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PURPOSE The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. METHODS Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis. RESULTS Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm. CONCLUSION T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

BackgroundCIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC.MethodsPatients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a “3+3” dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF.FindingsThe combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.

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.

Purpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133

Background Axitinib plus pembrolizumab showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) versus sunitinib in a randomised phase III trial in patients with advanced renal-cell carcinoma (RCC). We report long-term efficacy and safety of the axitinib/pembrolizumab from the phase I trial (NCT02133742), after 46–55 months from study initiation (data cut-off date, 23rd July 2019). Methods Fifty-two treatment-naive patients with advanced RCC were treated with oral axitinib 5 mg twice daily and intravenous pembrolizumab 2 mg/kg every 3 weeks. PFS, duration of response (DoR) and OS were summarised using the Kaplan–Meier method. Results At a median follow-up of 42.7 months (95% confidence interval [CI]: 41.1–44.1), median OS was not reached; 38 (73.1%) patients were alive. The probability of being alive at 4 years was 66.8% (95% CI: 49.1–79.5). Median PFS in the overall population was 23.5 months (95% CI: 15.4–30.4). ORR was 73.1%; five patients had complete response. Median DoR was 22.1 months (95% CI: 15.1–34.5). Grade III/IV adverse events (AEs) were reported in 38 (73.1%) patients and 20 (38.5%) discontinued treatment because of AEs: 17 (32.7%) discontinued axitinib, 13 (25.0%) discontinued pembrolizumab, and 10 (19.2%) discontinued both drugs. Common AEs included diarrhoea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%) and dysphonia (48.1%). There were no new AE terms reported and no treatment-related deaths. Conclusions In patients with advanced RCC with ~4 years of follow-up, combination axitinib/pembrolizumab continued to demonstrate clinical benefit, with no new safety signals.

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor.Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 106plaque-forming units (PFU)/mL in week 1, followed by 108PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported.At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number:NCT01740297.

Introduction: In this study, we investigated the prognostic role of the immune cell state atlas in predicting therapeutic benefits of patients treated with immune checkpoint inhibitors (ICI) within the ORIEN network of 18 collaborating cancer centers under the Total Cancer Care protocol. Methods: We utilized RNA-seq data of 926 samples generated from 875 individuals. Gene expression data were deconvoluted for immune cell states using the Carcinoma EcoTyper software. We then conducted a series of survival analyses to test the association between survival outcomes and predicted cell types and states in five malignant tumors: Genitourinary (GU), Gastrointestinal (GI), Thoracic (THO), Cutaneous (CUT), Head & Neck (H&N). The regularized Cox regression model in R package ‘glmnet’ was then applied to select the complementary pathway signatures (including gene ontology and KEGG pathways) to the immune cell states in predicting survival outcomes. We also explored the immune-related long non-coding RNAs (lncRNA) as potential biomarkers for cell states and patient outcomes. Results: EcoTyper analysis revealed that 692 (~80%) of patients were assigned to the 10 pre-identified Carcinoma Ecotypes (CE1 to CE10) or cell state atlas group. Overall, two immune deficiency ecotype patient groups (CE1 and CE2) pre-identified based on the independent training data were linked to worse survival, while two proinflammatory ecotype groups (CE9 and CE10) were associated with favorable surxvival. Those ecotype groups showed strong prognostic significance in predicting OS in melanoma and H&N. Meanwhile, CE6, a non-neoplastic tissue enriched cell subtype, was also found to be highly associated with longer OS in H&N and GU. CE7, an age-related mutation patient subgroup, contributed to shorter survival in both melanoma and GI. We also found that a subset of activated B cell state and the exhausted/effector CD4 T cell state were significantly associated with patient survival in melanoma and GU, respectively. The penalized Cox regression model revealed that β-catenin signaling pathway, P53 pathway and heme metabolism in the MSigDB Hallmark gene sets are the most complementary pathways to the ecotype scores in multiple cancer types. In additional, multiple pathways in KEGG such as endocytosis were found to jointly contribute to the ecotype-pathway composite prognostic model. In anazlying immune-related lncRNA biomarkers, we highlighted the prognostic role of NKILA in our dataset, which has been studied to promote tumor immune evasion. Conclusion: Our analysis has successfully established the utility of immune cell state atlas in predicting therapeutic benefits with ICIs. We expect that the discovered complementary signatures in the cancer-cell compartment will also lead to a novel spectrum of tumor-based biomarkers to ICI. Citation Format: Tingyi Li, Vineeth Sukrithan, Aakrosh Ratan, Martin McCarter, John Carpten, Howard Colman, Alexandra P. Ikeguchi, Igor Puzanov, Susanne Arnold, Michelle Churchman, Patrick Hwu, Paulo C. Rodriguez, William S. Dalton, George J. Weiner, Ahmad Tarhini, Xuefeng Wang. The immune cell state atlas analysis predicts therapeutic benefits with immune checkpoint inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5703.

Nonmelanoma skin cancers (NMSCs) are some of the most commonly diagnosed malignancies. In general, early-stage NMSCs have favorable outcomes; however, a small subset of patients develop resistant, advanced, or metastatic disease, or aggressive subtypes that are more challenging to treat successfully. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC). Although ICIs have demonstrated activity against NMSCs, the routine clinical use of these agents may be more challenging due to a number of factors including the lack of predictive biomarkers, the need to consider special patient populations, the management of toxicity, and the assessment of atypical responses. With the goal of improving patient care by providing expert guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their own clinical experience to develop recommendations for healthcare professionals on important aspects of immunotherapeutic treatment for NMSCs, including staging, biomarker testing, patient selection, therapy selection, post-treatment response evaluation and surveillance, and patient quality of life (QOL) considerations, among others. The evidence- and consensus-based recommendations in this CPG are intended to provide guidance to cancer care professionals treating patients with NMSCs.

Purpose: Combined axitinib/pembrolizumab is approved for advanced renal cell carcinoma (aRCC). This exploratory analysis examined associations between angiogenic and immune-related biomarkers and outcomes following axitinib/pembrolizumab treatment. Patients and Methods: Prospectively defined retrospective correlative exploratory analyses tested biospecimens from 52 treatment-naïve patients receiving axitinib and pembrolizumab (starting doses 5 mg twice daily and 2 mg/kg respectively, every 3 weeks). Tumor tissue, serum, and whole blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and end of treatment (EOT) for blood-based samples. Clinical outcomes were objective response rate (ORR) and progression-free survival (PFS). Results: Higher baseline tumor levels of CD8 showed a trend toward longer PFS (HR 0.4; P = 0.091). Higher baseline serum levels of CXCL10 (P = 0.0197) and CEACAM1 (P = 0.085) showed a trend toward better ORR and longer PFS, respectively. Patients for whom IL6 was not detected at baseline had longer PFS versus patients for whom it was detected (HR 0.4; P = 0.028). At C2D1 and/or EOT, mainly immune-related biomarkers showed any association with better outcomes. The genes CA9 (P = 0.084), HIF1A (P = 0.064), and IFNG (P = 0.073) showed trending associations with ORR, and AKT3 (P = 0.0145), DDX58 (P = 0.0726), GZMA (P = 0.0666), LCN2 (NGAL; P = 0.0267), and PTPN11 (P = 0.0287) with PFS. Conclusions: With combined axitinib/pembrolizumab treatment in patients with aRCC, mostly immune-related biomarkers are associated with better treatment outcomes. This exploratory analysis has identified some candidate biomarkers to consider in future prospective testing.

BRAF V600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAFV600 mutations have historically been considered a clear demonstration of tumor lineage context–dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort “basket” study of the BRAF inhibitor vemurafenib in non-melanoma BRAFV600 mutation–positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized. Significance: These data suggest that BRAFV600 mutations lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers, including tumor types in which RAF inhibition is not currently considered standard of care. See related commentary by Ribas and Lo, p. 640. This article is highlighted in the In This Issue feature, p. 627

Purpose: To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study. Patients and Methods: This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAFV600-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy–progressive disease (PD); n = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7). Results: Median OS was 31.8 months [95% confidence interval (CI), 24.5–not estimable] in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy–PD cohort, the median OS was 8.5 months (95% CI, 6.7–11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events. Conclusions: A subset of patients with advanced BRAFV600-mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.

Purpose: Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated antitumor activity in preclinical models. The ILLUMINATE-101 phase I study explored the safety, dose, efficacy, and immune effects of intratumoral (it) tilsotolimod monotherapy in multiple solid tumors. Patients and Methods: Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the safety, establishing the dose, efficacy, and immunologic assessment. Blood samples and tumor biopsies of injected and noninjected lesions were obtained at baseline and 24 hours after treatment for immune analyses. Results: Thirty-eight and 16 patients were enrolled into the dose escalation and melanoma expansion cohorts, respectively. Deep visceral injections were conducted in 91% of patients. No dose-limiting toxicities (DLT) or grade 4 treatment-related adverse events were observed. Biopsies 24 hours after treatment demonstrated an increased IFN pathway signature and dendritic cell maturation. Immunologic profiling revealed upregulation of IFN-signaling genes and modulation of genes for checkpoint proteins. In the dose escalation cohort, 12 (34%) of 35 evaluable patients achieved a best overall response rate (ORR) of stable disease (SD), whereas 3 (19%) of 16 evaluable patients in the melanoma cohort achieved stable disease. Conclusions: Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment. See related commentary by Punekar and Weber, p. 5007

BackgroundWhile IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, IL-15 does not directly expand regulatory T cells (Tregs)or mediate activation-induced cell death and may have an improved therapeutic index. KD033 is a fusion antibody combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 and its mouse cross-reactive surrogate molecule, srKD033, have been extensively characterized in multiple in vitro and in vivo nonclinical studies and have demonstrated robust efficacy and therapeutic benefits compared to IL-15 alone.MethodsThis is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety, tolerability, and MTD of KD033. Secondary objectives include characterization of PK and immunogenicity, evaluation of CD8+ T and NK cell activation, and assessment of best overall response and duration of response. KD033 is administered by IV infusion over 30 minutes every 14 days. The study design follows 3+3 escalation investigating dose ranges from 3µg/kg to 600µg/kg.ResultsA total of 12 patients have received treatment. Three patients were dosed in Cohort 1 (C1), four patients were dosed in Cohort 2 (C2), and three patients were dosed in Cohort 3 (C3). Two patients in Cohort 4 (C4) have been dosed. Through three dose escalation cohorts (3 µg/kg – 50 µg/kg), no dose-limiting toxicities have been reported. Grade 1–2 treatment-related toxicities resolved within 24 hours with supportive management. Grade 4 decreases in lymphocytes were noted the day after dosing in C3 and C4, which resolved on day 3 and were expected. One patient (adenoid cystic carcinoma) in C1 was shown to have stable disease for more than 6 months and one patient (metastatic gastric adenocarcinoma) in C3 was shown to have stable disease for more than 4 months.ConclusionsTo date, KD033 has been well tolerated in all subjects with on-mechanism pharmacodynamics consistent with IL-15 agonism.Ethics ApprovalThis study obtained ethics approval from WIRB.

BackgroundONCR-177 is a recombinant oncolytic herpes simplex virus (oHSV) that retains γ34.5 and is engineered to express five immunomodulatory transgenes (IL-12, FLT3LG ECD, CCL4 and anti-PD-1 and anti-CTLA-4 antibodies) for the intratumoral treatment of solid tumors. Attenuation by miRNA leads to selective replication in tumor cells, and mutations in UL37 act as an orthogonal safety strategy. Transgenes elicit potent systemic stimulation of anti-tumor immunity.1 ONCR-177 is being tested in an open-label, multicenter, phase 1 study alone and in combination with pembrolizumab (NCT04348916), for surface lesion injection and intrahepatic injection. Here we present the surface lesion escalation data.MethodsThe objectives were determination of safety and recommended phase 2 dose (RP2D) of ONCR-177 monotherapy in subjects with advanced and/or refractory injectable surface lesions using a modified toxicity probability interval-2 (mTPI-2) escalation design at four dose levels: (Cohort 1: 1×106 PFU in 1 mL, Cohort 2: 1×107 PFU in 1 mL, Cohort 3: 1×108 PFU in 1 mL and Cohort 4: 4×108 PFU in 4 mL). Subjects received ONCR-177 by intratumoral injection once every 2 weeks (up to 10 times) until disease progression or unacceptable toxicity. There was no intrapatient dose escalation.ResultsAs of June 28, 2021, 14 subjects with injectable tumors were enrolled in the dose escalation phase (3 in cohort 1, 4 in cohort 2, 3 in cohort 3 and 4 in cohort 4). Enrolled tumor types included: melanoma (3), breast (3), anal squamous cell (1), lung (1), duodenal (1), basal cell (1), chondrosarcoma (1), thyroid (1), oropharyngeal (1) and papillary renal cell (1). Subject median age was 67 years. Median number of prior lines of therapy was 4 (range 2–11), including 11 of 14 subjects with prior immunotherapy. Nine subjects were HSV-1 seropositive at baseline, 4 were negative, one was unknown. Treatment-related Adverse Events were all Grade 1–2. Most commonly reported were: cytokine release syndrome (2 occurrences in Cohort 4), fatigue, nausea, chills, headache, decreased appetite, hypotension, and injection site pain. There were no dose-limiting toxicities. The RP2D was selected as 4×108 PFU in 4 mL every 2 weeks up to 10 doses. Clinical data, including safety, viral shedding and exploratory biomarker data including peripheral payloads, peripheral cytokines and immune infiltration and PD-L1 expression in the tumor microenvironment will be presented.ConclusionsONCR-177 monotherapy in heavily pretreated subjects with advanced, injectable, solid tumors at the RP2D was safe and tolerable. Enrollment at the RP2D is underway in monotherapy expansion.Trial RegistrationNCT04348916ReferencesHaines BB, Denslow A, Grzesik P, Lee JS, Farkaly T, Hewett J, Wambua D, Kong L, Behera P, Jacques J, et al. ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity. Cancer Immunol Res 2021;9: 291–308Ethics ApprovalThis study was approved by the following institutional Ethics Boards:-University Health Network Research Ethics Board (ID Number: 20-5069)-Integreview IRB (ID Number RM 694) -WCG IRB (ID Number: 20200150)-Advarra (ID Number: 00000971)-Roswell Park IRB (ID Number: STUDY00001189/P-553719)-The Ohio State University Cancer IRB (ID Number: 2020C0139) -Dana Farber Cancer Institute IRB (ID Number 354020)All participants gave informed consent before taking part in this clinical trial.

Background: Patients with sarcoma often require individualized treatment strategies and are likely to receive aggressive immunosuppressive therapies, which may place them at higher risk for severe COVID-19. We aimed to describe demographics, risk factors, and outcomes for patients with sarcoma and COVID-19. Methods: We performed a retrospective cohort study of patients with sarcoma and COVID-19 reported to the COVID-19 and Cancer Consortium (CCC19) registry (NCT04354701) from 17 March 2020 to 30 September 2021. Demographics, sarcoma histologic type, treatments, and COVID-19 outcomes were analyzed. Results: of 281 patients, 49% (n = 139) were hospitalized, 33% (n = 93) received supplemental oxygen, 11% (n = 31) were admitted to the ICU, and 6% (n = 16) received mechanical ventilation. A total of 23 (8%) died within 30 days of COVID-19 diagnosis and 44 (16%) died overall at the time of analysis. When evaluated by sarcoma subtype, patients with bone sarcoma and COVID-19 had a higher mortality rate than patients from a matched SEER cohort (13.5% vs 4.4%). Older age, poor performance status, recent systemic anti-cancer therapy, and lung metastases all contributed to higher COVID-19 severity. Conclusions: Patients with sarcoma have high rates of severe COVID-19 and those with bone sarcoma may have the greatest risk of death.

International audience; Background: Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death–ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti–programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs. Methods: Patients with PD-L1–positive, locally advanced or metastatic carcinoid or well–differentiated or moderately-differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint. Results: Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD-L1–positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow-up was 20 months (range, 2-35 months) and 21 months (range, 5-32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%-31.2%) and 6.3% (95% CI, 0.2%-30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9-11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment-related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune-mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort). Conclusions: Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well-tolerated.

BackgroundInterferon (IFN) pathway activation in tumors can have dual, sometimes opposing, influences on immune responses. Therapeutic inhibition of programmed cell death ligand (PD-L1) – a treatment that reverses PD-1-mediated suppression of tumor-killing T-cells - is linked to alterations in IFN signaling; however, less is known about the role of IFNs after treatment resistance. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined the consequences of PD-L1 blockade on IFN-related secretory changes in preclinical models of acquired resistance.MethodsTherapy-resistant cell variants were derived from orthotopically grown mouse tumors initially sensitive or insensitive to PD-L1 antibody treatment. Cells representing acquired resistance were analyzed for changes to IFN-regulated secretory machinery that could impact tumor progression.ResultsWe identified a PD-L1 treatment-induced secretome (PTIS) that was enriched for several IFN-stimulated genes (ISGs) and significantly enhanced when stimulated by type I IFNs (IFNα or IFNβ). Secretory changes were specific to treatment-sensitive tumor models and found to suppress activation of T cellsex vivowhile diminishing tumor cell cytotoxicity, revealing a tumor-intrinsic treatment adaptation with potentially broad tumor-extrinsic effects. When reimplantedin vivo, resistant tumor growth was slowed by the blockade of individual secreted PTIS components (such as IL6) and stopped altogether by a more generalized disruption of type I IFN signaling.In vitro, genetic or therapeutic methods to target PD-L1 could only partially recapitulate the IFN-enhanced PTIS phenotype, showing thatin vivo-based systems with intact tumor:immune cell interactions are needed to faithfully mimic acquired resistance as it occurs in patients.ConclusionsThese results suggest that prolongedin vivoPD-L1 inhibition can ‘rewire’ type I IFN signaling to drive secretory programs that help protect tumors from immune cell attack and represent a targetable vulnerability to overcome acquired resistance in patients.

Purpose: To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity. Patients and Methods: From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO). CSF1 transcripts and gene expression were explored in TGCT biopsies. Results: Ninety-one patients were treated: TGCT patients (n = 39) had a median treatment duration of 511 days, while other solid tumor patients (n = 52) had a median treatment duration of 56 days. TGCT patients had response rates of 62% (RECIST 1.1) and 56% (TVS) for the full analysis set. PRO assessments for pain showed improvement in patient symptoms, and 76% (19/25) of TGCT tissue biopsy specimens showed evidence of abnormal CSF1 transcripts. Pexidartinib treatment of TGCT resulted in tumor regression and symptomatic benefit in most patients. Pexidartinib toxicity was manageable over the entire study. Conclusions: These results offer insight into outcome patterns in cancers whose biology suggests use of a CSF1R inhibitor. Pexidartinib results in tumor regression in TGCT patients, providing prolonged control with an acceptable safety profile.

BackgroundImmune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs.MethodsWe retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors.ResultsAmong patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes.ConclusionsRoutine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.

Immunotherapy represents the third important wave in the history of the systemic treatment of cancer after chemotherapy and targeted therapy and is now established as a potent and effective treatment option across several cancer types. The clinical success of anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4, first, and anti-programmed death (PD)-1/PD-ligand (L)1 agents in melanoma and other cancers a few years later, has encouraged increasing focus on the development of other immunotherapies (e.g. monoclonal antibodies with other immune targets, adoptive cell transfer, and vaccines), with over 3000 immuno-oncology trials ongoing, involving hundreds of research institutes across the globe. The potential use of these different immunotherapeutic options in various combinations with one another and with other treatment modalities is an area of particular promise. The third Immunotherapy Bridge meeting (29-30 November, 2017, Naples, Italy) focused on recent advances in immunotherapy across various cancer types and is summarised in this report.

Talimogene laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB–IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single ≥25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7 [18.4%]; ipilimumab, n = 1 [5.6%]) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors. Trial Registration {"type":"clinical-trial","attrs":{"text":"NCT01740297","term_id":"NCT01740297"}}NCT01740297 (ClinicalTrials.gov; date of registration, December 4, 2012); 2012-000307-32 (ClinicalTrialsRegister.eu; date of registration, May 13, 2014).

Background: Aurora A (AURKA) is a mitotic kinase responsible for centrosome segregation and mitotic spindle formation. In normal cells, expression of AURKA is highly regulated and is predominantly restricted to G2/M phases of the cell cycle. Unlike healthy cells, cancer cells overexpress AURKA through all phases of the cell cycle resulting in the acquisition of alternate non-mitotic functions. Little is known about cellular functions regulated by AURKA and its interaction with other signaling molecules. Here, we report a novel interaction between AURKA and the mitogen-activated protein kinase (MAPK) pathway at the level of MEK1 in breast cancer cells. This interaction may serve as a novel target as well as demonstrate by an additive cytotoxic effect of AURKA- and MEK1/2-specific inhibitors against estrogen positive (ER+) and triple negative breast cancer (TNBC) cells. Results: We show that treatment of ER+ HER2- MCF-7, ER- HER2+ SKBR3 and ER- HER2- BT549 cells with AURKA specific inhibitors alisertib, MK8745 and Aurora A Inhibitor I resulted in over 2-fold increase in relative levels of poMEK1/2 and poERK1/2 compared to untreated controls. The activation of the MAPK pathway was rapid with changes seen within 5 min after treatment with AURKA inhibitors and was sustained for at least 48 hours. Treatment with the pan RAF inhibitor TAK-632 did not diminish alisertib-induced poERK and poMEK1/2. Alternatively, treatment with the MEK1/2 specific inhibitor PD0325901 completely abrogated alisertib-induced phosphorylation of MEK1/2 and ERK1/2. In situ proximity ligation and pull down assays demonstrated AURKA and MEK1/2 direct interaction. In vitro kinase assay showed direct phosphorylation of MEK1 by AURKA. Combined treatment of alisertib and PD0325901 in vitro revealed significant additive cytotoxic effect in MCF-7 and BT549 cells when compared to either agent used alone (p< 0.008 and p Conclusions: Our data shows a novel AURKA-MEK1 interaction in breast cancer cells. In depth in vivo analysis is ongoing. The results reveal a promising new strategy for the treatment TNBC patients using a combination of AURKA and MEK1/2 inhibitors. Citation Format: Gandhi S, Gil M, Khoury T, Takabe K, Puzanov I, Gelman I, D'Assoro A, Opyrchal M. A novel interaction of AURKA with MAPK pathway in breast cancer cells as a potential therapeutic target [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-17.

Background: Effective immune therapies depend on the presence of cytotoxic T-lymphocytes (CTLs) in the tumor microenvironment (TME). Our preclinical data showed synergy between TLR3 ligands and interferon-α (IFN-α) in reprogramming the TME, but not healthy tissues, to selectively enhance CTL attraction, providing rationale for their systemic application to enhance local CTL densities in “cold” tumors. The pilot study NCT03599453 evaluated the safety of systemic chemokine modulating regimen (CKM) composed of i.v. rintatolimod (Ampligen; selective TLR3 ligand) and IFN-α, and its ability to promote local CTL influx to mTNBC lesions. Methods: Six evaluable patients (33-75 years) with mTNBC received 6 doses of rintatolimod (200 mg i.v.), IFN-α (INTRON-A; 20MU/m2 i.v.) and COX-2 inhibitor (celecoxib; 2 x 200 mg, p.o.) over 2 weeks, with tumor biopsies obtained before (within 6 days) and after (within 5 days) CKM. All patients received follow-up pembrolizumab (200 mg, i.v, Q3 weeks). The primary endpoint was the change in the CTL marker CD8α in the TME with a planned interim analysis after 3 patients (α=0.03) and final analysis after 6 patients (α=0.084). Correlative studies analyzed additional markers of CTLs, regulatory T-cells (Tregs), and CTL- and Treg-attracting chemokines in the TME and blood. Results: Treatment was well tolerated with mostly grade 1/2 adverse events and one grade 3 clinically significant pneumonitis and immune thrombocytopenic purpura observed during follow up pembrolizumab treatment. We observed uniform increases of intratumoral type-1 immune markers upon treatment: CD8α mRNA (6.1-fold; p=0.034), GZMB (3.5-fold; p=0.058), ratios of CD8α/FOXP3 and GZMB/FOXP3 (5.7-fold; p=0.036, and 7.6-fold; p=0.024 respectively), and CTL attractants CXCL10 (2.6-fold; p=0.104) and CCL5 (3.3-fold; p=0.019), successfully meeting the primary endpoint. In contrast, neither Treg marker Foxp3 nor Treg attractants CCL22 or CXCL12 were enhanced. These TME changes were accompanied by transient decreases in circulating CD3+CD8+ CTLs and CD3-CD56+ NK cells (but not Tregs), selectively affecting the cells expressing CXCR3 (receptor for CXCL10), but not CCR4 or CXCR4 (receptors for CCL22 and CXCL12). Three patients had stable disease lasting 2.4, 2.5 and 3.8 months, as of September 1, 2021 cut-off. An additional patient had a partial response (breast auto-amputation) with massive tumor necrosis observed in the post-CKM biopsy. Conclusion: This proof-of-concept study shows that short-term systemic CKM followed by pembrolizumab is safe and selectively enhances local CTL infiltration in the TME, providing rationale for concurrent CKM and PD1 blockade in prospective phase II studies. Citation Format: Shipra Gandhi, Mateusz Opyrchal, Melissa Grimm, Ronald Slomba, Kathleen Kokolus, Sebastiano Battaglia, Kristopher Attwood, Adrienne Groman, Lauren Williams, Mary Lynne Tarquini, Paul Wallace, Kah Teong Soh, Tracey O'Connor, Amy Early, Ellis Levine, Igor Puzanov, Marc Ernstoff, Pawel Kalinski. Systemic rintatolimod and interferon-α2b selectively reprogram local tumor microenvironment in patients with metastatic triple negative breast cancer for enhanced influx of cytotoxic T-lymphocytes but not regulatory T-cells [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 CT145.

Background: Adrenergic stress (AS) reduces anti-tumor response by decreasing the frequency and function of CD8+ T- cells in the tumor microenvironment (TME), resulting in an increase in those with an “exhausted” phenotype.1 Additionally, AS increases the quantity and immunosuppressive phenotype of myeloid-derived suppressor cells (MDSC) in the TME.2 The data above suggests that β-2 AR acts akin to a tumorigenic IC which can be abrogated by using P, a well-known and highly cost efficient non-selective β-blocker. Synergistic activity of anti-PD-1 with P has been reported in several murine tumor models, including the B-16 OVA mouse model.3,4 A retrospective study has shown an improvement in overall survival (OS) in patients (pts) with metastatic melanoma (MM) treated concurrently with non-selective β-blocker and immunotherapy.5 This formed the basis for our phase I study of the combination of P (at dose levels; 10 mg, 20 mg BID, and 30mg BID) and pem 200 mg every 3 weeks in pts with MM. Our published phase I results found all 3 dose levels of P to be well tolerated, and an objective response was observed in 7/9 pts.6 A decrease in perceived stress score (PSS) in pts over time was observed. Intra-tumor ratio of (CD4+T cells + CD8+T-cells)/(MDSC+ Treg) >1 in the pre-treatment biopsy was predictive of treatment response. Based on the results of the phase I study, we chose P 30 mg BID as the recommended phase II dose. These results, though preliminary, strongly support our subsequent phase II clinical trial. Methods: In this prospective, single-arm, phase II, multicenter trial, pts with unresectable stage III/IV MM and measurable disease per RECIST v1.1 will be treated with P (30 mg BID) + Pem. Pts with active CNS disease, prior therapy with PD-1/PD-L1 inhibitors, or contraindications to β-blocker are excluded. The primary objective is to evaluate the overall response rate (ORR) by immune-modified RECIST v1.1. The secondary objectives are the assessment of progression free survival and OS. A Simon two-stage design will be employed, requiring a minimum of 29 pts (17 in stage 1 and 12 in stage 2) to achieve approximately 80% power to detect a 20% increase (0.35 to 0.55) in the ORR. As an exploratory analysis, we will further report a) Baseline and on-treatment PSS and b) Chronotropic effect of P after 5-minute treadmill walk as a biomarker of response; c) Post therapy changes in the TME, with a 12 week on therapy optional biopsy d) Peripheral blood changes in T cell and MDSC subsets, and cytokines/chemokines. To date, 10 pts have been accrued on the study (NCT0384836). Citation Format: Benjamin Switzer, Manu R. Pandey, Alexandra Valentine, Agnieszka Witkiewicz, Erik Knudsen, Kristopher Attwood, Joseph Tario, Pauline Funchain, Joseph J. Drabick, Hemn Mohammadpour, Marc S. Ernstoff, Igor Puzanov, Elizabeth A. Repasky, Shipra Gandhi. β-2 adrenergic receptor (AR): Another immune checkpoint (IC)" A phase II clinical trial of propranolol (P) with pembrolizumab (Pem) in patients with unresectable stage III and stage IV melanoma [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 CT568.

Background: Oncolytic viruses selectively infect tumors and activate antitumor immune responses via innate and adaptive pathways, leading to immunogenic cell death and potentiating the efficacy of immune checkpoint inhibitors. MEDI9253 is a recombinant Newcastle disease virus (NDV) that incorporates a human transgene encoding the immunostimulatory cytokine interleukin (IL)-12, which leads to tumor cell lysis and localized IL-12 expression. Preclinical studies show that MEDI9253 induces PD-L1 expression and recruits innate and adaptive immune cells to the tumor microenvironment (TME) and indicate that its antitumor activity is enhanced by concurrent PD-L1 blockade. This clinical study is evaluating intravenous (IV) MEDI9253 in combination with the anti-PD-L1 antibody durvalumab in patients with selected advanced solid tumors. Methods: This is a phase I, multicenter, open-label, dose escalation and dose expansion trial (NCT04613492) enrolling patients with microsatellite-stable colorectal cancer (MSS-CRC), renal cell carcinoma (RCC) or melanoma. Eligibility criteria include progressed/refractory disease or intolerance to all prior lines of therapy with proven survival benefit for recurrent/metastatic disease. Patients must have life expectancy ≥12 weeks by GRIm score; histologically documented disease; adequate performance status (ECOG 0-1); adequate organ function; and presence of RECIST v1.1 measurable disease amenable to repeated biopsy. Exclusion criteria include untreated/uncontrolled metastatic CNS involvement. Patients must take precautions to prevent the theoretical risk of NDV transmission to humans and birds. The trial will enroll up to ~192 patients across 30 centers globally. The dose escalation phase will evaluate a single dose of IV MEDI9253 with sequential IV durvalumab, then multiple-dose cohorts of up to 4 ascending dose levels of MEDI9253 with sequential or concurrent durvalumab. The dose expansion phase will include 3 cohorts of ~20 patients, each enrolling a single tumor type. In both phases, durvalumab will be dosed for up to 2 years or until disease progression, clinical deterioration, withdrawal of consent or unacceptable toxicity. Pretreatment and on-treatment tumor biopsies are required for patients in multiple-dose cohorts. The primary objectives are evaluating the safety, tolerability and incidence of dose-limiting toxicities of MEDI9253 and identifying the optimal dose/schedule in combination with durvalumab. Secondary objectives include assessing initial efficacy (response and progression-free survival by RECIST v1.1, and overall survival), pharmacodynamics in the TME, immunogenicity, and pharmacokinetics (viremia and IL-12). The trial is recruiting. Citation Format: Noelia Purroy, Nicholas Durham, Marc Phillips, Maureen M. Hattersley, Lindsey Jung, Diwakar Davar, Dmitriy Zamarin, Tanner M. Johanns, Igor Puzanov. First-in-human trial of intravenous MEDI9253, an oncolytic virus, in combination with durvalumab in patients with advanced solid tumors [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 CT218.

Background: Cami, an investigational anti-CD25, pyrrolobenzodiazepine-based antibody drug conjugate, imparts cytotoxicity on CD25+ regulatory T cells (Tregs), leading to immunomodulatory effects (eg, modifying effector T cell [Teff]:Treg intratumoral balance). Objective: Describe the pharmacokinetics (PK) and circulating immune cell profile of Cami monotherapy and in combination with PEM in patients with advanced solid tumors. Methods: In the dose-escalation phase 1b trial of Cami (NCT03621982) in patients with advanced solid tumors after failure of recommended therapies, we investigated Cami monotherapy (n=44; doses: 20, 30, 45, 60, 80, 100, 125, and 150 µg/kg every 3 weeks [Q3W]) and Cami combination therapy (n=12; doses: 30, 45, and 60 µg/kg with PEM 200 mg Q3W). Serum conjugated antibody (cAb) and total antibody (tAb) were quantified by a validated chemoimmunoluminescence assay. Soluble CD25 was quantified by a qualified enzyme-linked immunoassay. Circulating immune cell absolute counts were assessed by flow cytometry for Tregs (FoxP3+CD25+CD127low) as a fraction of absolute CD4+ cells, Teff (CD8+), and Teff:Treg. Statistical analyses were performed using a linear mixed-effects model (maximum likelihood) for the biomarker effects model with cAb area under the curve (AUC) during cycle 1, therapy (monotherapy vs combination), and treatment cycle as fixed effects and log AUC slope with intercept by subject or visit day as random effects. Results: PK analysis found Cmax and AUC of cAb and tAb increased during cycles 1 and 2 with Cami monotherapy and combination therapy across the range of doses. Variability of AUCinf for cAb in cycle 1 appeared modest to marked across discrete dose groups (CV=14.7-98.1%). The clearance of cAb ranged from 1.34 to 3.52 L/day in cycle 1 with no apparent differences between monotherapy and combination therapy. Biomarker modeling demonstrated that cAb AUC and cycle were associated with a significant Tregs depletion and a significant positive effect on Teff:Treg ratio but with no relevant effect on Teff. Within cycle, treatment-related modulation of Teff and Tregs was observed for all doses and conditions. Soluble CD25 appears to be significantly positively affected by cycle 2 treatment. Conclusions: PK exposure of Cami was dose-related with varying degrees of interpatient variability. Circulating Tregs were significantly decreased and Teff:Treg was significantly increased by Cami exposure, demonstrating the intended immunomodulatory effect of Cami in circulation and suggesting that a combination approach with Cami could address an immune-resistance mechanism. Future analyses will consider discrete PEM effect, correlates to tumor biopsy expression and response, and combined Cami+PEM effect in tumor biopsies. Funding: ADC Therapeutics; medical writing: CiTRUS Health Group. Citation Format: Igor Puzanov, Christopher T. Chen, Patricia LoRusso, Kyriakos P. Papadopoulos, Shivaani Kummar, Erika Hamilton, Yvan LeBruchec, Karin Havenith, Serafino Pantano, Marie Toukam, Jens Wuerthner, Joseph Boni. Effect of camidanlumab tesirine (Cami) as monotherapy and in combination with pembrolizumab (PEM) on the immune cell profile in patients with selected advanced solid tumors [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 4151.

LBA4500 Background: Patients (pts) who undergo resection of renal cell carcinoma (RCC) with curative intent remain at risk for disease relapse. We conducted a phase III, double-blind, placebo (PB)-controlled, intergroup study to determine the effect of adjuvant treatment with the mTOR inhibitor everolimus (EVE) on recurrence-free survival (RFS). Methods: Pts with treatment-naïve, non-metastatic, fully-resected RCC at intermediate high- (pT1 G3-4 N0 to pT3a G1-2 N0) or very high-risk (pT3a G3-4 to pT4 G-any or N+) for recurrence were randomized 1:1 to EVE 10 mg PO daily x 54 weeks or PB within 12 weeks of radical or partial nephrectomy. Randomization was stratified by risk group, histology (clear vs. non-clear cell), and performance status (0 vs. 1). RFS was the primary end point; secondary endpoints included overall survival (OS) and adverse events (AEs). The study was designed to detect an 18% reduction in the risk of RFS with EVE compared to PB, corresponding to an improvement of median RFS from 6.75 (based on E2805 ASSURE) to 8.23 years. Final analysis, using a stratified logrank test, was to occur after 804 total events or by 3/2022, whichever occurred first. Results: Between 4/2011 and 9/2016, 1545 pts were randomized to EVE (n = 775) or PB (n = 770). Overall pt characteristics included: intermediate high-/very high-risk 45%/55%; clear cell/non-clear cell 83%/17%. The DSMC recommended study continuation after each of 4 pre-specified interim analyses. 556 DFS events among 1499 eligible pts occurred by the time of final study analysis on 2/23/2022. The median follow-up was 76 months. RFS was improved with EVE vs. PB (HR 0.85, 95% CI, 0.72 – 1.00; P1-sided= 0.0246), narrowly missing the pre-specified, one-sided significance level of 0.022 which accounted for interim analyses. Median RFS was not reached; the 6-year RFS estimate was 64% for EVE and 61% for PB. RFS improvement with EVE vs. PB was observed in the very high-risk group (HR 0.79, 95% 0.65-0.97; P1-sided= 0.011) but not in the intermediate high-risk group (HR 0.99, 95% CI 0.73-1.35, P1-sided= 0.48) ( P for interaction = 0.22). With 290 deaths, OS was similar between arms (HR 0.90, 95% CI, 0.71 – 1.13; P1-sided= 0.178). Fewer pts completed all 54 weeks of study treatment in the EVE group (45% v 69%). In the EVE group, 37% withdrew due to AEs (vs 5% in PB). Grade 3-4 AEs occurred in 46% of pts treated with EVE and 11% with PB. The most common grade 3-4 AEs were mucositis (14% v 0%), hypertriglyceridemia (11% vs. 2%), and hyperglycemia (5% vs. 0%). Conclusions: Adjuvant EVE improved RFS in RCC pts after nephrectomy, but the nominal significance level was narrowly missed. The RFS improvement was seen despite a high rate of early treatment discontinuation. A 21% improvement in RFS with EVE was observed in pts with very high-risk disease, a group for whom adjuvant therapy may be most relevant. Clinical trial information: NCT01120249.

2619 Background: Immune checkpoint inhibitors (ICIs) have made significant improvements in the treatment of cancer patients (pts), but many continue to experience primary or secondary resistance. Here, we leveraged clinical and genomic data to identify prognostic biomarkers in pts treated with ICIs utilizing a pan-cancer approach. Methods: Pts were enrolled to the Total Cancer Care protocol across 18 cancer centers within the Oncology Research Information Exchange Network (ORIEN). RNA-seq was performed on tumors following the RSEM pipeline and gene expressions were quantified as Transcript Per Million (TPM) and were logarithmically normalized. An Auto-Encoder Survival Deep Network (AE-SDN) architecture was developed that combined the reconstruction loss of AE with Cox regression for modeling time to event. For comparison, immunoscore for each pt was calculated based on the estimated densities of tumor CD3+ and CD8+ T cells (Galon, 2020) utilizing CIBERSORTx. The quality of overall survival (OS) predictions was assessed using Harrell’s concordance index (C-index). Log-rank test was used to assess stratified group differences (by ICI or cancer histology) along with Kaplan-Meier (KM) survival analysis of AE-SDN and immunoscore. Results: Pts (n=522) with 4 cancer types including melanoma (n=125), renal cell carcinoma (n=149), non-small cell lung cancer (n=128) and head and neck cancer (n=120) treated with 6 ICI regimens were included in this analysis. ICI regimens were nivolumab (n=219), pembrolizumab (n=202), ipilimumab+nivolumab (n=69), ipilimumab (n=30), avelumab (n=1) and cemiplimab (n=1). The Table summarizes the overall C-index and associated 95% CIs and log-rank P values for the entire cohort (regardless of histology) resulting from our proposed AE-SDN model and the separate estimated immunoscore categorization. AE-SDN top selected genes were mostly related to immunity, carcinogenesis and tumor suppression. The corresponding KM plots showed significantly wider separations of the survival curves in favor of our proposed AE-SDN model relative to the immunoscore with more than 20% improvement in prediction power. Conclusions: Deep network machine learning analysis is a promising approach to identifying relevant prognostic biomarkers in cancer pts treated with ICI. This may lead to novel therapeutic predictive signatures and identification of mechanisms of ICI resistance. Our AE-SDN gene expression signature was significantly prognostic and outperformed the estimated CD3+, CD8+ T Cell immunoscore. Further refinements to our prediction power are ongoing along with more advanced neural network architectures to elucidate related functional pathways. [Table: see text]

2618 Background: Despite the significant improvements in treating cancer with immune checkpoint inhibitors (ICIs), many patients (pts) do not achieve disease control. Using Oncology Research Information Exchange Network (ORIEN) Avatar real-world data conducted under the Total Cancer Care protocol we investigate predictive biomarkers of ICI benefits in pts with advanced malignancies. Methods: Clinical data were normalized as part of ORIEN Avatar. RNA-seq was performed on tumor samples following the RSEM pipeline and gene expressions were quantified as Transcript Per Million (TPM). Gene expressions (GE) were log2(TPM+1) transformed. Mann-Whitney U-test was used to compute differences between groups, and Kaplan-Meier survival analysis was performed. Results: Pts (n=1214) with 27 cancer types treated with ICIs were retrieved from the database, where 1143 and 875 patients were profiled by WES and RNA-seq, respectively. 804 pts had both WES and RNA-seq data. The top six cancer types were renal cell carcinoma (n=206), non-small cell lung cancer (n=173), head and neck cancer (n=157), melanoma (n=154), sarcomas (n=99) and bladder cancer (n=87). The ICI regimens included therapy with atezolizumab (n=87), avelumab (n=12), cemiplimab (n=6), ipilimumab (n=47), nivolumab (n=424), pembrolizumab (n=525) and ipilimumab+nivolumab (n=113). Median overall survival (OS) for the entire cohort was 21.9 months. Patients had significant improvement in OS if ICI was given in the first line ( P

TPS9589 Background: The treatment of melanoma has improved markedly with the emergence of new immune therapies, and both anti-PD-1 monotherapy and the combination of the anti-PD-1 antibody nivolumab and anti-CTLA-4 therapy ipilimumab are now considered standard-of-care in the unresectable or metastatic (advanced) melanoma setting. However, many patients have primary or acquired resistance to these therapies, thereby underpinning the need for more effective approaches. IO102-IO103 is a potentially first-in-class, dual-antigen, immune-modulatory therapy targeting the key cancer immune resistance pathways mediated by IDO and PD-L1. The ability of IO102 and IO103 to respectively activate the specific T cells that recognize these checkpoint molecules and directly modulate immune regulation has previously been demonstrated both preclinically and in human clinical trials. A synergistic anti-tumor response upon treatment against both IDO and PD-L1 has also previously been demonstrated in a preclinical model where IDO and PD-L1 were expressed by different cells in the tumor microenvironment. Due to the distinctive mechanisms of action of IO102-IO103 and anti-PD-1 antibodies, there may be a further synergistic effect when treatment is combined. A previous Phase 1/2 trial investigating the use of IO102-IO103 plus nivolumab in patients with anti-PD-1-naïve metastatic melanoma has demonstrated promising anti-tumor activity with an overall response rate (ORR) of 80%, median progression-free survival (PFS) of 26 months and a manageable safety profile (NCT03047928; Kjeldsen et al, Nat Med 2021). Methods: This is a Phase 3, multicenter, open-label, randomized, 2-arm trial investigating the efficacy and safety of IO102-IO103 plus pembrolizumab versus pembrolizumab alone (EudraCT: 2021-004594-32; ClinicalTrials.gov No: NCT05155254). Inclusion criteria include: adult patients with untreated, unresectable (Stage III), or metastatic (Stage IV) melanoma; > 6 months since last dose of (neo)adjuvant treatment with targeted or immune therapy (in those previously treated); and ≥1 measurable lesion by RECIST v1.1. Primary endpoint is PFS by blinded independent central review. Secondary endpoints include ORR, durable response rate, complete response rate, duration of response, time to response, disease control rate, overall survival, and safety/tolerability. Target enrollment is 300 patients at > 100 sites in 20 countries. Patients are randomized 1:1 to receive either pembrolizumab 200 mg intravenously (IV) every 3 weeks up to 2 years or pembrolizumab 200 mg IV every 3 weeks up to 2 years with dual-antigen IO103-IO102 85-85 µg and Montanide adjuvant subcutaneously on Day 1 and 8 of cycle 1 and 2 and on Day 1 of each cycle thereafter. Enrolment for the study is ongoing. Clinical trial information: EudraCT: 2021-004594-32; ClinicalTrials.gov No: NCT05155254.

Purpose BRAFV600 mutations are frequently found in several glioma subtypes, including pleomorphic xanthoastrocytoma (PXA) and ganglioglioma and much less commonly in glioblastoma. We sought to determine the activity of vemurafenib, a selective inhibitor of BRAFV600, in patients with gliomas that harbor this mutation. Patients and Methods The VE-BASKET study was an open-label, nonrandomized, multicohort study for BRAFV600-mutant nonmelanoma cancers. Patients with BRAFV600-mutant glioma received vemurafenib 960 mg twice per day continuously until disease progression, withdrawal, or intolerable adverse effects. Key end points included confirmed objective response rate by RECIST version 1.1, progression-free survival, overall survival, and safety. Results Twenty-four patients (median age, 32 years; 18 female and six male patients) with glioma, including malignant diffuse glioma (n = 11; six glioblastoma and five anaplastic astrocytoma), PXA (n = 7), anaplastic ganglioglioma (n = 3), pilocytic astrocytoma (n = 2), and high-grade glioma, not otherwise specified (n = 1), were treated. Confirmed objective response rate was 25% (95% CI, 10% to 47%) and median progression-free survival was 5.5 months (95% CI, 3.7 to 9.6 months). In malignant diffuse glioma, best response included one partial response and five patients with stable disease, two of whom had disease stabilization that lasted more than 1 year. In PXA, best response included one complete response, two partial responses, and three patients with stable disease. Additional partial responses were observed in patients with pilocytic astrocytoma and anaplastic ganglioglioma (one each). The safety profile of vemurafenib was generally consistent with that of previously published studies. Conclusion Vemurafenib demonstrated evidence of durable antitumor activity in some patients with BRAFV600-mutant gliomas, although efficacy seemed to vary qualitatively by histologic subtype. Additional study is needed to determine the optimal use of vemurafenib in patients with primary brain tumors and to identify the mechanisms driving differential responses across histologic subsets.

Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1+CD8+ T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8+ T cells. Furthermore, an increase in the frequency of the CX3CR1+ subset in circulating CD8+ T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy., There is an urgent need to discover blood-based biomarkers to predict response to immune checkpoint inhibitors (ICI). Here the authors show that effective ICI therapy correlates with increased frequency of circulating CX3CR1+CD8+ T cells in preclinical tumor models and in a cohort of patients with non-small cell lung cancer treated with anti-PD-1.

ObjectiveLong-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.Patients and methodsAnalysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147.ResultsAdverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n=79) versus did not (n=384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p=0.1104). Patients who did (n=17) versus did not (n=62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.ConclusionsThese results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.Clinical trial registryNCT01295827, NCT01704287, NCT01866319.

Purpose: Biomarkers are needed in patients with non–clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. Patients and Methods: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS). Results: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib. Conclusions: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.

Background This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). Results Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. Clinical trial registration ClinicalTrials.gov, NCT01058707.

International audience; As part of the 2019 Immunotherapy Bridge congress (December 4–5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report.

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.

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI will markedly improve current treatment regimens. Here, we investigated a role of CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, in predicting response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increased the frequency and T-cell receptor clonality of the peripheral CX3CR1+CD8+ T-cell subset that included an enriched repertoire of tumor-specific and tumor-infiltrating CD8+ T cells. Furthermore, an increase in the frequency of the CX3CR1+ subset in circulating CD8+ T cells early after initiation of anti-PD-1 therapy correlated with response and survival in patients with non-small cell lung cancer (NSCLC). Taken together, these data support T-cell CX3CR1 expression as a blood-based dynamic biomarker to predict response to ICI therapy.

BackgroundUveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined.MethodsWe conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology.Results89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%).ConclusionsDual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.

Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions.

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAF-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety. Planned (V600K vs. non-V600K mutations) subgroup analyses were carried out. Thirty-one patients were enrolled; 13 (42%) had V600K mutations and 18 (58%) had other mutations. Investigator-assessed confirmed that the best overall response rate was 23% (95% confidence interval=10-41%) in the overall population, and was similar between patients with V600K mutations (23%; 95% confidence interval=5-54%) versus other mutations (22%; 95% confidence interval=6-48%). Responses were observed in patients with V600K (n=3), V600E2 (n=1), V600R (n=1), L597S (n=1) and D594G (n=1) mutations. No new safety signals were reported. Vemurafenib showed activity in patients with advanced melanoma with rarer BRAF mutations.

BackgroundMupadolimab (mupa) is a humanized FcγR binding-deficient IgG1 anti-CD73 antibody that has agonistic properties.1 CD73 is involved in production of adenosine and in cellular trafficking. Mupa reacts with the majority of circulating B cells leading to activation and expression of differentiation markers CD69, CD138 and CD38, and transformation into plasmablasts with secretion of IgM and IgG. B cell activation provided the rationale to develop mupa for immunotherapy of cancer and Covid-19. Intratumor HPV specific B cells have been reported in HNSCC.2 This report describes properties of mupa and the early signs of clinical activity in HPV+ HNSCC.MethodsELISA and flow cytometry were used to measure binding of anti-CD73. Humanized NSG-SGM3 mice were used to evaluate effects of Mupa on human anti-SARS CoV2 spike protein (SP) response. CD73 expression in biopsies was measured by immunohistochemistry. Mupa (IV q 3 weeks) with or without pembrolizumab is being evaluated in an ongoing phase 1 trial in patients with refractory cancers.ResultsMupa binding to CD73 was blocked by APCP, an analog of adenosine diphosphate that locks CD73 in the closed conformation, indicating mupa binding to the open conformation. Cross blocking and cellular internalization studies showed that mupa is distinct from other anti-CD73 antibodies such as MEDI9447 and AD2. NSG-SGM3 mice were immunized with 50 µg SP subcutaneously and treated with mupa 10mg/kg or control IgG IP. Mupa treated animals mounted an antigen specific human anti-SP response; no antibody responses were seen in controls (P=0.02). In the dose-escalation portion of the phase 1 trial, mupa doses of ≥12 mg/kg saturated CD73 sites on circulating B cells. High stromal CD73 expression was observed in HPV+ HNSCC biopsies from 5 evaluable patients with chemotherapy and anti-PD1 refractory disease, and tumor regression was seen in 2 of these patients receiving 7 and 16 cycles of ≥12 mg/kg mupa without pembrolizumab. Safety of mupa+pembrolizumab was evaluated in 16 patients with no MTD reached and no changes in serum immunoglobulins. Transient reductions in circulating CD73 B cells were observed consistent with redistribution to lymphoid tissues.ConclusionsCD73 plays a role in B cell activation and differentiation. Mupa is an antibody with agonistic activity that stimulates B cells and enhances antigen specific antibody production. This activity supports a strategy to combine mupa with pembrolizumab to enhance both humoral and cellular immunity in the treatment of viral associated cancers such as HPV+HNSCC, and viral infections.Trial RegistrationNCT03454451ReferencesWillingham S, Criner G, Hill C, Hu S, Rudnick J, Daine-Matsuoka B, Hsieh J, Mashhedi H, Hotson A, Brody J, Marron T, Piccione E, Buggy J, Mahabhashyam S, Jones W, Mobasher M, Miller R. Characterization and Phase 1 trial of a B cell activating anti-CD73 antibody for the immunotherapy of COVID-19. medRxiv, 2020; https://doi.org/10.1101/2020.09.10.20191486.Wieland A, Patel M, Cardenas M, Eberhardt C, Hudson W, Obeng R, Griffith C, Wang X, Chen Z, Kissick H, Saba N, Ahmed R. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature 2020; https://doi.org/10.1038/s41586-020-2931-3.Ethics ApprovalThe study was approved by Western IRB, approval number 1-1066703-1. Participants gave informed consent before taking part.

BackgroundIntratumoral (IT) cancer therapies may enhance T cell activation and tumor infiltration when combined with systemic checkpoint blockade. This approach may improve treatment of advanced breast cancer, which is commonly resistant to immune therapy.MethodsA multicenter basket-style trial (NCT02643303) was performed in patients with advanced solid tumors, who received polyICLC IT 1mg x 6, then intramuscular (IM) x 3, combined with intravenous (IV) durvalumab 1500 mg q4W. Most were assigned to cohorts also receiving tremelimumab: 10 mg IT or 75 mg IV. Goals were to assess tolerability and clinical activity. Treated tumors were evaluated for immune infiltrates on days (d) 0, 15, and 29 by multiparameter immunofluorescence histology. A strong signal for clinical response was in breast cancer patients; thus, an expansion cohort was enrolled. We report analysis of that breast cancer subgroup.ResultsNineteen participants with treatment-refractory recurrent breast cancer with median 4 prior lines of therapy were enrolled and treated with IV durvalumab and IT/IM polyICLC. Seventeen also received tremelimumab (15 IT, 2 IV). Common treatment-related AEs were fatigue, injection site pain, and chills. There was one dose-limiting toxicity in a participant who received tremelimumab IV, and died with severe hyponatremia (DLT) and progressive disease. Objective clinical responses (1 complete; 4 partial (1 unconfirmed)) were observed in 5 (26%), including 2/9 patients with triple-negative breast cancer (TNBC) and 3/10 with non-TNBC. Median OS was longer for those with CR, PR, or SD (not reached) vs. those with PD or not evaluable (5 months): two responders remain alive at 34+ and 40+ months. In injected tumors, there were significant increases from d0 to d29 in numbers/mm2 of CD8+ T cells, CD20+ B cells, mature dendritic cells (DC), macrophages, and CD56+ NK cells, and in CD8+ cells with antigen-experience (CD45RO), cytotoxic function (granzyme B), activation (ICOS1), or proliferation (Ki67). CD8+ cells expressing LAG3 and TIM3 increased, as did PDL1+ tumor cells and stromal cells. There were no differences in cells expressing IDO, ARG1, CD39, or CD73. Among patients with objective response, vs. all others, proportions of intratumoral CD8+ cells expressing Ki67 increased (p < 0.04).ConclusionsIT tremelimumab and polyICLC plus systemic durvalumab is safe and has clinical activity in patients with advanced TNBC and non-TNBC. The therapy enhances intratumoral immune effectors and markers of T cell function in hypothesis-generating data that warrant confirmatory studies. Clinical response was associated with longer survival and increased CD8 T cell proliferation.Trial RegistrationNCT02643303Ethics ApprovalThe study has been performed with approval of the institutional review boards of each participating institution (Roswell Park Cancer Institute: STUDY 00000121/I291016; Mount Sinai School of Medicine: IRB-17-01692; University of Virginia: IRB # 19276; Cleveland Clinic: 18-694; Toledo: 300176; Dartmouth: STUDY00031630; Emory: IRB00099445). All participants give informed consent before enrolling and participating. The study was also performed with approval from the FDA

The clinical and immunologic implications of the SARS-CoV-2 pandemic for patients with cancer receiving systemic anticancer therapy have introduced a multitude of clinical challenges and academic controversies. This review summarizes the current evidence, discussion points, and recommendations regarding the use of immune checkpoint inhibitors (ICIs) in patients with cancer during the SARS-CoV-2 pandemic, with a focus on patients with melanoma and renal cell carcinoma (RCC). More specifically, we summarize the theoretical concepts and available objective data regarding the relationships between ICIs and the antiviral immune response, along with recommended clinical approaches to the management of melanoma and RCC patient cohorts receiving ICIs throughout the course of the COVID-19 pandemic. Additional insights regarding the use of ICIs in the setting of current and upcoming COVID-19 vaccines and broader implications toward future pandemics are also discussed.

Background: IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, but unlike IL-2, IL-15 does not expand regulatory T cells (Tregs). In addition, unlike IL-2, IL-15 does not mediate activation-induced cell death and is expected to have an improved therapeutic index compared to IL-2. KD033 is a fusion antibody molecule generated by combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 (or its mouse cross reactive surrogate molecule, srKD033) has been extensively characterized in multiple in vitro and in vivo nonclinical studies to understand the pharmacology, pharmacokinetic (PK) and toxicology properties. The fusion of anti-PD-L1 antibody to IL-15 significantly increases the maximal-tolerated dose (MTD) of srKD033 in mice compared to free-IL-15. The increased safety and efficacy of PD-L1-targeted IL-15 observed in pre-clinical studies warranted evaluation of KD033 in humans. Methods: This is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety and tolerability and the MTD of KD033. KD033 is administered as an IV infusion over 30 minutes every 14 days (i.e., a cycle equals 2 weeks). The starting dose of KD033 is 3 µg/kg, with step-up dosing to 12.5 µg/kg in the first cohort of 3 subjects. After the first cohort, the dose escalation will use a standard 3+3 design with planned doses from 25 µg/kg to 600 µg/kg. The dose escalation phase will be followed by one expansion cohort, which will enroll patients who received PD-1/PD-L1 inhibitor but have either progressed or are refractory to therapy. Secondary objectives include characterization of PK and immunogenicity, evaluation of immune correlates that will potentially differentiate the impact of KD033 versus monotherapy as well as investigate IL-15 biology and determine best overall response and duration of response. (NCT04242147) Citation Format: Jason J. Luke, Anthony J. Olszanski, Igor Puzanov, Dan Lu, Adrian Hackett, Stella Martomo, Jeegar Patel, Olivier Schueller, Alessandro Mora, Miranda L. Schlitt, Linghui Li. A phase 1 multiple ascending dose study to investigate the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of KD033 in subjects with metastatic or locally advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT227.