Lutzky, Jose

9525 Background: Melanocortin-1 receptor (MC1R) is a novel target for radiopharmaceutical therapy and is highly expressed on melanoma tumor cells. VMT01 is an MC1R-targeted peptide. 203 Pb is used for patient selection via SPECT imaging. Peptide radiolabeling with 212 Pb delivers alpha-particle therapy. Here, we present data on the treatment of adult patients with MC1R-positive metastatic melanoma receiving [ 212 Pb]VMT01 either as a monotherapy or in combination with the programmed death-1 (PD-1) checkpoint inhibitor, nivolumab. Methods: This is an ongoing phase I/IIa, first-in-human, prospective, multicenter, open-label, radioactive dose-finding and dose-expansion trial. The objectives are to investigate safety, pharmacokinetics, dosimetry, and efficacy. Participants receive up to 3 treatment cycles with either [ 212 Pb]VMT01 3 mCi, 5 mCi, or 1.5 mCi monotherapy, or combination therapy with [ 212 Pb]VMT01 (1.5 mCi) + nivolumab (480 mg, Q4W) or [ 212 Pb]VMT01 (3 mCi) + nivolumab. Participants are evaluated for any DLTs for the first 6 weeks after cycle 1. Efficacy is assessed by RECIST v1.1 criteria by the investigator. Results: As of 24 December 2025, 26 participants (53.8% male; median age: 68 years [range: 27-81]) with MC1R-positive metastatic melanoma were enrolled. The median prior systemic therapies was 4. All 26 enrolled participants received ≥1 dose of [²¹²Pb]VMT01. No DLTs were reported. All SAEs (including one grade 5 SAE) were attributed to disease progression. Most TEAEs were grade 1 (19.2%) and grade 2 (34.6%). Grade 3 TEAEs occurred in 8 participants (30.8%), 5 on monotherapy and 3 on combination therapy (3 mCi + nivolumab). Of the 22 evaluable participants, 1 PR, 9 SD, and 12 PD were reported. Four participants had progression-free survival of ≥6 months. Conclusions: [ 212 Pb]VMT01 as a monotherapy and in combination with nivolumab was generally safe and well-tolerated in 26 enrolled participants, with antitumor activity observed at the 3 mCi dose level. These data may be supplemented with a more complete follow-up at the time of the meeting. Clinical trial information: NCT05655312 .

Abstract BACKGROUND Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and METHODS Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results. RESULTS 331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine. CONCLUSION Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.

TPS9595 Background: There is a need for novel immunotherapies to address the patient population that never or no longer responds to immune checkpoint inhibitors (CPI). VV1 is an oncolytic vesicular stomatitis virus engineered to express human interferon beta (IFNβ) to enhance cellular anti-tumor immune responses and tumor selectivity. Phase 1 studies demonstrated VV1 anti-tumor activity in several malignancies with or without a CPI. We are exploring ways to optimize VV1 efficacy in combination with cemiplimab, an anti-PD1 antibody approved for lung, basal and squamous cell skin cancers. Recent clinical data support a 5-fold higher dose of VV1 than was previously explored, and pre-clinical data show synergy between the oncolytic and an anti-CTLA4 antibody, in addition to cemiplimab, supporting exploration of a triplet. What was originally a five-arm study of intravenous (IV) VV1 in combination with IV cemiplimab has been amended to focus on 2 means of optimizing efficacy: use of a higher dose of VV1 and triplet combination in proof-of-concept populations. Methods: We are now enrolling pts with advanced melanoma (after progression on anti-PD1) and plan to include 1 st -line NSCLC pts with PD-L1 expression ≥50%. The study is first exploring the preliminary anti-tumor activity, safety, and immunogenic activity of the combination of IV VV1 at a dose of 1.0 x 10 11 TCID 50 once on D1 followed by IV cemiplimab Q3W starting on D8, or the same regimen with an additional intratumoral injection of VV1 1.0 x 10 9 TCID 50 once on D1 for pts with accessible lesions. Pts receive IV cemiplimab Q3W until confirmed disease progression or intolerable toxicity. Once at least 6 pts have been treated with acceptable safety across the 2 melanoma doublet cohorts using this higher dose of VV1, a 3 rd melanoma cohort will open to add a single dose of ipilimumab 50 mg on D1 (all IV triplet). Once 6 melanoma pts have received the triplet safely, the 1 st -line NSCLC cohort will open. All cohort decisions are guided by a Data Review Committee. Cohorts will be expanded based on a Simon 2-stage design using a type I error rate of 0.05 and power of 85%. Null ORR is 10% with a target of 35% for 2 nd line melanoma and null ORR is 40% in 1 st line NSCLC with a target of 70%. Each melanoma cohort will require a response in ≥2 of 10 pts in the 1 st stage to add 11 more in the 2 nd stage, while NSCLC will first need 5/9 evaluable pts to respond, then an additional 13 to complete the design. Response is assessed at week 7 then Q9W per RECIST v1.1. The study includes serial biopsies in ≥3/10 pts in Stage 1 of each of the IV melanoma cohorts (doublet and triplet therapy), all pts in Stage 2 of these IV melanoma cohorts, and all pts in both Stage 1 and Stage 2 of the IV/IT melanoma cohort, to permit a thorough investigation of the impact of the 3 immunotherapies under investigation. The study is currently ongoing in the USA. Clinical trial information: NCT04291105.

Background Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. Methods Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. Results For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). Conclusions Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. Trial registration number NCT01546571.

10017 Background: Seviprotimut-L is a vaccine prepared from antigens of 3 human melanoma cell lines, administered with alum. Prior formulations induced T cell and antibody responses and improved survival in a small phase II clinical trial. Part B1 of MAVIS (Melanoma Antigen Vaccine Immunotherapy Study, a three part, Phase III clinical program), was a multicenter, double-blind, placebo-controlled trial to assess efficacy of seviprotimut-L, with the primary endpoint of relapse-free survival (RFS). The goal of Part B1 was to guide design of the pivotal Part B2. Methods: Patients with AJCC v7 stage IIB-III cutaneous melanoma, after surgical resection, age 18-75, ECOG PS 0-1, were randomized 2:1 to seviprotimut-L 40 mcg or placebo, injected subcutaneously every 2 weeks x 5, then monthly x 4, then every 3 months x 9. Patients were stratified by stage (IIB/C, IIIA, IIIB/C). Target enrollment was 325. The study was powered for assessment of RFS, with target hazard ratio (HR) of 0.625, one-sided alpha of 0.10, and power 80%. Final data are presented. Results: 347 patients were randomized. Arms were well-balanced. Treatment-related adverse events (AEs) led to discontinuation in 0.4% and 0%, respectively, for vaccine and placebo arms. There were no treatment-related SAEs. By intent-to-treat (ITT) analysis, RFS was not significantly longer for seviprotimut-L in the full study population but trended toward benefit (HR 0.88). Subgroup analysis based on planned stratification revealed the hazard ratio (HR) for the Stage IIB/IIC subset (randomization stratum, n=111) to be 0.65 (95% CI [0.37, 1.17]), favoring seviprotimut-L. Age can decrease immune competence: RFS was longer with vaccine for patients age <60 overall (N = 191, HR = 0.64 [0.38, 1.08]) and among Stage IIB/C patients (N = 52, HR = 0.32 [0.12, 0.86]). The effect modification interaction p value for age for stage IIB/IIC patients was 0.056. In a multivariable RFS model, for IIB/IIC patients <60 with ulceration (n=38), HR = 0.209 [0.07,0.61]. For overall survival, for patients < 60, HR = 0.41 [0.33,1.14] (n=191, 19 deaths) and for those ≥60, HR = 0.92 [0.39,2.12] (n = 156, 24 deaths). Conclusions: Seviprotimut-L is very well-tolerated. Subgroup efficacy analyses identified populations who may benefit from Seviprotimut-L: those with Stage IIB/IIC melanoma and those under age 60. These data support design of the definitive part B2 of the MAVIS phase III trial to test seviprotimut-L for stage IIB/C patients, with stratification by age and ulceration. Clinical trial information: NCT01546571.

10006 Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) leverages and enhances the body’s natural defense against cancer and has shown durable responses in heavily pretreated melanoma patients. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of efficacy & safety of lifileucel in patients with unresectable metastatic melanoma who have progressed on checkpoint inhibitors and BRAF/MEK inhibitors, if BRAFv600 mutant. We report on Cohort 2 (N = 66) patients who have received TIL. Tumors were resected at local institutions, processed in central GMP facilities for TIL production, manufactured, cryopreserved & shipped back to sites in a 22-day process. Therapy consisted of one week of lymphodepletion, a single lifileucel infusion, and up to 6 IL-2 doses. ORR was based on RECIST v1.1 by investigator assessment. Data cutoff was Feb 2, 2020. Results: Baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), high baseline tumor burden (106 mm mean target lesion sum of diameters), 44% liver/brain lesions, 40.9% LDH > ULN. ORR by investigator was 36.4% (2 CR, 22 PR) and DCR was 80.3%. Mean time to response was 1.9 months (range: 1.3-5.6). After a median study follow-up of 17.0 months, median DOR (mDOR) was still not reached. Six responders have progressed, 2 have died and 2 started other anti-cancer therapy without progression. The adverse event profile was consistent with the underlying advanced disease and the lymphodepletion and IL-2 regimens. Additional follow-up data will be available for presentation. Conclusions: Lifileucel treatment results in a 36.4% ORR and mDOR was not reached at 17.0 months of median study follow up in a heavily pretreated metastatic melanoma patients with high baseline disease burden who progressed on multiple prior therapies, including anti-PD1 and BRAF/MEK inhibitors, if BRAFv600 mutant. Clinical trial information: NCT02360579.

TPS3161 Background: VV1 is an oncolytic vesicular stomatitis virus engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and the human sodium iodide symporter (NIS) for virus tracking by SPECT imaging. Cancer cells are often hyporesponsive to IFNβ, enabling the efficient spread of VV1 and resulting in increased oncolysis. Differently from other oncolytic viruses, VV1 is suitable for both intra-tumoral (IT) and/or intra-venous (IV) administration. Despite considerable anti-tumor activity with checkpoint inhibitors (CPI) among some malignancies, long term survival and overall cures remain elusive. Prior Ph 1 studies have shown significant anti-tumor activity among several malignancies when VV1 was administered either as monotherapy or in combination with a CPI, despite progression on prior CPI monotherapy. Furthermore, pre- and post-treatment biopsy evaluations after VV1 treatment have demonstrated T cell infiltration and inflammation in both IT injected and non-injected lesions. Among IV treated patients (pts), IFNβ was detectable in the serum correlating with viral replication, making it an effective biomarker. C is a high-affinity potent human IgG4 anti-PD-1 monoclonal antibody. Though approved for use in cutaneous squamous cell carcinoma, C has shown anti-tumor activity, similar to other CPI, in several other indications. Therefore, VV1 and C could be an attractive combination for the immunotherapy for several solid tumors. This study represents the first clinical evaluation of VV1 in combination with C in pts with advanced solid tumors. Methods: The Ph 2 Simon 2 stage five-arm study of IV administration VV1 in combination with IV C will enroll pts with advanced NSCLC, HCC, melanoma & endometrial cancer. Enrolled pts with NSCLC & melanoma will be recent CPI-progressors, whereas enrolled HCC & endometrial cancer will be CPI-naïve. The study’s objectives include assessment of preliminary anti-tumor activity, safety, & immuno-regulatory activity of the combination. Pts will receive IV VV1 once on D1 and IV C once every 3 weeks until confirmed disease progression or intolerable toxicity. Pts enrolled in one melanoma cohort will also receive IT VV1 administered to palpable lesions. Response will be assessed every 9 weeks per RECIST v1.1. The null hypothesis of each cohort’s ORR will be tested versus a one-sided alternative yielding a Type I error rate of 5% and power of 80%. Cohorts will be expanded based on signal of activity. Clinical trial information: NCT .

CRA9003 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.

Abstract Background: Peripheral neuropathy (PN) is associated with multiple myeloma (MM) and often worsened with thalidomide (THAL) and vincristine (VCR) therapy. Bortezomib (BTZ) is a proteasome inhibitor approved for the treatment of MM that has been also shown to cause PN. An increased risk of BTZ-induced PN has been associated with the presence of both PN and diabetes mellitus (DM) before treatment. However, the incidence and characteristics of BTZ-induced PN among MM patients (pts) retreated with another BTZ-containing regimen is unknown. We analyzed the incidence, severity and risk factors for PN after treatment of MM pts with a second BTZ-containing regimen. Methods: Retrospective chart analysis. MM pts that had progressed from at least one prior BTZ-containing regimen and had received treatment with another BTZ-containing regimen were eligible. Pts had to have experienced PN during the course of the first BTZ regimen and could not have received therapy with THAL or VCR. The protocol was later amended to allow inclusion of pts without PN during their first BTZ treatment and those who had received THAL or VCR. Statistical significance was assessed using Fisher’s or McNemar’s tests as appropriate. The relationship between comorbidities, prior THAL or VCR treatment and PN grade after BTZ treatment and re-treatment was analyzed using a multivariate logistics regression model. All statistical analyses were two-sided and were performed at the 0.05 level of significance. Results: As of July 3, 2014, 83 pts have been accrued to the retrospective analysis, and 58 chart reviews have been completed. The median age of pts included in the analysis was 64 years (range: 31-84 years); 57% of the pts were male and 69% were Caucasian. Pts had received a median of 2 prior regimens (range: 2-10); 43% of the pts had received prior regimens containing THAL and 15% of those had also received therapy with VCR. Prior to the protocol amendment, the eligibility criteria required pts to have experienced PN after the first BTZ treatment; therefore, most pts included in this analysis (88%) had PN.During their first BTZ treatment, the most severe grade of PN experienced by the majority of the pts was grade 1 (N=34), followed by grade 2 (N=13) and grade 3 (N=4). A comparison of the symptoms assessed when pts had their most severe grade of PN during this treatment and the severity reported at its onset showed that PN worsened in only 16% of pts. Nearly half (48%) of pts showed no change in PN whereas symptoms improved or resolved in 15% and 9% of the pts, respectively. During treatment with the second BTZ-containing regimen, a comparable proportion of pts (N=44; 76%) reported having experienced PN. Among those experiencing PN upon re-treatment, the most severe grade of PN experienced by the majority of the pts (N=29) was also grade 1, followed by grade 2 (N=12) and grade 3 (N=3). During the second BTZ treatment, a comparison of the symptoms that pts had when PN was at its worst and those recorded at its onset demonstrated that PN worsened in only 7% of the pts. PN showed no change in 47%, improved in 15%, or resolved in 7% of the pts.Interestingly, 17% of the pts (N=10) who had reported PN while receiving their first BTZ-containing regimen did not report this complication during their second BTZ treatment, while 7% of the pts (N=4) experienced PN only upon re-exposure. There was no association between the incidence of PN during the first BTZ treatment and its incidence during re-treatment (p=0.1213) or between the severity of PN (defined as worsening vs. not worsening) after first BTZ treatment and its severity after BTZ re-exposure (p=0.1306). Fifty-four percent of the pts presented with comorbidities, including DM (26%), hypertension (HTN, 22%) and peripheral vascular disease (PVD, 13%). There were no associations between PN grade after BTZ treatment and prior THAL or VCR exposure (p=0.5569) or between PN grade and comorbidities (DM, p=0.6657; HTN, p=0.9966; PVD, p=0.9966). Similar results were found for BTZ re-exposure (THAL or VCR, p=0.8672; DM, p=0.4137; HTN, p=0.2033; PVD, p=0.9954). Conclusions: Results from this retrospective study show that the severity and incidence of PN did not change with a second BTZ-containing regimen. Comorbidities or prior therapy with other PN-inducing agents such as THAL or VCR did not significantly increase the risk of PN after BTZ re-treatment. Enrollment into the study continues and updated results will be presented at the meeting. Disclosures Berenson: Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Tabbara:Millennium: Speakers Bureau. Lutzky:Millennium: Speakers Bureau. Ailawadhi:Millennium: Consultancy. Moezi:Millennium: Speakers Bureau.