Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial

Background: Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients. Methods: This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confi rmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratifi ed by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m(2) on day 1 of each cycle) and fl uorouracil (1000 mg/m(2) on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defi ned retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identifi cation of patients and treatment. This trial is registered with ClinicalTrials. gov, number NCT00460265. Findings: Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11.1 months (95% CI 9.8-12.2) in the panitumumab group and 9.0 months (8.1-11.2) in the control group (hazard ratio [HR] 0.873, 95% CI 0.729-1.046; p = 0.1403). Median progression-free survival was 5.8 months (95% CI 5.6-6.6) in the panitumumab group and 4.6 months (4.1-5.4) in the control group (HR 0.780, 95% CI 0.659-0.922; p = 0.0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11.7 months [95% CI 9.7-13.7] vs 8.6 months [6.9-11.1]; HR 0.73 [95% CI 0.58-0.93]; p = 0.0115), but this difference was not shown for p16-positive patients (11.0 months [7.3-12.9] vs 12.6 months [7.7-17.4]; 1.00 [0.62-1.61]; p = 0.998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0.70 [95% CI 0.47-1.04]). Interpretation: Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings

Quantifying the average of the time-varying hazard ratio via a class of transformations

The hazard ratio derived from the Cox model is a commonly used summary statistic to quantify a treatment effect with a time-to-event outcome. The proportional hazards assumption of the Cox model, however, is frequently violated in practice and many alternative models have been proposed in the statistical literature. Unfortunately, the regression coefficients obtained from different models are often not directly comparable. To overcome this problem, we propose a family of weighted hazard ratio measures that are based on the marginal survival curves or marginal hazard functions, and can be estimated using readily available output from various modeling approaches. The proposed transformation family includes the transformations considered by [18] as special cases. In addition, we propose a novel estimate of the weighted hazard ratio based on the maximum departure from the null hypothesis within the transformation family, and develop a Kolmogorov–Smirnov type of test statistic based on this estimate. Simulation studies show that when the hazard functions of two groups either converge or diverge, this new estimate yields a more powerful test than tests based on the individual transformations recommended in [18], with a similar magnitude of power loss when the hazards cross. The proposed estimates and test statistics are applied to a colorectal cancer clinical trial

Bayesian gamma frailty models for survival data with semi-competing risks and treatment switching

Motivated from a colorectal cancer study, we propose a class of frailty semi-competing risks survival models to account for the dependence between disease progression time, survival time, and treatment switching. Properties of the proposed models are examined and an efficient Gibbs sampling algorithm using the collapsed Gibbs technique is developed. A Bayesian procedure for assessing the treatment effect is also proposed. The Deviance Information Criterion (DIC) with an appropriate deviance function and Logarithm of the Pseudomarginal Likelihood (LPML) are constructed for model comparison. A simulation study is conducted to examine the empirical performance of DIC and LPML and as well as the posterior estimates. The proposed method is further applied to analyze data from a colorectal cancer study

Baichuan 2: Open Large-scale Language Models

Large language models (LLMs) have demonstrated remarkable performance on a variety of natural language tasks based on just a few examples of natural language instructions, reducing the need for extensive feature engineering. However, most powerful LLMs are closed-source or limited in their capability for languages other than English. In this technical report, we present Baichuan 2, a series of large-scale multilingual language models containing 7 billion and 13 billion parameters, trained from scratch, on 2.6 trillion tokens. Baichuan 2 matches or outperforms other open-source models of similar size on public benchmarks like MMLU, CMMLU, GSM8K, and HumanEval. Furthermore, Baichuan 2 excels in vertical domains such as medicine and law. We will release all pre-training model checkpoints to benefit the research community in better understanding the training dynamics of Baichuan 2.Comment: Baichuan 2 technical report. Github: https://github.com/baichuan-inc/Baichuan

Efficacy and safety results from a randomized double-blind study comparing proposed biosimilar ABP 798 with rituximab reference product in subjects with moderate-to-severe rheumatoid arthritis

Background/objectives: ABP 798 is a proposed biosimilar to the originator biologic rituximab, an anti-CD20 monoclonal antibody. This comparative clinical study evaluated the pharmacokinetics (PK), safety, and efficacy of ABP 798 versus rituximab reference product (RP) in patients with moderate-to-severe rheumatoid arthritis (RA). Methods: Adults with moderate-to-severe RA with an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs including 1 or more tumor necrosis factor inhibitor therapies (n = 311) received ABP 798, US-sourced rituximab RP (rituximab US), or EU-sourced rituximab RP (rituximab EU) (1000 mg, 2 weeks apart). At week 24, ABP 798- or rituximab EU-treated subjects received a second dose of the same treatment, while rituximab US-treated subjects transitioned to receive ABP 798. The key efficacy endpoint was DAS28-CRP change from baseline at week 24. Other efficacy endpoints included DAS28-CRP at other time points; ACR20, ACR50, and ACR70 criteria; and hybrid ACR. The rituximab RP groups were pooled for all efficacy endpoints since PK equivalence had been established between rituximab US and rituximab EU. Results: Clinical equivalence between ABP 798 and rituximab RP was established as the 90% confidence interval for DAS28-CRP change from baseline at week 24 fell within the prespecified equivalence margin (− 0.6, 0.6). Safety and immunogenicity profiles of ABP 798 were comparable across treatment groups and not affected by single transition from RP to ABP 798. Conclusions: Clinical equivalence in terms of efficacy, safety, and immunogenicity was established between ABP 798 and rituximab RP in this comparative clinical trial in patients with moderate-to-severe RA