This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus ...paclitaxel alone in advanced, recurrent, or persistent endometrial cancer.
Patients with histologic diagnosis of endometrial cancer (1–2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2–4, 9–11, 16–18, and 23–25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117200 mg on days 1–3, 8–10, 15–17, and 22–24.
Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 3 ongoing; paclitaxel+sapanisertib, n = 86 3 ongoing; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio HR 0.82; 95% confidence interval CI 0.58–1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43–1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib.
Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable.
Trial registration:ClinicalTrials.gov number, NCT02725268
•Patients with endometrioid tumors showed improvement (PFS, CBR, and CBR-16) with paclitaxel + sapanisertib vs paclitaxel.•There were no significant differences in PFS between the paclitaxel and paclitaxel + sapanisertib arms.•Treatment with paclitaxel + sapanisertib had limited toxicity with no new safety signals.
Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue ...factor-directed antibody–drug conjugate, in this patient population.
This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396.
102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1–13·0). The confirmed objective response rate was 24% (95% CI 16–33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 38% of 101 patients), epistaxis (30 30%), nausea (27 27%), conjunctivitis (26 26%), fatigue (26 26%), and dry eye (23 23%). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three 3% patients), fatigue (two 2%), ulcerative keratitis (two 2%), and peripheral neuropathies (two 2% each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two 2% patients) and pyrexia (two 2%). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes.
Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer.
Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.
BackgroundmRNA-based-drugs can be applied for cancer immunotherapy.1 SAR441000 is a novel saline-formulated mixture of four mRNAs encoding interleukin-12 single chain, interferon alpha-2b, ...granulocyte-macrophage colony-stimulating factor, and interleukin-15 sushi that we have identified as mediators of tumor regression across different murine tumor models. Local intratumoral administration of SAR441000 in immunocompetent mice, mediates successful antitumor immunity leading to tumor eradication. Effective antitumor activity of these cytokines involved multiple immune cell populations and was accompanied by intratumoral interferon gamma induction, systemic antigen-specific T-cell expansion, increased granzyme B+ T-cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of non-injected distant tumors. Combining the mRNAs with checkpoint inhibitors enhanced antitumor responses in both injected and non-injected tumors, improving survival and tumor regression in mice. Based on these preclinical observations a clinical study was initiated.MethodsIn a phase 1 dose escalation study, patients with advanced solid tumors were treated with weekly intratumoral administration of SAR441000 monotherapy and in combination with fixed dose of cemiplimab 350 mg. Plasma samples for cytokine analysis and tumor biopsies were collected at baseline and throughout the study to characterize the PK/PD profile of SAR441000, immune cell tumor infiltration by immunohistochemistry and the presence of corresponding tumor proinflammatory signatures by RNA sequencing.ResultsAs of July 2020, 17 patients received SAR441000 monotherapy (melanoma 7, breast 4, sarcoma 2, Cutaneous Squamous Cell 2, Basal Cell 1, and Merkel Cell 1) at dose levels 1 through 7. Six patients received SAR441000 in combination therapy (melanoma 3, breast 3) at dose levels 4 and 5. No patient experienced a Dose Limiting Toxicity. No grade 3, 4 or 5 adverse events related to study treatment were reported. Adverse events related to study treatment in two or more subjects in both treatment groups combined were nonserious grade 1 or 2 fatigue (43%;10/23), vomiting (17%; 4/23), nausea (13%;3/23); local injection site reaction (11.7%, 2/23); and chills, diarrhea, and rash were reported as 9% (2/23), respectively (table 1 and 2). In some patients, increases in plasma IP10 and IFN gamma and CD8+ T cell infiltration in tumor biopsies were observed.Abstract 391 Table 1Frequency of patients with a TEAE related to SAR44100* by dose group and gradeAbstract 391 Table 2Frequency of patients with a TEAE related to study treatment (SAR441000+cemiplimab) * by dose group and gradeConclusionsSAR441000 administered as monotherapy and in combination with cemiplimab was generally well tolerated. An immunomodulatory effect is suggested by downstream effector cytokines and T cell infiltration. These data support further clinical evaluation of SAR441000.Ethics ApprovalThe study was approved by each participating Institution’s Ethics or Institutional Review Board(s).ReferenceSahin U, Karikó K, Türeci Ö. mRNA-based therapeutics-developing a new class of drugs. Nat. Rev. Drug Discov 2014;13:759–780.
Female mice of inbred strain CBA do not reject syngeneic male skin grafts even though they mount a T-cell response against the male-specific HY antigen. We show that local immunostimulation performed ...by injecting cytokines and Toll-like receptor ligands in close vicinity to the graft causes rejection. We feel that this approach should be tested in tumor-bearing human patients in combination with antitumor vaccination. Relief of intratumor immunosuppression may increase considerably the fraction of patients who respond to vaccination directed against tumor antigens recognized by T cells.
Nearly all melanoma patients with a BRAF‐activating mutation will develop resistance after an initial clinical benefit from BRAF inhibition (BRAFi). The aim of this work is to evaluate whether ...metabolic imaging using hyperpolarized (HP) 13C pyruvate can serve as a metabolic marker of early response to BRAFi in melanoma, by exploiting the metabolic effects of BRAFi. Mice bearing human melanoma xenografts were treated with the BRAFi vemurafenib or vehicle. In vivo HP 13C magnetic resonance spectroscopy was performed at baseline and 24 hours after treatment to evaluate changes in pyruvate‐to‐lactate conversion. Oxygen partial pressure was measured via electron paramagnetic resonance oximetry. Ex vivo qRT‐PCR, immunohistochemistry and WB analysis were performed on tumour samples collected at the same time‐points selected for in vivo experiments. Similar approaches were applied to evaluate the effect of BRAFi on sensitive and resistant melanoma cells in vitro, excluding the role of tumour microenvironment. BRAF inhibition induced a significant increase in the HP pyruvate‐to‐lactate conversion in vivo, followed by a reduction of hypoxia. Conversely, the conversion was inhibited in vitro, which was consistent with BRAFi‐mediated impairment of glycolysis. The paradoxical increase of pyruvate‐to‐lactate conversion in vivo suggests that such conversion is highly influenced by the tumour microenvironment.
The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival ...with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 98·4% CI 0·43–0·74; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint.
This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.
Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8–16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 SD 18·20 in the pembrolizumab group and 76·54 17·81 in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was −2·2 points (95% CI −4·3 to −0·2). The difference in average score during treatment was −1·1 points (95% CI −3·2 to 0·9) and the difference in average score after treatment was −2·2 points (−4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.
Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.
Merck Sharp & Dohme.
Many serum biomarkers have been evaluated in melanoma but their clinical significance remains a matter of debate. In this paper, a review of the serum biomarkers for melanoma will be detailed and ...will be discussed from the point of view of their practical usefulness. The expression of biomarkers can be detected intracellularly or on the cell membrane of melanoma cells or noncancer cells in association with the melanoma. Some of these molecules can then be released extracellularly and be found in body fluids such as the serum. Actually, with the emergence of new targeted therapies for cancer and the increasing range of therapeutic options, the challenge for the clinician is to assess the unique risk/response ratio and the prognosis for each patient. New serum biomarkers of melanoma progression and metastatic disease are still awaited in order to provide efficient rationale for followup and treatment choices. LDH as well as S100B levels have been correlated with poor prognosis in AJCC stage III/IV melanoma patients. However, the poor sensitivity and specificity of those markers and many other molecules are serious limitations for their routine use in both early (AJCC stage I and II) and advanced stages of melanoma (AJCC stage III and IV). Microarray technology and proteomic research will surely provide new candidates in the near future allowing more accurate definition of the individual prognosis and prediction of the therapeutic outcome and select patients for early adjuvant strategies.
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