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  • 1
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    Final analysis of overall survival (OS) and relapse-free-survival (RFS) in the intergroup S1404 phase III randomized trial comparing either high-dose interferon (HDI) or ipilimumab to pembrolizumab in patients with high-risk resected melanoma.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 9501-9501
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 9501-9501
    Abstract: 9501 Background: We assessed whether or not adjuvant pembrolizumab given over 1 year would improve OS and RFS in comparison to high dose ipilimumab (ipi10) or HDI - the two FDA-approved adjuvant treatments for high risk resected melanoma at the time of study design. Methods: Patients age 18 or greater with resected stages IIIA(N2), B, C and IV were eligible. Patients with CNS metastasis were excluded. At entry, patients must have had complete staging and adequate surgery to render them free of melanoma including completion lymph node dissection for those with sentinel node positive disease. Prior therapy with PD-1 blockade, ipilimumab or interferon was not allowed. Two treatment arms were assigned based on stratification by stage, PD-L1 status (positive vs. negative vs. unknown), and intended control arm (HDI vs. Ipi10). Patients enrolled between 10/2015 and 8/2017 were randomized 1:1 to either the control arm [(1) interferon alfa-2b 20 MU/m2 IV days 1-5, weeks 1-4, followed by 10 MU/m2/d SC days 1, 3, and 5, weeks 5-52 (n=190), or (2) ipilimumab 10 mg/kg IV q3w for 4 doses, then q12w for up to 3 years (n=465)], or the experimental arm [pembrolizumab 200 mg IV q3w for 52 weeks (n=648)] . The study had three primary comparisons: 1) RFS among all patients, 2) OS among all patients, 3) OS among patients with PD-L1+ baseline biopsies. Results: 1,426 patients were screened and 1,345 patients were randomized with 11%, 49%, 34%, and 6% AJCC7 stage IIIA(N2), IIIB, IIIC and IV, respectively. This final analysis was performed per-protocol 3.5 years from the date the last patient was randomized, with 512 RFS and 199 OS events. The pembrolizumab group had a statistically significant improvement in RFS compared to the control group (pooled HDI and ipi10) with HR 0.740 (99.618% CI, 0.571 to 0.958). There was no statistically signifcant improvement in OS in the 1,303 eligible randomized overall patient population with HR 0.837 (96.3% CI, 0.622 to 1.297), or among the 1,070 (82%) patients with PD-L1 positive baseline biopsies with HR 0.883 (97.8% CI, 0.604 to 1.291). Gr 3/4/5 event rates were as follows: HDI 69/9/0%, ipi10 43/5/0.5% and pembrolizumab 17/2/0.3%. Conclusions: Pembrolizumab improves RFS but not OS compared to HDI or ipi10 in the adjuvant treatment of patients with high-risk resected melanoma. Pembrolizumab is a better tolerated adjuvant treatment regimen than HDI or Ipi10. Support: NIH/NCI NCTN grants CA180888, CA180819, CA180820, CA180863; and in part by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Editorial Acknowledgement: With special thanks to Elad Sharon, MD, MPH, and Larissa Korde, MD, MPH. National Cancer Institute, Investigational Drug Branch, for their contributions to this trial, as well as Nageatte Ibrahim, MD, and Sama Ahsan, MD Merck. Clinical trial information: NCT02506153.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.9501
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 2
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    Alliance A071701: Genomically guided treatment trial in brain metastases.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. TPS2573-TPS2573
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. TPS2573-TPS2573
    Abstract: TPS2573 Background: Brain metastases, most commonly derived from melanoma, lung and breast cancers, are the most common brain tumor, with approximately 200,000 cases diagnosed annually in the United States. Median survival is on the order of months. For patients with clinically symptomatic brain metastases, approximately half succumb due to intracranial progression. In preclinical work, we demonstrated that brain metastases and primary tumors are often genetically distinct with frequent alterations in the CDK and PI3K pathway (Brastianos, Carter et al. Cancer Discovery 2015). Methods: We are currently accruing to a prospective multi-arm phase II study of CDK, PI3K/mTOR, and NTRK/ROS1 inhibitors in patients with brain metastases harboring alterations associated with sensitivity to these inhibitors (abemaciclib, paxalisib and entrectinib), respectively. Patients with new, recurrent or progressive brain metastases are eligible for this trial. Previously obtained tissue from brain metastases and extracranial sites (primary or extracranial metastases) are screened for the presence of these alterations, and if present in both tumor sites, patients will receive the appropriate corresponding targeted treatment. Screening is carried out with the SNaPshot NGS assay, which is a fully validated clinical test designed and developed at the MGH Center for Integrated Diagnostics. The primary endpoint of response rate (RR) in the central nervous system as per RANO criteria will be evaluated separately for each inhibitor, stratified by histology within each arm. There will be 21 evaluable patients assigned to each of the CDK and PI3K inhibitor and tumor type cohorts (breast, lung and other) and 10 patients assigned to the NTRK/ROS1 inhibitor cohort (lung) for a total of 136 evaluable patients. Although current systemic therapy for brain metastases is often ineffective, we hypothesize that targeted therapies will demonstrate efficacy in patients harboring the appropriate mutations. This study represents a novel individualized therapeutic approach in brain metastases, a disease with a critical need for effective therapy. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org ; Genentech, Kazia Therapeutics Limited, Eli Lilly; Clinical trial information: NCT03994796 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.TPS2573
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 3
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    Phase II trial of pembrolizumab in patients with brain metastases.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 2006-2006
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2006-2006
    Abstract: 2006 Background: Brain metastases are an increasing challenge in oncology due to increasing incidence and limited treatments. Recent studies suggest that brain metastases harbor a tumor microenvironment characterized by immunosuppressive phenotypes, which contribute to treatment resistance. Therefore, a logical therapeutic strategy for brain metastases is to evaluate immune-based strategies that augment T cell cytotoxicity. Methods: This study was designed as an open-label, single-stage, single-arm phase 2 clinical trial evaluating the intracranial efficacy of pembrolizumab, a PD-1 inhibitor, in patients with brain metastases of diverse histologies. The target accrual was 58 patients to achieve at least 52 evaluable patients (i.e., received at least one dose of pembrolizumab). The primary endpoint was intracranial benefit, defined as a best response of complete response, partial response, or stable disease by RANO criteria during treatment. The study design compared a null intracranial benefit rate of 10% against an alternative of 24%. If at least 8 patients among the total of 52 had intracranial benefit, the primary efficacy endpoint would be met and pembrolizumab would be considered worthy of further study in this patient population. This design has a type-I error of 10% and power of 89% (target type-II error of 15%). Results: In the 57 evaluable patients, median age was 53 (range 28-80) and 81% were female. Tumor histologies included breast (n = 35), non-small cell lung cancer (n = 7), melanoma (n = 2), small-cell lung cancer (n = 2), sarcoma (n = 2), ovarian (n = 1), pituitary carcinoma (n = 1), pituitary neuroendocrine tumor (n = 1), esophageal adenocarcinoma (n = 1), prostate (n = 1), renal cell carcinoma (n = 1), neuroendocrine carcinoma (n = 1), unknown primary (n = 1) and sinonasal adenocystic carcinoma (n = 1). For the patients with breast cancer, 16 patients had HER-2 positive disease, 17 patients had hormone receptor-positive disease, and 11 patients had the triple-negative subtype. The study met its primary endpoint and achieved an intracranial benefit rate of 42.1% (90% confidence interval [CI]: 31-54%). In addition, seven patients, who had either breast cancer, melanoma or sarcoma, had durable intracranial anti-tumor activity ( 〉 2 years). The extracranial benefit rate in patients with evaluable extracranial disease based on RECIST 1.1 criteria was 45% (18/40; 90% CI: 31-59%). Median overall survival was 8.0 months (90% CI: 5.5-8.7 months). Grade 4 toxicities at least possibly related to treatment were observed in 2 patients: cerebral edema (n = 2). Thirteen patients discontinued treatment for adverse events. Conclusions: Our study of pembrolizumab met overall primary endpoint for intracranial benefit in patients with brain metastases. These results suggest that PD-1 blockade may serve as the backbone of therapeutic strategies for a select group of patients with brain metastases and warrants further evaluation. Clinical trial information: NCT02886585 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.2006
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Phase 1b study of the novel first-in-class G protein-coupled estrogen receptor (GPER) agonist, LNS8801, in combination with pembrolizumab in patients with immune checkpoint inhibitor (ICI)-relapsed and refractory solid malignancies and dose escalation update.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 2574-2574
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 2574-2574
    Abstract: 2574 Background: LNS8801 is an oral, highly selective, small molecule agonist of the G protein-coupled estrogen receptor (GPER). LNS8801 normalizes c-Myc levels in cancer cells, inhibits proliferation, suppresses invasion, and enhances immune recognition. In preclinical models, LNS8801 has demonstrated increased activity with ICIs. In the first-in-human dose escalation study, LNS8801 was safe and tolerable alone and in combination with pembrolizumab in patients with metastatic solid tumors (NCT04130516). Methods: Patients who are relapsed and refractory (r/r) to PD-1/L1 ICIs and have measurable disease are enrolling in a Phase 1b cohort and receive LNS8801 (125 mg, QD, PO) and pembrolizumab (200 mg, Q3W, IV) (NCT04130516). The primary objective is safety and tolerability assessed according to NCI CTCAE v5.0. Secondary endpoints include pharmacokinetic, pharmacodynamics (eg., increase in serum prolactin over the initial 10 hours of dosing to assess GPER engagement), objective response rate and clinical benefit rate per RECIST v1.1. Results: Updates from the dose escalation portion of the study include long term benefit in a monotherapy patient with cutaneous melanoma on treatment for 2 years with RECIST stable, metabolically inactive disease by PET; a metastatic uveal melanoma patient on therapy for a year, and growing confidence in LNS8801’s favorable safety profile and predictive systemic biomarkers. As of 2/1/22, 13 ICI r/r patients were treated with LNS8801 and pembrolizumab, including those who entered the study directly after confirmed progression on ICIs. Cancer types include lung (3), colorectal, vaginal, nasopharyngeal, neuroendocrine, uterine, and pancreatic cancer, mesothelioma (2), and cutaneous and uveal melanoma. 46% of patients had AEs possibly related to study drugs (31% grades 1-2 and 31% grade 3), with colitis (15%) and fatigue (23%) appearing in more than 10% of patients. Of the 10 evaluable patients, 7 had stable disease (SD), with 4 patients demonstrating tumor regression. At the data cut-off, duration of treatment ranged from 0.7–7.5 months with 4 patients treated between 4.8 and 7.5 months and 4 patients continuing on treatment. All evaluated patients with SD had a prolactin response indicative of systemic target engagement. Conclusions: The combination of LNS8801 and pembrolizumab is tolerable without unanticipated toxicities and demonstrates encouraging anti-tumor activity in patients that are r/r to ICIs, including patients who enrolled immediately after confirmed progression on pembrolizumab alone. These data, as well as continued follow-up on patients with long-term benefit from dose escalation, support further development of LNS8801 as a cancer therapeutic. Clinical trial information: NCT04130516.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.2574
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 5
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    Heterogeneous response and irAE patterns in advanced melanoma patients treated with anti-PD-1 monotherapy from different ethnic groups: Subtype distribution discrepancy and beyond.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 10020-10020
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 10020-10020
    Abstract: 10020 Background: Programmed cell death receptor-1 (PD-1) monotherapy is the standard first line therapy for advanced cutaneous melanoma, with efficacy, toxicity, and their correlations well established. Yet these remain poorly characterized for non-Caucasians and for certain rarer melanoma subtypes. Methods: Clinical data from melanoma patients treated with anti-PD-1 monotherapy between 2009 and 2018 was collected retrospectively from three independent institutions from the US and China. Tumor response, survival outcome, and organ/system-specific immune-related adverse effects (irAEs) were directly compared between different subgroups. Results: Among 626 patients, 411 were Caucasian, 214 non-Caucasian; 369 had cutaneous melanoma, and 257 other subtypes. Both ethnicity and melanoma subtype were independently associated with benefit and irAEs. In multivariate analyses, Caucasians had significantly higher objective response rate (ORR) (OR 2.0, 95% CI 1.1-3.5), but this did not translate into a survival advantage (PFS, HR 0.8, 95% CI 0.6-1.1; OS, HR 1.0, 95% CI 0.7-1.4); melanoma of unknown primary shared similar response and survival profile with cutaneous, while acral (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.6, 95% CI 1.1-2.2; OS, HR 1.3, 95% CI 0.8-1.9), mucosal (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.4, 95% CI 1.0-2.0; OS, HR 1.7, 95% CI 1.1-2.6) and ocular (ORR, OR 0.1, 95% CI 0-0.6; PFS, HR 2.3, 95% CI 1.4-3.6; OS, HR 2.2, 95% CI 1.3-3.6) melanomas had inferior outcomes. Non-Caucasian cutaneous patients had a significantly worse ORR than Caucasians with cutaneous melanoma (P 〈 .01). Distinct irAE patterns were observed, exemplified by lower incidence of most irAEs (although more frequent pneumonitis) in Caucasians, and higher and lower liver irAE incidence in ocular and mucosal melanomas, respectively. Endocrine, musculoskeletal and skin irAEs were associated with improved PFS and OS across ethnicities and nearly all melanoma subtypes, whereas heterogeneity existed for other irAE types. Conclusions: Ethnicity and melanoma subtype are associated with distinct response patterns, survival outcomes, and irAE profiles in the setting of anti-PD-1 monotherapy. More research is needed to elucidate the molecular and immunologic determinants of these variable outcomes.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.10020
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 6
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    A phase II study of ERK inhibition by ulixertinib (BVD-523) in metastatic uveal melanoma.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 10036-10036
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 10036-10036
    Abstract: 10036 Background: Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. This has led to efforts to treat uveal melanoma with MEK inhibition with mixed results. Ulixertinib (BVD-523) is a potent and reversible small molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases which has undergone phase I testing. Methods: We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a total sample size of 25 patients (pts) and an initial evaluation of efficacy after 13 pts. Two responses were required to continue to the second stage. Results: From April 2018 to April 2019 thirteen pts were enrolled. Pts were predominantly female (69%) with a median age of 64 yrs. (34 -76). Sites of metastasis included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with BVD-523 and other ERK inhibitors and included LFT elevation, hyponatremia, pruritis, amylase elevation, anemia and rash. The best response, per RECIST 1.1, was stable disease (SD) in 4 pts, and disease progression (PD) in 7 patients. Two patients were unevaluable for response due to withdrawing themselves from the study. Median time to progression was 2.0 months (90% CI: 1.8 – 3.6 mos.). There were eight deaths due to disease progression with a median survival time of 6.9 months (90%CI: 3.2 to 8.3 mos.). Analysis of correlative data from pre- and on-treatment biopsies exploring the change in expression of key signaling proteins relating to treatment is underway. Conclusions: ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed on study were consistent with what would be expected with MAPK pathway inhibition. Clinical trial information: NCT03417739.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.10036
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Investigating the tumor immune infiltrate for populations that predict immune-related adverse events (irAEs) in patients receiving PD-1 inhibitors.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 3116-3116
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3116-3116
    Abstract: 3116 Background: The mechanistic relationship between clinical benefit and immune-related adverse events (irAEs) in response to immune checkpoint inhibitors (ICIs) remains unclear, with several clinical studies reporting that irAEs are biomarkers of responses. Single-cell RNA sequencing (scRNAseq) analysis of tumors from patients with advanced melanoma before and after treatment with ICIs have identified immune cells that correlate with response to ICIs. We sought to evaluate if these populations were also associated with irAEs. Methods: A published scRNAseq data set generated with the Smart-Seq2 protocol (Sade-Feldman M, et al. Cell 2018.) was re-analyzed, stratified by two definitions of irAEs: (1) toxicity requiring systemic immunosuppression (prednisone 〉 10mg/day) or (2) systemic immunosuppression and/or endocrinopathy. Unbiased single-cell analysis was performed, followed by sub-clustering of T cell populations. The percentage of cells in each cluster was determined on a per sample basis. Results: 13,184 immune cells from 39 samples collected from 25 patients were re-analyzed. 27 samples were from patients who did not respond to ICIs, while 12 samples came from responding patients. 21 samples came from patients who required immunosuppression, 5 samples from patients with isolated thyroiditis, and 13 samples from patients who met neither irAE criteria. Unsupervised scRNAseq analyses focused on ICI efficacy re-capitulated published associations between response and populations that included B-cells (p 〈 0.01) and TCF7 expressing T-cells (p 〈 0.01). While these cell populations were not associated with either definition of toxicity, we observed a non-Treg CD4 expressing T cell population (0.8-10.5% cells/sample) that positively correlated with either definition of toxicity (p 〈 0.05) but not efficacy. Conclusions: In a patient cohort with advanced melanoma, tumor-infiltrating immune cell populations associated with response to ICI therapy were not associated with irAEs. This suggests that biomarkers of ICI response may not function as biomarkers of irAEs, and ongoing analysis will seek to validate this result. Understanding the differences between ICI response and irAEs may identify new therapeutic targets for maximizing efficacy while mitigating toxicity.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.3116
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 8
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    CTEP 9557: A dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF mutant solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 3609-3609
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3609-3609
    Abstract: 3609 Background: Combination BRAF and MEK inhibitor therapy is associated with response in patients (pts) with BRAF mutant (mut) solid tumors; however critical limitations for the durable activity of these agents remains. Preclinically, the addition of heat shock protein 90 (HSP90) inhibitors improves the efficacy of BRAF inhibitor (BRAFi) therapy in both BRAFi -sensitive and resistant mutant cell lines. Methods: CTEP study 9557 (NCT02097225) is a phase I study designed to determine the safety and efficacy of the small molecule HSP90inhibitor, AT13387, in combination with dabrafenib (dab) and trametinib (tram) in patients with BRAF V600E/K mut solid tumors. Prior chemotherapy, immunotherapy, BRAF and/or MEK exposure was permitted. The primary objective was to determine the maximum tolerated dose (MTD). Results: From July 2015 to June 2018, 22 patients with previously treated, metastatic BRAF V600E/K mut solid tumors were enrolled using a 3 + 3 design at four dose levels (DL) (Table). Pts were predominantly female (59%) with a median age of 57.5yrs (37 -75). The most common tumor type was BRAF V600E mut colon cancer (N=12). Dose limiting toxicities (DLTs) occurred in one patient in DL3 and one in DL4, specifically grade 3 myelosuppression and fatigue, respectively. The MTD was Dab 150mg [BID/PO], Tram 2mg [QD/PO] and AT1187 260mg/m2 [D1,8,15/IV]. Twenty-one of 22 pts were eligible for efficacy assessment. Best response, per RECIST 1.1, was partial response (PR) in 2 pts – one with colon ca (TKI-naïve), one with melanoma (TKI-resistant) - stable disease (SD) in 8 pts, and disea se progression (PD) in 11 with a disease control rate (PR + SD) of 47.6% (90% CI: 29% - 67%). Median time to progression was significantly longer in DL3 (3.9 mths; 1.8-9.2) compared to DL1 (1.6mths; 0.9-1.7) or DL2 (1.5; 0.6-3.6). Median PFS and OS were 1.8mths (90% CI: 1.6 – 3.7mths) and 5.1 mths (90% CI: 2.5 -10.6mths), respectively. Median OS was not reached in DL3/4. Correlative data on the expression of the key signaling proteins relating to response will be presented at the meeting. Conclusions: HSP90 inhibition combined with BRAF/MEK inhibition was determined to be safe with evidence of disease control in a heavily pre-treated population of pts with BRAF V600E/K mut solid tumors. Clinical trial information: NCT02097225 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.3609
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 9
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    Characterizing the tumor and immune landscape of melanoma patients treated with combined checkpoint blockade and MAPK targeted therapy.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 9522-9522
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 9522-9522
    Abstract: 9522 Background: Melanoma therapy has been revolutionized by two novel therapeutic approaches: mitogen activated protein kinase (MAPK) targeted therapy (MTT) and immune checkpoint blockade therapy (ICB). Less than half of patients respond to ICB monotherapy, in part due to non-responsive tumor microenvironment (TME). It previously has been shown that MTT enhances anti-tumor immunity within the TME, thus providing a strong rationale for its combination with immunotherapy. Regimens combining MTT with ICB have had mixed results, and which patients should be treated with these combinations is unknown. Methods: The first arm (NCT03149029) of a planned two stage design was to enroll 14 patients (pts) harboring BRAF V600 mutation treated with 2 weeks (wks) of MTT (dabrafenib plus trametinib) then 6 wks of concomitant MTT and pembrolizumab, followed by single-agent pembrolizumab thereafter. The primary endpoint is clinical benefit (CB) defined as partial/complete response or stable disease (per RECIST1.1) persisting at 24 wks. If 9 of 14 pts had CB, then 11 more pts would be enrolled for a total cohort of 25. Serial biopsies were performed prior to MTT, following the 2-week lead-in of MTT, and following six wks of combination immune therapy and MTT. Single-cell RNA-seq profiling of CD45 + and CD45 - cells was performed using both the smart-seq2 plate-based protocol and 10x genomics platform. Results: Sixteen pts were enrolled, with 14 receiving both MTT and ICB. Two pts did not receive ICB due to MTT toxicity. Only 5 had CB, and the second stage did not open. A 6 th pt had CB extracranially with a new small brain met at wk 24 scans was considered CB for tumor analysis. A clustering analysis of 25 samples (n = 9 pts) showed that following MTT the abundance of CD8 T-cells as well as tumor IFNγ levels were significantly elevated in CB vs. no CB (NCB) patients. In addition, tumor associated macrophages (TAM) in NCB patients possessed mainly an M2 phenotype and expressed a significantly higher level of immune suppressor genes, such as HLA-G and CD52. Interestingly, NCB pts had a significantly higher expression of tumor TGFβ, which is a strong inducer of M2 macrophages. In contrast, most of the TAMs occupying the tumor of the CB pts had the M1 phenotype, and significantly expressed CD9, CD81 and CD82, important factors during antigen recognition and immunological synapse formation. Conclusions: Abbreviated MTT with ICB did not lead to increased clinical benefit at 24 wks in this small study. It is theorized that the tumor’s ability to create a unique microenvironment by producing certain factors (e.g. TGFβ), modifies the immune system and may tilt its path into immune suppression thereby reducing the efficacy of this combinatorial therapy in melanoma pts with metastatic disease. These results may help identify pts most likely to benefit from combined MTT plus ICB and new targets to overcome resistance to these regimens. Clinical trial information: NCT03149029.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.9522
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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    Impact of immune checkpoint inhibition on ovarian reserve in patients with melanoma enrolled in the ECOG-ACRIN E1609 adjuvant trial.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 12013-12013
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    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 12013-12013
    Abstract: 12013 Background: Immunotherapy with immune checkpoint inhibition (ICI) is being widely adopted in the treatment of patients with a wide range of malignancies. However, we have no data on how these therapies influence fertility or ability to undergo fertility treatments after therapy. Within the melanoma community numerous women of childbearing age have been treated with ICI including ipilimumab, nivolumab and pembrolizumab. Anti-mullerian hormone (AMH) is a biomarker of ovarian reserve and a predictor of response to fertility treatments, including in vitro fertilization (IVF). In women under the age of 35 who have no reproductive pathology, AMH should be detectable and remain relatively stable over time. Above the age of 35 AMH decline accelerates as the number of eggs decreases more rapidly due to normal ovarian aging. Methods: Pre and post-treatment samples from women aged 20-35 whose melanoma was treated with 3 mg/kg ipilimumab (57%) or 10 mg/kg ipilimumab (43%) in the adjuvant setting on trial ECOG-ACRIN E1609 were analyzed in collaboration with the BWH Reproductive Endocrine Laboratory. Serum samples were tested for luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, AMH and prolactin. Results: Samples from E1609 were available from 28 female patients with a median age of 28 (min 20, max 35). The median time between samples was 8.0 months (min 0.7, max 16.4). 53% of patients had stage IIIB melanoma, 43% stage IIIC and one patient had M1a disease. AMH, estradiol and LH significantly decreased after treatment (p 〈 0.001, p = 0.016, p = 0.012, respectively) (Figure 1); there was no significant difference in the level of FSH and prolactin before and after the treatment (p = 0.68, p = 0.12, respectively). The median AMH was 4.24 ng/mL in the pre-treatment group and 3.51 in the post-treatment group. Conclusions: In this study of young women treated with ipilimumab there was a significant decrease in AMH before and after ICI therapy suggesting that ovarian reserve and possibly female fertility may be impacted by immune checkpoint inhibition. Further investigation is needed to look at PD-1 inhibition and combination immunotherapy effects on ovarian reserve and female fertility. In addition, there is a similar need to examine ICI effects on male fertility.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.12013
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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