BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...

/pdf/pd-1-blockade-in-tumors-with-mismatch-repair-deficiency-1eb0ztv7j7.pdf

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.

https://science.sciencemag.org/content/sci/early/2015/03/11/science.aaa1348.full.pdf

Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

Thank you very much for downloading modern applied statistics with s. As you may know, people have search hundreds times for their favorite readings like this modern applied statistics with s, but end up in harmful downloads. Rather than reading a good book with a cup of coffee in the afternoon, instead they cope with some harmful virus inside their laptop. modern applied statistics with s is available in our digital library an online access to it is set as public so you can download it instantly. Our digital library saves in multiple countries, allowing you to get the most less latency time to download any of our books like this one. Kindly say, the modern applied statistics with s is universally compatible with any devices to read.

Modern Applied Statistics With S

BackgroundWe assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non–small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. MethodsWe assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. ResultsCommon side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1501824

Pembrolizumab for the treatment of non-small cell lung cancer

BackgroundNivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. MethodsA total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. ResultsThe median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The haz...

/pdf/nivolumab-versus-everolimus-in-advanced-renal-cell-carcinoma-4qkp9zdhuq.pdf

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma

‘Estimates suggest that approximately 200 million individuals are infected with HBV or HCV without HIV co-infection, and that diagnosis rates are increasing’

New therapies for hepatitis infection

LBA4500 Background: ICI-based regimens are the standard of care for first-line (1L) treatment of metastatic clear cell (cc) RCC. Treatment options following disease progression during or after ICI therapy are limited but can include single-agent TKIs, such as cabozantinib (cabo). CONTACT-03 evaluated anti–PD-L1 atezolizumab (atezo) + cabo vs cabo alone in patients (pts) with metastatic RCC that progressed during or after prior ICI treatment and is the first phase 3 randomized trial to test the benefit of ICI rechallenge by direct addition to a control arm. Methods: CONTACT-03 enrolled pts with histologically confirmed, inoperable, locally advanced or metastatic cc or non-cc RCC, regardless of PD-L1 status, that progressed on or after ICI treatment. Randomization was 1:1 to atezo (1200 mg IV q3w) plus cabo (60 mg oral qd) or cabo alone. Stratification factors were IMDC risk factors (0 vs 1-2 vs ≥3); most recent line of prior ICI therapy (adjuvant vs 1L vs 2L); and histology (dominant cc without sarcomatoid vs dominant non-cc [papillary or unclassified] without sarcomatoid vs cc or non-cc with any sarcomatoid component). The multiple primary efficacy endpoints were centrally reviewed RECIST 1.1 PFS and OS. Key secondary endpoints were investigator (INV)-assessed PFS, centrally reviewed RECIST 1.1 ORR and DOR and safety. Results: Of 522 pts randomized to atezo + cabo (n=263) or cabo (n=259), 55% and 51% had most recent ICI in the 1L setting and 10% and 11% had sarcomatoid RCC, respectively. At the data cutoff (Jan 3, 2023), median follow-up was 15.2 mo. No PFS or OS benefit was observed with atezo + cabo vs cabo. ORR was 41% in both arms; DOR was 12.7 (95% CI: 10.5, 17.4) mo with atezo + cabo and 14.8 (95% CI: 11.3, 20.0) mo with cabo. All-cause Grade 3/4 adverse events (AEs) occurred in 68% (177/262) and 62% (158/256) of safety-evaluable pts receiving atezo + cabo or cabo, respectively; all-cause Grade 5 AEs occurred in 6% and 4%. AEs leading to treatment withdrawal occurred in 16% of pts on atezo + cabo and 4% on cabo. Conclusions: The addition of atezo to cabo did not improve clinical outcomes and led to increased toxicity in patients with RCC that progressed on or after prior ICI treatment. CONTACT-03 is the first randomized, phase III oncology trial to test the benefit of PD-(L)1 inhibitor continuation by direct addition to a standard control arm; the results prompt caution with this approach in other cancers. Clinical trial information: NCT04338269 . [Table: see text]

Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): Primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study.

Reply to Alessia Cimadamore, Liang Cheng, Marina Scarpelli, et al's Letter to the Editor re: Alfonso Gómez de Liaño Lista, Nick van Dijk, Guillermo de Velasco Oria de Rueda, et al. Clinical Outcome After Progressing to Frontline and Second-line Anti-PD-1/PD-L1 in Advanced Urothelial Cancer. Eur Urol 2020;77:269-76. Progression and Hyperprogression Versus Pseudoprogression: Morphologic Documentation.

/pdf/reply-to-m-horiguchi-et-al-5g5c1fop3n.pdf

Reply to M. Horiguchi et al.

Background Several preclinical and clinical studies demonstrated a strong correlation between androgen receptor (AR) signaling and bladder tumorigenesis. This study aims to evaluate the prognostic significance of AR expression in metastatic urothelial carcinoma (mUC). Methods Samples from a phase III trial (LaMB, NCT00949455) which compared maintenance lapatinib versus placebo after completion of first-line platinum-based chemotherapy in patients with HER 1/2-positive mUC of the bladder were collected. Corresponding baseline and follow-up data included patients enrolled in the study and those who screen failed. AR expression was assessed independently by a single pathologist who was blinded to the study. Samples were grouped according to AR expression (negative vs. positive) and correlated with baseline tumor characteristics and survival. Results Of the 446 screened samples in the LaMB study, 90 were retrospectively analyzed for AR expression. There were no correlations between AR expression and tumor stage (r = −0.10), tumor grade (r = 0.05) at diagnosis, or subsequent treatment with lapatinib (r = −0.04). The median progression-free survival was 6 months (95% CI, 3.20–6.80) in the AR-negative group and 5 months (95% CI, 3.41–6.59) in the AR-positive group [HR 0.54 (95% CI, 0.31–0.92), p = 0.02]. Similarly, patients with AR-negative disease had more favorable overall survival (OS) with 16 months (95% CI, 6.6–25.4) and 11 months (95% CI, 7.0–15.0) in the AR-positive group [HR 0.55 (95% CI, 0.31–0.98), p = 0.04]. In the multivariate analysis, AR expression was significantly associated with worse OS (p = 0.045). Conclusions AR expression is a predictor of poor outcome and presents a targetable alteration in patients with mUC.

Thomas Powles

Papers

New therapies for hepatitis infection

Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): Primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study.

Reply to M. Horiguchi et al.

Androgen Receptor Expression Is a Predictor of Poor Outcome in Urothelial Carcinoma