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Purpose: IL15 induces the activation and proliferation of natural killer (NK) and memory CD8+ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL15N72D:IL15RαSu/IgG1 Fc complex) over recombinant human IL15 (rhIL15) in animal models, we performed this first-in-human phase I trial of ALT-803 in patients with advanced solid tumors.Patients and Methods: Patients with incurable advanced melanoma, renal cell, non–small cell lung, and head and neck cancer were treated with ALT-803 0.3 to 6 μg/kg weekly intravenously or 6 to 20 μg/kg weekly subcutaneously for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, and lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity.Results: Twenty-four patients were enrolled; 11 received intravenous and 13 received subcutaneous ALT-803. Of these patients, nine had melanoma, six renal, three head and neck, and six lung cancer. Although total lymphocyte and CD8+ T-cell expansion were modest, NK cell numbers rose significantly. Neither anti–ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well tolerated, with adverse effects including fatigue and nausea most commonly with intravenous administration, whereas painful injection site wheal was reported most commonly with subcutaneous ALT-803.Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in patients with advanced cancer. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anticancer agents. Clin Cancer Res; 24(22); 5552–61. ©2018 AACR.

Supplemental Figure 1. Effect of ALT-803 treatment on white blood cell and lymphocyte counts in i.v. dose cohorts Supplemental Figure 2. Circulating NK cell expansion during ALT-803 treatment Supplemental Figure 3. Effect of subcutaneous ALT-803 on circulating T cell expression of HLA-DR

Supplementary Figure 1-3 Legends

Background: Patients with oligometastatic breast cancer (oMBC) may benefit from aggressive local therapy. We sought to assess the effects of consolidative radiation therapy (RT) on outcomes in oMBC patients treated on a prospective phase II trial of high-dose chemotherapy (HDCT). Methods: Between 2005 and 2009, 12 patients with oMBC (≤3 metastatic sites) cancer were treated on protocol. Patients were to receive tandem HDCT supported by hematopoietic cell rescue (HCR). All radiographically identifiable oligometastatic sites received targeted radiation. Results: HDCT was initiated at a median of 6.7 (3.5–12.7) months after diagnosis of oMBC. Hormone receptors (HR) were positive in 91.6% of patients, and HER2 was overexpressed in 25% of patients. Median radiation dose (EQD2) was 41.2 (37.9–48.7) Gy. Median follow-up was 13.1 (6.8–15.1) years for living patients. Ten-year PFS and OS were 33% (95%CI, 10–59%) and 55% (95%CI, 22–79%), respectively. Durable local control of treated lesions was 87.5%. At the last follow up, two patients remained progression free and two more were without evidence of disease following additional salvage treatment. Conclusions: Although modern systemic therapies have obviated the use of HDC, aggressive local therapy warrants further evaluation and fractionated radiotherapy is a viable alternative if SBRT is not available.

Background In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients. Methods Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months). Results Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed. Conclusions Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

Melanoma of unknown primary (MUP) accounts for approximately 3% of melanoma diagnoses. This study sought to evaluate treatment and outcomes for a modern MUP cohort. A retrospective review of MUP was performed at a tertiary referral cancer center. Of 815 melanoma patients, 67 (8.2%) had MUP. Men were more likely to have MUP than women (67% vs. 55%; p = 0.04). The most common sites of MUP were lymph nodes (28%), visceral solid organs (25%), brain (16%), and skin/subcutaneous tissues (10%). Of the patients who underwent tumor genomic profiling, 52% harbored pathogenic BRAF mutations. Of the 24 patients who underwent multi-gene panel testing, all had pathogenic mutations and 21 (88%) had mutations in addition to or exclusive of BRAF, including 11 patients (46%) with telomerase reverse transcriptase promoter mutations. Checkpoint inhibitors (39%) and BRAF-MEK inhibitors (7%) were the most common first-line treatments. Upfront surgical resection was used for 25% of the MUP patients, and 12 of these resections were for curative intent. During a median follow-up period of 22.1 months, the median overall survival (OS) was not met for the patients with MUP isolated to lymph nodes. At 56.8 months, 75% of these patients were alive. The median OS was 37.4 months for skin/soft tissue MUP, 33.3 months for single solid organ viscera MUP, and 29.8 months for metastatic brain MUP. Multigene panel testing identified pathogenic mutations in all tested MUP patients and frequently identified targets outside BRAF. Despite advanced stage, aggressive multimodal therapy for MUP can be associated with 5-year OS and should be pursued for appropriate candidates.

Advances in the understanding of biology and therapy of melanoma have occurred at an astonishing pace over the past approximately 15 years, and successful melanoma therapy has led the way for similar advances in many other solid tumors that are continuing to improve outcomes for all patients with cancer. Although the 2018 Nobel Prize was awarded to two investigators who discovered that therapeutic targeting of immune checkpoints held the key to major patient benefits, there are many additional immunotherapeutic strategies that warrant further study and discussion at scientific and medical meetings. This article provides the newest information on three areas of immunotherapy that have been successfully applied to melanoma and continue to pave the way for new developments: cytokines, adoptive cell therapies (ADTs), and intratumoral injection of immunomodulatory agents.

BackgroundThere are limited therapeutic options for patients with progressive disease (PD) on or after PD-1–blocking antibody therapy. Vidutolimod (CMP-001) is a first-in-class, immunostimulatory virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist. This phase 1b study evaluated the safety and clinical activity of intratumoral vidutolimod with and without pembrolizumab in patients with refractory melanoma.MethodsThis two-part, open-label, multicenter, phase 1b study (NCT02680184) enrolled adults with histologically confirmed metastatic or unresectable cutaneous melanoma who had stable disease after ≥12 weeks or PD on anti−PD-1 treatment, measurable disease per RECIST v1.1, ECOG PS 0/1, and ≥1 lesion accessible for intratumoral injection. Part 1 evaluated vidutolimod + pembrolizumab and Part 2 evaluated vidutolimod monotherapy. Key objectives included assessment of safety and clinical activity, and exploratory analyses were performed on available tumor biopsies using immunohistochemistry and RNAseq.ResultsAt data cutoff (August 17, 2021), 159 patients had enrolled in Part 1 and 40 patients in Part 2. The median age was 64 years in Part 1 (range, 30-90) and 68 years in Part 2 (range, 30-89). Most patients had PD as their last response to prior anti–PD-1 therapy (Part 1, 93.1%; Part 2, 80.0%). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 37.1% of patients treated with vidutolimod + pembrolizumab and in 22.5% of patients treated with vidutolimod monotherapy. No treatment-related deaths occurred. Based on the efficacy data presented in Table 1, vidutolimod polysorbate 20 (PS20) A was selected for further development as this formulation in combination with pembrolizumab had a best objective response rate (ORR; RECIST v1.1) of 23.5%, with a median duration of response (DOR) of 25.2 months. Vidutolimod monotherapy had an ORR of 20.0%, with a median DOR of 5.6 months. Exploratory translational analyses identified association of unique biomarkers with response among patients with T cell–inflamed versus non-T cell–inflamed tumors at baseline.Abstract 950 Table 1Safety and clinical activity of vidutolomod ± pembrolizumabConclusionsPromising clinical activity was observed with vidutolimod + pembrolizumab and vidutolimod monotherapy in patients with PD-1 blockade–refractory melanoma. A manageable safety profile was observed. The DOR with vidutolimod + pembrolizumab was substantially longer than with vidutolimod monotherapy. Clinical studies to confirm the efficacy of vidutolimod + PD-1 blockade in patients with previously untreated unresectable/metastatic melanoma (phase 2/3, NCT04695977) or PD-1 blockade–refractory melanoma (phase 2, NCT04698187) are ongoing.AcknowledgementsThis work was supported by Checkmate Pharmaceuticals. Medical writing assistance was provided by Steffen Biechele, PhD (ApotheCom, San Francisco, CA, USA), and funded by Checkmate Pharmaceuticals.Trial RegistrationNCT02680184Ethics ApprovalThis study was approved by the WCG-WIRB; WIRB approval tracking number: 20152597.

CD8+ tumor-infiltrating lymphocytes (TILs) are associated with improved survival in triple-negative breast cancer (TNBC) yet have no association with survival in estrogen receptor-positive (ER+) BC. The basis for these contrasting findings remains elusive. We identified subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibited a distinct tumor microenvironment marked by amplified interferon-γ signaling-related pathways and higher programmed death ligand 1 expression. Paradoxically, higher levels of tumor-infiltrating CD8+ TEX associated with decreased overall survival of patients with ER+ BC but not patients with TNBC. Moreover, high tumor expression of a CD8+ TEX signature identified dramatically reduced survival in premenopausal, but not postmenopausal, patients with ER+ BC. Finally, we demonstrated the value of a tumor TEX signature score in identifying high-risk premenopausal ER+ BC patients among those with intermediate Oncotype DX Breast Recurrence Scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and ER status in BC patient survival. This work identifies tumor-infiltrating CD8+ TEX as a key feature of reduced survival outcomes in premenopausal patients with early-stage ER+ BC.

Summary Background Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. Methods This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5–3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0–2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov , NCT02320058 . Findings Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7–36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2–35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2–67·2]) of 101 patients in cohort A and three (16·7% [3·6–41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3–63·5]) patients in cohort A and three (16·7% [3·6–41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7–64·1) and overall survival was 71·9% (61·8–79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6–40·5) and overall survival was 36·6% (14·0–59·8). The most common grade 3–4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). Interpretation The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. Funding Bristol Myers Squibb.

Cemiplimab (Libtayo, Regeneron Pharmaceuticals, Tarrytown, NY) is a monoclonal antibody that targets the programmed cell death receptor 1. In 2018, the Food and Drug Administration approved cemiplimab for the treatment of patients with metastatic cutaneous squamous cell carcinoma (SCC) or locally advanced cutaneous SCC that is not a candidate for surgery or radiation.1 Immune checkpoint inhibitors have been implicated in the development of bullous disorders.2,3 We report the first case, to our knowledge, of a patient who developed severe steroid-resistant bullous pemphigoid shortly after initiating therapy with cemiplimab, requiring discontinuation of the programmed cell death receptor 1 inhibitor and treatment with rituximab.

Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.

Metastases to the central nervous system (CNS) are associated with considerable morbidity and mortality in patients with cancer. Historically, very few systemic therapies have shown efficacy in this patient population. Emerging data are now demonstrating that whole-brain radiation therapy, previously considered the mainstay of treatment of brain metastases, is associated with high rates of neurotoxicity. In this new era of targeted therapy and immunotherapy, clinical outcomes are improving, and patients are living longer. Despite these improvements, there is an urgent need to design central nervous system–penetrant compounds that target the genetic mutations enriched in brain metastases and to bring these to clinical trials.

The processes controlled by cytokines may be co-opted by pathologic states, contributing to processes that threaten host well-being. A nuanced understanding of this immense web of chemical communications will allow us to understand the mechanisms and limitations of current therapies and to enhance their therapeutic benefits while minimizing their toxicities. This article reviews the current state of cytokine science in malignancy, focusing on agents that are approved for therapy or are in late-stage development. Promising new directions, including novel engineered.

Lung cancer patients undergoing systemic treatment with immune checkpoint inhibitors (ICIs) can lead to severe immune-related adverse events (irAEs) that may warrant immediate hospitalization. Patients with thoracic malignancies hospitalized at City of Hope while undergoing treatment with ICIs were identified. Pathology and available next-generation sequencing (NGS) data, including the programmed death-ligand 1 (PD-L1) status and clinical information, including hospitalizations, invasive procedures, and the occurrence of irAEs, were collected. Unpaired T-tests, Chi-square/Fisher’s exact test, and logistic regression were used to analyze our cohort. The overall survival (OS) was calculated and compared using univariate and multivariate COX models. Ninety patients with stage IV lung cancer were admitted after ICI treatment. Of those patients, 28 (31.1%) had documented irAEs. Genomic analyses showed an enrichment of LRP1B mutations (n = 5/6 vs. n = 7/26, 83.3% vs. 26.9%, odds ratio (OR) (95% confidence interval (CI): 13.5 (1.7–166.1), p &lt, 0.05) and MLL3 mutations (n = 4/6, 66.7% vs. n = 5/26, 19.2%, OR (95% CI): 8.4 (1.3–49.3), p &lt, 0.05) in patients with irAE occurrences. Patients with somatic genomic alterations (GAs) in MET (median OS of 2.7 vs. 7.2 months, HR (95% CI): 3.1 (0.57–17.1), 0.05) or FANCA (median OS of 3.0 vs. 12.4 months, HR (95% CI): 3.1 (0.70–13.8), 0.05) demonstrated a significantly shorter OS. Patients with irAEs showed a trend toward improved OS (median OS 16.4 vs. 6.8 months, p = 0.19) compared to hospitalized patients without documented irAEs. Lung cancer patients who required treatment discontinuance or interruption due to irAEs (n = 19) had significantly longer OS (median OS 18.5 vs. 6.2 months, HR (95% CI): 0.47 (0.28–0.79), 0.05). Our results showed a significant survival benefit in lung cancer patients hospitalized due to irAEs that necessitated a treatment interruption. Patients with positive somatic GAs in MET and FANCA were associated with significantly worse OS compared to patients with negative GAs.

Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell–engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.

In locally advanced basal cell carcinoma (BCC) patients who are not surgical candidates and where radiation therapy (RT) alone would offer lower control rates, the combination of vismodegib and RT delivered concurrently may potentially improve outcomes compared to single modality treatment. The current study presents a case of very advanced, multifocal BCC who received concurrent vismodegib and RT. The patient initially came in with four large primary areas of disease including the left preauriculum, right shoulder, chest wall and right lateral ankle. All sites achieved a clinical complete response, with a pathologic complete response at the right shoulder. The ankle lesion did not require RT and continues to have a clinical complete response. The findings from our case report support several other cases with similar efficacy when vismodegib and RT are combined.

Background: Immunotherapy (IOT) of cancer depends on intratumoral CD8+ cells overcoming multiple obstacles to their localization and function. CD8+ cell content and its changes with treatment are important to understand tumor immunobiology, prognosis, and to guide therapy. Trial design: ImaginAb has developed an imaging agent, 89Zr-crefmirlimab berdoxam (formerly 89Zr-Df-IAB22M2C/89Zr-Df-crefmirlimab), with an 80 kDa minibody lacking a functional Fc domain, conferring high affinity to CD8, conjugated via deferoxamine to 89Zr for PET imaging: specific binding is to both CD8αα and CD8αβ, facilitating recognition of mature CD8+ cells and a small number of other cell types expressing CD8. The minibody structure was optimized for organ perfusion and pharmacokinetics, thereby maximizing the signal-to-background ratio. The long T1/2 (~3 d) of 89Zr permits repeat scanning during the week following an infusion. A previous Phase I study of single-dose 89Zr-crefmirlimab berdoxam was designed to select the optimum Phase II dose [Pandit-Taskar et al J Nuc Med 2020; Farwell et al J Nuc Med 2021]. After establishing the lack of toxicity across several dose levels, 1 mCi of 89Zr and 1.5 mg of minibody are now being used in Phase II studies. Our recently-completed Ph IIA study was designed to test the correlation of CD8+ cells in tumor biopsies with CD8 PET/CT before and during IOT in several tumor types routinely treated with IOT (including melanoma, renal, driver oncogene-negative lung). The present Ph IIB study, (first patient/first visit accomplished in 12/2021) tests the correlation of CD8 PET/CT with subject response by RECIST 1.1 (primary objective), and with lesion response (secondary objective). Adults with solid tumors receive 89Zr-crefmirlimab berdoxam i.v. and undergo PET-CT scan 24 hours later (non-contrast CT for localization). IOT (usually one or two immune checkpoint antibodies, using most commonly-used standard-of-care regimen for the disease) is then initiated. A second 89Zr-crefmirlimab berdoxam infusion and PET/CT are performed 4-6 weeks after the start of IOT followed 6-8 weeks later by standard tumor assessments (preferably CT with i.v. contrast to obtain RECIST-qualifying measurements). Thereafter, IOT and standard tumor assessments are continued according to standard practice and data for the present study collected up to 12 months after the start of treatment. For participants who progress on treatment there is an optional third 89Zr-crefmirlimab berdoxam infusion and PET/CT. For all participants optional biopsies are collected to coincide with PET/CT timepoints. Accrual is ongoing at three sites in USA, and up to 20 sites globally (USA, Europe and Australia) will participate. The overall accrual goal is 80 patients, distributed across the four tumor types. Citation Format: Kim Margolin, David Hays, Delphine L. Chen, Gary Ulaner, Ron Korn, Katherine Young, Michael Ferris, William Le, Ian Wilson. iPREDICT trial: A phase IIb, open label study of 89Zr-Crefmirlimab Berdoxam PET/CT in subjects with selected advanced malignancies (melanoma, merkel cell, renal cell and non-small cell lung cancers), scheduled to receive standard-of-care immunotherapy, to predict response to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT132.

Background Therapeutic options are limited for patients with advanced melanoma that is refractory to PD-1 blockade. This study was performed in this patient population to assess the safety and antitumor activity of CMP-001, a CpG-A TLR9 agonist packaged within a virus-like particle. Methods Patients were eligible for this 2-part, open-label, multicenter, phase 1b study if they had metastatic/unresectable melanoma and stable disease after =12 weeks or progressive disease (PD) on/after anti-PD-1 therapy. Part 1 evaluated CMP-001 plus pembrolizumab dose-escalation and dose-expansion. Part 2 evaluated CMP-001 monotherapy. Accessible lesion(s) were injected intratumorally with CMP-001, at a polysorbate 20 (PS20) concentration of either 0.01% or 0.00167%. The Part 1 primary objective was to identify the recommended phase 2 dose (RP2D) and schedule of CMP-001 plus pembrolizumab, while the Part 2 primary objective was to assess the safety of CMP-001 monotherapy. Secondary objectives for both parts were a preliminary assessment of antitumor activity of CMP-001 plus pembrolizumab and CMP-001 monotherapy, and the overall safety profile and pharmacodynamics of the combination. Results In Part 1 (N=159) and Part 2 (N=40), 93.1% and 80.0% of patients had PD as their last response to prior anti–PD-1 therapy, respectively. The most common treatment-related adverse events (TRAEs; >25%) were flu-like symptoms (Parts 1 and 2) and injection-site reactions (Part 1). Grade 3/4 TRAEs were reported in 36.5% (Part 1) and 22.5% (Part 2) of patients, the most common being hypotension (Part 1: 6.9%; Part 2: 5.0%). No Grade 5 TRAEs were observed. In Part 1, the best objective response rate (ORR; RECIST v1.1) in patients treated with pembrolizumab and CMP-001 (PS20 0.01%) was 23.5% (23/98), while CMP-001 PS20 (0.00167%) resulted in a lower ORR of 11.5% (7/61). Seven additional patients had a delayed response after initial PD (table 1). The median duration of response was >1 year. In the 37 RECIST v1.1 and post-progression responders, the mean regression in injected and noninjected target lesions was 54.7% and 52.7%, respectively. In Part 2, the best ORR with CMP-001 monotherapy was 17.5% (7/40 patients); the response duration was shorter than in Part 1. Intratumoral CMP-001 PS20 0.01% 10 mg was selected as the RP2D. Conclusions Intratumoral CMP-001 was well-tolerated and provided both local and distant responses in patients with advanced melanoma with disease progression on prior PD-1 blockade. CMP-001 monotherapy induced systemic tumor regression in some patients, but duration of response was substantially increased by the addition of pembrolizumab. Acknowledgements This work was supported by Checkmate Pharmaceuticals. Medical writing assistance was provided by Cindy Rigby, PhD, of ApotheCom (San Francisco, CA) and was funded by Checkmate Pharmaceuticals. Trial Registration NCT02680184 Ethics Approval This study was approved by the WCG-WIRB, WIRB approval tracking number 20152597. Consent N/A References N/A

IMPORTANCE: The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAF V600E/K-mutant melanoma is not well established. OBJECTIVE: To assess the association of BRAF wild-type (WT) or BRAF V600E/K-mutant status and BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy with response to pembrolizumab. DESIGN, SETTING, AND PARTICIPANTS: This study is a post hoc subgroup analysis of pooled data from 3 multinational, multisite studies: KEYNOTE-001 (data cutoff September 1, 2017), KEYNOTE-002 (data cutoff May 30, 2018), and KEYNOTE-006 (data cutoff December 4, 2017). Patients included in this analysis were adults with advanced melanoma and known BRAF V600E/K tumor status who had received pembrolizumab. INTERVENTIONS: Patients received pembrolizumab in dosages of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks. MAIN OUTCOMES AND MEASURES: End points were objective response rate (ORR) and progression-free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival (OS). Objective response rates, 4-year PFS, and OS rates were compared in the following patient subgroups: BRAF WT vs BRAF V600E/K-mutant melanoma and BRAF V600E/K-mutant melanoma with vs without previous treatment with BRAFi with or without MEKi therapy. RESULTS: The overall study population (N = 1558) included 944 men (60.6%) and 614 women (39.4%). The mean (SD) age was 60.0 years (14.0). The ORR was 38.3% (596/1558), 4-year PFS rate was 22.0%, and 4-year OS rate was 36.9%. For patients with BRAF WT (n = 1124) and BRAF V600E/K-mutant melanoma (n = 434), ORR was 39.8% (n = 447) and 34.3% (n = 149), 4-year PFS rate was 22.9% and 19.8%, and 4-year OS rate was 37.5% and 35.1%, respectively. Patients with BRAF V600E/K-mutant melanoma who had (n = 271) vs had not (n = 163) previously received BRAFi with or without MEKi therapy had baseline characteristics with worse prognosis; ORR was 28.4% (n = 77) and 44.2% (n = 72), 4-year PFS rate was 15.2% and 27.8%, and 4-year OS rate was 26.9% and 49.3%, respectively. CONCLUSIONS AND RELEVANCE: Results of this subgroup analysis support the use of pembrolizumab for treatment of advanced melanoma regardless of BRAF V600E/K mutation status or receipt of prior BRAFi with or without MEKi therapy.

The hypoxia and profound inflammatory response associated with the pneumonitis observed with the severe acute respiratory virus coronavirus-2 (SARS-COV-2) virus responsible for the recent COVID-19 pandemic has overwhelmed intensive care facilities in the epicenters of infection including Wuhan

Background Intratumoral (IT) injection of CMP-001, a CpG-A TLR9 agonist packaged within a virus-like particle, is designed to activate tumor-associated plasmacytoid dendritic cells, inducing an interferon-rich tumor microenvironment and anti-tumor CD8+ T cell responses. Methods CMP-001-001 is an ongoing Phase 1b trial evaluating the safety and efficacy of CMP-001 in combination with pembrolizumab (Part 1; N = 144) or alone (Part 2; N = 23) in patients with advanced melanoma resistant to prior anti-PD-1 therapy (Tables 1). CMP-001 is administered IT into accessible lesion(s) either with, or without on-site saline dilution (table 1), and response assessed by RECIST v1.1. Monotherapy patients who progress can be rolled over onto combination therapy and continue on study. Baseline and on-therapy serum is analyzed for cytokines, and immunohistochemistry and RNA-Seq are performed on available tumor biopsies. Results Adverse events (AEs) attributed to CMP-001 in combination with pembrolizumab or as monotherapy consisted predominately of transient low-Grade flu-like symptoms and injection site reactions: Grade 3+ related AEs were reported in 33% of patients treated with combination therapy and 22% of patients with monotherapy. The Objective Response Rate (ORR) with undiluted CMP-001 in combination with pembrolizumab was 24% (18/75; 95% confidence interval: 15%-35% (table 1); on-site dilution of CMP-001 was associated with a substantial decrease in ORR to 12% (7/61; 95% confidence interval: 5%-22% (table 1). Three additional patients had a delayed partial response after an initial period of disease progression. Anti-tumor response was comparable between injected and uninjected lesions. The median duration of response to combination therapy has not been reached. The ORR to CMP-001 monotherapy was 22% (5/23; 95% confidence interval: 7%-44% (table 1); time from last anti-PD-1 therapy before CMP-001 was 1.5 to >20 months in responders; 3 of the patients responding to CMP-001 monotherapy achieved PR at the first evaluation, but progressed by the second evaluation. Serum and tumor biopsy translational studies in the patients receiving combination therapy supported the proposed mechanism of TLR9 activation and identified a possible association between induction of serum CXCL10 and response. Conclusions IT CMP-001 alone and in combination with pembrolizumab appears well tolerated, can reverse resistance to anti-PD-1 therapy, and can produce deep and durable clinical responses in patients with advanced melanoma. Ethics Approval CMP-001-001 was centrally approved by the WCG-WIRB, WIRB approval tracking number 20152597.

Summary Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).

The NCCN Guidelines for Uveal Melanoma include recommendations for staging, treatment, and follow-up of patients diagnosed with uveal melanoma of the choroid or ciliary body. In addition, because distinguishing between uveal melanoma and benign uveal nevi is in some cases difficult, these guidelines also contain recommendations for workup of patients with suspicious pigmented uveal lesions, to clarify the tests needed to distinguish between those who should have further workup and treatment for uveal melanoma versus those with uncertain diagnosis and low risk who should to be followed and later reevaluated. These NCCN Guidelines Insights describe recommendations for treatment of newly diagnosed nonmetastatic uveal melanoma in patients who have already undergone a complete workup.

In February 2018, the Melanoma Research Foundation and the Moffitt Cancer Center hosted the Second Summit on Melanoma Central Nervous System Metastases in Tampa, Florida. The meeting included investigators from multiple academic centers and disciplines. A consensus summary of the progress and challenges in melanoma parenchymal brain metastases was published (Eroglu et al., Pigment Cell & Melanoma Research, 2019, 32, 458). Here, we will describe the current state of basic, translational, clinical research, and therapeutic management, for melanoma patients with leptomeningeal disease. We also outline key challenges and barriers to be overcome to make progress in this deadly disease.

Purpose: IL15 induces the activation and proliferation of natural killer (NK) and memory CD8+ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL15N72D:IL15RαSu/IgG1 Fc complex) over recombinant human IL15 (rhIL15) in animal models, we performed this first-in-human phase I trial of ALT-803 in patients with advanced solid tumors. Patients and Methods: Patients with incurable advanced melanoma, renal cell, non–small cell lung, and head and neck cancer were treated with ALT-803 0.3 to 6 μg/kg weekly intravenously or 6 to 20 μg/kg weekly subcutaneously for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, and lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity. Results: Twenty-four patients were enrolled; 11 received intravenous and 13 received subcutaneous ALT-803. Of these patients, nine had melanoma, six renal, three head and neck, and six lung cancer. Although total lymphocyte and CD8+ T-cell expansion were modest, NK cell numbers rose significantly. Neither anti–ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well tolerated, with adverse effects including fatigue and nausea most commonly with intravenous administration, whereas painful injection site wheal was reported most commonly with subcutaneous ALT-803. Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in patients with advanced cancer. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anticancer agents. Clin Cancer Res; 24(22); 5552–61. ©2018 AACR.

BACKGROUND Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2. METHODS NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS). RESULTS A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in favor of arm A, with a median of 6.9 months (95% confidence interval [95% CI], 4.1-8.7 months) versus 2.3 months (95% CI, 1.6-3.5 months) (P