Showing papers by "Richard D. Carvajal published in 2021"

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

Abstract: Background Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with meta...

OncoTree: A Cancer Classification System for Precision Oncology.

Abstract: PURPOSECancer classification is foundational for patient care and oncology research. Systems such as International Classification of Diseases for Oncology (ICD-O), Systematized Nomenclature of Medi...

Clinical impact of COVID-19 on patients with cancer treated with immune checkpoint inhibition.

Abstract: Background Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer. Methods We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality. Findings Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off. Interpretation COVID-19–related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.

OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and/or Ipilimumab in Patients With Advanced Solid Tumors.

Abstract: Purpose: This phase I/IIa study (NCT02737475) evaluated the safety and activity of BMS-986178, a fully human OX40 agonist IgG1 mAb, ± nivolumab and/or ipilimumab in patients with advanced solid tumors. Patients and Methods: Patients (with non–small cell lung, renal cell, bladder, other advanced cancers) received BMS-986178 (20–320 mg) ± nivolumab (240–480 mg) and/or ipilimumab (1–3 mg/kg). The primary endpoint was safety. Additional endpoints included immunogenicity, pharmacodynamics, pharmacokinetics, and antitumor activity per RECIST version 1.1. Results: Twenty patients received BMS-986178 monotherapy, and 145 received combination therapy in various regimens (including two patients receiving nivolumab monotherapy). With a follow-up of 1.1 to 103.6 weeks, the most common (≥5%) treatment-related adverse events (TRAEs) included fatigue, pruritus, rash, pyrexia, diarrhea, and infusion-related reactions. Overall, grade 3–4 TRAEs occurred in one of 20 patients (5%) receiving BMS-986178 monotherapy, six of 79 (8%) receiving BMS-986178 plus nivolumab, zero of two receiving nivolumab monotherapy, six of 41 (15%) receiving BMS-986178 plus ipilimumab, and three of 23 (13%) receiving BMS-986178 plus nivolumab plus ipilimumab. No deaths occurred. No dose-limiting toxicities were observed with monotherapy, and the MTD was not reached in either the monotherapy or the combination escalation cohorts. No objective responses were seen with BMS-986178 alone; objective response rates ranged from 0% to 13% across combination therapy cohorts. Conclusions: In this study, BMS-986178 ± nivolumab and/or ipilimumab appeared to have a manageable safety profile, but no clear efficacy signal was observed above that expected for nivolumab and/or ipilimumab.

A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors.

Abstract: Background LY3022855 is a recombinant, immunoglobulin, human monoclonal antibody targeting the colony-stimulating factor-1 receptor. This phase 1 trial determined the safety, pharmacokinetics, and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments. Methods In Part A (dose-escalation), patients received intravenous (IV) LY3022855 25/50/75/100 mg once weekly (QW) combined with durvalumab 750 mg once every two weeks (Q2W) IV or LY3022855 50 or 100 mg QW IV with tremelimumab 75/225/750 mg once every four weeks. In Part B (dose-expansion), patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC) received recommended phase 2 dose (RP2D) of LY3022855 from Part A and durvalumab 750 mg Q2W. Results Seventy-two patients were enrolled (median age 61 years): Part A = 33, Part B = 39. In Part A, maximum tolerated dose was not reached, and LY3022855 100 mg QW and durvalumab 750 mg Q2W was the RP2D. Four dose-limiting equivalent toxicities occurred in two patients from OC cohort. In Part A, maximum concentration, area under the concentration-time curve, and serum concentration showed dose-dependent increase over two cycles of therapy. Overall rates of complete response, partial response, and disease control were 1.4%, 2.8%, and 33.3%. Treatment-emergent anti-drug antibodies were observed in 21.2% of patients. Conclusions LY3022855 combined with durvalumab or tremelimumab in patients with advanced NSCLC or OC had limited clinical activity, was well tolerated. The RP2D was LY3022855 100 mg QW with durvalumab 750 mg Q2W. ClinicalTrials.gov ID: NCT02718911 (Registration Date: May 3, 2011).

The Latest on Uveal Melanoma Research and Clinical Trials: Updates from the Cure Ocular Melanoma (CURE OM) Science Meeting (2019).

Abstract: Uveal melanoma (UM) is a rare cancer in adults but its treatment is one of the clinical unmet needs in the melanoma field. Metastatic disease develops in approximately 50% of patients and is associated with poor survival due to the lack of effective treatment options. It provides a paradigm for cancers that show evidence of aberrant G-protein coupled receptor signaling, tumor dormancy, liver-selective metastatic tropism and are associated with the loss of the BAP1 tumor suppressor. At the Melanoma Research Foundation (MRF) CURE OM Science Meeting at the Society for Melanoma Research (SMR) Meeting held in Utah, on November 20, 2019, clinicians and researchers presented findings from their studies according to three themes within UM: 1) ongoing clinical trials; 2) molecular determinants; and 3) novel targets that could be translated into clinical trials. This meeting underscored the high interest in the UM research field and the unmet need for effective treatment strategies for late-stage disease. Findings from ongoing clinical trials are promising and multiple studies show how novel combinatorial strategies increase response rates. Novel targets and tumor vulnerabilities identified bioinformatically or through high-throughput screens also reveal new opportunities to target UM. The future directions pursued by the UM research field will likely have impact of other cancer types, which harbor similar genetic alterations and/or show similar biological properties.

LY3022855, an anti–colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial

Abstract: Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti–CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non–weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non–weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4–6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non–weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).

Co-primary endpoint of overall survival for tebentafusp (tebe)-induced rash in a phase 3 randomized trial comparing tebe versus investigator’s choice (IC) in first-line metastatic uveal melanoma.

Abstract: 9527Background: Tebe is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells. In this Phase (Ph) 3, randomi...

A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma

Abstract: Uveal melanoma (UM) is a rare subset of melanoma characterized by the presence of early initiating GNAQ/11 mutations, with downstream activation of the PKC, MAPK, and PI3Kα pathways. Activity has been observed with the PKC inhibitors sotrastaurin (AEB071) and darovasertib (IDE196) in patients with UM. Inhibition of the PI3K pathway enhances PKC inhibition in in vivo models. We therefore conducted a phase Ib study of sotrastaurin in combination with the PI3Kα inhibitor alpelisib to identify a tolerable regimen that may enhance the activity of PKC inhibition alone. Patients with metastatic uveal melanoma (n = 24) or GNAQ/11 mutant cutaneous melanoma (n = 1) were enrolled on escalating dose levels of sotrastaurin (100-400 mg BID) and alpelisib (200-350 mg QD). The primary objective was to identify the maximum tolerated dose (MTD) of these agents when administered in combination. Treatment-related adverse events (AE) occurred in 86% (any grade) and 29% (Grade 3). No Grade 4-5-related AEs occurred. Dose Level 4 (sotrastaurin 200 mg BID and alpelisib 350 mg QD) was identified as the maximum tolerated dose. Pharmacokinetic analysis demonstrated increasing concentration levels with increasing doses of sotrastaurin and alpelisib, without evidence of interaction between agents. Pharmacodynamic assessment of pMARCKS and pAKT protein expression with drug exposure suggested modest target inhibition that did not correlate with clinical response. No objective responses were observed, and median progression-free survival was 8 weeks (range, 3-51 weeks). Although a tolerable dose of sotrastaurin and alpelisib was identified with pharmacodynamic evidence of target inhibition and without evidence of a corresponding immunosuppressive effect, limited clinical activity was observed.

Comparing RECIST 1.1 and iRECIST in advanced melanoma patients treated with pembrolizumab in a phase II clinical trial

Abstract: To compare tumor best overall response (BOR) by RECIST 1.1 and iRECIST, to explore the incidence of pseudoprogression in melanoma treated with pembrolizumab, and to assess the impact of pseudoprogression on overall survival (OS). A total of 221 patients with locally advanced/unresectable melanoma who received pembrolizumab as part of KEYNOTE-002 trial were included in this study. Radiological assessment of imaging was centrally reviewed to assess tumor response. Incidence of discordance in BOR between RECIST 1.1 and iRECIST as well as rate of pseudoprogression were measured. OS of patients with pseudoprogression was compared with that of those with uncontrolled disease. Of the 221 patients in this cohort, 136 patients developed PD as per RECIST v1.1 and 78 patients with PD continued treatment and imaging beyond initial RECIST 1.1-defined PD. Among the 78 patients who continued therapy and imaging post-progression, RECIST 1.1 and iRECIST were discordant in 10 patients (12.8%) and pseudoprogression was encountered in 14 patients (17.9%). OS of patients with pseudoprogression was longer than that of patients with uncontrolled disease/true progression (29.9 months versus 8.0 months, p value < 0.001). Effectiveness of immunotherapy in clinical trials depends on the criterion used to assess tumor response (RECIST 1.1 vs iRECIST) with iRECIST being more appropriate to detect pseudoprogression and potentially prevent premature termination of effective therapy. Pseudoprogression was associated with improved OS in comparison with that of patients with uncontrolled disease. • Discordance between iRECIST and RECIST 1.1 was found in 12.8% of unresectable melanoma patients on pembrolizumab who continued therapy beyond initial RECIST 1.1-defined progression. • Pseudoprogression, captured with iRECIST, occurred in 17.9% and was significantly associated with improved overall survival in comparison with uncontrolled disease.

Abstract CT002: Phase 3 randomized trial comparing tebentafusp with investigator's choice in first line metastatic uveal melanoma

Abstract: Background: Metastatic uveal melanoma (mUM) has a poor prognosis with a 1-yr OS rate of 52%. No systemic treatment has proven an OS benefit in randomized trials. Tebentafusp (tebe), a bispecific consisting of an affinity-enhanced T cell receptor (TCR) fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells, has shown promising activity in previously treated mUM pts. Here, we report the primary analysis of overall survival (OS) in the intention-to-treat population (ITT) of a Ph3 trial of tebe vs. investigator9s choice (IC) as first line (1L) therapy in pts with mUM [NCT03070392]. Materials and Methods: In this randomized, open-label, Ph3 trial, 1L HLA-A*02:01+ pts with mUM were randomized 2:1 to receive tebe or IC of pembrolizumab, ipilimumab or dacarbazine, stratified by LDH. The primary endpoint was OS, defined as the time from randomization to death from any cause. Dual primary objectives were to evaluate 1) OS in the ITT population by comparing all tebe-randomized pts to all IC-randomized pts; and 2) OS in tebentafusp-treated patients with rash during week 1 versus all IC-treated patients. Secondary endpoints included safety and RECIST-defined overall response rate (ORR), progression free survival (PFS) and disease control rate (DCR). Here we present the OS in the ITT population. The study was unblinded by an independent data monitoring committee at the first pre-specified interim analysis. Investigator-reported radiographic-based endpoints were not mature at the first interim analysis. This analysis was conducted on the first interim analysis (data extracted Nov 2020). Results: 378 pts were randomized to tebe (252) or IC, including pembrolizumab (103), ipilimumab (15) or dacarbazine (7). Tebe significantly prolonged OS compared to IC (HR 0.51; 95% CI 0.36-0.71; P ULN and versus pembrolizumab IC. Most common TRAEs were skin-related (gp100+ melanocytes) or cytokine-mediated (T cell activation) and included pyrexia, pruritus, and rash. These AEs decreased in frequency and severity after the first 3-4 doses and were generally manageable with standard interventions. In the tebe arm, the rate of treatment discontinuation due to TRAEs was low ( Conclusions: In 1L treatment of mUM pts, tebe monotherapy significantly improved OS compared to IC; the first investigational therapy to improve OS in pts with mUM. Tebe had a predictable and manageable AE profile with a low rate of related discontinuation. Tebe is the first TCR therapeutic to demonstrate an OS benefit. Citation Format: Sophie Piperno-Neumann, Jessica C. Hassel, Piotr Rutkowski, Jean-Francois Baurain, Marcus O. Butler, Max Schlaak, Ryan J. Sullivan, Sebastian Ochsenreither, Reinhard Dummer, John M. Kirkwood, Anthony M. Joshua, Joseph J. Sacco, Alexander N. Shoushtari, Marlana Orloff, Richard D. Carvajal, Omid Hamid, Shaad E. Abdullah, Chris Holland, Howard Goodall, Paul Nathan. Phase 3 randomized trial comparing tebentafusp with investigator9s choice in first line metastatic uveal melanoma [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 CT002.

Abstract OT-03-02: Phase 1/2 study of a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), BDC-1001, as a single agent and in combination with an immune checkpoint inhibitor in patients with advanced HER2-expressing solid tumors

Abstract: Background: To date, no immune-based therapies beyond anti-HER2 monoclonal antibodies are approved for treating patients (pts) with HER2-driven or -expressing cancers. However, pts still develop progressive disease, and new treatment options that could achieve durable antitumor efficacy are needed. Recent studies indicate that intratumoral delivery of immunostimulatory adjuvants such as toll-like receptor (TLR) 7/8 agonists can activate tumor resident antigen-presenting cells (APCs), driving uptake, processing, and presentation of tumor neoantigens to T cells that mediate antitumor immunity. To overcome limitations associated with intratumoral delivery while leveraging superior preclinical biology, BDC-1001, a novel, systemically delivered ISAC was developed. BDC-1001 consists of an investigational biosimilar of the humanized monoclonal antibody trastuzumab that is chemically conjugated to a TLR 7/8 agonist (payload) with an intervening non-cleavable linker. BDC-1001 activates human myeloid APCs while retaining antibody-mediated effector functions such as antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). Xenograft and syngeneic tumor resistant models indicate that trastuzumab ISACs elicit potent and durable immune-mediated antitumor efficacy including complete tumor regression in a TLR- and Fc receptor-dependent manner (Ackerman et al. Cancer Res. 2019:79 [13 Suppl]; Ackerman et al. J Immunother Cancer. 2019;7:283). Importantly, BDC-1001 did not induce interstitial lung disease, cytokine release syndrome, or thrombocytopenia in non-human primate studies. A four-part phase 1/2, first-in-human study has been initiated that evaluates BDC-1001 with or without (+/-) an immune checkpoint inhibitor targeting PD-1 in pts with HER2-expressing or HER2-amplified advanced/metastatic solid tumors. Study Description: This phase 1/2 dose-escalation and dose-expansion study is enrolling up to 390 pts with advanced solid tumors that are HER2-expressing (IHC2+ or 3+ protein irrespective of gene amplification) or HER2-amplified (by in situ hybridization or next-generation sequencing) and ineligible for approved anti-HER2 treatments. The primary objectives of the dose-escalation phase are to define safety and tolerability and to determine the recommended phase 2 dose of BDC-1001 as monotherapy (Part 1) and in combination with an immune checkpoint inhibitor (Part 2). Primary endpoints of Parts 1 and 2 include incidence of 1) adverse events and severe adverse events graded according to NCI CTCAE v5.0; 2) dose-limiting toxicities within a 3+3 design; and 3) potential immune-related toxicities. BDC-1001 is administered IV over 60 min q3w at increasing doses. Once safety data are available for BDC-1001, initiation of the immune checkpoint inhibitor combination is planned. The dose-expansion phase 2 portion of the trial will evaluate preliminary antitumor activity of BDC-1001 alone (Part 3) and in combination with an immune checkpoint inhibitor (Part 4) using RECIST v1.1 and iRECIST. The primary endpoint of this dose-expansion phase is overall response rate, with secondary endpoints of duration of response, disease control rate, and progression-free survival. Exploratory objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers associated with drug exposure. These exploratory studies will help elucidate the mechanism of action and seek to identify biomarkers to improve selection of pts most likely to benefit from treatment with BDC-1001 +/- immune checkpoint inhibitor. This global study is currently recruiting pts. For further information, visit ClinicalTrials.gov (NCT04278144). Citation Format: Ecaterina Ileana Dumbrava, Manish R. Sharma, Richard D. Carvajal, Daniel Catenacci, Leisha A. Emens, Shirish M. Gadgeel, Glenn J. Hanna, Dejan Juric, Yoon-Koo Kang, Jeeyun Lee, Keun-Wook Lee, Bob T. Li, Kathleen Moore, Mark D. Pegram, Paula R. Pohlmann, Drew Rasco, Alexander Spira, Antoinette R. Tan, Shelley E. Ackerman, Heidi LeBlanc, David Dornan, Marcin Kowanetz, Michael N. Alonso, Edith A. Perez. Phase 1/2 study of a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), BDC-1001, as a single agent and in combination with an immune checkpoint inhibitor in patients with advanced HER2-expressing solid tumors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-02.

Clinical characteristics of SF3B1 mutant (mut) uveal melanoma (UM) and response to immune checkpoint inhibition (ICI).

Abstract: 9535Background: Metastatic UM is associated with a median overall survival (OS) < 1 year (yr) and overall response rate (RR) to ICI < 18%. SF3B1 mut UM represent a clinically unique subset of UM, d...

Pre-clinical validation of an RNA-based precision oncology platform for patient-therapy alignment in a diverse set of human malignancies resistant to standard treatments

Abstract: Predicting tumor sensitivity to antineoplastics remains an elusive challenge, with no methods demonstrating predictive power. Joint analysis of tumors-from patients with distinct malignancies who had progressed on multiple lines of therapy-and drug perturbation transcriptional profiles predicted sensitivity to 28 of 350 drugs, 26 of which (93%) were confirmed in low-passage, patient-derived xenograft (PDX) models. Drugs were prioritized based on their ability to either invert the activity of individual Master Regulator proteins, with available high-affinity inhibitors, or of the modules they comprise (Tumor-Checkpoints), based on de novo mechanism of action analysis. Of 138 PDX mice enrolled in 16 single and 18 multi-protein treatment arms, a disease control rate (DCR) of 68% and 91%, and an objective response rate (ORR) of 12% and 17%, were achieved respectively, compared to 6% and 0% in the negative controls arm, with multi-protein drugs achieving significantly more durable responses. Thus, these approaches may effectively complement and expand current precision oncology approaches, as also illustrated by a case study.

A Case Report of Papillary Digital Adenocarcinoma With BRAFV600E Mutation and Quantified Mutational Burden.

Abstract: Papillary digital adenocarcinoma (PDA) is a rare eccrine tumor that is most often found on the digits. Few case reports have described PDAs located on atypical sites. It is now accepted that PDAs cannot be distinguished from benign adenomas based on histological features, and it is recommended to excise all of these lesions. Even with excision, recurrence and metastasis rates are high. Only limited genomic analyses have been performed to date, and no driver mutations have been identified. We report a case of a 63-year-old woman with a PDA on the right forearm. Biopsy showed moderate cytologic atypia and mitotic figures. Next-generation DNA sequencing of the tumor showed a BRAFV600E mutation and high tumor mutational burden (5.51 mutations/Mb). This mutation is known for its response to small molecular inhibitors of BRAF and Mitogen-activated protein kinase kinase. Such therapy may be a consideration should our patient develop recurrent unresectable disease.

Multiregional genetic evolution of metastatic uveal melanoma

Abstract: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and leads to deadly metastases for which there is no approved treatment. Genetic events driving early tumor development are well-described, but those occurring later during metastatic progression remain poorly understood. We performed multiregional genomic sequencing on 22 tumors collected from two patients with widely metastatic UM who underwent rapid autopsy. We observed multiple seeding events from the primary tumors, metastasis-to-metastasis seeding, polyclonal seeding, and late driver variants in ATM, KRAS, and other genes previously unreported in UM. These findings reveal previously unrecognized temporal and anatomic complexity in the genetic evolution of metastatic uveal melanoma, and they highlight the distinction between early and late phases of UM genetic evolution with implications for novel therapeutic approaches.

Treatment of recurrent mucosal melanoma of the oral cavity with topical imiquimod and pembrolizumab achieves complete histopathologic remission.

Abstract: Mucosal melanomas constitute a subtype of melanoma with less effective treatments than cutaneous melanomas. We present a case of oral mucosal melanoma that recurred despite multiple resections and adjuvant temozolomide. Treatment with topical imiquimod combined with pembrolizumab achieved remission. A 56-year-old woman presented with a pigmented mass on her left anterior hard palate. Biopsy revealed malignant melanoma. The patient had resection with neck dissection with 3 months of adjuvant temozolomide due to positive margins. Malignant melanoma involving the hard palate recurred 1 year later requiring additional resection. Two years later, two additional pigmented lesions were found; further resections were deferred due to expected morbidity. Following 6 weeks of topical imiquimod treatment, the lesions shrunk significantly. Adjuvant pembrolizumab was added and complete histopathologic remission was observed in 6 months. The patient remained in remission for 4 years before new melanoma in situ was diagnosed, requiring five additional months of imiquimod. As of April 2021, there is no clinical evidence of melanoma. There are limited reports of oral melanoma treated with topical imiquimod. Here, imiquimod administered in combination with pembrolizumab achieved complete pathologic response.

Would the Recommended Dose Have Been Different Using Novel Dose-Finding Designs? Comparing Dose-Finding Designs in Published Trials.

Abstract: PURPOSESimulation studies have shown that novel designs such as the continual reassessment method and the Bayesian optimal interval (BOIN) design outperform the 3 + 3 design by recommending the max...

MicroRNA-Based Cancer Mortality Risk Scoring System and hTERT Expression in Early-Stage Oral Squamous Cell Carcinoma.

Abstract: We have previously constructed a novel microRNA (miRNA)-based prognostic model and cancer-specific mortality risk score formula to predict survival outcome in oral squamous cell carcinoma (OSCC) patients who are already categorized into "early-stage" by the TNM staging system. A total of 836 early-stage OSCC patients were assigned the mortality risk scores. We evaluated the efficacy of various treatment regimens in terms of survival benefit compared to surgery only in patients stratified into high (risk score ≥0) versus low (risk score <0) mortality risk categories. For the high-risk group, surgery with neck dissection significantly improved the 5-year survival to 75% from 46% with surgery only (p < 0.001); a Cox proportional hazard model on time-to-death demonstrated a hazard ratio of 0.37 for surgery with neck dissection (95% CI: 0.2-0.6; p=0.0005). For the low-risk group, surgery only was the treatment of choice associated with 5-year survival benefit. Regardless of treatment selected, those with risk score ≥2 may benefit from additional therapy to prevent cancer relapse. We also identified hTERT (human telomerase reverse transcriptase) as a gene target common to the prognostic miRNAs. There was 22-fold increase in the hTERT expression level in patients with risk score ≥2 compared to healthy controls (p < 0.0005). Overexpression of hTERT was also observed in the patient-derived OSCC organoid compared to that of normal organoid. The DNA cancer vaccine that targets hTERT-expressing cells currently undergoing rigorous clinical evaluation for other tumors can be repurposed to prevent cancer recurrence in these high-risk early-stage oral cancer patients.

Analysis of malignant melanoma risk and outcomes in solid organ transplant recipients: Assessment of transplant candidacy and the potential role of checkpoint inhibitors

Abstract: Malignant melanoma (MM) causes tremendous morbidity and mortality in the solid organ transplant population and may arise in three different clinical scenarios: (1) pretransplant melanoma; (2) de novo melanoma post transplantation and (3) donor-derived melanoma. This manuscript primarily addresses the first two scenarios with respect to the evaluation and management of pretransplant MM, consideration of transplant candidacy and the occurrence and management of de novo MM post transplantation. The authors outline current evidence describing risks associated with pre-transplant melanoma to support recently established expert opinion for transplant candidacy.