Purpose/Objective(s) Immune checkpoint inhibitors (ICI) are increasingly used to treat patients with brain metastases, while stereotactic radiosurgery (SRS, 1 fraction) and stereotactic radiotherapy (SRT, 3-5 fractions) are established modalities. Emerging data suggest that ICI and SRS/SRT may work synergistically, with reports of increased efficacy and toxicity. We characterized factors associated with intracranial control and radiation necrosis in patients receiving both ICI and SRS/SRT. Materials/Methods We retrospectively identified patients treated with ICI and SRS/SRT for intact brain metastases at two institutions from 2013-2020. Patients had diagnoses of non-small cell lung cancer, renal cell carcinoma, or melanoma and were followed for a minimum of 2 months after receipt of both SRS/SRT and ICI with brain MRI. The analysis was completed on a per-metastasis basis. Local failure (LF) and radiation necrosis (determined radiographically with clinical impression or pathologically; included grade 2 (symptomatic) or higher) were analyzed by univariate and multivariate logistic regression which included tumor diameter, timing of ICI relative to SRS/SRT, PD-L1 (positive defined as ≥ 1%), and SRT vs. SRS. Progression-free survival (PFS) was defined as time from SRS/SRT to local or distant brain failure, death, or last follow up for those without progression. Results There were 179 patients with 549 metastases, 492 metastases treated with SRS, and 57 metastases treated with SRT. Median follow up from the time of SRS/SRT was 14.7 months. Median tumor size was 7mm (< 5mm: 253, ≥ 5 & < 10mm: 159, ≥ 10 and < 20mm: 91, and ≥ 20mm: 46). Rates of LF and grade 2+ radiation necrosis for the entire cohort were 5.8% (32/549) and 6.9% (38/549), respectively (15.6% (28/179) rate of grade 2+ radiation necrosis per-patient). LF rates for those who received ICI outside +/- 3 months from SRS/SRT vs. within +/- 3 months from SRS/SRT were 9.0% and 4.4%, respectively. Rates of grade 2+ radiation necrosis for those with positive vs. negative PD-L1 were 9.2% vs. 1.6%, respectively. Positive PD-L1 status was associated with improved intracranial PFS (HR 0.53, p = 0.03). Conclusion Combination ICI and SRS/SRT is increasingly used to treat brain metastases. Our study showed improved local control when ICI is given within 3 months from time of SRS/SRT without an associated increase in radiation necrosis. Increasing tumor size was associated with LF and radiation necrosis. Positive PD-L1 was associated with improved intracranial PFS and increased radiation necrosis. We recommend further study, ideally prospectively, to better characterize this treatment combination.

Prognosis of advanced and metastatic cutaneous squamous cell carcinoma (CSCC) remains dismal. The anti-PD1 antibody cemiplimab was the first agent approved for the treatment of advanced CSCC. RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity. In preliminary study, high response rates including complete response have been observed in patients with CSCC treated with RP1 combined with nivolumab. The objective of this trial is to evaluate the safety and efficacy of RP1 + cemiplimab versus cemiplimab alone in advanced CSCC (NCT04050436). This global, multicenter, randomized phase II study is enrolling patients (pts) with metastatic CSCC or with unresectable, locally advanced CSCC who are not candidates for/refuse surgery or radiotherapy. Key eligibility criteria include no prior treatment with anti-PD1/PD-L1 antibodies or oncolytic viruses. The clinical trial will enroll approximately 180 pts at approximately 75 centers in the EU, Australia, Canada and USA. Pts will be randomized in a 2:1 ratio favoring the RP1 + cemiplimab arm. Pts will receive 350 mg of cemiplimab intravenously (IV) Q3W for up to 108 weeks. In the RP1 + cemiplimab arm, RP1 will be injected intratumorally at a starting RP1 dose of 1 × 106 plaque forming units (PFU)/mL alone, followed by up to 7 doses of RP1 at 1 × 107 PFU/mL Q3W together with cemiplimab. Pts in the combination arm may receive up to 8 additional RP1 doses. No crossover will be allowed. Pts will be stratified by disease status and prior systemic therapy. Tumor assessments will be performed every 9 weeks. Primary endpoints are overall response rate and complete response rate by blinded central review. Secondary endpoints include safety, progression free survival, duration of response and overall survival. Exploratory endpoints include viral shedding and biodistribution, and immune biomarker analyses. This trial is currently enrolling pts. NCT04050436. Replimune Group Inc. Replimune Group Inc.

Background ITM (defined as intralymphatic local, satellite, and regional cutaneous/subcutaneous metastases) is associated with significant morbidity; optimal therapy is poorly defined. T-VEC is an oncolytic immunotherapy approved for melanoma treatment based on results from the phase III OPTiM trial. This retrospective analysis of OPTiM assessed T-VEC in pts with unresectable AJCC 7 stage IIIB/C melanoma who had LR disease, including ITM, as the site of first recurrence following primary surgery. Methods In OPTiM, pts were randomised to intralesional T-VEC or subcutaneous recombinant GM-CSF. All pts were treated for ≥6 months, after which treatment was continued until clinically relevant disease progression, intolerability, consent withdrawal, complete response (CR), lack of response by 1 yr, or disappearance of injectable lesions (T-VEC arm only). Results 109 patients (T-VEC n = 79; GM-CSF n = 30) had LR disease as the site of first recurrence (including ITM, local surgical scar, and regional lymph nodes). Most pts (63%) had ITM. Median time from primary melanoma diagnosis to first LR recurrence was 10.4 months. Time from first recurrence to randomisation into OPTiM was 6.6 months. At primary diagnosis, 45% of 109 pts had melanoma in the lower limbs, 25% in the head/neck, 15% on the trunk, and 11% upper limbs. At baseline, median age was 65 yrs, 94% had LDH ≤ULN, 76% had ECOG PS 0 and 35% had nodular melanoma. T-VEC vs GM-CSF led to objective response rates of 56% vs 1%, CR rates of 24% vs 0%, and durable response rates of 34% vs 0% (all p Table . 1342P Outcome OPTiM locoregional subpopulation, incl. ITM * OPTiM overall study population (ITT; stage IIIB-IVM1c melanoma) T-VEC (n = 79) GM-CSF (n = 30) Difference (p value or 95% CI) T-VEC (n = 295) GM-CSF (n = 141) Difference (p value or 95% CI) Objective response rate, % (n) 56 (44) 3 (1) 52.4 (p 26 (78) 6 (8) 20.8 (p Complete response, % (n) 24 (19) 0 (0) 24.1 (p 11 (32) 10.1 (p Durable response rate (response for ≥6 consecutive months), % (n) 34 (27) 0 (0) 34.2 (p 16 (48) 2 (3) 14.1 (p Deaths, % (n) 42 (33) 67 (20) HR: 0.48 (p = 0.0088) 64 (189) 72 (101) HR: 0.79(0=0.051) OS probability at landmark times (KM estimate), % 1 year 2 years 3 years 4 years 92 75 62 52 80 50 40 30 12.4 (-3.1, 27.9) 24.7 (4.4, 45.0) 21.9 (1.3, 42.4) 22.8 (-0.6, 46.2) 74 50 39 33 69 40 30 21 4.6 (-4.7, 13.8) 9.5 (-0.5, 19.6) 8.5 (-1.2, 18.1) 11.3 (1.0, 21.5) HR, hazard ratio; ITT, intent-to-treat; KM, Kaplan-Meier; NR, not reported; OS, overall survival. * Grouped term including in-transit/satellitosis (ITM), local surgical scar, and regional lymph nodes (LNs). 59 pts had ITM only as the site of 1st recurrence, 17 had regional LNs only, 20 had surgical scar only, 2 had ITM AND regional LNs, 3 had surgical scar AND regional LNs, 5 had ITM AND surgical scar, and 3 pts had ITM, regional LNs AND surgical scar as the sites of 1st recurrence. Conclusions This analysis suggests that T-VEC may be of particular benefit in melanoma pts with LR recurrence, including ITM. Clinical trial identification NCT00769704. Editorial acknowledgement Ryan Woodrow, PhD, CMPP of Aspire Scientific (Bollington, UK), funded by Amgen (Europe) GmbH (Rotkreuz, Switzerland). Legal entity responsible for the study Amgen Inc. Funding Amgen Inc. Disclosure M.R. Middleton: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Immunocore; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Millennium; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Physiomics; Advisory / Consultancy, Research grant / Funding (institution): Rigontec; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Vertex; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Immunocore; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Millennium; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Physiomics; Advisory / Consultancy, Research grant / Funding (institution): Rigontec; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Vertex. K. Harrington: Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy: Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD. M. Ross: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen. K. Ohrling: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. H. Radcliffe: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. F. Collichio: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Merck.

Background: The IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and molecular targeting and/or pharmacologic inhibition of ITK in preclinical melanoma models suppresses cell proliferation without inducing cell death (Carson CCR 2015). Ibrutinib suppresses proliferation of melanoma cell lines in low nM concentrations (Moschos ASCO 2017, TPS9592). We hypothesize that targeting DMCM with ibrutinib will induce antitumor responses, especially in high ITK-expressing melanomas. Methods: This is an open-label, single-arm, Simon’s 2-stage design, multicenter, phase II study for patients (pts) with DMCM refractory to or ineligible for PD-1 and MAPK inhibitors, if BRAFV600-mutant. Given that the IC50 of ibrutinib for ITK is > 10 times than Bruton’s tyrosine kinase’s, we administered ibrutinib at 840mg qd. We hypothesized that an ineffective drug will have a = <5% response rate and = <18% 6-month PFS rate. We present the results of the first stage. Results: 18 pts (13 males; median age 63.5, range 37-82; 14 with M1c disease; 4 with BRAFV600 mutation; 12 with performance status 1 or 2; 4 with resistance to 4 treatments; 5 with resistance to = >5 treatments) were enrolled. Median exposure to ibrutinib was 27.5 days (range 4-155). The most frequent all-grade side effects were fatigue (55%), anorexia (50%), gastrointestinal upset (44%), and anemia (39%). 4 grade IV (hyponatremia, sepsis, cytokine release syndrome, and constipation occurred 6% each) and 9 grade III events [hyponatremia (17%); pneumonia, hypertension, anemia, hypoalbuminemia, dehydration, lymphopenia occurred 6% each] were seen. No antitumor responses were seen. At a median follow-up of 5 months, all pts had progressed (median PFS was 1.3 months, range 0.2-5.5). 15 pts were discontinued from study due to progression and 14 pts had died from melanoma. Median OS was 5 months (range 0.3-10.4 months) in pts who died. Conclusions: In this treatment-refractory DMCM, high-dose ibrutinib did not induce any meaningful clinical benefit; therefore the study will not proceed to stage 2. Correlation between PFS and expression of ITK by melanoma cells and density of tumor-infiltrating T- and B-cells in pretreatment tumor specimens will be reported at the time of the meeting. Clinical trial identification: NCT03427398. Legal entity responsible for the study: NCI-CTEP. Funding: NCI-CTEP, Pharmacyclics. Disclosure: All authors have declared no conflicts of interest.

Background: In May 2017, the Alliance for Academic Internal Medicine (AAIM) published guidelines intending to standardize and improve internal medicine residency program director (PD) letters of recommendation (LORs) for fellowship applicants. Objectives: This study aimed to examine fellowship PDs impressions of the new guidelines, letter writers’ adherence to the guidelines, and the impact of LORs that conformed to guidelines compared to non-standardized letters. Methods: The authors anonymously surveyed fellowship PDs from January to March 2018 to gather input about LORs submitted to their programs during the 2017 fellowship application cycle. Results: A total of 78% of survey respondents were satisfied with letters that followed the AAIM guidelines, whereas 48% of respondents were satisfied with letters that did not. Fellowship PDs felt that letters that followed the AAIM guidelines were more helpful than letters that did not, especially for differentiating between applicants from the same institution and for understanding residents’ performance across the six core competency domains. Fellowship PDs provided several suggestions for residency PDs to make the LORs even more helpful. Conclusion: Fellowship PD respondents indicated that LORs that followed the new AAIM guidelines were more helpful than letters that did not.

Talimogene laherparepvec is an oncolytic virus recently approved for targeted treatment of advanced melanoma. Because of an inflammatory reaction, treated lesions may increase in size and develop infiltrative margins that can be construed as disease progression or extracapsular spread. In this report, we describe our initial experience imaging the response of metastatic nodes injected with talimogene laherparepvec. Six of 12 nodes (50%) showed growth from baseline followed by decreased size, 5 of 12 nodes (42%) showed a downward size trend, and 1 node showed continued increase in size. Seven of 9 nodes (78%) developed infiltrative margins at a median of 79 days, and 6 of 9 (67%) nodes became necrotic at a median of 76 days after injection, all showing decreased size at final follow-up. An increase in the size of nodes injected with talimogene laherparepvec does not necessarily indicate progression. Infiltrative margins are also frequently seen and may be confused with extracapsular disease.

ESTRO 36 _______________________________________________________________________________________________ 70.2% infratentorial, the tumor grade was anaplastic in 62.0%, the extent of resection was complete in 85.1% and 64.5% of patients received a dose >54 Gy.The median PRTV was 43.8 cc (1.1-287.9),and the median CEPTV was 13.3 cc (0-71.4).The median PRTVF was 49.4 cc (0-336.7)and the median POTVF was 4.6 cc (0-118.7).A statistically significant benefit in survival was seen with a POTVF equal to 0 cc in univariate analysis for the DFS and the OS (71.9% versus 40.3% p=0.006) and (93.7% versus 72.37% p=0.023) respectively.In multivariate analysis, POTVF was also statistically significant for OS (p=0.05) and almost significant for DFS (p=0.06). ConclusionIn this retrospective study, POTVF was found to be significant predictor of overall survival after ependymoma radiotherapy.POTVF was the more significant predictor of survival compared with PRTV, suggesting that this volume and residual contrast-enhancing tumor may be a more accurate and meaningful reflection of the pathobiology of ependymoma.

T is a herpes simplex virus 1-based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF, and stimulate antitumor immune responses. I (anti-CTLA-4 Ab) blocks inhibition of antitumor T-cells and improves overall survival (OS) in advanced melanoma. This phase 1b/2 study of T + I evaluates safety and efficacy in unresected stage IIIB-IV melanoma. The 1° endpoint for phase 2 is ORR by immune-related response criteria. Key 2° endpoints are safety, progression-free survival, time to response, duration of response, and OS. Key eligibility criteria are unresectable stage IIIB-IV melanoma, ≤1 prior treatment (tx) if BRAF WT or 2 prior tx if BRAF MT, measurable/injectable tumor(s), and no symptomatic autoimmunity or clinically significant immunosuppression. T was given ≤4x106 plaque forming units (PFU) on d1, w1; ≤4x108 PFU d1, w4, then q2w in arm 1 until no injectable tumors, disease progression, or intolerance. I started with the 3rd dose of T in arm 1 or alone in arm 2 at 3 mg/kg IV q3w x 4. An ORR interim analysis (IA) was performed when 82 patients (pts) had ≥48 w of follow up. 173 pts were randomized: 88 T + I; 85 I. Characteristics for all pts were similar: 54% stage IIIB-IVM1a, 45% IVM1b/c. Median follow up time for 82 pts was 61.2 w (range: 0.14-113.9). Confirmed ORR was 35.7% (T + I) and 17.5% (I); unconfirmed ORR was 50% (T + I) and 27.5% (I; table). Of 165 pts in the safety set (85 T + I, 80 I), most common adverse events (AEs) for T + I, I (%) were fatigue (52, 39), chills (51, 3), diarrhea (39, 34), pyrexia (39, 8), rash (39, 31), and pruritus (38, 35). 20% T + I and 18% I pts had grade 3/4 tx-related AEs. A grade 5 autoimmune hepatitis occurred in the T + I arm (attributed to I per investigator).Tabled 1Confirmed* n (%)Unconfirmed^ n (%)T + I n = 42I n = 40T + I n = 42I n = 40ORR - n (%) (95% CI)15 (35.7) (21.6, 52.0)7 (17.5) (7.3, 32.8)21 (50.0) (34.2, 65.8)11 (27.5) (14.6, 43.9)CR4 (9.5)4 (10.0)6 (14.3)7 (17.5)PR11 (26.2)3 (7.5)15 (35.7)4 (10.0)SD13 (31.0)11 (27.5)7 (16.7)7 (17.5)PD6 (14.3)5 (12.5)11 (26.2)17 (42.5)UE5 (11.9)13 (32.5)0 (0.0)1 (2.5)DCR - n (%) (95% CI)28 (66.7) (50.5, 80.4)18 (45.0) (29.3, 61.5)28 (66.7) (50.5, 80.4)18 (45.0) (29.3, 61.5)*Confirmation of initial CR/PR/PD by subsequent assessment by ≥4 w apart. A CR/PR without confirmation is classified as SD and an unconfirmed PD is classified as UE.^Unconfirmed is response or PD without confirmation requirement.CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; UE: unable to evaluate; DCR: disease control rate (SD or better). Open table in a new tab *Confirmation of initial CR/PR/PD by subsequent assessment by ≥4 w apart. A CR/PR without confirmation is classified as SD and an unconfirmed PD is classified as UE. ^Unconfirmed is response or PD without confirmation requirement. CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; UE: unable to evaluate; DCR: disease control rate (SD or better). ORR was higher for T + I vs I alone at this IA. AEs were comparable between arms except for increased fatigue, chills, and pyrexia in the T + I arm.

LBA9008 Background: T-VEC is an oncolytic immunotherapy (OI) derived from herpes simplex virus type-1 designed to selectively replicate within tumors and to produce GM-CSF to enhance systemic antitumor immune responses. OPTiM is a randomized, phase III trial of T-VEC or GM-CSF in patients (pts) with unresected melanoma with regional or distant metastases. We report the primary results of the first phase III study of OI. Methods: Key criteria: age ≥18 yrs; ECOG ≤1; unresectable melanoma stage IIIB/C or IV; injectable cutaneous, SC, or nodal lesions; LDH ≤1.5X upper limit of normal; ≤3 visceral lesions (excluding lung), none >3 cm. Pts were randomized 2:1 to intralesional T-VEC (initially ≤ 4 mL x106 pfu/mL then after 3 wks, ≤ 4 mL x108 pfu/mL Q2W) or SC GM-CSF (125 µg/m2qd x 14 days q28d). The primary endpoint was durable response rate (DRR): partial or complete response (CR) continuously for ≥6 mos starting within 12 mos. Responses were per modified WHO by blinded central review. A planned interim analysis of overall survival (OS; key secondary endpoint) was performed. Results: 436 pts are in the ITT set: 295 (68%) T-VEC, 141 (32%) GM-CSF. 57% were men; median age was 63 yrs. Stage distribution was: IIIB/C 30%, IVM1a 27%, IVM1b 21%, IVM1c 22%. Objective response rate with T-VEC was 26% (95% CI: 21%, 32%) with 11% CR, and with GM-CSF was 6% (95% CI: 2%, 10%) with 1% CR. DRR for T-VEC was 16% (95% CI: 12%, 21%) and 2% for GM-CSF (95% CI: 0%, 5%), p<0.0001. DRR by stage (T-VEC, GM-CSF) was IIIB/C (33%, 0%), M1a (16%, 2%), M1b (3%, 4%), and M1c (8%, 3%). Interim OS showed a trend in favor of T-VEC; HR 0.79 (95% CI: 0.61, 1.02). Most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. Serious AEs occurred in 26% of T-VEC and 13% of GM-CSF pts. No ≥ grade 3 AE occurred in ≥ 3% of pts in either arm. Conclusions: T-VEC demonstrated both a statistically significant improvement in DRR over GM-CSF in pts with unresectable stage IIIB-IV melanoma and a tolerable safety profile; an interim analysis showed a trend toward improved OS. T-VEC represents a novel potential tx option for melanoma with regional or distant metastases. Clinical trial information: NCT00769704.

Simulation tool mimics the underlying processes in a 3D organotypic skin-melanoma spheroid model and allows for fast in silico pre-testing of agents M. Albrecht, T. Sauter Systems Biology, University of Luxembourg, Belvaux, Luxembourg; MEL-PLEX, Exploiting MELanoma disease comPLEXity to address European research training needs in translational cancer systems biology and cancer systems medicine, Luxembourg City, Luxembourg Recently, an experimental 3D skin-model, harboring melanoma metastasis, has been created that can better reproduce the clinical observations with cutaneous malignant melanoma than 2D cell culture basedmethodsbefore.According to this improvement,we are developing a computational representation of this laboratory tool, encompassing the relevant networks for proliferation, the biomechanic properties and the impact of different cell types on the systems behavior in a 3D growth model. This tool facilitates the interpretation of the ongoing underlying biological dynamics in this complex structure and entails the perspective to envisage in silico the outcome of melanoma metastasis growth and relapse after treatment with different drugs or combination of different drugs. Funded by Horizon 2020 Marie S. Curie Actions Programme via Mel-PLEX European Training Network. Circulating BRAF to monitor disease progression and treatment in patients with advanced melanoma E. Seelenfreund, C. M. Amato, K. Do, T. Sheehan, S. Robinson, A. Applegate, W. Robinson University of Colorado Denver, Aurora, CO, USA No effective means of monitoring patients with melanoma during treatment is available. Recently it has been shown that tumor derived DNA can be detected in the blood including BRAF, a major current melanoma treatment. In this study we did serial measurement of circulating levels of BRAF in melanoma patients whose tumors had this mutation and were undergoing treatment. Serial blood samples were obtained from patients with Stage 4 melanoma before and during treatment with targeted and immune based therapy. Levelswere correlatedwith response and recurrence of disease using RECIST criteria. Copy numbers of circulating BRAF were detected and quantitated using mutation specific primers and probes on the Fluidigm Biomark digital PCR (dPCR) system. Two ml of serum or plasma was concentrated to obtain data at each time point. Levels are expressed as copy number of BRAF/ml. Serial samples from eight patients followed from 2 to 8 months were studied. Most received both BRAF inhibitors and anti PD-1 or anti CTLA-4 therapy. There was a clear, but not perfect, correlation between circulating copy numbers and clinical correlates. This, and similar, techniques offer great promise as a means of diagnosing and monitoring patients with melanoma, but require refinement to make them more quantitative and useful on a regular basis. Network Meta Analysis (NMA) of Progression Free Survival (PFS) and Overall Survival (OS) in First-Line (1L) treatment of Metastatic Melanoma (MM) J. B. Amdahl, T. E. Delea, M. Thabane, M. M. Amonkar PAI,Brookline,MA,USA;NovartisPharmaceuticals,Mississauga, ON,Canada; NovartisPharmaceuticals,Wayne,PA,USA To inform an economic evaluation of dabrafenib (D) and trametinib (T) combination (D + T) as 1L treatment of MM, an NMA was conducted to estimate hazard ratios (HRs) for PFS and OS of D + T versus other 1L treatments of MM including D, T, vemurafenib (V), ipilimumab (IPI), and dacarbazine (DTIC). HRs for PFS and OS (adjusted for cross-over as appropriate) were from RCTs identified from systematic literature reviews supplemented with targeted searches and included COMBI-d and BRF113220 (D + T versus D), COMBI-v (D + T versus V), BREAK-3 (D versus DTIC), BRIM-3 (V versus DTIC), the 1L subgroup of METRIC (T versus DTIC), and CA184-024 (IPI + DTIC versus DTIC). HRs for PFS and OS were analyzed simultaneously using multivariable Bayesian NMA to account for correlation of treatment effects on PFS and OS. In base-case analyses, all HRs (95% CI) for PFS and OS favored D + T [PFS: 0.23 (0.18–0.29) versus DTIC, 0.32 (0.24–0.42) versus IPI, 0.52 (0.32–0.83) versus T, 0.57 (0.48–0.69) versus V, and 0.59 (0.50– 0.71) versus D; OS, 0.41 (0.29–0.56) versus DTIC, 0.52 (0.38– 0.71) versus IPI, 0.68 (0.47–0.95) versus T, 0.69 (0.57–0.84) versus V, and 0.72 (0.60–0.85) versus D]. When HRs for PFS and OS were estimated independently, the beneficial effects on OS of D + T versus IPI and D + T versus T were attenuated versus the base case. Results were similar assuming class effects for BRAF inhibitors (D and V) and excluding the Phase II BRF113220 trial. This NMA confirms results of the COMBI-d and COMBI-v trials and demonstrates improved PFS and OS with D + T versus T and DTIC as 1L treatment of MM. Comparisons with IPI should be interpreted cautiously given differences in trial populations and timing of treatment effects with immunotherapy. Simultaneous estimation of treatment effects on PFS and OS using multivariable Bayesian NMAs should be considered given known correlation of these effects in advanced cancers. Reduced risk of developing visceral/bone metastasis (VM) in patients (pts) with stage IIIB/C/IVM1a melanoma treated with talimogene laherparepvec (T-VEC) versus GM-CSF R. H. I. Andtbacka, H. L. Kaufman, F. A. Collichio, K. Delman, J. S. Zager, E. Hsueh, L. Chen, M. Shilkrut, M. Ross Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; University of North Carolina Medical Center, Chapel Hill, NC, USA; Emory University, Atlanta, GA, USA; Moffitt Cancer Center, Tampa, FL, USA; Saint Louis University Cancer Center, St. Louis, MO, USA; Amgen Inc., Thousand Oaks, CA, USA; MD Anderson Cancer Center, Houston, TX, USA The risk of developing VM is high in pts with stage IIIB/C/IVM1a melanoma. T-VEC, a systemically active oncolytic immunotherapy, significantly improved durable response rate (≥6 months continuous response; primary endpoint) from 2% with GM-CSF to 16%, P < 0.0001) in OPTiM, a phase 3 trial in 436 pts with unresected stage IIIB/C/IVM1a melanoma. In the primary overall survival (OS) analysis, median OS was 23.3 months for T-VEC versus 18.9 months for GM-CSF (HR = 0.79, 95% CI: 0.62–1.00, P = 0.051). Here we report the effect of T-VEC versus GM-CSF on the risk to develop VM in pts with stage IIIB/C/IVM1a melanoma in OPTiM. Baseline pt data in OPTiM was retrospectively analyzed to identify investigatorreported visceral sites of disease during the study. Of 225 pts with stage IIIB (14%), IIIC (37%), and IVM1a (49%) melanoma, 152 (68%) received T-VEC and 73 (32%) GM-CSF; 51% were ≥65 years, 72% had ECOG PS 0, 54% were treated as 1st-line a 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 753 doi: 10.1111/pcmr.12419

ABSTRACT Background: T-VEC is a herpes simplex virus-1 based oncolytic immunotherapy designed to selectively replicate in cancer cells and produce GM-CSF to initiate systemic antitumor immune responses. OPTiM, a phase 3 trial of T-VEC vs GM-CSF in unresected stage IIIB-IV melanoma, met its primary endpoint of higher durable response rate in favor of T-VEC. Objective response rate (ORR) was 26.4% vs 5.7%, with complete response (CR) 10.8% vs 0.7% in favor of T-VEC. Immune checkpoint blockade with ipi improves overall survival (OS) in advanced melanoma. Ipi has a 10-15% ORR with 1-2% CR by immune-related response criteria (irRC). A phase 1b/2 study was designed to evaluate safety and efficacy when T-VEC is added to ipi as a priming regimen (clinicaltrials.gov #NCT01740297). Phase 1b showed the combination was tolerable, and phase 2 opened in Aug 2013. Trial design: Phase 2 evaluates the efficacy and safety of T-VEC + ipi vs ipi alone in untreated, unresectable stage IIIB-IV melanoma. Approximately 140 patients will be randomized 1:1. The primary endpoint is OS. Secondary endpoints: safety, ORR, time to response, duration of response, progression-free survival, resection rate, 1- and 2-yr survival. Key eligibility criteria: unresectable stage IIIB-IV melanoma naive to systemic therapy (except adjuvant); ECOG performance status 0-1; measurable disease; ≥1 injectable cutaneous/ subcutaneous/ nodal tumor; no brain metastases; no symptomatic autoimmunity; no immunosuppression; no HIV/HBV/HCV; no antiherpetic therapy. T-VEC is injected into nonvisceral lesions up to 4 × 106 plaque forming units/mL (pfu/mL) on d1, wk 1; up to 4 × 108 pfu/mL d1, wk 4; then q2w. Ipi is dosed 3 mg/kg IV q3w × 4 starting wk 6 with the 3rd T-VEC dose. Treatment with T-VEC continues until all injectable tumors have disappeared, disease progression per irRC, or intolerance. Enrollment began in the USA and is expected to open in France/Germany by Dec 2014. Combining T-VEC and ipi represents a novel immunotherapeutic approach to promote the initiation of antitumor immunity and simultaneously enhance antitumor T-cell responses. Disclosure: F.A. Collichio: Dr. Collichio has served on an advisory board and received consultant fees from Amgen, Inc. She receives clinical trial research support from Amgen, Novartis, GlaxoSmithKline, Morphotec, and Bristol-Myers Squibb; M. Milhem: Dr. Milhem has participated on advisory boards for Genentech and Amgen, Inc.; R.H. Andtbacka: Dr. Andtbacka has participated in advisory boards for Amgen, Inc.; I. Puzanov: Dr. Puzanov has received honoraria for participation on advisory boards for Amgen, Inc. His institution receives research funding from Amgen, Inc.; Y. Saenger: Dr. Saenger has participated in advisory boards for Amgen, Inc.; J. Chesney: Dr. Chesney has served on an advisory board for Amgen, Inc. O. Hamid: Dr. Hamid has served as a consultant for Amgen, Inc. and has received clinical trials support from Amgen, Inc.; T. Logan: Dr. Logan's institution has received grant money, and writing assistance, medicines, equipment, or administrative support from Amgen, Inc.; J. Glaspy: Dr. Glaspy has served as a consultant to and received research support from Amgen, Inc.; C. Lebbe: Dr. Lebbe has participated in advisory boards for Roche, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, and Amgen, Inc.; J. Gansert: Dr. Gansert is a compensated employee and stockholder of Amgen, Inc.; A. Li: Ai Li is a compensated employee and stockholder of Amgen, Inc.; J. Chou: Dr. Chou is a compensated employee and stockholder of Amgen, Inc.; H. Kaufman: Dr. Kaufman has received honoraria from Amgen, Inc. for participation in advisory boards and has received research funding from Amgen, Inc. for conducting clinical trials. All other authors have declared no conflicts of interest.

Background: T-VEC is a herpes simplex virus-1 based oncolytic immunotherapy designed to selectively replicate in cancer cells and produce GM-CSF to initiate systemic antitumor immune responses. OPTiM, a phase 3 trial of T-VEC vs GM-CSF in unresected stage IIIB-IV melanoma, met its primary endpoint of higher durable response rate in favor of T-VEC. Objective response rate (ORR) was 26.4% vs 5.7%, with complete response (CR) 10.8% vs 0.7% in favor of T-VEC. Immune checkpoint blockade with ipi improves overall survival (OS) in advanced melanoma. Ipi has a 10-15% ORR with 1-2% CR by immune-related response criteria (irRC). A phase 1b/2 study was designed to evaluate safety and efficacy when T-VEC is added to ipi as a priming regimen (clinicaltrials.gov #NCT01740297). Phase 1b showed the combination was tolerable, and phase 2 opened in Aug 2013.

Aim: T-VEC is an HSV-1-derived oncolytic immunotherapy designed to selectively replicate in tumors and produce GM-CSF to enhance systemic antitumor immune responses. Compared to GM-CSF alone, T-VEC significantly improved durable response rate (DRR; partial response [PR] or complete response [CR] lasting continuously for ≥ 6 months [m]) from 2% to 16% (p < 0.0001) in patients (pts) with stage IIIB-IV melanoma (Andtbacka et al, ASCO 2013). Here we report the results of an extension trial of OPTiM as of Mar 2013.

To evaluate the outcomes and patterns of failure for desmoplastic melanoma. We reviewed an IRB-approved, prospective Melanoma Database and identified 2249 melanoma patients, 36 (2%) with desmoplastic melanoma, treated at the University of North Carolina between 1998 and 2011. For these 36 patients the median follow-up was 46 months (range, 8-161). The average age of the patients was 68 years old (range, 46-88). 21 (58%) of the patients were male and 15 (42%) of the patients were female. 34 (94%) of the patients were white. The location of the primary site was: head and neck (25, 69%), extremity (8, 22%), and trunk (3, 8%). The mean Breslow Thickness was 4.51 mm (range, 0.61-42 mm), 8 (22%) had ulceration, and 14 (39%) were staged T4. All of the patients were treated with a wide local excision, 35 (97%) had a sentinel node biopsy (SNB). Of the 35 patients who had a SNB, 3 contained metastatic melanoma and had subsequent completion lymphadenectomy. 14 (39%) received postoperative radiation therapy. 13 of the 14 patients (93%) who received postoperative radiation therapy had a head and neck melanoma. 1 patient was treated with adjuvant chemotherapy. Kaplan-Meier estimates of local-regional control (LRC), disease free survival (DFS), distant metastasis free survival (DMFS) and overall survival (OS) were calculated. Five-year LRC, DFS, DMFS, and OS were 70%, 62%, 80%, and 62%, respectively. 10 (28%) patients died following treatment, 7 due to melanoma, and 3 from other causes that were not treatment related. Nine (25%) patients had recurrences, 2 had isolated distant, 2 had local and regional, 4 had regional and distant, and 1 had local and distant failures. There were no isolated local or regional failures. Of the 9 patients who had a recurrence 7 had a head and neck, 1 extremity, and 1 truncal primary. Of these 7 head and neck patients with recurrences only 3 had radiation. 1 of the head and neck patients that received postoperative radiation therapy had an in-field local recurrence. The 2 patients with non-head and neck primaries both had regional and distant failures. Although an uncommon form of melanoma, novel locoregional control methods need to be considered to improve locoregional control rates. Novel radiation therapy options, possibly including radiosensitizers, need to be considered.