POLARIS: A phase 2 trial of encorafenib plus binimetinib evaluating high-dose and standard-dose regimens in patients with BRAF V600-mutant melanoma with brain metastasis.

Background: POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases. Methods: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined. Results: RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n = 10), 1 achieved complete response and 5 achieved partial responses (PR); the brain metastasis response rate (BMRR) was 60% (95% CI: 26.2, 87.8). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data. Conclusions: Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2, and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.

Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations.

BACKGROUND: Cutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 mutant and triple wild-type (TWT) tumors lacking any of these three alterations. In the era of immune checkpoint inhibition (ICI) and targeted molecular therapy, the clinical significance of these groups remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical follow-up in CM patients. METHODS: This was a retrospective cohort study that assessed clinical and molecular features from patients with localized or metastatic CM who underwent targeted next-generation sequencing as part of routine clinical care. A total of 254 patients with CM who had a CLIA-certified targeted sequencing assay performed on their tumor tissue were included. RESULTS: Of the 254 patients with cutaneous melanoma, 77 were BRAF mutant (30.3%), 77 were NRAS mutant (30.3%), 47 were NF1 mutant (18.5%), 33 were TWT (13.0%) and the remaining 20 (7.9%) carried mutations in multiple driver genes (BRAF/NRAS/NF1 co-mutated). The majority of this co-mutation group carried mutations in NF1 (n = 19 or 90%) with co-occurring mutations in BRAF or NRAS, often with a weaker oncogenic variant. Consistently, NF1 mutant tumors harbored numerous significantly co-altered genes compared to BRAF or NRAS mutant tumors. The majority of TWT tumors (n = 29, 87.9%) harbor a pathogenic mutation within a known Ras/MAPK signaling pathway component. Of the 154 cases with available TMB data, the median TMB was 20 (range 0.7-266 mutations/Mb). A total of 14 cases (9.1%) were classified as having a low TMB (≤5 mutations/Mb), 64 of 154 (41.6%) had an intermediate TMB (>5 and ≤20 mutations/Mb), 40 of 154 (26.0%) had a high TMB (>20 and ≤50 mutations/Mb) and 36 of 154 (23.4%) were classified as having a very high TMB (>50 mutations/Mb). NRAS mutant melanoma demonstrated significantly decreased overall survival on multivariable analysis (HR for death 2.95, 95% CI 1.13-7.69, p = 0.027, log-rank test) compared with other TCGA molecular subgroups. Of the 116 patients in our cohort with available treatment data, 36 received a combination of dual ICI with anti-CTLA4 and anti-PD1 inhibition as first-line therapy. Elevated TMB was associated with significantly longer progression-free survival following dual-agent ICI (HR 0.26, 95% CI 0.07-0.90, p = 0.033, log-rank test). CONCLUSIONS: NRAS mutation in CMs correlated with significantly worse overall survival. Elevated TMB was associated with increased progression-free survival for patients treated with a combination of dual ICI, supporting the potential utility of TMB as a predictive biomarker for ICI response in melanoma.

Metastatic melanoma to small bowel: metastasectomy is supported in the era of immunotherapy and checkpoint inhibitors.

BACKGROUND: Metastatic melanoma to the small bowel is an aggressive disease often accompanied by obstruction, abdominal pain, and gastrointestinal bleeding. With advancements in melanoma treatment, the role for metastasectomy continues to evolve. Inclusion of novel immunotherapeutic agents, such as checkpoint inhibitors, into standard treatment regimens presents potential survival benefits for patients receiving metastasectomy. CASE PRESENTATION: We report an institutional experience of 15 patients (12 male, 3 female) between 2014-2022 that underwent small bowel metastasectomy for metastatic melanoma and received perioperative systemic treatment. Median age of patients was 64 years (range: 35-83 years). No patients died within 30 days of their surgery, and the median hospital length of stay was 5 days. Median overall survival in these patients was 30.1 months (range: 2-115 months). Five patients died from disease (67 days, 252 days, 426 days, 572 days, 692 days postoperatively), one patient died of non-disease related causes (1312 days postoperatively), six patients are alive with disease, and three remain disease free. CONCLUSIONS: This case series presents an updated perspective of the utility of metastasectomy for small bowel metastasis in the age of novel immunotherapeutic agents as standard systemic treatment. Small bowel metastasectomy for advanced melanoma performed in conjunction with perioperative systemic therapy is safe and appears to promote long-term survival and enhanced quality of life.

COVID-19 pandemic stress and cancer symptom burden.

OBJECTIVES: In a sample of patients with cancer (n=1145) who were assessed during the height of the COVID-19 pandemic, latent profile analysis was used to identify subgroups of patients with distinct stress profiles and to evaluate for differences in demographic and clinical characteristics and symptom severity scores among these subgroups. METHODS: Patients completed measures of cancer-specific and COVID-19 stress, global stress, social isolation, loneliness, depression, state and trait anxiety, morning and evening fatigue, morning and evening energy, sleep disturbance, cognitive function, and pain. Latent profile analysis was used to identify subgroups of patients with distinct stress profiles. Differences among the subgroups in study measures were evaluated using parametric and non-parametric tests. RESULTS: Using clinically meaningful cut-off scores for the stress measures, four distinct stress profiles were identified (ie, none class (51.3%); low stress and moderate loneliness class (24.4%), high stress and moderate loneliness class (14.0%), and very high stress and moderately high loneliness class (high, 10.3%)). Risk factors associated with membership in the high class included: younger age, lower annual household income, lower functional status and higher comorbidity burden. The two worst stress profiles reported clinically meaningful levels of all of the common symptoms associated with cancer and its treatments. CONCLUSION: Findings from this study, obtained prior to the availability of COVID-19 vaccines and anti-viral medications, provide important 'benchmark data' to evaluate for changes in stress and symptom burden in patients with cancer in the postvaccine era and in patients with long COVID-19.

Risk Factors for a Higher Symptom Burden in Patients With Cancer During the COVID-19 Pandemic.

OBJECTIVES: To evaluate for subgroups of patients with distinct symptom profiles and differences in demographic and clinical characteristics and stress and resilience among these subgroups. SAMPLE & SETTING: 1,145 patients with cancer aged 18 years or older completed a survey online. Data were collected between May 2020 and February 2021. METHODS & VARIABLES: Patients completed measures for depression, state anxiety, cognitive function, morning fatigue, evening fatigue, morning energy, evening energy, sleep disturbance, pain, stress, and resilience. Latent class profile analysis was used to identify subgroups of patients with distinct symptom profiles. Differences among the subgroups on study measures were evaluated using parametric and nonparametric tests. RESULTS: Four distinct profiles were identified (none, low, high, and very high). Patients in the high and very high classes reported clinically meaningful levels of all nine symptoms. Differences among the four profiles for stress and resilience exhibited a dose-response effect. IMPLICATIONS FOR NURSING: Findings can serve as benchmark data of the symptom burden of patients with cancer following the COVID-19 pandemic.

Molecular Features of Resected Melanoma Brain Metastases, Clinical Outcomes, and Responses to Immunotherapy.

Importance: Central nervous system (CNS)-penetrant systemic therapies have significantly advanced care for patients with melanoma brain metastases. However, improved understanding of the molecular landscape and microenvironment of these lesions is needed to both optimize patient selection and advance treatment approaches. Objective: To evaluate how bulk and single-cell genomic features of melanoma brain metastases are associated with clinical outcome and treatment response. Design, Setting, and Participants: This cohort study analyzed bulk DNA sequencing and single nuclear RNA-sequencing data from resected melanoma brain metastases and included 94 consecutive patients with a histopathologically confirmed diagnosis of melanoma brain metastasis who underwent surgical resection at a single National Comprehensive Cancer Network cancer center in San Francisco, California, from January 1, 2009, to December 31, 2022. Exposure: A Clinical Laboratory Improvement Amendments-certified targeted sequencing assay was used to analyze tumor resection specimens, with a focus on BRAF V600E alteration. For frozen pathologic specimens from CNS treatment-naive patients undergoing surgical resection, commercial single nuclear RNA sequencing approaches were used. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary outcomes included CNS progression-free survival (PFS), microenvironmental composition with decreased T-cell and macrophage populations, and responses to immunotherapy. Results: To correlate molecular status with clinical outcome, Kaplan-Meier survival analysis of 94 consecutive patients (median age, 64 years [range, 24-82 years]; 70 men [74%]) with targeted BRAF alteration testing showed worse median intracranial PFS (BRAF variant: 3.6 months [IQR, 0.1-30.6 months]; BRAF wildtype: 11.0 months [IQR, 0.8-81.5 months]; P < .001) and OS (BRAF variant: 9.8 months [IQR, 2.5-69.4 months]; BRAF wildtype: 23.2 months [IQR, 1.1-102.5 months]; P = .005; log-rank test) in BRAF V600E variant tumors. Multivariable Cox proportional hazards regression analysis revealed that BRAF V600E status was an independent variable significantly associated with both PFS (hazard ratio [HR], 2.65; 95% CI, 1.54-4.57; P < .001) and OS (HR, 1.96; 95% CI, 1.08-3.55; P = .03). For the 45 patients with resected melanoma brain metastases undergoing targeted DNA sequencing, molecular classification recapitulated The Cancer Genome Atlas groups (NRAS variant, BRAF variant, NF1 variant, and triple wildtype) with no subtype enrichment within the brain metastasis cohort. On a molecular level, BRAF V600E variant lesions were found to have a significantly decreased tumor mutation burden. Moreover, single nuclear RNA sequencing of treatment-naive BRAF V600E variant (n = 3) brain metastases compared with BRAF wildtype (n = 3) brain metastases revealed increased immune cell populations in BRAF wildtype tumors (mean [SD], 11% [4.1%] vs 3% [1.6%] CD45-positive cells; P = .04). Survival analysis of postoperative immunotherapy responses by BRAF status revealed that BRAF wildtype lesions were associated with a response to checkpoint inhibition (median OS: with immunotherapy, undefined; without immunotherapy, 13.0 months [range, 1.1-61.7 months]; P = .001; log-rank test) while BRAF variant lesions (median OS: with immunotherapy, 9.8 months [range, 2.9-39.8 months]; without immunotherapy, 9.5 months [range, 2.5-67.2 months]; P = .81; log-rank test) were not. Conclusions and Relevance: This molecular analysis of patients with resected melanoma brain metastases found that BRAF V600E alteration is an important translational biomarker associated with worse clinical outcomes, differential microenvironmental composition, and benefit from immunotherapy. Patients with BRAF V600E variant melanoma brain metastases may thus benefit from alternative CNS-penetrant systemic regimens.

Systemic Therapy for Melanoma: ASCO Guideline Update.

PURPOSE: To provide guidance to clinicians regarding the use of systemic therapy for melanoma. METHODS: American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature. RESULTS: The updated review identified 21 additional randomized trials. UPDATED RECOMMENDATIONS: Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti-PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF-mutated disease after progression on other therapies.This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update.Additional information is available at www.asco.org/melanoma-guidelines.

Systemic therapy for melanoma: ASCO guideline update

To provide guidance to clinicians regarding the use of systemic therapy for melanoma. American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature. The updated review identified 21 additional randomized trials. Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti­PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF-mutated disease after progression on other therapies. This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update. Additional information is available at www.asco.org/melanoma-guidelines

Mutational Status and Clinical Outcomes Following Systemic Therapy with or without Focal Radiation for Resected Melanoma Brain Metastases.

BACKGROUND: Brain metastases occur frequently in advanced melanoma and traditionally require surgery and radiation therapy. New evidence demonstrates that systemic therapies are effective for controlling metastatic melanoma brain metastases. This study evaluated outcomes after resection of melanoma brain metastases treated with systemic therapy, with or without focal radiotherapy. METHODS: All patients received immunotherapy or BRAF/MEK inhibitors preoperatively or in the immediate 3 months postoperatively. Resection cavity failure, distant central nervous system progression, and adverse radiation effects were reported in the presence and absence of focal radiotherapy using the Kaplan-Meier method. RESULTS: Between 2011 and 2020, 37 resection cavities in 29 patients met criteria for analysis. Of lesions, 22 (59%) were treated with focal radiotherapy, and 15 (41%) were treated with targeted therapy or immunotherapy alone. The 12- and 24-month freedom from local recurrence was 64.8% (95% confidence interval [CI] 42.1%-99.8%) and 46.3% (95% CI 24.5%-87.5%), respectively, for systemic therapy alone and 93.3% (95% CI 81.5%-100%) at both time points for focal radiotherapy (P = 0.01). On univariate analysis, focal radiotherapy was the only significant factor associated with reduction of local recurrence risk (hazard ratio 0.10, 95% CI 0.01-0.85; P = 0.04). There were no significant differences in central nervous system progression-free survival or overall survival between patients who received systemic therapy plus focal radiotherapy compared with systemic therapy alone. BRAF mutation status was reviewed for either the brain metastasis (n = 9 patients, 31%) or the primary site (n = 20 patients, 69%), and patients harboring BRAFV600E mutations had worse progression-free survival (P = 0.043). CONCLUSIONS: Focal radiotherapy with systemic therapy for resected melanoma brain metastases significantly decreased resection cavity recurrence compared with systemic therapy alone. BRAF mutation status correlated with poorer outcomes.

Neurological adverse effects associated with anti-PD1 antibodies alone or in combination with ipilimumab: a multicenter case series.

Anti-programmed cell death protein 1 (PD1) antibodies, pembrolizumab and nivolumab, alone or in combination with ipilimumab, have become standard treatment for melanoma and multiple other malignancies. Neurological adverse effects are rare and have not been well characterized to date. Patients who developed neurological adverse effects while being treated with PD1, alone or in combination with ipilimumab, were retrospectively identified from 10 cancer centers. Fifty-eight patients were included, and the median time from treatment initiation to development of neurological adverse effects was 7 weeks (range, 1-86.5 weeks). Thirty-seven (64%) toxicities affected the peripheral nervous system. Fifty (86%) patients were treated with corticosteroids, with 22 (37%) patients requiring further immunomodulation including intravenous immunoglobulin (16), plasmapheresis (7), mycophenolate mofetil (4), cyclophosphamide (1), and rituximab (1). Twenty-seven (46%) had a complete resolution of their neurological symptoms, and two (4%) patients died secondary to complications from their neurological adverse effects. The response rate of the cancer to immunotherapy was 78%, and the median progression free survival was not reached. Neurological adverse effects can occur with PD1 treatment, do not appear to impact treatment response, but may be irreversible or worsen in some patients. Management may require immunomodulation beyond corticosteroids.

Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses.

BACKGROUND: There are no validated biomarkers that can aid clinicians in selecting who would best benefit from anticytotoxic T lymphocyte-associated antigen 4 monotherapy versus combination checkpoint blockade in patients with advanced melanoma who have progressive disease after programmed death 1 (PD-1) blockade. METHODS: We conducted a randomized multicenter phase II trial in patients with advanced melanoma. Patients were randomly assigned to receive either 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab or 3 mg/kg of ipilimumab every 3 weeks for up to four doses. Patients were stratified by histological subtype and prior response to PD-1 therapy. The primary clinical objective was overall response rate by week 18. Translational biomarker analyses were conducted in patients with blood and tissue samples. RESULTS: Objective responses were seen in 5 of 9 patients in the ipilimumab arm and 2 of 10 patients in the ipilimumab+nivolumab arm; disease control rates (DCRs) (66.7% vs 60.0%) and rates of grade 3-4 adverse events (56% vs 50%) were comparable between arms. In a pooled analysis, patients with clinical benefit (CB), defined as Response Evaluation Criteria in Solid Tumors response or progression-free for 6 months, showed increased circulating CD4+ T cells with higher polyfunctionality and interferon gamma production following treatment. Tumor profiling revealed enrichment of NRAS mutations and activation of transcriptional programs associated with innate and adaptive immunity in patients with CB. CONCLUSIONS: In patients with advanced melanoma that previously progressed on PD-1 blockade, objective responses were seen in both arms, with comparable DCRs. Findings from biomarker analyses provided hypothesis-generating signals for validation in future studies of larger patient cohorts. TRIAL REGISTRATION NUMBER: NCT02731729.

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.

PURPOSE: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown. METHODS: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined. RESULTS: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred. CONCLUSIONS: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.

Mechanisms of Cardiovascular Toxicities Associated With Immunotherapies.

Immune-based therapies have revolutionized cancer treatments. Cardiovascular sequelae from these treatments, however, have emerged as critical complications, representing new challenges in cardio-oncology. Immune therapies include a broad range of novel drugs, from antibodies and other biologics, including immune checkpoint inhibitors and bispecific T-cell engagers, to cell-based therapies, such as chimeric-antigen receptor T-cell therapies. The recognition of immunotherapy-associated cardiovascular side effects has also catapulted new research questions revolving around the interactions between the immune and cardiovascular systems, and the signaling cascades affected by T cell activation, cytokine release, and immune system dysregulation. Here, we review the specific mechanisms of immune activation from immunotherapies and the resulting cardiovascular toxicities associated with immune activation and excess cytokine production.

Loneliness and symptom burden in oncology patients during the COVID-19 pandemic.

BACKGROUND: Loneliness and social isolation are significant public health problems that are being exacerbated during the coronavirus disease 2019 pandemic. Little is known about the associations between loneliness and symptom burden in oncology patients before and during the pandemic. Study purposes include determining the prevalence of loneliness in a sample of oncology patients; evaluating for differences in demographic, clinical, and symptom characteristics between lonely and nonlonely patients; and determining which demographic, clinical, and symptom characteristics were associated with membership in the lonely group. METHODS: A convenience sample (n = 606) completed online surveys that evaluated the severity of loneliness, social isolation, and common symptoms (ie, anxiety, depression, fatigue, sleep disturbance, cognitive dysfunction, and pain) in oncology patients. Parametric and nonparametric tests were used to evaluate for differences in scores between the lonely and nonlonely groups. Logistic regression analysis was used to determine risk factors for membership in the loneliness group. RESULTS: Of the 606 patients, 53.0% were categorized in the lonely group. The lonely group reported higher levels of social isolation, as well as higher symptom severity scores for all of the symptoms evaluated. In the multivariate model, being unmarried, having higher levels of social isolation, as well as higher levels of anxiety and depressive symptoms were associated with membership in the lonely group. CONCLUSIONS: Study findings suggest that a significant number of oncology patients are experiencing loneliness, most likely as a result of mandate social distancing and isolation procedures. The symptom burden of these patients is extremely high and warrants clinical evaluation and interventions.

Mechanisms and clinical manifestations of cardiovascular toxicities associated with immune checkpoint inhibitors.

Immunotherapies have greatly expanded the armamentarium of cancer-directed therapies in the past decade, allowing the immune system to recognize and fight cancer. Immune checkpoint inhibitors (ICIs), in particular, have revolutionized cancer treatment and have demonstrated survival benefit in numerous types of cancer. These monoclonal antibodies increase anti-cancer immunity by blocking down-regulators of adaptive immunity, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1), resulting in anti-tumor activity. As ICIs increase immune system activation, they can cause a wide range of inflammatory side effects, termed immune-released adverse events. Though these toxicities can affect nearly any organ, the most fatal toxicity is myocarditis. Here, we discuss the diverse spectrum of cardiovascular toxicities associated with ICI use. In addition, we provide insight and future directions on mechanisms and treatments for immune-related adverse events (irAEs) involving the myocardium, pericardium, vasculature, and conduction system.

Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment.

The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA and TCR sequencing to detect and characterize "tumor-matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors or melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared with nonmatching T cells in blood and were less exhausted than matching cells in tumors. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome, we identified candidate cell surface markers for TM cells in mice and patients and validated NKG2D, CD39, and CX3CR1 in mice. These data show that the TCR can be used to identify tumor-relevant cells for characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells.

Oncology patients' perceptions of and experiences with COVID-19.

PURPOSE: No information is available on cancer patients' knowledge of and experiences with COVID-19. We undertook an evaluation of differences in COVID-19 symptom occurrence rates, COVID-19 testing rates, clinical care activities, knowledge of COVID-19, and use of mitigation procedures between patients who were and were not receiving active cancer treatment. METHODS: Patients enrolled were > 18 years of age; had a diagnosis of cancer; and were able to complete the emailed study survey online. RESULTS: Of the 174 patients who participated, 27.6% (n = 48) were receiving active treatment, 13.6% were unemployed because of COVID-19, 12.2% had been tested for COVID-19, and 0.6% had been hospitalized for COVID-19. Patients who were not on active treatment reported a higher mean number of COVID-19 symptoms (3.1 (± 4.2) versus 1.9 (± 2.6)), and patients who reported a higher number of COVID-19 symptoms were more likely to be tested. Over 55% of the patients were confident that their primary care provider could diagnose COVID-19, and the majority of the patients had high levels of adherence with the use of precautionary measures (e.g., social distancing, use of face coverings). CONCLUSION: The high level of COVID-19 symptoms and the significant overlap of COVID-19 and cancer-related symptoms pose challenges for clinicians who are assessing and triaging oncology patients for COVID-19 testing. For patients on active treatment, clinicians face challenges with how to assess and manage symptoms that, prior to COVID-19, would be ascribed to acute toxicities associated with cancer treatments or persistent symptoms in cancer survivors.

Multidisciplinary Management of Cancer During Pregnancy.

Cancer during pregnancy is relatively rare but is increasing in frequency in countries in which the maternal child-bearing age continues to rise. The complexities of medical decision making are underscored by the need to weigh the potential benefits of any intervention for the mother against the risks to the fetus. A majority of diagnostic evaluations can be performed safely in the setting of pregnancy and should not be delayed. Noninvasive prenatal testing that shows discordance with fetal karyotype can be a clue to an underlying maternal malignancy. After diagnosis, a multidisciplinary team should formulate a care plan for both the mother and the fetus. Key topics for discussion should include the mother's prognosis, standard treatment plan, and predictions of how modifications for a continuing pregnancy will affect the treatment plan and overall prognosis. In the context of this knowledge, frank discussions about pregnancy termination should be addressed with the patient, if appropriate. Selection of a plan for oncologic management in the case of a pregnant woman is based on the type of cancer, the tumor biology, and the tumor stage. Additional complexities for pregnant patients are typically related to the gestational age of the fetus, the dynamic physiologic changes of pregnancy, and the limited safety data for administration of most anticancer therapies during pregnancy. In this article, we summarize data related to different classes of anticancer therapies as well as considerations for the management of selected cancers. Finally, we provide some key principles that should be considered in the management of patients with cancer during pregnancy.

Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study.

BACKGROUND: Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined. METHODS: We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology. RESULTS: 89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%). CONCLUSIONS: Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.

Tumor Immune Profiling-Based Neoadjuvant Immunotherapy for Locally Advanced Melanoma.

BACKGROUND: The frequency of "exhausted" or checkpoint-positive (PD-1+CTLA-4+) cytotoxic lymphocytes (Tex) in the tumor microenvironment is associated with response to anti-PD-1 therapy in metastatic melanoma. The current study determined whether pretreatment Tex cells in locally advanced melanoma predicted response to neoadjuvant anti-PD-1 blockade. METHODS: Pretreatment tumor samples from 17 patients with locally advanced melanoma underwent flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the criteria for neoadjuvant checkpoint blockade were treated with either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. Best overall response was evaluated by response evaluation criteria in solid tumors version 1.1, with recurrence-free survival (RFS) calculated by the Kaplan-Meier test. The incidence and severity of adverse events were tabulated by clinicians using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. RESULTS: Of the neoadjuvant treated patients, 10 received anti-PD-1 monotherapy and 7 received anti-CTLA-4/PD-1 combination therapy. Of these 17 patients, 12 achieved a complete response, 4 achieved partial responses, and 1 exhibited stable disease. Surgery was subsequently performed for 11 of the 17 patients, and 8 attained a complete pathologic response. Median RFS and overall survival (OS) were not reached. Immune-related adverse events comprised four grade 3 or 4 events, including pneumonitis, transaminitis, and anaphylaxis. CONCLUSION: The results showed high rates of objective response, RFS, and OS for patients undergoing immune profile-directed neoadjuvant immunotherapy for locally advanced melanoma. Furthermore, the study showed that treatment stratification based upon Tex frequency can potentially limit the adverse events associated with combination immunotherapy. These data merit further investigation with a larger validation study.