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Degenerative changes in the lumbar spine significantly reduce the quality of life of people. In order to fully understand the biomechanics of the affected spine, it is crucial to consider the biomechanical alterations caused by degeneration of the intervertebral disc (IVD). Therefore, this study is aimed at the development of a discrete element model of the mechanical behavior of the L4–L5 spinal motion segment, which covers all the degeneration grades from healthy IVD to its severe degeneration, and numerical study of the influence of the IVD degeneration on stress state and biomechanics of the spine. In order to analyze the effects of IVD degeneration on spine biomechanics, we simulated physiological loading conditions using compressive forces. The results of modeling showed that at the initial stages of degenerative changes, an increase in the amplitude and area of maximum compressive stresses in the disc is observed. At the late stages of disc degradation, a decrease in the value of intradiscal pressure and a shift in the maximum compressive stresses in the dorsal direction is observed. Such an influence of the degradation of the geometric and mechanical parameters of the tissues of the disc leads to the effect of bulging, which in turn leads to the formation of an intervertebral hernia.

This article reviews the role of ALK tyrosine kinase inhibitors (TKIs) in the literature and provides expert commentary on local use in Argentina, Brazil, China, Russia, South Korea, and Turkey. We identified 56 articles involving patients with ALK-positive non-small cell lung cancer (NSCLC) and brain metastases (BM) treated with ALK TKIs published between January 2000 and June 2021. In first-line settings, central nervous system response rates in clinical trials with alectinib (86-94%), brigatinib (67-78%), and lorlatinib (42-82%) were generally higher than those reported with crizotinib (16-71%). Median progression-free survival in patients receiving crizotinib (5.6-7.4 months) was lower than alectinib (not reached), brigatinib (24.0 months), and ceritinib (10.7-25.2 months). Across these counties, next-generation TKIs are preferred for patients with progressing BM lesions. Although next-generation ALK TKIs demonstrate significant activity in these patients and following progression on crizotinib, access remains a challenge for personalized therapy.

In the phase 1/3 IMpower133 study, atezolizumab plus carboplatin and etoposide (CP/ET) followed by maintenance atezolizumab for first-line treatment of extensive-stage SCLC (ES-SCLC) led to improvement in both overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET followed by maintenance placebo. We explored the benefit of atezolizumab versus placebo in the subset of patients who reached the IMpower133 maintenance phase and the safety profile of maintenance therapy.Patients with untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo, followed by maintenance atezolizumab or placebo. The primary end points were OS and investigator-assessed PFS. A multivariate Cox model from the start of maintenance treatment was used to evaluate the treatment effect and account for lead-time bias; a generalized linear model was used to identify prognostic or predictive characteristics for reaching the maintenance phase.A similar proportion of patients in each arm received at least the first dose of maintenance therapy (atezolizumab: 77%, n = 154 of 201; placebo: 81%, n = 164 of 202) and were included in the maintenance analysis population. An Eastern Cooperative Oncology Group performance status of 0 and absence of liver metastases at baseline were identified as prognostic factors for reaching the maintenance phase. The positive treatment effect with atezolizumab remained after adjusting for baseline characteristics. Median OS and PFS from the start of maintenance therapy in the atezolizumab versus placebo arm were 12.5 versus 8.4 months (hazard ratio = 0.59, 95% confidence interval: 0.43-0.80) and 2.6 versus 1.8 months (hazard ratio = 0.63 [95% confidence interval: 0.49-0.80]), respectively. Treatment-related adverse events from the start of maintenance therapy occurred in 41% (n = 64 of 155) and 25% (n = 41 of 163) of safety-evaluable patients in the atezolizumab and placebo arms, respectively, and were grade 3 or 4 in 28% (n = 43 of 155) and 23% (n = 37 of 163) of the respective populations; no patient in the atezolizumab arm and one patient in the placebo arm had a grade 5 treatment-related adverse event.These data in the context of other immunotherapy trials in ES-SCLC suggest that induction with atezolizumab plus CP/ET and maintenance treatment with atezolizumab are important components that contributed to the OS benefit observed in IMpower133. Safety results from randomization and from the start of maintenance therapy were similar between the treatment arms despite the continuation of atezolizumab in the maintenance phase.

TPS8606 Background: Current standard of care immunotherapy plus chemotherapy options for first-line extensive-stage small-cell lung cancer (ES-SCLC) are associated with modest improvements in median OS and PFS. In the KEYNOTE-604 study, first-line pembrolizumab plus etoposide/platinum (EP) significantly improved PFS (HR 0.75; 95% CI, 0.61‒0.91; P = 0.0023) compared with placebo plus EP in ES-SCLC; OS was also longer with pembrolizumab plus EP vs placebo plus EP but did not reach statistical significance (HR 0.80; 95% CI, 0.64‒0.98; P = 0.0164). Preclinical and clinical data suggest that blocking the interaction between the T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) and its ligands CD112 and CD155 with the anti-TIGIT humanized monoclonal antibody vibostolimab (MK-7684) yields promising antitumor activity when combined with pembrolizumab, with or without chemotherapy, including in patients with lung cancer. The current phase 3 study, KeyVibe-008 (NCT05224141), is comparing the efficacy and safety of first-line treatment with MK-7684A, a co-formulation of vibostolimab plus pembrolizumab, in combination with EP vs atezolizumab plus EP in patients with ES-SCLC. Methods: This multicenter, randomized, double-blind, phase 3 study is enrolling patients aged ≥18 years with histologically or cytologically confirmed, previously untreated ES-SCLC. Patients must have measurable disease per RECIST v1.1; ECOG PS of 0 or 1; no active CNS metastases/carcinomatous meningitis, autoimmune disease, neurologic paraneoplastic syndromes, pneumonitis, or interstitial lung disease; and must provide a pretreatment tumor sample. Patients are randomized 1:1 to receive up to 4 cycles of EP (cisplatin or carboplatin) in combination with MK-7684A (vibostolimab 200 mg + pembrolizumab 200 mg) Q3W or atezolizumab (1200 mg) Q3W, followed by MK-7684A or atezolizumab, respectively, until disease progression, unacceptable AEs, intercurrent illness, protocol violation, or investigator/patient decision. Randomization is stratified by ECOG PS (0 vs 1), LDH (≤ULN vs > ULN), liver metastases (yes vs no), and brain metastases (yes vs no). The primary endpoint is OS. Secondary endpoints include PFS, ORR, and duration of response per RECIST v1.1 by blinded independent central review; safety; and patient-reported outcomes (PROs). Tumor imaging occurs at baseline, every 6 weeks until 48 weeks, and every 9 weeks thereafter until disease progression, start of new anticancer treatment, withdrawal of consent, or death. PROs are assessed using validated instruments including the EORTC quality of life and EuroQol questionnaires. AEs are graded according to NCI CTCAE v5.0. Enrollment is ongoing worldwide. Clinical trial information: NCT05224141.

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.Funding: AstraZeneca.

Contains fulltext : 225429.pdf (Publisher’s version ) (Open Access) IMPORTANCE: Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer. OBJECTIVE: To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018. INTERVENTIONS: Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. MAIN OUTCOMES AND MEASURES: The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory. RESULTS: Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively. CONCLUSIONS AND RELEVANCE: The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab. TRIAL REGISTRATION: ClinicalT rials.gov Identifier: NCT02453282.

Background High TMB is predictive of PFS benefit with anti-PD-(L)1 ± anti-CTLA-4 therapy in mNSCLC. Preliminary results from MYSTIC (NCT02453282), an open-label, Phase III trial of first-line durvalumab (D; anti-PD-L1), ± tremelimumab (T; anti-CTLA-4), vs platinum-based chemotherapy (CT) in mNSCLC, indicate that blood TMB (bTMB, ≥16 mut/Mb; GuardantOMNI [Guardant Health]) from circulating tumor DNA (ctDNA) correlates positively with tissue (t) TMB (≥10 mut/Mb) (Spearman’s correlation coefficient = 0.6) and is predictive of survival benefit with D±T vs CT. Efficacy outcomes were assessed using additional exploratory cut-offs for bTMB and ≥10 mut/Mb for tTMB. Methods Pts with EGFR and ALK wild-type, immunotherapy/CT-naïve mNSCLC were randomized (1:1:1) to D (20 mg/kg i.v. q4w); D (20 mg/kg i.v. q4w) + T (1 mg/kg i.v. q4w up to 4 doses); or CT. bTMB was evaluated with the GuardantOMNI platform. tTMB was evaluated with the FoundationOne tissue NGS platform. bTMB cut-off was defined as ≥20 mut/Mb (bTMB≥20). Data cut-off: Oct 4, 2018 (OS); Jun 1, 2017 (PFS). Results 1118 pts were randomized. Baseline sample datasets were: bTMB 809; tTMB 460 pts, with baseline characteristics balanced between treatment arms. bTMB≥20 was associated with improved OS (D+T vs CT: HR 0.49 [95% CI 0.32, 0.74]; D vs CT: HR 0.72 [95% CI 0.50, 1.05]) and PFS (D+T vs CT: HR 0.53 [95% CI 0.34, 0.81]; D vs CT: HR 0.77; [95% CI 0.52, 1.13]); 24-mo survival: D+T 48.1% (95% CI 35.5, 59.7), D 33.8% (95% CI 23.4, 44.5) and CT 19.4% (95% CI 11.0, 29.5). Data for tTMB are shown (table). Additional cut-offs will be presented. Conclusion MYSTIC provides the most comprehensive data set to date supporting TMB as a predictive biomarker of OS benefit with immunotherapy. In exploratory analyses, bTMB≥20 was associated with OS and PFS benefit with D±T vs CT, with the greatest magnitude of benefit observed for pts receiving D+T. bTMB ≥20 mut/MbbTMB Citation Format: Solange Peters, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myung-Ju Ahn, Paul Baas, Manuel Cobo Dols, Alexey Smolin, David Vicente, Vladimir Moiseyenko, Scott J. Antonia, Kazuhiko Nakagawa, Sarah B. Goldberg, Edward Kim, Rajiv Raja, Philip Brohawn, Delyth Clemett, Piruntha Thiyagarajah, Urban Scheuring, Feng Liu, Naiyer Rizvi. Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): Blood and tissue TMB analysis from MYSTIC, a Phase III study of first-line durvalumab ± tremelimumab vs chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT074.

9016 Background: MYSTIC, an open-label, Ph3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs platinum-based CT, showed an improvement in OS with D vs CT in pts with tumor cell PD-L1 expression ≥25% (PD-L1 TC ≥25%; HR 0.76 [97.54% CI 0.56–1.02], p = 0.036). Exploratory analyses showed bTMB was a predictive biomarker for OS with D±T vs CT. We report further exploratory analyses of OS according to PD-L1 and bTMB. Methods: Immunotherapy/CT-naïve pts with mNSCLC were randomized (1:1:1) to D, D+T or CT. bTMB levels (mut/Mb) were evaluated with the GuardantOMNI platform (Guardant Health), and PD-L1 TC expression with the VENTANA PD-L1 (SP263) IHC assay. Results: D improved OS vs CT in pts with PD-L1 TC ≥25% across bTMB levels (PD-L1 TC ≥25%/bTMB≥20 HR 0.79 [95% CI 0.45, 1.39]; PD-L1 TC ≥25%/bTMB < 20 HR 0.64 [95% CI 0.45, 0.90]). In contrast, D+T improved OS vs CT in pts with bTMB≥20 across different PD-L1 TC expression levels (Table; PD-L1 TC ≥25%/bTMB≥20 HR 0.44 [95% CI 0.23, 0.84]; PD-L1 TC < 1%/bTMB≥20 HR 0.42 [95% CI 0.17, 0.97]). Additional cutoffs and outcomes in subgroups defined by both biomarkers will be presented. Conclusions: These exploratory analyses from MYSTIC support PD-L1 TC expression as an appropriate predictive biomarker for OS with D vs CT, while suggesting bTMB as a predictive biomarker for OS with D+T in mNSCLC. These biomarkers appear to be independent and both may be important for mNSCLC treatment decisions. Interpretation of these data may be limited by small sample sizes; further investigations are warranted. Clinical trial information: NCT02453282. [Table: see text]