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First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced NSCLC. We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival.Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). OS, PFS, ORR, DOR, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor-burden reduction in responders to nivolumab plus ipilimumab were also assessed.In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). ORR was 36%; median DOR was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor PD-L11%, ≥1%, 1-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor-burden reduction ≥80%, 50-80%, or 30-50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population.Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC.

Background: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. Patients and methods: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). Results: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1. Conclusions: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.

Delta-8-tetrahydrocannabinol (Δ

Das Lungenkarzinom ist immer noch die haufigste Krebstodesursache beim Mann und die zweithaufigste bei der Frau. Durch den Nachweis molekular therapierbarer Mutationen und den Erfolg der zielgerichteten Therapien von Treibermutationen sowie den Durchbruch der Checkpointinhibitoren haben sich in den letzten Jahren fur PatientInnen im metastasierten Stadium die Therapieoptionen grundlegend verandert und – damit einhergehend – das Uberleben deutlich verbessert. Damit PatientInnen vom Fortschritt der zielgerichteten, personalisierten Therapie des metastasierten nichtkleinzelligen Lungenkarzinoms (NSCLC) profitieren konnen, sind molekulare und (immun)histologische Analysen in Bezug auf die entsprechenden Marker eine unabdingbare Voraussetzung. Im metastasierten Stadium kann eine umfangreiche Diagnostik mittels entnommener Biopsien am Tumorgewebe oder an zytologischem Material erfolgen, sofern der Zustand der PatientInnen dies erlaubt. Zukunftig konnten molekulare Analysen auch an zirkulierender Tumor-DNA aus „liquid biopsies“ durchgefuhrt werden, hierzu ist lediglich eine Blutentnahme erforderlich. Aktuell konnen EGFR-Mutationen, ALK- oder ROS1-Translokationen sowie BRAF-Mutationen und NTRK-Translokationen zielgerichtet therapiert werden. Die Immuntherapie mit Pembrolizumab kommt in der Erstlinientherapie dann zum Einsatz, wenn eine PD-L1-Expression von ≥50 % vorliegt und gleichzeitig keine EGFR-Mutation oder ALK-Translokation nachgewiesen wird. In Kombination mit einer Chemotherapie konnen Checkpointinhibitoren in der Erstlinientherapie des metastasierenden NSCLC eingesetzt werden, unabhangig von der PD-L1-Expression. Auch fruhere Stadien konnen von Checkpointinhibitoren profitieren: Fur PatientInnen mit PD-L1-positivem NSCLC im Stadium III ist die Immuntherapie mit Durvalumab nach Radiochemotherapie eine Option.

Defined surface micrcotextures offer potential for the friction reduction in elastohydrodynamic contacts and can thus increase the energy efficiency of technical systems. The production of prostheses, where microtextured surfaces can provide anti-bacterial effects is another application area. To manufacture these components economically in large quantities, forming processes are to be aimed at. Since lightweight parts are crucial in most application areas, the forming of sheet metal is the subject of current research. A major aspect of the presented investigation is the behavior of tool materials for the production of such microtextured sheet metal parts. Applying microtextures of varying geometries to the tools is a key challenge. Limitations in the accuracy of electrical discharge machining processes for the fabrication of micro cylinders, prisms and cuboids are therefore analyzed on the high-speed steels 1.3343 and 1.3244. In addition, the tool surfaces are characterized regarding their friction properties with case hardening steel as a contact partner. In this paper, the tool friction is analyzed for the steel 1.7131 (16MnCr5) with an initial sheet thickness of t0 = 2.4 mm, which is often utilized for high-wear applications due to its high strength and toughness. In this context, the friction behavior of the wax-containing lubricant Beruforge 150 DL made for bulk forming processes is compared with zinc-free high-performance lubricants Raziol CLF 65-400 of varying viscosity.

Immunotherapies have recently gained traction as highly effective therapies in a subset of late-stage cancers. Unfortunately, only a minority of patients experience the remarkable benefits of immunotherapies, whilst others fail to respond or even come to harm through immune related adverse events. For immunotherapies within the PD-1/PD-L1 inhibitor class, patient stratification is currently performed using tumor (tissue-based) PD-L1 expression. However, PD-L1 is an accurate predictor of response in only ∼30% of cases. There is pressing need for more accurate biomarkers for immunotherapy response prediction.We sought to identify peripheral blood biomarkers, predictive of response to immunotherapies against lung cancer, based on whole blood microRNA profiling. Using three well characterized cohorts consisting of a total of 334 stage IV NSCLC patients, we have defined a 5 microRNA risk score (miRisk) that is predictive of overall survival following immunotherapy in training and independent validation (HR 2.40, 95% CI 1.37-4.19; P < 0.01) cohorts. We have traced the signature to a myeloid origin and performed miRNA target prediction to make a direct mechanistic link to the PD-L1 signalling pathway and PD-L1 itself. The miRisk score offers a potential blood-based companion diagnostic for immunotherapy that outperforms tissue-based PD-L1 staining.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR)= 1.02 (0.66-1.58), two-sided P= 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR= 0.95 (0.59-1.52), P= 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade =3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Background Immunotherapy represents the standard of care in the first-line treatment of advanced non-small-cell lung cancer (NSCLC), either as monotherapy in high programmed death-ligand 1 (PD-L1)-positive tumors (≥50%) or in combination with platinum-based chemotherapy regardless of PD-L1 status. However, most pivotal clinical trials of immune checkpoint inhibitors (ICIs) did not include patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. Hence, a consensus is lacking on the safety and efficacy of ICIs in this specific subgroup of patients. Materials and methods A virtual International Expert Panel took place in July 2021 with the aim of reviewing the available evidence on the use of ICIs in NSCLC patients with ECOG PS 2, both in clinical practice and in a research setting. Results All panelists expressed concern about the applicability of currently available PS scales to evaluate patients for ICI treatment. The panelists agreed that, though limited, the available data support the safety of single-agent immunotherapy in PS 2 NSCLC patients, whereas concern was raised on the safety of ICI combinations, mainly related to chemotherapy and/or anti-cytotoxic T-lymphocyte-associated antigen 4 toxicity. On the basis of reviewed data, ICI efficacy may be speculated in PS 2 NSCLC patients; however, PS 2 remains a negative prognostic category as compared to PS 0-1 in patients treated with ICI, as it is for chemotherapy. The panelists defined high, medium and low priorities in clinical research. High priority was attributed to the inclusion of PS 2 patients in prospective clinical trials and the specific evaluation of combined ICI treatments with attenuated chemotherapy doses. Conclusions Based on the current evidence, the panelists outlined the major limitations affecting PS 2 patients with NSCLC and reached common considerations on the feasibility, safety and effectiveness of ICI monotherapy and ICI combinations in the first-line setting., Highlights • A consensus on the use of ICIs in lung cancer patients with PS 2 is lacking. • An International Expert Panel Meeting was held in 2021 to review and discuss available evidence on this topic. • Overall, agreement was reached on the safety of ICI monotherapy in PS 2 patients, with concerns for chemo–ICI combinations. • Common considerations were reached on the priorities for clinical research to investigate PS 2 lung cancer population.

In industrial sectors like medical and automotive engineering, the demand for metal components with a high function integration brings conventional production technologies to their limits. This motivates research on innovative processes, which can meet the present requirements on fabricated parts and consequently also the demands on the applied manufacturing process. Part-sided, a high strength, narrow dimensional tolerances and a large functionality is often desired. In addition, an economical component production calls for processes with high material utilization as well as the achievement of short cycle times. The process class of sheet-bulk metal forming, characterized by the application of bulk forming operations on sheet metal, offers the potential to meet these requirements. Currently, sheet-bulk metal forming is mainly used for the fabrication of components with functional elements of macroscopic size. However, microscopic elements and micro-textured surfaces are of high interest for applications in prosthetics and automotive engineering. The objective of this study is therefore to develop an application-oriented method for the design, production and testing of 16MnCr5 metal components, manufactured by a combined process of sheet-bulk metal forming, creating a defined microstructure on the surface. Since the selection of a suitable texture layout and geometry is crucial for tribological optimization, these are designed for their application using numerical elastohydrodynamic lubricant simulations. The contact conditions occurring in the application are modelled as realistically as possible so that texture designs suitable for production can subsequently be compared in test bench trials. It is shown that the tappets produced by forming technology can be efficiently investigated with the test rig presented.

Purpose/Objective(s) Pembrolizumab, an anti‒PD-1 antibody is standard of care therapy for metastatic non‒small-cell lung cancer (NSCLC) as monotherapy and in combination with chemotherapy. Durvalumab, an anti–PD-L1 antibody, is approved for unresectable, stage III NSCLC without disease progression following CCRT. Early trials of pembrolizumab in combination with chemoradiotherapy, either concurrently or as consolidation, showed acceptable tolerability and promising PFS in patients with unresectable stage III NSCLC. Early data suggest the combination of poly(ADP-ribose) polymerase (PARP) plus anti–PD-(L)1 inhibition can enhance treatment effects. KEYLYNK-012 (NCT04380636) is evaluating pembrolizumab plus CCRT followed by pembrolizumab with/without the PARP inhibitor olaparib vs CCRT followed by durvalumab in patients with unresectable, locally advanced, stage III NSCLC. Materials/Methods This global phase 3, randomized, placebo- and active-controlled, double-blind study is enrolling patients aged ≥18 y with previously untreated, pathologically confirmed, stage IIIA–C NSCLC, an ECOG PS of 0 or 1, and a tumor sample available for PD-L1 evaluation. Patients are randomized 1:1:1 to CCRT (platinum-doublet chemotherapy [cisplatin plus pemetrexed or etoposide; or carboplatin plus paclitaxel] plus radiotherapy 60 Gy over 6 wks [cycles 2–3]) with pembrolizumab 200 mg Q3W (groups A and B) or CCRT alone (group C) for 3 cycles. This is followed by pembrolizumab 200 mg Q3W for 17 cycles plus placebo (group A) or olaparib 300 mg BID (group B); or durvalumab 10 mg/kg Q2W for 26 cycles (group C). Randomization is stratified by disease stage (IIIA vs IIIB/IIIC), tumor histology (squamous vs nonsquamous), PD-L1 tumor proportion score (≥50% vs Results forthcoming Conclusion forthcoming