations typically occur in an emergency department (ED), but there is increasing interest in providing this care in other settings. We report on a novel care model whereby a nursing hotline is used to triage patients to the ED or to the North Carolina Cancer Hospital Infusion Center (NCCHIC). METHODS: A retrospective study of adult patients with a neoplasm diagnosis seeking acute care at a large academic hospital pre- and post-initiation of the novel care model in January of 2016. Patients were identified by querying the electronic medical record and clinic administrative data during matched 6 month pre- and post-periods. RESULTS: During the pre-initiation period, 1346 patients visited the ED on 1651 occasions (76.1% admission rate). In the post-initiation period, 1434 patients visited the ED on 1797 occasions (81.5% admission rate), and 246 patients visited the NCCHIC on 322 occasions (68.9% admission rate). The emergency severity index (ESI) in the pre-initiation ED group was primarily ESI 2 (30.6%) and ESI 3 (65.4%). In the post-initiation ED group, the ESI was similar (32.6% ESI 2 and 64.2% ESI 3). In contrast, the NCCHIC predominantly treated lower acuity patients (65.8% calculated ESI of 4/5). CONCLUSIONS: This model demonstrates a multidisciplinary partnership to providing acute unscheduled care for patients with cancer. In the early implementation phase of this model, approximately 15% of patients, generally of lower acuity, were seen in the NCCHIC.

How well do documented goals-of-care discussions for patients with stage IV cancer reflect communication best practices?

BACKGROUND: Written clinical communication regarding patients' disease understanding and values may facilitate goal-concordant care, yet little is known about the quality of electronic health record (EHR) documentation. We sought to (1) describe frequency of communication best practices in EHR-documented goals-of-care discussions, and (2) assess whether templated notes improve quality of documentation. METHODS: Researchers pulled text of EHR-documented goals-of-care discussions for hospitalized patients with Stage IV cancer from admission to 60-days follow-up. Text was included when in a single encounter the clinician addressed: (a) prognosis and/or illness understanding; and (b) goals and/or treatment options. Researchers qualitatively coded text based on guidelines for communication best practices, and noted if an EHR template was used. RESULTS: Forty-two percent (206/492) of patients had EHR-documented goals-of-care discussions. Text frequently described communication of cancer progression (89%), though rarely included prognosis (22%). Text often included patients' goals and values (83%), and at least on specific treatment decision (82%). Communication about treatments was included for 98% of patients; common examples included cancer treatment (62%), hospice (62%), resuscitation (51%), or intensive care (38%). Clinicians documented making recommendations for 40% of patients. Text addressing patient emotional and spiritual concerns was uncommon (15%). Compared to free text, use of a template was associated with increased documentation of goals and values (80% vs. 61%, p < 0.01), but not other best practices. CONCLUSION: Insights from the study can be used to guide future training and research to study and improve the quality of documentation about goal of care, and its impact on goal-concordant care.

Chemotherapy Following PD-1 Inhibitor Blockade in Patients with Unresectable Stage III/Stage IV Metastatic Melanoma: A Single Academic Institution Experience.

Retrospective case studies in various cancers have shown clinical benefit from chemotherapy following PD-1 inhibitor progression. We asked whether we see a similar clinical benefit with chemotherapy following PD-1 inhibitor progression in metastatic melanoma. We performed a retrospective study in patients with metastatic melanoma, who had received PD-1 inhibitor-based treatments, subsequently progressed, and eventually received chemotherapy. We identified 25 patients (median age 58 years; range 31-77 years; 13 females). Most patients had cutaneous melanoma (72%), were BRAFV600E-negative (75%), and received single-agent temozolomide (84%). At a median follow-up of 21.0 months (range: 4.1-154.2 months), 2 patients had durable response to chemotherapy (progression-free survival is 31.9+ and 21.6+ months, respectively), and 1 patient had a partial, short-term response. We conclude that in this poor prognosis group administration of chemotherapy has a 12% response rate that can be durable. Overall, the clinical benefit is not inferior to that of PD-1 inhibitor-based treatments.

THYROID DYSFUNCTION, RECOVERY, AND PROGNOSIS IN MELANOMA PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS: A RETROSPECTIVE REVIEW.

Objective: To describe thyroid dysfunction, factors associated with thyroid recovery, and survival in melanoma patients treated with immune checkpoint inhibitors that developed thyroid immune-related adverse events (irAEs). Methods: This was a retrospective study in a tertiary center from 2010-2017. We reviewed the charts of patients with melanoma that developed thyroid dysfunction after checkpoint inhibitor therapy. Cases with thyroid irAEs were grouped by recovery of thyroid function at 1 year. We collected a timeline of thyroid function tests, medication exposure, and survival and compared variables between the groups. We studied survival in comparison to a matched group without thyroid dysfunction. Results: A total of 186 melanoma patients received checkpoint inhibitors, and 17 (9%) had thyroid irAEs. Median time to abnormal thyroid-stimulating hormone was 38 days and followed a pattern of thyroiditis. Seven of 17 had thyroid recovery. In the no-recovery group, free thyroxine (T4) was often above 2 ng/dL (5/10 in no recovery, 0/7 in recovery; P = .04). In the recovery group, irAE grade was significantly lower, with 7/7 grade 1 (P = .004). Exposure to glucocorticoids was associated with recovery (3/10 in no recovery, 6/7 in recovery; P = .049). There was no difference in overall survival between the thyroid dysfunction group and controls, or between those that received glucocorticoids or not. Conclusion: Certain aspects of thyroid irAEs may correlate with thyroid recovery, including grade 1 thyroid irAEs, exposure to glucocorticoids, and peak free T4 levels less than 2 ng/dL. Thyroid irAEs did not appear to be associated with change in survival nor did exposure to glucocorticoids. Abbreviations: ASCO = American Society of Clinical Oncology; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; irAE = immune-related adverse event; PD-1 = programmed cell death protein 1; T4 = thyroxine; TSH = thyroid-stimulating hormone.

A phase 2 study of ontuxizumab, a monoclonal antibody targeting endosialin, in metastatic melanoma.

Objectives Ontuxizumab (MORAB-004) is a first-in-class monoclonal antibody that interferes with endosialin function, which is important in tumor stromal cell function, angiogenesis, and tumor growth. This Phase 2 study evaluated the 24-week progression-free survival (PFS) value, pharmacokinetics, and tolerability of 2 doses of ontuxizumab in patients with metastatic melanoma. Patients and methods Patients with metastatic melanoma and disease progression after receiving at least 1 prior systemic treatment were randomized to receive ontuxizumab (2 or 4 mg/kg) weekly, without dose change, until disease progression. Results Seventy-six patients received at least 1 dose of ontuxizumab (40 received 2 mg/kg, 36 received 4 mg/kg). The primary endpoint, 24-week PFS value, was 11.4% (95% Confidence Interval [CI]: 5.3%-19.9%) for all patients (13.5% for 2 mg/kg and 8.9% for 4 mg/kg). The median PFS for all patients was 8.3 weeks (95% CI: 8.1-12.3 weeks). One patient receiving 4 mg/kg had a partial response, as measured by Response Evaluation Criteria in Solid Tumors v1.1. Twenty-seven of 66 response evaluable patients (40.9%) had stable disease. The median overall survival was 31.0 weeks (95% CI: 28.3-44.0 weeks). The most common adverse events overall were headache (55.3%), fatigue (48.7%), chills (42.1%), and nausea (36.8%), mostly grade 1 or 2. Conclusions Ontuxizumab at both doses was well tolerated. The 24-week PFS value was 11.4% among all ontuxizumab-treated patients. The overall response rate was 3.1% at the 4 mg/kg dose, with clinical benefit achieved in 42.4% of response evaluable patients. Efficacy of single-agent ontuxizumab at these doses in melanoma was low.

The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy.

Stereotactic radiotherapy (SRT) is the standard treatment for patients with limited number of brain metastases. In the past few years, newer immunotherapies (immune checkpoint inhibitors) have been proven to prolong survival in patients with metastatic melanoma. The safety of the combination of SRT and immunotherapy for brain metastases is unknown. We retrospectively identified patients with melanoma brain metastases treated with SRT between 2007 and 2015. Patients who did not have at least 3 months of follow-up with imaging after SRT were excluded from the analysis. Outcomes were compared between patients who were treated with or without immunotherapy. A total of 58 patients were included; of these, 29 were treated with SRT and immunotherapy. MAPK inhibitors (BRAF, MEK inhibitors) were used more often in the immunotherapy group (nine vs. two patients). There was a higher incidence of intracranial complications in patients treated with immunotherapy and SRT. Eight patients had radiation necrosis; all occurred in patients who were treated with immunotherapy. Nine patients had hemorrhage, of which seven occurred in patients who were treated with immunotherapy (P=0.08). However, patients treated with immunotherapy and SRT had a significant overall survival advantage compared with SRT without immunotherapy (15 vs. 6 months, P=0.0013). Patients treated with SRT and immunotherapy have a higher incidence/risk of intracranial complications, but a longer overall survival.

Medical Knowledge Assessment by Hematology and Medical Oncology In-Training Examinations Are Better Than Program Director Assessments at Predicting Subspecialty Certification Examination Performance.

The Accreditation Council for Graduate Medical Education's Next Accreditation System requires training programs to demonstrate that fellows are achieving competence in medical knowledge (MK), as part of a global assessment of clinical competency. Passing American Board of Internal Medicine (ABIM) certification examinations is recognized as a metric of MK competency. This study examines several in-training MK assessment approaches and their ability to predict performance on the ABIM Hematology or Medical Oncology Certification Examinations. Results of a Hematology In-Service Examination (ISE) and an Oncology In-Training Examination (ITE), program director (PD) ratings, demographic variables, United States Medical Licensing Examination (USMLE), and ABIM Internal Medicine (IM) Certification Examination were compared. Stepwise multiple regression and logistic regression analyses evaluated these assessment approaches as predictors of performance on the Hematology or Medical Oncology Certification Examinations. Hematology ISE scores were the strongest predictor of Hematology Certification Examination scores (ß = 0.41) (passing odds ratio [OR], 1.012; 95 % confidence interval [CI], 1.008-1.015), and the Oncology ITE scores were the strongest predictor of Medical Oncology Certification Examination scores (ß = 0.45) (passing OR, 1.013; 95 % CI, 1.011-1.016). PD rating of MK was the weakest predictor of Medical Oncology Certification Examination scores (ß = 0.07) and was not significantly predictive of Hematology Certification Examination scores. Hematology and Oncology ITEs are better predictors of certification examination performance than PD ratings of MK, reinforcing the effectiveness of ITEs for competency-based assessment of MK.

Use of Susceptibility-Weighted Imaging (SWI) in the Detection of Brain Hemorrhagic Metastases from Breast Cancer and Melanoma.

PURPOSE: Susceptibility-weighted imaging (SWI) has significantly increased our sensitivity in detecting hemorrhagic brain lesions. We sought to explore the prevalence of intratumoral hemorrhage as detected by SWI in brain metastases from melanoma and breast cancer. METHODS: Lesions with a size of 0.1 cm were categorized as micrometastases, whereas larger lesions were categorized as macrometastases. Susceptibility-weighted imaging findings on locations corresponding to enhancing lesions were categorized as either positive or negative based on presence/absence of signal dropout. The percentage of SWI positivity was then estimated as a function of lesion size. Two-tailed Fisher exact test was performed to examine differences in the contingency tables. RESULTS: Magnetic resonance imaging studies from 73 patients with 1173 brain metastases, which enhanced on postcontrast T1-weighted imaging (T1WI) were selected for analysis. Of these lesions, 952 had SWI data available, and 342 of 952 were micrometastases. Only 10 of the 342 micrometastases and 410 (67.2%) of the 610 macrometastases were SWI positive (P < 0.0001). When examined by tumor type, 76.9% (melanoma) versus 55.6% (breast cancer) were SWI positive (P < 0.0001), regardless of tumor size. All melanoma lesions (8/8) and only 1 of 15 breast cancer lesions larger than 1.5 cm were SWI positive. CONCLUSION: With the use of combined SWI and contrast-enhanced high-resolution T1 imaging, we found that presence of intratumoral brain hemorrhage is uncommon in micrometastases but common in metastases greater than 0.1 cm from breast cancer or melanoma. Large metastases commonly harbored hemorrhage, and this occurred more frequently in patients with melanoma than with breast cancer.

Talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone for advanced melanoma: 5-year final analysis of a multicenter, randomized, open-label, phase II trial.

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor.Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 106 plaque-forming units (PFU)/mL in week 1, followed by 108 PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported.At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297.

Increased tryptophan, but not increased glucose metabolism, predict resistance of pembrolizumab in stage III/IV melanoma.

Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors (n = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUVmax of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUVmax was associated with longer progression-free survival in our clinical trial (n = 26). We saw no such trends with pretreatment FDG PET SUVmax. Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid.

Outcomes with adjuvant anti-PD-1 therapy in patients with sentinel lymph node-positive melanoma without completion lymph node dissection.

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.

Pre-Post Evaluation of Collaborative Oncology Palliative Care for Patients With Stage IV Cancer.

CONTEXT: The Collaborative Care Model improves care processes and outcomes but has never been tested for palliative care. OBJECTIVES: To develop and evaluate a model of collaborative oncology palliative care for Stage IV cancer. METHODS: We conducted a pre-post evaluation of Collaborative Oncology Palliative Care (CO-Pal), enrolling patients with Stage IV lung, breast or genitourinary cancers and acute illness hospitalization. CO-Pal has 4 components: 1) oncologist communication skills training; 2) patient tracking; 3) palliative care needs assessment; and 4) care coordination stratified by high vs. low palliative care need. Health record reviews from hospital admission through 60 days provided data on outcomes - goals-of-care discussions (primary outcome), advance care planning, symptom treatment, specialty palliative care and hospice use, and hospital transfers. RESULTS: We enrolled 256 patients (n = 114 pre and n = 142 post-intervention); 60-day mortality was 32%. Comparing patients pre vs post-intervention, CO-Pal did not increase overall goals-of-care discussions, but did increase advance care planning (48% vs 63%, P = 0.021) and hospice use (19% vs 31%, P = 0.034). CO-Pal did not impact symptom treatment, overall treatment plans, or 60-day hospital transfers. During the intervention phase, high-need vs low-need patients had more goals-of-care discussions (60% vs. 15%, P < 0.001) and more use of specialty palliative care (64% vs 22%, P < 0.001) and hospice (44% vs 16%, P < 0.001). CONCLUSION: Collaborative oncology palliative care is efficient and feasible. While it did not increase overall goals-of-care discussions, it was effective to increase overall advance care planning and hospice use for patients with Stage IV cancer.

Mortality Risk for Patients With Stage IV Cancer and Acute Illness Hospitalization.

CONTEXT: Cancer prognosis data often come from clinical trials which exclude patients with acute illness. OBJECTIVES: For patients with Stage IV cancer and acute illness hospitalization to 1) describe predictors of 60-day mortality and 2) compare documented decision-making for survivors and decedents. METHODS: Investigators studied a consecutive prospective cohort of patients with Stage IV cancer and acute illness hospitalization. Structured health record and obituary reviews provided data on 60-day mortality (outcome), demographics, health status, and treatment; logistic regression models identified mortality predictors. RESULTS: Four hundred ninety-two patients with Stage IV cancer and acute illness hospitalization had median age of 60.2 (51% female, 38% minority race/ethnicity); 156 (32%) died within 60 days, and median survival for decedents was 28 days. Nutritional insufficiency (odds rato [OR] 1.83), serum albumin (OR 2.15 per 1.0 g/dL), and hospital days (OR 1.04) were associated with mortality; age, gender, race, cancer, and acute illness type were not predictive. On admission, 79% of patients had orders indicating Full Code. During 60-day follow-up, 42% of patients discussed goals of care. Documented goals of care discussions were more common for decedents than survivors (70% vs. 28%, P < 0.001), as were orders for do not resuscitate/do not intubate (68% vs. 24%, P < 0.001), stopping cancer-directed therapy (29% vs. 10%, P < 0.001), specialty Palliative Care (79% vs. 44%, P < 0.001), and Hospice (68% vs. 14%, P < 0.001). CONCLUSION: Acute illness hospitalization is a sentinel event in Stage IV cancer. Short-term mortality is high; nutritional decline increases risk. For patients with Stage IV cancer, acute illness hospitalization should trigger goals of care discussions.

Targeting the IL-2 inducible kinase in melanoma; a phase 2 study of ibrutinib in systemic treatment-refractory distant metastatic cutaneous melanoma: preclinical rationale, biology, and clinical activity (NCI9922).

BACKGROUND: IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses. METHODS: We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930). RESULTS: Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets. CONCLUSION: Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis.