The Association between a Decrease in On-Treatment Neutrophil-to-Eosinophil Ratio (NER) at Week 6 after Ipilimumab Plus Nivolumab Initiation and Improved Clinical Outcomes in Metastatic Renal Cell Carcinoma.

A lower baseline neutrophil-to-eosinophil ratio (NER) has been associated with improved responses to immune checkpoint inhibitors (ICI)-treated metastatic renal cell carcinoma (mRCC). This study investigated the decrease in NER at week 6 after ipilimumab/nivolumab (ipi/nivo) initiation and treatment responses in mRCC. A retrospective study of ipi/nivo-treated mRCC at two US academic cancer centers was conducted. A landmark analysis at week 6 was performed to assess the association between the change in NER and clinical responses (progression-free survival (PFS)/overall survival (OS)). Week 6 NER was modeled as a continuous variable, after log transformation (Ln NER), and a categorical variable by percent change. There were 150 mRCC patients included: 78% had clear cell histology, and 78% were IMDC intermediate/poor risk. In multivariable regression analysis, every decrease of 1 unit of Ln NER at week 6 was associated with improved PFS (adjusted hazard ratio (AHR): 0.78, p-value:0.005) and OS (AHR: 0.67, p-value: 0.002). When NER was modeled by percent change, decreased NER > 50% was associated with improved PFS (AHR: 0.55, p-value: 0.03) and OS (AHR: 0.37, p-value: 0.02). The decrease in week 6 NER was associated with improved PFS/OS in ipi/nivo-treated mRCC. Prospective studies are warranted to validate NER change as a biomarker to predict ICI responses.

Association of baseline neutrophil-to-eosinophil ratio with response to nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma.

BACKGROUND: The identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC. METHODS: We performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients. RESULTS: A total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with mNER (OR 2.39, p = 0.04). The median PFS for patients with mNER (HR 0.50, p < 0.01). Median OS was not reached (NR) for patients with mNER (HR 0.31, p < 0.01). The median NLR (mNLR) was 3.42. While patients with mNLR group. CONCLUSIONS: A lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted.

An autoimmune-based, paraneoplastic neurologic syndrome following checkpoint inhibition and concurrent radiotherapy for merkel cell carcinoma: case report.

PURPOSE: Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae. METHODS: Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab. RESULTS: After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration. CONCLUSION: This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.

Blood-Based Surveillance Monitoring of Circulating Tumor DNA From Patients With SCLC Detects Disease Relapse and Predicts Death in Patients With Limited-Stage Disease.

INTRODUCTION: Most patients (70%) with limited-stage SCLC (LS-SCLC) who are treated with curative-intent therapy suffer disease relapse and cancer-related death. We evaluated circulating tumor DNA (ctDNA) as a predictor of disease relapse and death after definitive therapy in patients with LS-SCLC. METHODS: In our previous work, we developed a plasma-based ctDNA assay to sequence 14 genes (TP53, RB1, BRAF, KIT, NOTCH1-4, PIK3CA, PTEN, FGFR1, MYC, MYCL1, and MYCN) that are frequently mutated in SCLC. In this work, we evaluated 177 plasma samples from 23 patients with LS-SCLC who completed definitive chemoradiation (n = 21) or surgical resection (n = 2) and had an end-of-treatment blood collection (median 4 d, range 0-40 d from treatment completion) plus monthly surveillance blood sampling. Median overall survival (OS) and progression-free survival (PFS) were compared using a Wilcoxon test. RESULTS: The median OS among patients in whom we ever detected ctDNA after definitive treatment (n = 15) was 18.2 months compared with a median OS of greater than 48 months among patients in whom we never detected ctDNA after definitive treatment (n = 8; p = 0.081). The median PFS among patients in whom we ever detected ctDNA after definitive treatment was 9.1 months compared with a median PFS of greater than 48 months among patients in whom we never detected ctDNA after definitive treatment (p < 0.001). CONCLUSIONS: Detection of ctDNA in patients with LS-SCLC after curative-intent therapy predicts disease relapse and death. Prospective trials using ctDNA as an integral biomarker for therapeutic selection should be considered in SCLC.

Correlates of response and outcomes with talimogene laherperpvec.

BACKGROUND AND OBJECTIVES: Patients with in-transit or limited cutaneous metastatic melanoma may benefit from intralesional injections with talimogene laherparepvec (TVEC), a modified oncolytic herpesvirus. However, its use in patients with adverse prognostic scores in a real-life clinical setting has not been studied. METHODS: We performed a two-center retrospective analysis of 40 patients with metastatic melanoma treated with TVEC from 2015-2017. Demographics, overall response, and survival after therapy were noted. RESULTS: Overall, there was a durable response rate of 40%; median progression-free survival (PFS) was 10.5 months and median overall survival (OS) was not reached. Bulky disease was associated with decreased OS (15.7 months vs not reached, P < .05) and mPFS (2.3 months vs not reached, P < .05), when compared with smaller tumors. Poor performance status (ECOG 2-3) was associated with worse OS (10.2 months vs not reached, P < .05) and PFS (2.1 months vs not reached, P < .05) compared to patients with ECOG 0-1. There was no difference in the outcomes with age greater than 75 or with prior therapies. Adverse events were relatively tolerable. CONCLUSIONS: These findings demonstrate that TVEC is an effective and safe treatment for metastatic melanoma in a real-life clinical setting, and suggest parameters to aid in appropriate therapy selection for optimal response.

Hematologic Complications of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organization's pharmacovigilance database of individual-case-safety-reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP (n = 68) and HA (n = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab-based therapy (monotherapy or combination with anti-programmed death-1 [PD-1]) was associated with earlier onset (median 23 vs. 47.5 days, p = .006) than anti-PD-1/programmed death ligand-1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. KEY POINTS: Immune-mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune-mediated hematologic toxicities.Further research is needed to define patient-specific risk factors and optimal management strategies for hematologic toxicities.

Response to Anti-PD-1 in Uveal Melanoma Without High-Volume Liver Metastasis.

Background: Uveal melanoma (UM) is an uncommon melanoma subtype with poor prognosis. Agents that have transformed the management of cutaneous melanoma have made minimal inroads in UM. Methods: We conducted a single-arm phase II study of pembrolizumab in patients with metastatic UM and performed bioinformatics analyses of publicly available datasets to characterize the activity of anti-PD-1 in this setting and to understand the mutational and immunologic profile of this disease. Results: A total of 5 patients received pembrolizumab in this study. Median overall survival was not reached, and median progression-free survival was 11.0 months. One patient experienced a complete response after one dose and 2 others experienced prolonged stable disease (20% response rate, 60% clinical benefit rate); 2 additional patients had rapidly progressing disease. Notably, the patients who benefited had either no liver metastases or small-volume disease, whereas patients with rapidly progressing disease had bulky liver involvement. We performed a bioinformatics analysis of The Cancer Genome Atlas for UM and confirmed a low mutation burden and low rates of T-cell inflammation. Note that the lack of T-cell inflammation strongly correlated with MYC pathway overexpression. Conclusions: Anti-PD-1-based therapy may cause clinical benefit in metastatic UM, seemingly more often in patients without bulky liver metastases. Lack of mutation burden and T-cell infiltration and MYC overexpression may be factors limiting therapeutic responses.ClinicalTrials.gov identifier: NCT02359851.

Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.

Importance: Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data. Objective: To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects. Design, Setting, and Participants: We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. Exposures: Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab). Main Outcomes and Measures: Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. Results: Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). Conclusions and Relevance: In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Phase II study of the Multikinase inhibitor of angiogenesis, Linifanib, in patients with metastatic and refractory colorectal cancer expressing mutated KRAS.

Background Targeting angiogenesis in advanced colorectal cancer (CRC) has been one of the many factors prolonging survival. Bevacizumab was the first agent to demonstrate this, but even after progression on bevacizumab, continued VEGF-inhibition continues to improve survival. Combining epidermal growth factor receptor monoclonal antibodies with standard frontline therapies have also improved clinical outcomes, yet the improved benefit is not observed in patients with mutant KRAS. Thus, an unmet medical need exists to develop additional therapeutic options for patients with KRAS mutant CRC. Methods Patients received the anti-angiogenic agent linifanib at the recommended phase II dose of 17.5 mg. Primary endpoint was objective response rate (ORR), with a goal of 10%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Simon's optimal two-stage design was used to assess futility. Linifanib was considered inactive if two or fewer patients among the first 30 achieved an objective response. Results Thirty patients were enrolled on study. Grade 3 treatment-related toxicities occurring in at least two patients were fatigue, hypertension, proteinuria, diarrhea, nausea, oral pain, vomiting, thrombocytopenia, and arthralgia. Although no responses were observed, 63.5% of patients achieved stable disease. The median PFS and OS were 4.7 months and 9.5 months, respectively. Stopping rules for lack of clinical efficacy led to study closure. Conclusion Despite observing zero responses, a majority of patients had stable disease and eight patients had stable disease lasting longer than 5 months. These results suggest that linifanib has some anti-tumor activity in KRAS mutant metastatic and refractory CRC.

Multiple simultaneous choroidal melanomas arising in the same eye: globe salvage by radiotherapy.

PURPOSE: Multiple choroidal melanomas arising in the same eye is a very rare entity, usually leading ophthalmologists to entertain other diagnoses. Historically, the only available treatment reported for this rare entity was enucleation. In this study we demonstrate in a series of patients with multiple simultaneous choroidal melanomas that eye salvage is possible using a variety of radiotherapy techniques. OBSERVATIONS: Both patients presented with two simultaneous choroidal melanomas in one eye. The first patient was only 30 years old and presented with two largely amelanotic tumours with large exudative retinal detachment. Cytology from fine needle aspiration biopsies from both tumours with immunohistochemistry confirmed two separate melanomas. Sequential radioactive iodine plaque brachytherapy led to regression of both tumours. The second, older patient's two tumours both had the typical appearance of choroidal melanoma and he underwent proton beam irradiation to the entire field leading to tumour regression. CONCLUSIONS: Multiple choroidal melanomas can rarely arise simultaneously in the same eye, and despite their variable appearance, a definitive diagnosis can be aided by cytology and immunohistochemistry in atypical-appearing cases. While all other previously reported cases have necessitated enucleation, we demonstrate that globe salvage is possible using either proton beam irradiation to the entire tumour field, or with sequential radioactive plaque brachytherapy.

Retinal metastasis from unknown primary: diagnosis, management, and clinicopathologic correlation.

A 75-year-old man was incidentally found to have a yellow-white retinal lesion with scattered hemorrhages. He was empirically treated elsewhere for viral retinitis without resolution and later transferred to the Vanderbilt Eye Institute, where retinal biopsy with silicone oil tamponade showed retinal metastasis. He had no prior history of cancer, and multiple systemic imaging evaluations failed to identify a primary site. Histopathology and immunohistochemistry of the biopsy were consistent with non-small-cell lung carcinoma. Due to the radiation-attenuating properties of silicone oil, the patient underwent silicone oil removal prior to receiving external beam radiotherapy (EBRT). The retinal metastasis responded completely to EBRT, and at final follow-up, 18 months after initial presentation, no primary tumor has been identified.

Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial.

IMPORTANCE: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE: To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS: One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES: Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS: Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE: In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01143402.