First-line Treatment For Patients Research Articles

A review on recent advances in the stability study of anti-mycobacterial drugs.

Several factors, including characteristic polymer composition of the cell wall, based on peptidoglycans cross-linked with arabinogalactans, together with the lipid layer contribute to the high resistance of Mycobacterium tuberculosis to antibiotics and other anti-tuberculosis drugs, leading to the development of new treatment methods. Implementation of therapeutic drug monitoring for anti-mycobacterial drugs in routine clinical practice requires understanding of the limited stability of these drugs. Rifampicin and isoniazid are the main anti-tuberculosis drugs that generate degradation products during sample handling and storage. Therefore, analytical methods used for analysis of clinical samples collected from tuberculosis patients treated with a combination of different drugs should enable the separation of the studied analytes from their metabolites and degradation products. Moreover, the samples require strictly regulated collection and storage conditions to prevent degradation processes. The purpose of this review was to present recent data on the stability studies of anti-mycobacterial drugs, specifically used as first-line treatment in patients with tuberculosis. Detailed degradation pathway of rifampicin was described, including conditions influencing the formation of specific rifampicin related substances. Moreover, the results of the stability studies of anti-mycobacterial drugs were presented in various matrices in conditions determined by international guidance such as U.S. Food and Drug Administration (FDA) or International Council for Harmonisation (ICH) guidelines. Particular attention was given to analytical methods designed for analysis of anti-mycobacterial drugs in the presence of their degradation products. Finally, recommendations proposed by different authors for collection, processing and storage of clinical samples to increase stability of anti-mycobacterial drugs were summarized.

Avelumab + axitinib vs sunitinib as first-line treatment for patients with advanced renal cell carcinoma: final analysis of the phase 3 JAVELIN Renal 101 trial

Avelumab + axitinib vs sunitinib as first-line treatment for patients with advanced renal cell carcinoma: final analysis of the phase 3 JAVELIN Renal 101 trial

Oral minocycline therapy as first-line treatment in patients with Myalgic encephalomyelitis and long COVID: A pilot study

BackgroundMyalgic encephalomyelitis (ME) is associated with long COVID and also untoward sequelae after anti-coronavirus vaccination. Recently, oral minocycline therapy has been reported to ameliorate symptoms in patients with ME, particularly at the initial stage of the disease. MethodsOral minocycline (100 mg × 2 on the first day, followed by 100 mg/day for 41 days) was administered to 55 patients with ME that emerged during the “Corona era,” including 19 patients with long COVID and 5 patients diagnosed with untoward sequalae following coronavirus vaccination. ResultsAcute adverse effects including nausea and/or dizziness caused four (7 %) patients to discontinue treatment in the first few days. Among the other 51 patients who completed therapy, favorable effects were observed, including a decrease in performance status score or index for restricted activities of daily living ≥2 points in 41 (80 %) patients. Disease duration was inversely associated with the favorable therapeutic effects (p = 0.02) and the disease duration within 6 months was significantly associated with the favorable therapeutic effects (27/30, 90 %, p = 0.02, hazard ratio: 3.6, 95 % confidence interval, 1.2–10.6). The favorable effects were observed in 16 (89 %) of 18 patients with long COVID. Significant amelioration of subjective symptoms of fatigue, post-exertional malaise, unrefreshing sleep, brain fog, disequilibrium, orthostatic intolerance, and neuropathic pain were observed. ConclusionsOral minocycline was effective at ameliorating symptoms in patients with ME including long COVID and post-coronavirus vaccination sequalae. It represents an effective first-line therapeutic option for these patients in the initial stage.

A case of delayed initial response to combination ipilimumab and nivolumab in malignant pleural mesothelioma

Malignant pleural mesothelioma has a poor prognosis with limited therapeutic options Although numerous trials have shown that combination immunotherapy with nivolumab and ipilimumab is one of the first line treatments for patients with unresectable MPM, there is limited data on delayed responses over a long follow up period. We report a case of a delayed response 7 months after the cessation of immunotherapy in a patient who initially had progressive malignant pleural mesothelioma with metastases.

A real-world study of first-line albumin-bound paclitaxel in the treatment of advanced pancreatic cancer in China

Objective: To observe and evaluate the clinical efficacy and safety of albumin-bound paclitaxel as first-line treatment for patients with advanced pancreatic cancer in China, and to explore the prognosis-related molecules in pancreatic cancer based on next-generation sequencing (NGS) of tumor tissues. Methods: From December 2018 to December 2020, patients with locally advanced or metastatic pancreatic cancer were recruited to accept albumin-bound paclitaxel as first-line treatment in the oncology departments of 24 hospitals in East China. The primary endpoints were overall survival (OS) and treatment related adverse events, and the secondary endpoint was progression-free survival (PFS). Adverse effects were graded using Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0). NGS sequencing on the primary or metastatic tissue samples of pancreatic cancer obtained through surgical resection or biopsy was performed. Results: This study recruited 229 patients, including 70 patients with locally advanced pancreatic cancer (LAPC) and 159 patients with metastatic pancreatic cancer (mPC). The disease control rate was 79.9% and the objective response rate is 36.3%.The common adverse effects during treatment were anaemia (159 cases), leucopenia (170 cases), neutropenia (169 cases), increased aminotransferases (110 cases), and thrombocytopenia (95 cases), and the incidence of grade 3-4 neutropenia is 12.2% (28/229). The median follow-up time was 21.2 months (95% CI: 18.5-23.1 months). The median PFS (mPFS) was 5.3 months (95% CI: 4.37-4.07 months) and the median OS (mOS) was 11.2 months (95% CI: 9.5-12.9 months). The mPFS of patients with LAPC was 7.4 months (95% CI: 6.6-11.2 months), and their mOS was 15.5 months (95% CI: 12.6-NA months). The mPFS of patients with mPC was 3.9 months (95% CI: 3.4-5.1 months), and their mOS was 9.3 months (95% CI: 8.0-10.8 months). Multivariate Cox regression analysis showed that clinical stage (HR=1.47, 95% CI: 1.06-2.04), primary tumor site (HR=0.64, 95% CI: 0.48-0.86), Eastern Cooperative Oncology Group Performance Status (ECOG PS) score (HR=2.66, 95% CI: 1.53-4.65), and whether to combine radiotherapy (HR=0.65, 95% CI: 0.42-1.00) were independent influencing factors for the PFS of these patients. The primary tumor site (HR=0.68, 95% CI: 0.48-0.95), ECOG score (HR=5.82, 95% CI: 3.14-10.82), and whether to combine radiotherapy (HR=0.58, 95% CI: 0.35-0.96) were independent influencing factors of the OS of these patients. The most frequent gene mutations in these advanced stage pancreatic patients were KRAS (89.66%), TP53 (77.01%), CDKN2A (32.18%), and SMAD4 (21.84%) by NGS of tumor tissues from 87 pancreatic cancer patients with sufficient specimens. Further analysis revealed that mutations in CDKN2B, PTEN, FGF6, and RBBP8 genes were significantly associated with an increased risk of death (P＜0.05). Conclusion: Albumin-bound paclitaxel as first-line treatment demonstrated feasible anti-tumor efficacy and manageable safety for patients with advanced pancreatic cancer in China.

Cost-Effectiveness Analysis of Lenvatinib plus Pembrolizumab or Everolimus as First-Line Treatment for Advanced Renal Cell Carcinoma

BackgroundRecently, due to its promising efficacy against advanced renal cell carcinoma (RCC), the combination therapy with lenvatinib and pembrolizumab or everolimus has been approved as a first-line treatment for patients with advanced RCC in China and the United States. However, the high costs of combination therapies, especially of those new drugs, may limit their viability as clinical treatment options. Thus, our study aimed to evaluate the cost-effectiveness of using lenvatinib plus pembrolizumab or everolimus as a first-line treatment for patients with advanced RCC from the perspective of the Chinese healthcare system and US third-party payers. MethodsWe established a Markov model using TreeAge Pro 2022 software to estimate and compare the cost and effectiveness of the therapy with lenvatinib plus pembrolizumab or everolimus with those of sunitinib therapy for treating advanced RCC based on the clinical data derived from a phase III randomized controlled trial (CLEAR, ClinicalTrials.gov number NCT02811861). Transition probabilities and other data were calculated and obtained by using parametric survival modeling. The direct medical costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were used as economic indicators in this analysis. The robustness of the model was assessed by performing one-way and probability sensitivity analyses (PSA). ResultsAmong the 3 treatment strategies, the sunitinib 1 was the least expensive option. All ICERs were far higher than the thresholds of $38,024 and $100,000 selected for China and the United States, respectively. The ICERs of the therapy with lenvatinib plus pembrolizumab versus sunitinib therapy were 106,749.06 US$/QALY and $414,672.19 US$/QALY in China and the United States, respectively. Thus, among these 2, the former strategy was less cost-effective than the latter. In addition, the ICERs of the lenvatinib plus everolimus treatment vs. sunitinib treatment were $44,353.18 US$/QALY and $292,653.10 US$/QALY in China and the United States, respectively. Thus, among these 2 strategies, the former was less cost-effective than the latter. The total cost of the lenvatinib plus everolimus treatment strategy was lower than that of lenvatinib plus pembrolizumab; however, the former treatment was less effective than the latter. ConclusionThe treatment with lenvatinib plus pembrolizumab or everolimus is less cost-effective than the sunitinib treatment for patients with advanced RCC in China and the United States.

Toripalimab Plus Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Lung Cancer

Patients with extensive-stage small cell lung cancer (ES-SCLC) have poor prognoses and unmet medical needs. To evaluate the efficacy and safety of toripalimab plus etoposide and platinum-based chemotherapy (EP) vs placebo plus EP as a first-line treatment for patients with ES-SCLC. This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (EXTENTORCH study) enrolled patients from September 26, 2019, to May 20, 2021, and was conducted at 49 sites in China. Eligible patients had histologically or cytologically confirmed ES-SCLC without previous systemic antitumor therapy for ES-SCLC. Data were analyzed between May 6, 2023, and June 1, 2024. Patients were randomized (1:1) to receive toripalimab, 240 mg, or placebo plus EP every 3 weeks for up to 4 to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxic effects, or up to 2 years of treatment. The primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing results identified correlative biomarkers for clinical efficacy. Among 595 screened patients, 442 eligible patients were randomized (median [range] age, 63 [30-77] years; 366 [82.8%] male); 223 patients were randomized to toripalimab plus EP, and 219 to placebo plus EP. By April 20, 2023, the median (range) survival follow-up was 13.7 (0.0-42.7) months. Compared with placebo, toripalimab improved investigator-assessed PFS (hazard ratio [HR], 0.67 [95% CI, 0.54-0.82]; P < .001), and significantly reduced the risk of death (HR, 0.80 [95% CI, 0.65-0.98]; P = .03). The median OS was 14.6 (95% CI, 12.9-16.6) months in the toripalimab group vs 13.3 (95% CI, 11.8-14.4) months in the placebo group. Whole-exome sequencing results from 300 patients identified low intratumor heterogeneity, HLA-A11+ HLA-B62- haplotype, wild-type KMT2D and COL4A4, or sequence variations in CTNNA2 or SCN4A correlated with favorable PFS and OS in the toripalimab group. No new safety signals were observed. Grade 3 or higher treatment-emergent adverse event incidence was similar between the toripalimab and placebo safety set groups (199 of 222 patients [89.6%] vs 193 of 216 patients [89.4%], respectively). In this phase 3 randomized clinical trial, adding toripalimab to first-line chemotherapy demonstrated significant improvements in PFS and OS for patients with ES-SCLC. The treatment exhibited an acceptable safety profile, supporting this combination regimen as a new treatment option for patients with ES-SCLC. ClinicalTrials.gov Identifier: NCT04012606.

Comparative analysis of efficacy and safety of combined immunotherapy and immune targeted therapy in the first-line treatment of advanced renal cell carcinoma: a real-world study

Aim. To compare of efficacy and safety of combined immune therapy (dual immune-oncology – IO combination therapies, IO-IO) and immune targeted therapy (ITT) in the first line treatment of patients with advanced renal cell carcinoma (RCC) treated in real world clinical practice. Materials and methods. The ambispective study enrolled patients with metastatic RCC aged ≥18 years, with measurable neoplastic lesions, who were treated with first-line IO-IO therapy or ITT. The primary endpoint was progression-free survival (PFS). Results. The study included data from 126 patients treated with IO-IO [46 (36.5%) patients of the IMDC intermediate and poor prognostic groups] or ITT [80 (63.5%) patients of all IMDC prognostic groups]. In a median follow-up of all patients of 16.1 (0.1–44.9) months, the median PFS was 16.1 (10.9–21.3) months, the median overall survival (OS) was not reached; one-year OS was 83.0%; the objective response rate on the first line of therapy was 44.4% with a complete response rate of 3.2%. The rate of tumor control was 88.1%. In the overall population, ITT versus IO-IO provided a significant benefit in terms of ORR (51.2% vs 32.6%; p=0.032), PFS (median 22.9 months vs 8.0 months; p=0.004) and one-year OS (87.5% vs 65.2%; p=0.042). In the IPTW population, multivariate analysis confirmed the independent prognostic significance of the treatment regimen for PFS (hazard ratio, 2.3; 95% confidence interval, 1.1–4.8; p=0.037) and OS (hazard ratio, 2.3; 95% confidence interval 1.1–4.8; p=0.037). No difference in the safety profile of IO-IO and ITT was identified. Conclusion. The results support the hypothesis that ITT is more effective than IO-IO in the first-line treatment of advanced RCC in patients of IMDC intermediate and poor prognostic groups.

Inflammatory stress determines the need for chemotherapy in patients with HER2-positive esophagogastric adenocarcinoma receiving targeted and immunotherapy.

Anti-PD-1, trastuzumab, and chemotherapy are used in the treatment of patients with advanced HER2-positive esophagogastric adenocarcinoma (EGA), but long-term survival remains limited. Herein, we report extended follow-up data from the INTEGA trial (NCT03409848), which investigated the efficacy of the anti-PD-1 nivolumab, trastuzumab, and FOLFOX chemotherapy (FOLFOX arm) in comparison to a chemotherapy-free regimen involving nivolumab, trastuzumab, and the anti-CTLA-4 ipilimumab (Ipi arm) in the first-line setting for advanced disease. The 12-month overall survival (OS) showed no statistical difference between the arms, with 57% OS (95% CI: 41%-71%) in the Ipi arm and 70% OS (95% CI: 54%-82%) in the FOLFOX arm. Crossing of the survival curves indicated a potential long-term benefit for some patients within the Ipi arm, but early progressors in the Ipi arm underlined the need for biomarker-guided strategies to optimize treatment selection. To this end, metabolomic and cytokine analysis demonstrated elevated levels of normetanephrine, cortisol, and interleukin 6 (IL-6) in immunotherapy-unresponsive patients in the Ipi arm, suggesting a role for systemic inflammatory stress in modulating antitumor immune responses. Patients with this signature also showed an increased neutrophil-to-lymphocyte ratio (NLR) that persisted in the Ipi arm, but not in the FOLFOX arm, and strongly correlated with survival. Furthermore, a low NLR characterized patients benefiting from immune- and targeted therapy without the need for additional chemotherapy. This data suggests that patient selection based on inflammatory stress-driven immune changes could help to customize first-line treatment in patients with advanced HER2-positive EGA to potentially improve long-term survival.

A comparison of isolated limb infusion/perfusion, immune checkpoint inhibitors, and intralesional therapy as first-line treatment for patients with melanoma in-transit metastases.

Isolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in-transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first-line ILI/ILP, ICI, and TVEC. Retrospective review from 12 international institutions included patients treated from 1990 to 2022 with first-line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM. A total of 551 patients were treated, with ILI/ILP (n=356), ICI (n=125), and TVEC (n=70) with median follow-up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p =.002). Breslow thickness was lowest with TVEC (p =.007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p =.01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p =.029) and a longer local progression-free survival (PFS) (hazard ratio [HR], 0.40; p =.003). ILI/ILP had shorter local PFS (HR, 1.72; p =.012), PFS (HR, 1.79; p <.001), distant metastasis-free survival (DMFS) (HR, 1.75; p =.014), overall survival (HR, 1.82; p =.009), and melanoma-specific survival (HR, 2.29; p =.004). Stage IIIB disease had longer DMFS (HR, 0.24; p <.001) compared to IIIC/D. TVEC as first-line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first-line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.

Androgen Receptor Mediates Dopamine Agonist Resistance by Regulating Intracellular Reactive Oxygen Species in Prolactin-Secreting Pituitary Adenoma.

Aims: Dopamine agonists (DAs) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between androgen receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance. Results: Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to bromocriptine (BRC) both in vitro and invivo. Mechanistically, we demonstrated that intracellular reactive oxygen species (ROS) function as upstream mediators of apoptosis and ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NFE2-like bZIP transcription factor 2 (NRF2) expression, which regulates intracellular ROS levels, thereby enhancing cell viability and conferring DA resistance to pituitary adenoma (PA) cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment. Conclusion and Innovation: We demonstrated that AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas. Antioxid. Redox Signal. 00, 000-000.

Cost-Effectiveness of Pembrolizumab as First-Line Treatment in Patients with Persistent, Recurrent, or Metastatic Cervical Cancer in the United States.

First-line treatment of persistent, recurrent, or metastatic (advanced) cervical cancer in patients who have a combined positive score (CPS) ≥ 1 with pembrolizumab + chemotherapy versus standard-of-care chemotherapy provides meaningful improvements in overall survival. We conducted a cost-effectiveness analysis from a US payer perspective. A societal perspective scenario was also considered, including productivity gains. The cost-effectiveness of pembrolizumab + chemotherapy versus chemotherapy was assessed using a state-transition model comprising the health states "pre-progression," "post-progression," and "death," with a 1-week cycle length and 50-year time horizon. Patient-level KEYNOTE-826 data informed the efficacy, safety, and health-related quality of life of pembrolizumab + chemotherapy versus chemotherapy at first-line and subsequent treatments. Real-world data were sought to cost subsequent treatments according to US clinical practice. Transition probabilities were derived from parametric survival models fit to time-to-progression, progression-free survival, and post-progression survival patient-level KEYNOTE-826 data. Sensitivity analyses explored the impact on outcomes from variables such as bevacizumab use. According to the state-transition model, pembrolizumab + chemotherapy extended mean life expectancy versus chemotherapy from 1.8 to 6.7 life-years. The mean gain of 4.9 life-years/patient was mostly caused by pembrolizumab delaying progression. Total discounted quality-adjusted life-years (QALY) were 5.0 and 1.3 per patient for pembrolizumab + chemotherapy and chemotherapy, respectively (mean gain: 3.7 QALY/patient). Pembrolizumab + chemotherapy had comparable safety outcomes to chemotherapy alone. Total costs incurred were US $320,247 (pembrolizumab + chemotherapy) versus US $105,446 (chemotherapy; mean incremental costs: US $214,801/patient). The incremental cost-effectiveness ratio of pembrolizumab + chemotherapy versus chemotherapy was US $58,446/QALY. Sensitivity analyses showed results were insensitive to bevacizumab use. Including productivity gains led to an incremental cost-effectiveness ratio of US $58,385 per QALY. Our model-based analysis suggests that first-line treatment of pembrolizumab + chemotherapy in advanced cervical cancer with a CPS ≥ 1 offers a substantial clinical benefit over standard-of-care chemotherapy alone and is cost-effective at a willingness-to-pay threshold of US $150,000. The approximate doubling of life-years and QALYs associated with pembrolizumab + chemotherapy represents a step improvement in the treatment of advanced cervical cancer. ClinicalTrials.gov Identification Number: NCT03635567.

Comparison of first-line chemotherapy regimens in unresectable locally advanced or metastatic pancreatic cancer: a systematic review and Bayesian network meta-analysis

In advanced pancreatic ductal adenocarcinoma (PDAC), first-line chemotherapy is the standard of care. Due to the absence of head-to-head comparisons in clinical trials, we performed this systematic review and network meta-analysis to compare treatment options for PDAC in terms of their efficacy and toxicity. PubMed, the Cochrane Central Register of Controlled Trials, Embase, and oncological meetings websites were searched until Nov 15, 2023. We included phase 2-3 randomised controlled trials published after Jan 1, 2000, evaluating first-line treatments in patients with previously untreated, unresectable, locally advanced or metastatic PDAC. Primary endpoints assessed were progression-free survival and overall survival. Summary data were extracted from published reports. The deviance information criterion was used to choose between a random-effects or fixed-effects model. Hazard ratios (HRs) with 95% credible intervals were estimated using a Bayesian approach. The risk of bias was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool and studies were graded as low, some concerns, or high risk of bias. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach. This systematic review and network meta-analysis is registered with PROSPERO, CRD42023450330. 6050 records were screened and 79 randomised controlled trials (22 168 patients) were included in the analysis. Gemcitabine was the most frequent comparator (in 50 [63%] of 79 trials) and was considered as the reference treatment. A fixed-effect model was used to analyse the primary outcomes. Regarding progression-free survival (71 trials, 19 479 patients), the most effective treatments were gemcitabine plus nab-paclitaxel alternating folinic acid, fluorouracil, and oxaliplatin ([FOLFOX] HR 0·32, 95% credible interval 0·22-0·47), cisplatin, nab-paclitaxel, capecitabine, and gemcitabine ([PAXG] 0·35, 0·22-0·55), and liposomal irinotecan in combination with fluorouracil, leucovorin, and oxaliplatin ([NALIRIFOX] 0·43, 0·34-0·54), followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin ([FOLFIRINOX] 0·55, 0·47-0·65) and gemcitabine plus nab-paclitaxel (0·62, 0·54-0·72). Similar results were observed for overall survival (79 trials, 22 104 patients): PAXG (HR 0·40, 95% credible interval 0·25-0·65), gemcitabine plus nab-paclitaxel alternating FOLFOX (0·46, 0·32-0·66), and NALIRIFOX (0·56, 0·45-0·70) had the highest benefit, followed by FOLFIRINOX (0·66, 0·56-0·78) and gemcitabine plus nab-paclitaxel (0·67, 0·59-0·77). The overall risk of bias was low to some concerns. Certainty of evidence was low. Our findings suggest that NALIRIFOX and FOLFIRINOX should be the preferred options for patients who can tolerate these regimens, with gemcitabine plus nab-paclitaxel remaining a viable alternative, particularly in patients unfit for triplet therapy. Phase 3 randomised controlled trials investigating concomitant or sequential quadruplets are warranted. None.

Durvalumab Versus Chemotherapy as First-line Treatment for Metastatic NSCLC With Tumor PD-L1 Expression of 25% or Higher: Results From the Randomized Phase 3 PEARL Study

IntroductionPEARL (NCT03003962) is an open-label, phase 3 study comparing first-line durvalumab monotherapy with chemotherapy in patients with metastatic NSCLC (mNSCLC [EGFR/ALK wild type]) with programmed cell death ligand 1 (PD-L1) tumor cell (TC) membrane expression status of 25% or higher. We report the final analysis of PEARL. MethodsAdults (N = 669) with previously untreated stage IV mNSCLC were randomized (1:1) to durvalumab 20 mg/kg every four weeks or chemotherapy every three weeks for four to six cycles. Dual primary endpoints were overall survival (OS) in the PD-L1 TC of 25% and higher and the PD-L1 TC of 25% and higher low risk of early mortality populations. ResultsDurvalumab was associated with a numerical reduction in the risk of death versus chemotherapy in the 25% and higher PD-L1 TC population (OS hazard ratio [HR] = 0.84, 95% confidence interval [CI]: 0.71–0.99, p = 0.037; median OS 14.6 months, 95% CI: 12.2–16.9 versus 12.8 months, 95% CI: 10.1–14.7, respectively). In the 25% and higher PD-L1 TC low risk of early mortality population the OS hazard ratio for durvalumab versus chemotherapy was 0.96 (95% CI: 0.79–1.15, p = 0.628); median OS 14.6 months (95% CI: 12.6–17.2) versus 15.0 months (95% CI: 13.1–16.8), respectively. In the safety population, the incidence of grade 3/4 treatment-related adverse events was 15.5% (durvalumab) and 45.9% (chemotherapy). ConclusionsDurvalumab did not statistically significantly improve OS versus chemotherapy as first-line treatment in patients with mNSCLC and 25% and higher PD-L1 TC. The numerical improvement in OS was consistent with previous studies of first-line immune checkpoint inhibitor monotherapy in patients with mNSCLC.

Prediction of the Short-Term Effectiveness of Ustekinumab in Patients with Moderate to Severe Crohn’s Disease

Prediction of the Short-Term Effectiveness of Ustekinumab in Patients with Moderate to Severe Crohn’s Disease

Metformin: Diverse molecular mechanisms, gastrointestinal effects and overcoming intolerance in type 2 Diabetes Mellitus: A review.

Metformin, the first line treatment for patients with type 2 diabetes mellitus, has alternative novel roles, including cancer and diabetes prevention. This narrative review aims to explore its diverse mechanisms, effects and intolerance, using sources obtained by searching Scopus, PubMed and Web of Science databases, and following Scale for the Assessment of Narrative Review Articles reporting guidelines. Metformin exerts it actions through duration influenced, and organ specific, diverse mechanisms. Its use is associated with inhibition of hepatic gluconeogenesis targeted by mitochondria and lysosomes, reduction of cholesterol levels involving brown adipose tissue, weight reduction influenced by growth differentiation factor 15 and novel commensal bacteria, in addition to counteraction of meta-inflammation alongside immuno-modulation. Interactions with the gastrointestinal tract include alteration of gut microbiota, enhancement of glucose uptake and glucagon like peptide 1 and reduction of bile acid absorption. Though beneficial, they may be linked to intolerance. Metformin related gastrointestinal adverse effects are associated with dose escalation, immediate release formulations, gut microbiota alteration, epigenetic predisposition, inhibition of organic cation transporters in addition to interactions with serotonin, histamine and the enterohepatic circulation. Potentially effective measures to overcome intolerance encompasses carefully objective targeted dose escalation, prescription of fixed dose combination, microbiome modulators and prebiotics, in addition to use of extended release formulations.

Prognostic Nutrition Index as a Biomarker for Treatment Sensitivity to Chemotherapy and Nivolumab as the First-Line Treatment in Patients with Unresectable Advanced or Recurrent Gastric Cancer: A Multicenter Study

Introduction: This multicenter study aimed to determine whether the pretreatment prognostic nutrition index (PNI) or a change in the index after two treatment courses could be a biomarker for predicting treatment sensitivity in patients with unresectable advanced or recurrent gastric cancer treated using chemotherapy and nivolumab as the first-line treatment. Methods: This multicenter retrospective study with 104 patients was conducted at 12 institutions. PNI was calculated before treatment and after two courses of treatment in each case. We also focused on changes in PNI from the pretreatment value. Results: After two courses of chemotherapy plus nivolumab treatment, the high PNI group had significantly better rates of overall survival (OS) (p = 0.0016) and time-to-treatment failure (p = 0.0060). Low PNI was an independent prognostic factor predicting both therapeutic sensitivity to chemotherapy plus nivolumab treatment and poorer OS. Furthermore, correlation with low pretreatment PNI transitioning to high after two courses of treatment was not noted in any patient in the progressive disease group (p = 0.0075). Conclusions: PNI is a score composed of a patient’s albumin level and lymphocyte count that can be easily assessed in daily clinical practice. Evaluating it is easy for each treatment; thus, when there is a focus on its transition, PNI could be a very powerful biomarker for predicting treatment sensitivity.

Ovarian Cancer Retrospective European (O'CaRE) study: first-line outcomes by number of risk factors for progression.

Aim: The Ovarian Cancer Retrospective European (O'CaRE) study assessed the cumulative impact of high-risk factors on progression-free survival (PFS) and overall survival (OS) following first-line treatment in patients diagnosed with advanced ovarian cancer.Patients & methods: Medical records were collected from five European countries (2014 and 2015). Patients were grouped by number of high-risk factors: stage IV diagnosis, no known BRCA mutation, interval debulking surgery or no surgery, or visible residual disease.Results: Our analysis included 405 patients grouped based on having one (20.4%); two (32.3%); three (33.7%) or four (11.9%) high-risk factors. Increasing cumulative numbers of high-risk factors were associated with numerically shorter PFS and OS.Conclusion: Risk profiles should be carefully considered when planning clinical care.

Effects of Atezolizumab plus Bevacizumab on Skeletal Muscle Volume and Cardiac Function in Patients with Hepatocellular Carcinoma

Introduction: Pharmacological treatment of unresectable hepatocellular carcinoma (uHCC) includes sorafenib and lenvatinib, a tyrosine kinase inhibitor, which are linked to low serum levels of carnitine and reduced skeletal muscle volume. Nowadays, atezolizumab plus bevacizumab (Atezo/Bev) combination therapy is recommended as the first-line treatment for patients with uHCC. However, the association with decreased muscle mass or cardiac function is unknown. Therefore, this study aimed to evaluate the effects of Atezo/Bev on skeletal muscle volume and cardiac function in patients with uHCC. Methods: This retrospective study included 55 adult Japanese patients with chronic liver diseases and uHCC treated with Atezo/Bev. Patients were divided into three groups according to age: middle, preold, and old. Serum levels of carnitine and cardiac function were measured before and after 3 weeks of treatment. The psoas muscle index (PMI) was measured before and after 6 weeks of treatment. Results: After treatment, the global longitudinal strain was significantly lower in the old group, whereas the PMI and ejection fraction were significantly lower in the preold and old groups. However, no significant difference in serum levels of total carnitine and those fractions with treatment in each group was found. Cardiac function decreased in the preold and old groups. Conclusion: When treating patients with uHCC by Atezo/Bev, caution should be taken in preold and old patients because they are vulnerable to decreased skeletal muscle mass and deterioration of cardiac function. Strength training and regular monitoring of cardiac function are encouraged in these groups.

Efficacy and safety of dual blockade of HER2 and PD-1 in patients with HER2-positive gastric cancer: a retrospective, multicentre study

Human epidermal growth factor receptor 2 (HER2) expression is one of the most important pathological characteristics of gastric cancer. The positive rate of HER2 expression in patients with gastric cancer is approximately 20%. The phase III Keynote-811 study revealed that anti-HER2 and anti-PD-1 therapy combined with chemotherapy could significantly improve the objective response rate as first-line treatment in patients with HER2-positive advanced gastric cancer. In the present study, we aimed to evaluate the efficacy of combination therapy with trastuzumab and PD-1 inhibitors in patients with advanced HER2-positive gastric cancer in a real-world setting. Seventy-two HER2-positive gastric cancer patients from three hospitals in China were retrospectively reviewed. These patients were treated with trastuzumab plus one anti-PD-1 agent with or without chemotherapy. The overall response rate, progression-free survival and overall survival were assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). From January 2018 to October 2021, 72 patients with HER2-positive gastric cancer received trastuzumab and a PD-1 inhibitor with or without chemotherapy as neoadjuvant chemotherapy, first-line therapy, second-line therapy or salvage therapy. The ORR was 54.2% for all patients and 79.4% for previously untreated patients. The median PFS and median OS were 10 months (95% CI: 8–13 months) and 26.1 months (95% CI: 18.5-NA months), respectively, for all patients. Grade 3 adverse effects occurred in approximately 25% of patients. Immune-related adverse effects occurred in approximately 12.5% of patients. Trastuzumab and PD-1 inhibitor combination therapy with or without chemotherapy achieved satisfactory survival outcomes in patients with HER2-positive gastric cancer with acceptable safety.