Metastatic uveal melanoma is an aggressive disease without an established standard treatment. In a randomized trial that evaluated tebentafusp, a soluble T-cell receptor bispecific protein, overall ...survival at 1 year was 73% among patients who received tebentafusp, as compared with 59% among those who received the investigator’s choice of therapy.
The utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced cancers receiving immunotherapy is uncertain. We therefore analyzed pretreatment (
= 978) and on-treatment (
= ...171) ctDNA samples across 16 advanced-stage tumor types from three phase I/II trials of durvalumab (± the anti-CTLA4 therapy tremelimumab). Higher pretreatment variant allele frequencies (VAF) were associated with poorer overall survival (OS) and other known prognostic factors, but not objective response, suggesting a prognostic role for patient outcomes. On-treatment reductions in VAF and lower on-treatment VAF were independently associated with longer progression-free survival and OS and increased objective response rate, but not prognostic variables, suggesting that on-treatment ctDNA dynamics are predictive of benefit from immune checkpoint blockade. Accordingly, we propose a concept of "molecular response" using ctDNA, incorporating both pretreatment and on-treatment VAF, that predicted long-term survival similarly to initial radiologic response while also permitting early differentiation of responders among patients with initially radiologically stable disease. SIGNIFICANCE: In a pan-cancer analysis of immune checkpoint blockade, pretreatment ctDNA levels appeared prognostic and on-treatment dynamics predictive. A "molecular response" metric identified long-term responders and adjudicated benefit among patients with initially radiologically stable disease. Changes in ctDNA may be more dynamic than radiographic changes and could complement existing trial endpoints.
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In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, ...open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2-10%), the 1 year overall survival rate was 62% (95% CI: 53-70%) with a median overall survival of 16.8 months (95% CI: 12.9-21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.
This phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to ...assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM).
In this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 μg once in week 1 and 30 μg once in week 2. Dose escalation (starting at 54 μg) began at week 3 in a standard 3 + 3 design to define RP2D. Expansion-phase patients were treated at the RP2D (20-30-68 μg). Blood and tumor samples were collected for pharmacokinetics/pharmacodynamics assessment, and treatment efficacy was evaluated for all patients with baseline efficacy data as of December 2017.
Between March 2016 and December 2017, 42 eligible patients who failed a median of two previous treatments were enrolled: 19 in the dose escalation cohort and 23 in an initial dose expansion cohort. Of the dose levels investigated, 68 μg was identified as the RP2D. Most frequent treatment-emergent adverse events regardless of attribution were pyrexia (91%), rash (83%), pruritus (83%), nausea (74%), fatigue (71%), and chills (69%). Toxicity attenuated following the first three doses. The overall response rate was 11.9% (95% CI, 4.0 to 25.6). With a median follow-up of 32.4 months, median overall survival was 25.5 months (range, 0.89-31.1 months) and 1-year overall survival rate was 67%. Treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators.
Using a step-up dosing regimen of tebentafusp allowed a 36% increase in the RP2D compared with weekly fixed dosing, with a manageable side-effect profile and a signal of efficacy in mUM.
Tebentafusp is a gp100xCD3-bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage–specific antigen gp100 on HLA-A∗02:01. Skin-related adverse ...events, predominantly rash, are frequent and occur within a few hours after initial infusions; yet, the mechanisms are unknown. In this study, we analyzed clinical data from the randomized phase 3 trial (NCT03070392) of tebentafusp (n = 252) versus investigator’s choice (n = 126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced, and expression of melanocytic genes decreased, whereas gene expression related to immunity and cytokine signaling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival as patients without a rash in the phase 3 randomized trial IMCgp100-202 (hazard ratio = 0.84, 95% confidence interval = 0.53–1.32). In summary, skin rash is an off-tumor, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.
Mutations in the
gene regulate resistance to PD-1/PD-L1 blockade. This study evaluated this association in patients with nonsquamous non-small cell lung cancer (NSCLC) enrolled in three phase I/II ...trials.
mutations were associated with resistance to the anti-PD-L1 antibody durvalumab (alone/with the anti-CTLA4 antibody tremelimumab) independently of
mutational status, highlighting
as a potential driver of resistance to checkpoint blockade. Retrospective assessments of tumor tissue, whole blood, and serum revealed a unique immune phenotype in patients with
mutations, with increased expression of markers associated with neutrophils (i.e.,
,
), Th17 contexture (i.e.,
), and immune checkpoints. Associated changes were observed in the periphery. Reduction of STAT3 in the tumor microenvironment using an antisense oligonucleotide reversed immunotherapy resistance in preclinical
knockout models. These results suggest that
mutations may hinder response to checkpoint blockade through mechanisms including suppressive myeloid cell biology, which could be reversed by STAT3-targeted therapy. SIGNIFICANCE: Patients with nonsquamous
-mutant (
mut) NSCLC are less likely than
wild-type (
wt) patients to respond to anti-PD-L1 ± anti-CTLA4 immunotherapies, and their tumors show increased expression of genes and cytokines that activate STAT3 signaling. Preclinically, STAT3 modulation reverses this resistance, suggesting STAT3-targeted agents as potential combination partners for immunotherapies in
mut NSCLC.
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Background
Durvalumab has shown meaningful clinical activity in patients with metastatic urothelial carcinoma (mUC) in Study 1108 (NCT01693562). An important focus in treatment is health‐related ...quality of life (HRQOL). Here, patient‐reported outcomes (PROs) from Study 1108 and their relationship with inflammatory biomarkers are explored.
Methods
Disease‐related symptoms, functioning, and HRQOL were assessed with the Functional Assessment of Cancer Therapy–Bladder (FACT‐Bl) and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ‐C30). Relationships between PRO improvements and the best changes in the tumor size, albumin level, and neutrophil‐lymphocyte ratio (NLR) were assessed with Spearman correlation analysis.
Results
The mean FACT‐Bl total score improved from 107.5 (standard deviation SD, 23.0) at the baseline to 115.4 (SD, 22.6) on day 113, with similar increases found for the Trial Outcome Index (TOI) and Bladder Cancer Subscale (BLCS) scores. The mean FACT‐Bl total scores improved over time, and the FACT‐Bl TOI scores significantly improved by day 113 (P < .05). The mean EORTC QLQ‐C30 Global Health Status/Quality of Life score improved from 57.1 (SD, 24.8) at the baseline to 69.0 (SD, 21.4) on day 113; the functional scale and symptom scores (day 113) were higher than the baseline scores (P < .05) for EORTC Social Functioning. The FACT‐Bl total, BLCS, and TOI scores improved in 32.6%, 34.9%, and 32.6% of the patients by day 113; 26.3% to 37.8% of the patients exhibited improvements in EORTC QLQ‐C30 functional scores. The best tumor shrinkage and posttreatment improvements in serum albumin and NLR correlated with increases in FACT‐Bl total, TOI, and BLCS scores and in EORTC Physical Functioning and Role Functioning scores (P < .05).
Conclusions
Durvalumab was associated with improvements in disease‐related symptoms, functioning, and HRQOL in patients with mUC. Improvements in systemic inflammation may contribute to PRO improvements in these patients.
In patients with locally advanced/metastatic urothelial carcinoma treated with durvalumab, improvements in patient‐reported outcomes correlate not only with objective tumor responses but also with reductions in markers of systemic inflammation. These findings provide insight into potential links between attenuation of inflammation in cancer and patient‐reported outcomes.
Lung cancer is the leading cause of death among all cancers. An estimated 29% of the global population older than 15 years currently smokes tobacco. The presence of a high risk population, relatively ...asymptomatic nature of the disease in the early phase, and relatively good prognosis when discovered early makes screening for lung cancer an attractive proposition. We performed a systematic review and a meta-analysis of the baseline results of randomized controlled trials so far published, which included more than 14,000 patients. Analysis was used to determine whether data was for or against the screening of lung cancers using low-dose computed tomography (LDCT).
Random effect meta regression model of meta-analysis and systematic review.
We performed a systematic review and a meta-analysis of the current literature to determine whether screening for lung cancer in a high-risk population with computed tomography improves outcomes. A search strategy using Medline was employed, studies selected based on preset criteria and application of exclusion criteria, and data collected and analyzed for statistical significance.
Screening for lung cancer using LDCT resulted in a significantly higher number of stage I lung cancers (odds ratio 3.9, 95% confidence interval CI 2.0–7.4), higher number of total non-small cell lung cancers (odds ratio 5.5, 95% CI 3.1–9.6), and higher total lung cancers (odds ratio 4.1, 95% CI 2.4–7.1). Screening using LDCT also resulted in increased detection of false-positive nodules (odds ratio 3.1, 95% CI 2.6–3.7) and more unnecessary thoracotomies for benign lesions (event rate 3.7 per 1000, 95% CI 3.5–3.8). For every 1000 individuals screened with LDCT for lung cancer, 9 stage I non-small cell lung cancer and 235 false-positive nodules were detected, and 4 thoracotomies for benign lesions were performed.
The baseline data from six randomized controlled trials offer no compelling data in favor or against the use of LDCT screening for lung cancer. We await the final results of these randomized controlled trials to improve our understanding of the effectiveness of LDCT in the screening for lung cancer and its effect on mortality.
Hyalinizing clear cell carcinoma (HCCC) is a rare neoplasm affecting mainly the minor salivary glands of the oral cavity. We describe an unusual case of HCCC involving the tonsil and its successful ...management. A 67-year-old Hispanic woman was discovered to have an asymptomatic right tonsillar mass on routine clinic visit that revealed HCCC on biopsy. A right radical tonsillectomy was performed and pathology confirmed HCCC with positive deep surgical margins. She declined the recommended adjuvant radiation therapy. A follow-up CT of the neck with contrast done a year later revealed a suspicious area of enhancement around the prior resection margin with regional cervical lymphadenopathy. Further workup, including biopsy, confirmed local recurrence. She was treated with definitive cisplatin-based chemoradiotherapy, achieving complete response. She remains without recurrence with more than 24 months of follow-up.
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