Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small-cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial.

BACKGROUND: The APPLE trial aimed to evaluate the feasibility of longitudinal plasma epidermal growth factor receptor (EGFR) T790M monitoring for the best sequencing strategy of gefitinib and osimertinib. METHODS: APPLE is a randomized, non-comparative, phase II study in patients with common EGFR-mutant, treatment-naive non-small-cell lung cancer including three arms: arm A (osimertinib upfront until RECIST progression, PD), arm B [gefitinib until emergence of circulating tumor DNA (ctDNA) EGFR T790M mutation by cobas EGFR test v2 or RECIST PD], and arm C (gefitinib until RECIST PD), and then switch to osimertinib in both arms. The primary endpoint is the progression-free survival (PFS) rate 'on osimertinib' at 18 months (PFSR-OSI-18) after randomization in arm B (H0: PFSR-OSI-18 of ≤40%). Secondary endpoints include response rate, overall survival (OS), and brain PFS. We report the results of arms B and C. RESULTS: From November 2017 to February 2020, 52 and 51 patients were randomized into arms B and C, respectively. Most patients were females (70%) and had EGFR Del19 (65%); one-third had baseline brain metastases. In arm B, 17% of patients (8/47) switched to osimertinib based on the emergence of ctDNA T790M mutation before RECIST PD, with a median time to molecular PD of 266 days. The study met its primary endpoint of PFSR-OSI-18 of 67.2% (84% confidence interval 56.4% to 75.9%) in arm B versus 53.5% (84% confidence interval 42.3% to 63.5%) in arm C, with a median PFS of 22.0 months versus 20.2 months, respectively. The median OS was not reached in arm B versus 42.8 months in arm C. Median brain PFS in arms B and C was 24.4 and 21.4 months, respectively. CONCLUSIONS: The serial monitoring of ctDNA T790M status in advanced EGFR-mutant non-small-cell lung cancer during treatment with first-generation EGFR inhibitors was feasible, and a molecular progression before RECIST PD led to an earlier switch to osimertinib in 17% of patients with satisfactory PFS and OS outcomes.

Circulating L-arginine predicts the survival of cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the systemic approach to cancer treatment. Most patients receiving ICIs, however, do not derive benefits. Therefore, it is crucial to identify reliable predictive biomarkers of response to ICIs. One important pathway in regulating immune cell reactivity is L-arginine (ARG) metabolism, essential to T-cell activation. We therefore aimed to evaluate the association between baseline plasma ARG levels and the clinical benefit of ICIs. PATIENTS AND METHODS: The correlation between ARG levels and clinical ICI activity was assessed by analyzing plasma samples obtained before treatment onset in two independent cohorts of patients with advanced cancer included in two institutional molecular profiling programs (BIP, NCT02534649, n = 77; PREMIS, NCT03984318, n = 296) and from patients in a phase 1 first-in-human study of budigalimab monotherapy (NCT03000257). Additionally, the correlation between ARG levels and ICI efficacy in preclinical settings was evaluated using a syngeneic mouse model of colorectal cancer responsive to ICIs. Using matched peripheral blood mononuclear cell (PBMC) plasma samples, we analyzed the correlation between ARG levels and PBMC features through multiplexed flow cytometry analysis. RESULTS: In both discovery and validation cohorts, low ARG levels at baseline (<42 µM) were significantly and independently associated with a worse clinical benefit rate, progression-free survival, and overall survival. Moreover, at the preclinical level, the tumor rejection rate was significantly higher in mice with high baseline ARG levels than in those with low ARG levels (85.7% versus 23.8%; P = 0.004). Finally, PBMC immunophenotyping showed that low ARG levels were significantly associated with increased programmed death-ligand 1 expression in several immune cell subsets from the myeloid lineage. CONCLUSIONS: We demonstrate that baseline ARG levels predict ICI response. Plasma ARG quantification may therefore represent an attractive biomarker to tailor novel therapeutic regimens targeting the ARG pathway in combination with ICIs.

Impact of acetaminophen on the efficacy of immunotherapy in cancer patients.

BACKGROUND: Acetaminophen (APAP) use has been associated with blunted vaccine immune responses. This study aimed to assess APAP impact on immunotherapy efficacy in patients with cancer. PATIENTS AND METHODS: Exposure to APAP was assessed by plasma analysis and was correlated with clinical outcome in three independent cohorts of patients with advanced cancer who were treated with immune checkpoint blockers (ICBs). The immunomodulatory effects of APAP were evaluated on a preclinical tumor model and on human peripheral blood mononuclear cells (PBMCs) from healthy donors. RESULTS: Detectable plasma APAP levels at treatment onset were associated with a significantly worse clinical outcome in ICB-treated cancer patients, independently of other prognostic factors. APAP significantly reduced ICB efficacy in the preclinical MC38 model, as well as the production of PD-1 blockade-related interferon-γ secretion by human PBMCs. Moreover, reduction of ICB efficacy in vivo was associated with significantly increased tumor infiltration by regulatory T cells (Tregs). Administration of APAP over 24 h induced a significant expansion of peripheral Tregs in healthy individuals. In addition, interleukin-10, a crucial mediator of Treg-induced immune suppression, was significantly up-regulated upon treatment with ICB in cancer patients taking APAP. CONCLUSIONS: This study provides strong preclinical and clinical evidence of the role of APAP as a potential suppressor of antitumor immunity. Hence, APAP should be used with caution in patients treated with ICB.

Is There a Role for Percutaneous Ablation for Early Stage Lung Cancer? What Is the Evidence?

PURPOSE OF REVIEW: For patients with early stage non-small-cell lung cancer (NSCLC), thermal ablation (TA) has become in the least two decades an option of treatment used worldwide for patients with comorbidities who are not surgical candidates. Here, we review data published with different TA techniques: radiofrequency ablation (RFA), microwave ablation (MWA) and cryoablation. This paper reviews also the comparison that has been made between TA and stereotactic radiotherapy (SBRT). RECENT FINDINGS: A majority of retrospective studies, the absence of comparative studies, and the variety of techniques make difficult to get evident data. Nevertheless, these stand-alone techniques have demonstrated local efficacy for tumors less than 3 cm and good tolerance on fragile patients. Many recent reviews and database analyses show that outcomes after TA (mainly RFA and MWA) are comparable to SBRT in terms of survival rates. For patients who are unfit for surgery, TA has demonstrated interesting results for safety, benefits in overall survival, and acceptable local control.

Programmed cell death 1 (PD-1) targeting in patients with advanced osteosarcomas: results from the PEMBROSARC study.

PURPOSE: There are some lines of evidence suggesting a potential role of immunotherapy for treating patients with osteosarcomas. PATIENTS AND METHODS: This was an open-label, multicentre, phase 2 study of pembrolizumab in combination with metronomic cyclophosphamide in patients with advanced osteosarcomas. All patients received 50 mg b.i.d. of cyclophosphamide one week on and one week off and 200 mg of intravenous pembrolizumab (every 3 weeks). There was a dual primary end-point, encompassing both the non-progression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. An objective response rate of 20% and/or a 6-month non-progression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from the patients' tumour samples. RESULTS: Between October 13 2015 and July 3 2017, 17 patients were included. Fifty were assessable for the efficacy end-point. Four patients experienced tumour shrinkage, resulting in a partial response (PR) in one patient (6.7%). The 6-month non-progression rate was 13.3% (95% confidence interval [CI]: 1.7-40.5). The most frequent adverse events were grade I or II nausea, anaemia, anorexia and fatigue. programmed death-ligand 1 (PD-L1) expression rate was low, observed in only 2 cases of 14 with available tumour material. The only patient who experienced PR had a PD-L1-negative tumour. CONCLUSION: Programmed cell death 1 (PD-1) inhibition has limited activity in osteosarcomas. Further studies investigating PD-1 inhibitor in combination with agents modulating the microenvironment are warranted. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT02406781.

Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors.

BACKGROUND: Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed. PATIENTS AND METHODS: In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000 mg/m2 (arm 2a) or 500 mg/m2 (arm 2b), followed by GDC-0575 (45 or 80 mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts. RESULTS: Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No pharmacokinetic drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2. CONCLUSION: GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine. CLINICAL TRIAL NUMBER: NCT01564251.

Homogeneous myxoid liposarcomas mimicking cysts on MRI: A challenging diagnosis.

OBJECTIVES: Myxoid liposarcoma (M-LPS) is the second most frequent subtype of liposarcoma. Foci of fat on MRI are strongly suggestive of this diagnosis. The aims of this study are to (i) assess the prevalence of perfectly homogeneous M-LPS-mimicking cyst and characterize their associated clinical and pathological features and to (ii) identify helpful clues to prevent misdiagnosis when encountered with a cyst-like lesion in soft tissue parts. METHODS: MR images from 32 consecutive pathologically proven M-LPS and round cell liposarcomas (RC-LPS) were retrospectively reviewed independently by two radiologists at our institution. Location, morphology, signals, lesion architecture, heterogeneity, margins and periphery were systematically assessed in each case. Medical records were checked for initial and definitive histopathological diagnosis, therapeutic managements and outcomes. Histopathological specimens of cyst-like M-LPS were reviewed for the study. RESULTS: We have identified seven perfectly homogeneous well-defined cyst mimickers (21.9%) located on the limbs, all but one being deep-seated. These tumors were significantly smaller than the conventional M-LPS (p = 0.0005). Six lesions were initially diagnosed as benign; 4 patients underwent marginal surgical resection without prior diagnosis and 2 cases were put under medical surveillance, one of which progressed towards classical RC-LPS on follow-up MRI. No specific pathological features could be identified nor were any clinical adverse outcomes recorded. CONCLUSION: "Cyst" on MRI, without pathological adjacent joint, necessitates ultrasonography with Doppler and intravenous Gadolinium agent injections as subsets of M-LPS can mimic cyst on MRI. Cyst-like M-LPS, due to their smaller size and relative favorable outcome, could have better prognosis.

CHK1 inhibition in soft-tissue sarcomas: biological and clinical implications.

Background: Inhibition of ChK1 appears as a promising strategy for selectively potentiate the efficacy of chemotherapeutic agents in G1 checkpoint-defective tumor cells such as those that lack functional p53 protein. The p53 pathway is commonly dysregulated in soft-tissue sarcomas (STS) through mutations affecting TP53 or MDM2 amplification. GDC-0575 is a selective ATP-competitive inhibitor of CHK1. Methods: We have performed a systematic screening of a panel of 10 STS cell lines by combining the treatment of GDC-0575 with chemotherapy. Cell proliferation, cell death and cell cycle analysis were evaluated with high throughput assay. In vivo experiments were carried out by using TP53-mutated and TP53 wild-type patient-derived xenograft models of STS. Clinical activity of GDC-0575 combined with chemotherapy in patients with TP53-mutated and TP53 wild-type STS was also assessed. Results: We found that GDC-0575 abrogated DNA damage-induced S and G2-M checkpoints, exacerbated DNA double-strand breaks and induced apoptosis in STS cells. Moreover, we observed a synergistic or additive effect of GDC-0575 together with gemcitabine in vitro and in vivo in TP53-proficient but not TP53-deficient sarcoma models. In a phase I study of GDC-0575 in combination with gemcitabine, two patients with metastatic TP53-mutated STS had an exceptional, long-lasting response despite administration of a very low dose of gemcitabine whereas one patient with wild-type TP53 STS had no clinical benefit. Genetic profiling of samples from a patient displaying secondary resistance after 1 year showed loss of one preexisting loss-of-function mutation in the helical domain of DNA2. Conclusion: We provide the first preclinical and clinical evidence that potentiation of chemotherapy activity with a CHK1 inhibitor is a promising strategy in TP53-deficient STS and deserves further investigation in the phase II setting.

Toxicity profiles of immunotherapy.

Immunotherapies are changing the landscape of advanced solid tumor treatment. These therapies have different mechanisms of action and include oncolytic viruses, checkpoint inhibitors, such as CTLA-4 or PD1/PD-L1 monoclonal antibodies, and CSF-1R antibodies. Given the growing therapeutic impact of these agents in oncology, it is important to better understand their properties. Immunotherapies generate new toxicity profiles that are called immune-related adverse events and require specific management. This review focuses on the mechanisms of action of such side effects, as well as their description and their general management.

Complication-related removal of totally implantable venous access port systems: Does the interval between placement and first use and the neutropenia-inducing potential of chemotherapy regimens influence their incidence? A four-year prospective study of 4045 patients.

BACKGROUND: Totally implantable venous access port systems are widely used in oncology, with frequent complications that sometimes necessitate device removal. The aim of this study is to investigate the impact of the time interval between port placement and initiation of chemotherapy and the neutropenia-inducing potential of the chemotherapy administered upon complication-related port removal. PATIENTS AND METHODS: Between January 2010 and December 2013, 4045 consecutive patients were included in this observational, single-center prospective study. The chemotherapy regimens were classified as having a low (<10%), intermediate (10-20%), or high (>20%) risk for inducing neutropenia. RESULTS: The overall removal rate due to complications was 7.2%. Among them, port-related infection (2.5%) and port expulsion (1%) were the most frequent. The interval between port insertion and its first use was shown to be a predictive factor for complication-related removal rates. A cut-off of 6 days was statistically significant (p = 0.008), as the removal rate for complications was 9.4% when this interval was 0-5 days and 5.7% when it was ≥6 days. Another factor associated with port complication rate was the neutropenia-inducing potential of the chemotherapy regimens used, with removal for complications involved in 5.5% of low-risk regimens versus 9.4% for the intermediate- and high-risk regimens (p = 0.003). CONCLUSION: An interval of 6 days between placement and first use of the port reduces the removal rate from complications. The intermediate- and high-risk for neutropenia chemotherapy regimens are related to higher port removal rates from complications than low-risk regimens.

0.5-keV Soft X-ray attosecond continua.

Attosecond light pulses in the extreme ultraviolet have drawn a great deal of attention due to their ability to interrogate electronic dynamics in real time. Nevertheless, to follow charge dynamics and excitations in materials, element selectivity is a prerequisite, which demands such pulses in the soft X-ray region, above 200 eV, to simultaneously cover several fundamental absorption edges of the constituents of the materials. Here, we experimentally demonstrate the exploitation of a transient phase matching regime to generate carrier envelope controlled soft X-ray supercontinua with pulse energies up to 2.9±0.1 pJ and a flux of (7.3±0.1) × 10(7) photons per second across the entire water window and attosecond pulses with 13 as transform limit. Our results herald attosecond science at the fundamental absorption edges of matter by bridging the gap between ultrafast temporal resolution and element specific probing.

High-flux table-top soft x-ray source driven by sub-2-cycle, CEP stable, 1.85-µm 1-kHz pulses for carbon K-edge spectroscopy.

We report on the first table-top high-flux source of coherent soft x-ray radiation up to 400 eV, operating at 1 kHz. This source covers the carbon K-edge with a beam brilliance of (4.3±1.2)×10(15) photons/s/mm(2)/strad/10% bandwidth and a photon flux of (1.85±0.12)×10(7) photons/s/1% bandwidth. We use this source to demonstrate table-top x-ray near-edge fine-structure spectroscopy at the carbon K-edge of a polyimide foil and retrieve the specific absorption features corresponding to the binding orbitals of the carbon atoms in the foil.

Computed tomographic measurements with and without myelography to characterise thoracolumbar extruded disc herniation.

OBJECTIVE: To determine association between computed tomography measurements of spinal cord compression and postoperative outcome. METHODS: A retrospective review of medical records of dogs presenting with intervertebral disease. Data were collected with a minimum of 2 years follow-up period. Computed tomography morphometric indices, particularly the ratio of spinal cord or herniated disc to vertebral canal dimensions, were obtained from survey and myelogram computed tomographic images. The pattern of disc disease was scored as single or continuous (multiple herniated discs), and was compared to postoperative outcome. RESULTS: Fifty-two dogs were included. There was no significant correlation between the degree of spinal cord compression and postoperative outcome. However, postoperative outcome differed significantly between dogs with single or continuous patterns of disc disease (P=0·001). Of those with single patterns, 75% had a postoperative outcome score greater than 75% while 75% of continuous pattern cases had scores lower than 83%. CLINICAL SIGNIFICANCE: Simple observation of the pattern of disc disease as revealed by computed tomography could be used as a prognostic indicator. The outcome tends to be better for single patterns of disc disease, whereas the outcome was poor for most cases with continuous patterns.

Correlation between overall survival and growth modulation index in pre-treated sarcoma patients: a study from the French Sarcoma Group.

BACKGROUND: Growth modulation index (GMI), the ratio of two times to progression measured in patients receiving two successive treatments (GMI = TTP2/TTP1), has been proposed as a criterion of phase II clinical trials. Nevertheless, its use has been limited until now. PATIENTS AND METHODS: We carried out a retrospective multicentre study in soft tissue sarcoma patients receiving a second-line treatment after doxorubicin-based regimens to evaluate the link between overall survival and GMI. Second-line treatments were classified as 'active' according to the EORTC-STBSG criteria (3-month progression-free rate >40% or 6-month PFR >14%). Comparisons used chi-squared and log-rank tests. RESULTS: The population consisted in 106 men and 121 women, 110 patients (48%) received 'active drugs'. Median OS from the second-line start was 317 days. Sixty-nine patients experienced GMI >1.33 (30.4%). Treatments with 'active drug' were not associated with OS improvement: 490 versus 407 days (P = 0.524). Median OS was highly correlated with GMI: 324, 302 and 710 days with GMI <1, GMI = [1.00-1.33], and GMI >1.33, respectively (P < 0.0001). In logistic regression analysis, the sole predictive factor was the number of doxorubicin-based chemotherapy cycles. CONCLUSION: GMI seems to be an interesting end point that provides additional information compared with classical criteria. GMI >1.33 is associated with significant OS improvement.