Vulnerable Neighborhoods Had Smaller Gains in Health Insurance Coverage During Early Covid-19

Background: The Covid-19 pandemic has illuminated the inequities that jeopardize health, prompting rapid interventions to promote care access. However, such efforts have had mixed success in eradicating disparities. One focus is the equity of improvements in insured rates. Methods: Self-reported health insurance coverage rates among adults aged 18-64 were obtained from the CDC’s PLACES datasets for collection years 2018 and 2021, at the Census Tract level. These data were merged with the CDC’s 2018 Social Vulnerability Index (SVI), which ranks Tracts on 15 measures of social determinants of health. Across Tracts nationally and by state, univariate correlations between Overall SVI and percentage change in uninsured rate from 2018 to 2021 were calculated. Then, national and state-specific multivariate models were created to assess the relationships between all 15 SVI variables and change in uninsured rate. Results: Health insurance coverage improved in all states. Nationally and across states, improvements were greater in lower-risk Census Tracts (34% average decrease in uninsured rate in lowest-risk decile nationally, vs. 16% in highest-risk decile, p \u3c 0.0001). Most state-specific multivariate models demonstrated high correlations between SVI variables and change in uninsured rate, with mean Multiple R of 0.74 (0.72 to 0.76 95% CI, F \u3c 0.0001 in all states). Conclusions: Nationally and in each state individually, pandemic-era improvements in health insurance access were disproportionately concentrated in lower-risk Census Tracts, which already had lower baseline uninsured rates. Multivariate models using SDOH inputs reliably identified vulnerable neighborhoods with lower health insurance access and smaller improvements in insured rates

A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer

Advanced; Colorectal cancerAvanzado; Cáncer colorrectalAvançat; Càncer colorrectalBackground Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC. Patients and methods Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS). Results At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab. Conclusions Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors.This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (no grant number)

Phase II Study of Gemcitabine and Docetaxel Combination in Patients with Previously Treated Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Purpose. To explore the safety and efficacy of gemcitabine and docetaxel (GEMDOC) in previously treated patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods. Patients with advanced SCCHN previously pretreated with one or two lines of palliative chemotherapy were treated with gemcitabine and docetaxel until disease progression. Results. Thirty-six patients were enrolled, and 29 were response evaluable. 16 (55%) experienced clinical benefit (response or stable disease). Six (21%) patients achieved partial response (PR), none achieved complete response (CR), and the overall response rate (ORR) was 21% (95% CI: 0.10–0.38). Ten (28%) patients had stable disease. The median response duration (RD) for the 6 PR patients was 3.2 months (80% CI: 2.0–6.1 months). Median overall survival was 4.2 months (95% CI: 2.4–7.0 months). Among the 33 treated patients: 13 (39%) patients had grade 3-4 anemia, 10 (30%) had grade 3-4 neutropenia. Conclusion. The study drugs were relatively safe, and the clinical benefit (PR + SD) rate was 55%. However, the efficacy objective for this regimen was not met. Given the good safety profile, further investigation of this regimen with the addition of a targeted agent may lead to better efficacy

Risk Factors Associated with a Second Primary Lung Cancer in Patients with an Initial Primary Lung Cancer

Objectives: Increased patient survivorship following initial primary lung cancer (IPLC) due to advancing clinical practice has uncovered new clinical challenges. With growing patient longevity, individuals post-IPLC continue to be at higher subsequent risk of developing secondary primary lung cancer (SPLC). Proper SPLC surveillance guidelines aimed at monitoring IPLC survivors is crucial to enhancing life expectancy in this population. This study aims to categorize risk factors associated with SPLC emergence in IPLC survivors for clinical use following IPLC treatment. Materials and Methods: Using the Karmanos Cancer Institute Tumor Registry, patients diagnosed with IPLC from 2000 to 2017 were identified. Patients diagnosed with SPLC were matched for histology, age and stage to individuals who did not develop SPLC. Logistic and Cox regression analyses were performed to identify potential risk factors for SPLC emergence and overall survival. Results: 121 patients diagnosed with IPLC who later developed SPLC were identified and compared to 120 patients with IPLC who did not develop SPLC. Patients who did not undergo surgical resection had a significantly lower probability of developing SPLC (OR 0.235, 95% confidence interval [CI]: 0.118 to 0.450; p\u3c0.001). Compared to surgical resection patients, individuals who did not have surgery as their primary treatment for IPLC had a significantly higher hazard of death (HR 3.088, 95% CI: 2.114 to 4.512; p\u3c0.001). Conclusion: This study uncovered notable associations and lack thereof between several competing risk factors and SPLC development as well as mortality. Further characterization of SPLC risk factors is essential for implementing effective surveillance recommendations

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Is this really just fatigue? A case series of immune-related central adrenal insufficiency secondary to immune checkpoint inhibitors.

While immunotherapy with programmed cell death protein 1 (PD1) checkpoint inhibition has shown promising activity against many tumor types, adverse events are common. Hypophysitis is a rare but serious immune-related event known to occur with anti-PD1 inhibition. It will become more prevalent as the usage of checkpoint inhibitors increases

A user\u27s guide to lorlatinib

Rearrangements of the ALK gene are found in approximately 5% of non-small-cell lung cancer. It is of particular importance to test for this rearrangement in patients with metastatic lung adenocarcinoma because these tumors are highly sensitive to therapy with ALK-targeted inhibitors. Lorlatinib is a reversible potent third generation tyrosine kinase inhibitor that is highly selective and targets ALK and ROS1. It was developed to target resistant ALK mutants including the most common G1202R. Lorlatinib has excellent central nervous system (CNS) penetration and its efficacy has also been demonstrated even in patients with intracranial metastases after progression on second generation ALK inhibitors. Potential toxicities include neurocognitive effects and hyperlipidemia. A User\u27s Guide to Lorlatinib reviews the mechanism of action, pharmacology and clinical trial data. Also covering the management of adverse events, this guide has been prepared to be a practical reference tool to both clinicians and basic researchers

KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne?

Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are among the most common aberrations in cancer, including non-small cell lung cancer (NSCLC). The lack of an ideal small molecule binding pocket in the KRAS protein and its high affinity towards the abundance of cellular guanosine triphosphate (GTP) renders the design of specific small molecule drugs challenging. Despite efforts, KRAS remains a challenging therapeutic target. Among the different known mutations; the KRASG12C (glycine 12 to cysteine) mutation has been considered potentially druggable. Several novel covalent direct inhibitors targeting KRASG12C with similar covalent binding mechanisms are now in clinical trials. Both AMG 510 from Amgen and MRTX849 from Mirati Therapeutics covalently binds to KRASG12C at the cysteine at residue 12, keeping KRASG12C in its inactive GDP-bound state and inhibiting KRAS-dependent signaling. Both inhibitors are being studied as a single agent or as combination with other targets. In addition, two novel KRAS G12C inhibitors JNJ-74699157 and LY3499446 will have entered phase 1 studies by the end of 2019. Given the rapid clinical development of 4 direct covalent KRAS G12C inhibitors within a short period of time, understanding the similarities and differences among these will be important to determine the best treatment option based on tumor specific response (NSCLC versus colorectal carcinoma), potential resistance mechanisms (i.e. anticipated acquired mutation at the cysteine 12 residue) and central nervous system (CNS) activity. Additionally, further investigation evaluating the efficacy and safety of combination therapies with agents such as immune checkpoint inhibitors will be important next steps