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Purpose: This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma.Experimental Design: One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CTL (12MP, group A), plus a tetanus peptide (group B), or a mixture of 6 melanoma helper peptides (6MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6 melanoma helper peptide (6MHP) alone (group D), in incomplete Freund's adjuvant plus granulocyte macrophage colony-stimulating factor. CTL responses were assessed using an in vitro-stimulated IFN-γ ELIspot assay, and HTL responses were assessed using a proliferation assay.Results: In groups A to D, respectively, CTL response rates to 12 melanoma peptides were 43%, 47%, 28%, and 5%, and HTL response rates to 6MHP were in 3%, 0%, 40%, and 41%. Best clinical response was partial response in 7 of 148 evaluable patients (4.7%) without significant difference among study arms. Median overall survival (OS) was 11.8 months. Immune response to 6 MHP was significantly associated with both clinical response (P = 0.036) and OS (P = 0.004).Conclusion: Each vaccine regimen was immunogenic, but MHPs did not augment CTL responses to 12 melanoma peptides. The association of survival and immune response to 6MHP supports further investigation of helper peptide vaccines. For patients with advanced melanoma, multipeptide vaccines should be studied in combination with other potentially synergistic active therapies. Clin Cancer Res; 19(15); 4228–38. ©2013 AACR.

CCR Translation for This Article from A Randomized Phase II Trial of Multiepitope Vaccination with Melanoma Peptides for Cytotoxic T Cells and Helper T Cells for Patients with Metastatic Melanoma (E1602)

Supplementary Table 1: Patient demographics. Supplementary Table 2: T cell response rates by arm. Supplementary Table 3: Peptide-specific immune response by HLA type. Supplementary Table 4: Number of patients in each group defined by sex, visceral disease and ECOG PS. Supplementary Table 5: Predicted 1-year OS rate (using Korn method) and observed 1-year OS rate for E1602 patients. Supplementary Table 6: treatment related toxicity.

PDF - 433K, Supplementary Figure 1: Study Schema. Supplementary Figure 2: Association of overall survival and immune response to 6MHP, detail by study arm (Arm C and Arm D.)

ImportanceTherapy for advanced melanoma has transformed during the past decade, but early detection and prognostic assessment of cutaneous melanoma (CM) remain paramount goals. Best practices for screening and use of pigmented lesion evaluation tools and gene expression profile (GEP) testing in CM remain to be defined.ObjectiveTo provide consensus recommendations on optimal screening practices and prebiopsy diagnostic, postbiopsy diagnostic, and prognostic assessment of CM.Evidence ReviewCase scenarios were interrogated using a modified Delphi consensus method. Melanoma panelists (n = 60) were invited to vote on hypothetical scenarios via an emailed survey (n = 42), which was followed by a consensus conference (n = 51) that reviewed the literature and the rationale for survey answers. Panelists participated in a follow-up survey for final recommendations on the scenarios (n = 45).FindingsThe panelists reached consensus (≥70% agreement) in supporting a risk-stratified approach to melanoma screening in clinical settings and public screening events, screening personnel recommendations (self/partner, primary care provider, general dermatologist, and pigmented lesion expert), screening intervals, and acceptable appointment wait times. Participants also reached consensus that visual and dermoscopic examination are sufficient for evaluation and follow-up of melanocytic skin lesions deemed innocuous. The panelists reached consensus on interpreting reflectance confocal microscopy and some but not all results from epidermal tape stripping, but they did not reach consensus on use of certain pigmented lesion evaluation tools, such as electrical impedance spectroscopy. Regarding GEP scores, the panelists reached consensus that a low-risk prognostic GEP score should not outweigh concerning histologic features when selecting patients to undergo sentinel lymph node biopsy but did not reach consensus on imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status.Conclusions and RelevanceFor this consensus statement, panelists reached consensus on aspects of a risk-stratified approach to melanoma screening and follow-up as well as use of visual examination and dermoscopy. These findings support a practical approach to diagnosing and evaluating CM. Panelists did not reach consensus on a clearly defined role for GEP testing in clinical decision-making, citing the need for additional studies to establish the clinical use of existing GEP assays.

IMPORTANCE: Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care. OBJECTIVE: To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies. EVIDENCE REVIEW: The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed. FINDINGS: The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility. CONCLUSIONS AND RELEVANCE: More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

Purpose In two phase III studies, nivolumab, a programmed death-1 (PD-1) inhibitor antibody, improved overall survival (OS) versus docetaxel in pretreated advanced non–small-cell lung cancer (NSCLC). We report 5-year follow-up results from an early phase I study of nivolumab in this patient population and describe characteristics of 5-year survivors. Patients and Methods Patients with pretreated, advanced NSCLC received nivolumab 1, 3, or 10 mg/kg every 2 weeks in 8-week cycles for up to 96 weeks. OS from the time of first dose was estimated by the Kaplan-Meier method. Results The estimated 5-year OS rate was 16% for all treated patients (N = 129); 5-year OS rates were similar for squamous (16%) and nonsquamous (15%) NSCLC. Of 16 5-year survivors, most (88%) were known current or former smokers. Of 10 5-year survivors with quantifiable PD-1 ligand 1 expression, 70% had ≥ 1% PD-1 ligand 1 expression at baseline. Twelve 5-year survivors (75%) achieved a partial response to nivolumab per Response Evaluation Criteria in Solid Tumors, version 1.0, and two each (12%) had stable disease and progressive disease as best response. Nine 5-year survivors (56%) completed the maximum 96 weeks of nivolumab; four (25%) discontinued owing to adverse events and three (19%) owing to disease progression. As of a November 2016 database lock, 12 5-year survivors (75%) received no subsequent therapy and were without evidence of progressive disease at last follow-up. Conclusions Nivolumab treatment resulted in long-term OS and durable responses in a proportion of patients with pretreated advanced NSCLC. Long-term survivors had diverse baseline and on-treatment characteristics.

179 Background: The estimated number of new cancer cases in the United States in 2020 is 1.8 million with an estimated 606,000 deaths. The science and technology of oncology has dramatically increased in recent years. EMR demands, RVU reimbursements, restriction of time/visit demanded by systems, bureaucratic hurdles, and physician burnout has resulted in reduced patient-focused time available for oncologists. A pilot project for 2020 was established to determine if a fully funded oncology second opinion consult program would be feasible and have value to patients/families and their physicians. Methods: Planning started December 2019 for an independent oncology second opinion program that was of no cost to the patient, funded by The Cincinnati Cancer Foundation. The first patient was seen January, 2020. Two hours of face to face or teleconference time was spent with the patient and family including a comprehensive history and physical in face to face cases. After the initial consultation, a comprehensive literature, clinical trial, and case data review was completed. A phone call was made to the treating physician to discuss the case and recommendations. A one-time follow-up was offered to the patient where recommendations were reviewed and the patient’s questions answered. Surveys were sent to the patient and treating physicians for real-time feedback. Results: From 1/2/2020 to 6/1/2020, 70 patients were seen in consultation from 12 different hospital systems with 29 different diagnoses. 4% (3) of consultations were done by video conferencing and 96% (67) were done in person. 54% (36/67) of patient surveys were returned. The overall value of the consultation (1-5 scale with 5 being the best) to the patient was: 97% (35)-5, 3% (1)-4. 20.5% (18/88) of physician surveys were returned. The overall value of the consultation to the physician was: 83% (15)-5, 17% (3)-4. Of the 70 patients, the amount of change in the patient’s plan of care due to the consultation was: None 28.5% (20), Small 50% (35), Moderate 18.5% (13), Significant 3% (2). Conclusions: Our findings establish the feasibility of a comprehensive second opinion service in cancer. The feedback from participants support the value and acceptance of an independent oncology second opinion consultation program to both patients and referring physicians.

Purpose Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non–small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients and Methods Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Results Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Conclusion Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.

Importance Nivolumab, a monoclonal antibody that inhibits programmed cell death 1, is approved by the US Food and Drug Administration for treating advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies. Data on long-term survival among patients receiving nivolumab are limited. Objectives To analyze long-term overall survival (OS) among patients receiving nivolumab and identify clinical and laboratory measures associated with tumor regression and OS. Design, Setting, and Participants This was a secondary analysis of the phase 1 CA209-003 trial (with expansion cohorts), which was conducted at 13 US medical centers and included 270 patients with advanced melanoma, RCC, or NSCLC who received nivolumab and were enrolled between October 30, 2008, and December 28, 2011. The analyses were either specified in the original protocol or included in subsequent protocol amendments that were implemented between 2008 and 2012. Statistical analysis was performed from October 30, 2008, to November 11, 2016. Intervention In the CA209-003 trial, patients received nivolumab (0.1-10.0 mg/kg) every 2 weeks in 8-week cycles for up to 96 weeks, unless they developed progressive disease, achieved a complete response, experienced unacceptable toxic effects, or withdrew consent. Main Outcomes and Measures Safety and activity of nivolumab; OS was a post hoc end point with a minimum follow-up of 58.3 months. Results Of 270 patients included in this analysis, 107 (39.6%) had melanoma (72 [67.3%] male; median age, 61 [range, 29-85] years), 34 (12.6%) had RCC (26 [76.5%] male; median age, 58 [range, 35-74] years), and 129 (47.8%) had NSCLC (79 [61.2%] male; median age, 65 [range, 38-85] years). Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC. In a multivariable analysis, the presence of liver (odds ratio [OR], 0.31; 95% CI, 0.12-0.83;P = .02) or bone metastases (OR, 0.31; 95% CI, 0.10-0.93;P = .04) was independently associated with reduced likelihood of survival at 5 years, whereas an Eastern Cooperative Oncology Group performance status of 0 (OR, 2.74; 95% CI, 1.43-5.27;P = .003) was independently associated with an increased likelihood of 5-year survival. Overall survival was significantly longer among patients with treatment-related AEs of any grade (median, 19.8 months; 95% CI, 13.8-26.9 months) or grade 3 or more (median, 20.3 months; 95% CI, 12.5-44.9 months) compared with those without treatment-related AEs (median, 5.8 months; 95% CI, 4.6-7.8 months) (P Conclusions and Relevance Nivolumab treatment was associated with long-term survival in a subset of heavily pretreated patients with advanced melanoma, RCC, or NSCLC. Characterizing factors associated with long-term survival may inform treatment approaches and strategies for future clinical trial development. Trial Registration ClinicalTrials.gov identifier:NCT00730639

e14539 Background: Circulating tumor DNA provides an opportunity to assess the genetic profile of a patient’s tumor without performing a tissue biopsy. The Guardant360 assay is one platform available to perform genetic sequencing of circulating tumor DNA from a blood sample. This can allow for assessing the BRAF mutation status of patients with malignant melanoma from a liquid biopsy. Methods: Retrospective chart review was done of patients with malignant melanoma with a positive BRAF V600 mutation based on a tissue biopsy. The BRAF V600 mutation status of these patents as determined by a Guardant360 assay, which was not necessarily done at the same time as the tissue biopsy, was gathered. The status of each patient’s malignancy at the time of each liquid biopsy was assessed and divided into three categories, which included active distant metastatic disease, active locoregional disease, and no evidence of active disease. Results: 51 total patients with a positive BRAF V600 mutation based on tissue biopsy were included in this analysis. Some patients had multiple Guardant360 assays which were done at different timepoints, which made for 83 total liquid biopsies. Out of 30 liquid biopsies done when the patient had evidence of active distant metastatic disease, 21 (70%) were positive for a BRAF V600 mutation. Out of 13 liquid biopsies done when the patient had evidence of active locoregional disease, 2 (15.4%) were positive for a BRAF V600 mutation. Out of 40 liquid biopsies done when the patient had no evidence of active disease, 3 (7.5%) were positive for a BRAF V600 mutation. Conclusions: The Guardant360 assay in detecting a BRAF V600 mutation had it’s highest sensitivity in the setting of active distant metastatic disease. This assay can allow for sparing patients more invasive tissue biopsies when the suspicion for metastatic melanoma is high and the BRAF mutation status is unknown.

This study systematically reviews outcomes after inferior vena cava (IVC) filtration in cancer-associated venous thromboembolism (VTE). A comprehensive review of the English language literature was performed using MEDLINE, COCHRANE library, Embase and CINAHL on outcomes (i.e., pulmonary embolism, recurrent DVT, postphlebitic syndrome and survival) following IVC filtration in cancer-associated VTE. Fourteen studies with 2,154 cancer patients receiving IVC filters post-VTE were included. All were observational studies. The mean duration of followup was 0.7–38 months and mean patient age was 56.8– 68 years. Among study participants, 47–87% had stage 3 or 4 cancers. Of the 47–93% of filters inserted for contraindications to anticoagulation (AC), 10–33% were placed for relative contraindications. Recurrent PE was seen in 0–6%, fatal PE in 0–4.5%, recurrent DVT in 0–18.2%, postphlebitic syndrome (PPS) in 0–2.7%, and IVC thrombosis (ICVT) in 3% of cancer patients. Median survival post-filter insertion was 2–10 months. Evidence supporting the utility of IVC filter insertion in cancer-associated VTE is limited to observational studies only. Preliminary data demonstrate similar safety and efficacy of filters in cancer and noncancer populations. The combination of filters and anticoagulation is no more effective than either modality alone. Retrievable filters are an attractive option for prevention of VTE in the presence of temporary risk factors or temporary contraindications to anticoagulation in patients who have a reasonable life expectancy, but there is no evidence to support their preferential use in patients with advanced malignancy.

Introduction: Prior to the introduction of immunotherapies, treatment options were limited for patients (pts) with NSCLC who progressed after first-line platinum doublet chemotherapy. The majority of pts with advanced disease died within 1 y of diagnosis, and 5-y survival for metastatic NSCLC was ~1%. Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, showed encouraging activity in pts with heavily pretreated advanced NSCLC in a phase 1 dose-escalation cohort expansion trial (CA209-003; NCT00730639). Based on improved overall survival (OS) versus docetaxel in 2 phase 3 studies in previously treated advanced NSCLC (CheckMate 017 and 057), nivolumab was approved in this population. Reports of long-term efficacy and safety with immune checkpoint inhibitors are limited. Here we report updated results from CA209-003 based on ~5 y of follow-up, representing the longest survival follow-up for an immune checkpoint inhibitor in advanced NSCLC to date. Methods: Pts with heavily pretreated (1-5 prior systemic regimens) advanced NSCLC received nivolumab (1, 3, or 10 mg/kg) every 2 wk in 8-wk cycles for up to 96 wk. The primary objective was safety and tolerability; secondary objectives included objective response rate and duration of response. OS from the time of first dose was an exploratory objective. The minimum follow-up for the current analysis was 58.25 mo. Results: At database lock, the Kaplan-Meier-estimated 5-y OS rate in all pts (N = 129) was 16% (95% confidence interval [CI]: 10, 23). OS rates at 5 y were similar in pts with squamous (SQ; n = 54; 16% [95% CI: 8, 28]) and non-SQ (n = 74; 15% [95% CI: 8, 25]) NSCLC (excludes 1 pt with unknown histology). Of the 16 pts who survived ≥5 y (median age: 61.5 y [range: 44, 80]), 9 pts were male and 12 were current smokers at baseline (2 former smokers; 2 unknown). In 10 evaluable pts, PD-1 ligand 1 (PD-L1) expression was ≥1% in 7 pts (≥50% in 5) and Conclusions: Nivolumab resulted in durable OS in a notable proportion of pts with pretreated advanced NSCLC, as demonstrated by a 5-y OS rate of 16%. Long-term survivors had diverse baseline and on-treatment characteristics including histology, PD-L1 expression level (including pts with Citation Format: Julie Brahmer, Leora Horn, David Jackman, David Spigel, Scott Antonia, Matthew Hellmann, John Powderly, Rebecca Heist, Lecia Sequist, David C. Smith, Philip Leming, William J. Geese, Dennis Yoon, Ang Li, Scott Gettinger. Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT077. doi:10.1158/1538-7445.AM2017-CT077

Importance Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade. Objective To compare the effect of ipilimumab plus sargramostim vs ipilimumab alone on overall survival (OS) in patients with metastatic melanoma. Design, Setting, and Participants The Eastern Cooperative Oncology Group (ECOG) conducted a US-based phase 2 randomized clinical trial from December 28, 2010, until July 28, 2011, of patients (N = 245) with unresectable stage III or IV melanoma, at least 1 prior therapy, no central nervous system metastases, and ECOG performance status of 0 or 1. Interventions Patients were randomized to receive ipilimumab, 10 mg/kg, intravenously on day 1 plus sargramostim, 250 μg subcutaneously, on days 1 to 14 of a 21-day cycle (n = 123) vs ipilimumab alone (n = 122). Ipilimumab treatment included induction for 4 cycles followed by maintenance every fourth cycle. Main Outcomes and Measures Primary end point: comparison of length of OS. Secondary end point: progression-free survival (PFS), response rate, safety, and tolerability. Results Median follow-up was 13.3 months (range, 0.03-19.9). Median OS as of December 2012 for ipilimumab plus sargramostim was 17.5 months (95% CI, 14.9-not reached) vs 12.7 months (95% CI, 10.0-not reached) for ipilimumab. The 1-year survival rate for ipilimumab plus sargramostim was 68.9% (95% CI, 60.6%-85.5%) compared to 52.9% (95% CI, 43.6%-62.2%) for ipilimumab alone (stratified log-rank 1-sided P = .01; mortality hazard ratio 0.64 [1-sided 90% repeated CI, not applicable-0.90]). A planned interim analysis was conducted at 69.8% of expected events (104 observed with 149 expected deaths). Planned interim analysis using the O’Brien-Fleming boundary was crossed for improvement in OS. There was no difference in PFS. Median PFS for ipilimumab plus sargramostim was 3.1 months (95% CI, 2.9-4.6) vs 3.1 months (95% CI, 2.9-4.0) for ipilimumab alone. Grade 3 to 5 adverse events occurred in 44.9% (95% CI; 35.8%-54.4%) of patients in the ipilimumab plus sargramostim group vs 58.3% (95% CI, 49.0%-67.2%) of patients in the ipilimumab-alone group (2-sided P = .04). Conclusion and Relevance Among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer OS and lower toxicity, but no difference in PFS. These findings require confirmation in larger studies with longer follow-up. Trial Registration clinicaltrials.gov Identifier:NCT01134614

Purpose Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. Patients and Methods Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Results Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. Conclusion Overall survival following nivolumab treatment in patients with advanced treatment–refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

Purpose: This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma. Experimental Design: One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CTL (12MP, group A), plus a tetanus peptide (group B), or a mixture of 6 melanoma helper peptides (6MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6 melanoma helper peptide (6MHP) alone (group D), in incomplete Freund's adjuvant plus granulocyte macrophage colony-stimulating factor. CTL responses were assessed using an in vitro-stimulated IFN-γ ELIspot assay, and HTL responses were assessed using a proliferation assay. Results: In groups A to D, respectively, CTL response rates to 12 melanoma peptides were 43%, 47%, 28%, and 5%, and HTL response rates to 6MHP were in 3%, 0%, 40%, and 41%. Best clinical response was partial response in 7 of 148 evaluable patients (4.7%) without significant difference among study arms. Median overall survival (OS) was 11.8 months. Immune response to 6 MHP was significantly associated with both clinical response (P = 0.036) and OS (P = 0.004). Conclusion: Each vaccine regimen was immunogenic, but MHPs did not augment CTL responses to 12 melanoma peptides. The association of survival and immune response to 6MHP supports further investigation of helper peptide vaccines. For patients with advanced melanoma, multipeptide vaccines should be studied in combination with other potentially synergistic active therapies. Clin Cancer Res; 19(15); 4228–38. ©2013 AACR.

Background: In previously treated MEL patients (pts), the results of an early phase I trial with NIVO monotherapy (CA209-003) demonstrated tumor responses that were durable even after treatment discontinuation (Topalian et al. J Clin Oncol 2014;32:1020). We report extended follow-up with 5-year overall survival (OS) data from this study. Methods: IPI-naïve pts (N = 107) who had received 1-5 prior systemic therapies for MEL were treated with NIVO (0.1, 0.3, 1, 3, or 10 mg/kg) every 2 weeks for ?96 weeks. Pts were followed for OS, progression-free survival (PFS), long-term safety, and response duration after discontinuing NIVO treatment. Pts began treatment in October 2008, and current data were analyzed in October 2015 with a minimum follow-up of 45 months (time from when the last pt received his or her first dose of NIVO). Results: Median age of the pts was 61 years, 67% were male, 97% had an ECOG performance status of 0 or 1, 62% had received ?2 prior systemic therapies, and 36% had elevated lactate dehydrogenase levels at baseline. In all 107 pts, the 60-month OS rate was 34% (95% confidence interval [CI]: 25-43) and median OS was 17.3 months (95% CI: 12.5-37.8) (Table). OS rates appeared to plateau at ∼48 months, although further follow-up is needed. Similar results were observed with NIVO at 3 mg/kg, the currently approved monotherapy dose (Table). At the last timepoint for tumor assessment, PFS rates at 30 months were 18.6% and 25.7% for all pts and those who received NIVO at 3 mg/kg, respectively. Conclusions: This analysis represents the longest survival follow-up of pts who received anti-PD-1 therapy in a clinical study. In this heavily pretreated population of MEL pts, these results suggest durable, long-term survival following NIVO monotherapy, with 34% of pts alive at 5 years. Characteristics of long-term survivors and updated safety data will also be presented. OS ratesNIVO 3 mg/kg (n=17)All Patients (N=107)OS rate, % (95% CI)*12-month64.7 (37.7-82.3)62.7 (52.6-71.2)24-month47.1 (23.0-68.0)48.0 (38.1-57.2)36-month41.2 (18.6-62.6)42.1 (32.4-51.4)48-month35.3 (14.5-57.0)34.8 (25.7-44.1)60-month35.3 (14.5-57.0)33.6 (24.6-42.9)Median OS, months (95% CI)20.3 (7.2-NR)17.3 (12.5-37.8)*Based on Kaplan-Meier estimates.NR, not reached. Citation Format: F. Stephen Hodi, Harriet Kluger, Mario Sznol, Richard Carvajal, Donald Lawrence, Michael Atkins, John Powderly, William Sharfman, Igor Puzanov, David Smith, Philip Leming, Evan Lipson, Janis Taube, Robert Anders, Christine Horak, Joel Jiang, David McDermott, Jeffrey Sosman, Julie Brahmer, Drew Pardoll, Suzanne Topalian. Durable, long-term survival in previously treated patients with advanced melanoma (MEL) who received nivolumab (NIVO) monotherapy in a phase I trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT001.

Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castrationresistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drugrelated adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)

e20105 Background: UM is the rarest subset of all melanomas and has a distinct molecular pathogenesis. Once metastasis develop, the prognosis becomes very poor, however, overall survival (OS) is no...

9002 Background: We have shown that nivolumab, a fully human IgG4 PD-1 immune-checkpoint inhibitor antibody, is tolerable and active in pts with advanced solid tumors in a large phase I trial (Topa...

8112^ Background: Nivolumab, a fully human IgG4, PD-1 immune-checkpoint inhibitor antibody, has shown durable clinical activity in a large phase I trial of pts with advanced solid tumors. For NSCLC...

CRA9007 Background: CTLA-4 blockade and GM secreting tumor vaccine combinations demonstrate therapeutic synergy in multiple preclinical models. GM has activity in prostate and ovarian carcinoma and is being evaluated in phase III adjuvant trials for melanoma and lymphoma. GM enhances dendritic cell activation and potentiates antitumor T and B cell responses. GM may induce regulatory immune responses. A key issue is whether systemic GM might synergize with CTLA-4 blockade. Methods: Eligibility: measureable disease, ≤1 prior therapy, no CNS mets, ECOG PS 0-1, > 4 wks prior therapy, adequate end organ function, no autoimmune disease, no prior CTLA-4 blockade/CD137 agonist. OS was primary endpoint. Pts randomized to Arm A Ipi 10 mg/kg q3 wks IV x 4 then q12 wks plus GM 250 μg SC days 1-14 of 21 day cycles vs. Arm B Ipi 10 mg/kg as in Arm A alone. Due to known inflammatory effects of treatments, pts were permitted to continue up to 100% increase in SPD and four new lesions in absence of declining performance s...

The use of mitomycin for metastatic colorectal cancer has been limited by mitomycin's myelosuppressive potential. The objective of this randomized study was to determine whether WR-2721 would decrease the hematologic toxicity of mitomycin in patients with colorectal cancer resistant to fluorouracil-based therapy. Ninety-seven patients with refractory colorectal cancer were randomized to receive either mitomycin 20 mg/m2 only or the same dose of mitomycin after pretreatment with WR-2721, 910 mg/m2. The principal toxicity in both groups was thrombocytopenia. The platelet nadirs were lower in patients receiving single-agent mitomycin (P = 0.026). Surprisingly, no clinical complete or partial responses were noted in either group, and survival was not different between the two groups. Thus, while WR-2721 decreased the thrombocytopenia associated with mitomycin therapy, mitomycin was ineffective in the treatment of refractory colorectal carcinoma.

8511 Background: Systemic treatment of metastatic melanoma has not advanced for decades, prompting investigation of novel approaches. Sorafenib is a kinase inhibitor active against RAF and VEGFR ty...

8508 Background: This multicenter randomized trial was designed to evaluate, in advanced previously treated melanoma, whether melanoma helper peptides augment CD8+ T-cell responses to a melanoma va...

An atypical presentation of herpes simplex virus type 1 (HSV-I) in the form of nodular tongue lesions was documented by histologic and immunohistochemical studies in a patient with advanced Hodgkin's disease. This represents yet another manifestation of HSV-I in the immunocompromised host and further emphasizes awareness of the oral complications of cancer chemotherapy.

Cholestatic jaundice induced by hepatic intra-arterial 5-fluorodeoxyuridine (FUDR) demonstrated marked improvement in three patients following treatment with oral corticosteroids. Subsequent "prophylactic" use allowed continuation of chemotherapy and improved quality of life. Corticosteroid use in selected patients with FUDR-induced cholestatic jaundice may be beneficial.

Excerpt Patients with iron deficiency, in addition to anemia, may have unusual dietary cravings termed pica. Although this is affected by social and cultural norms, patients may crave such substanc...