Some anti-cancer treatments (e. g., immunotherapies) determine, on the long term, a durable survival in a small percentage of treated patients; in graphical terms, long-term survivors typically give rise to a plateau in the right tail of the survival curve. In analysing these datasets, medians are unable to recognize the presence of this plateau. To account for long-term survivors, both value-frameworks of ASCO and ESMO have incorporated post-hoc corrections that upgrade the framework scores when a survival plateau is present. However, the empiric nature of these post-hoc corrections is self-evident. To capture the presence of a survival plateau by quantitative methods, two approaches have thus far been proposed: the milestone method and the area-under-the-curve (AUC) method. The first approach identifies a long-term time-point in the follow-up (“milestone”) at which survival percentages are extracted. The second approach, which is based on the measurement of AUC of survival curves, essentially is the rearrangement of previous methods determining mean lifetime survival; similarly to the milestone method, the application of AUC can be “restricted” to a pre-specified time-point of the follow-up. This Mini-Review examines the literature published on this topic. The main characteristics of these two methods are highlighted along with their advantages and disadvantages. The conclusion is that both the milestone method and the AUC method are able to capture the presence of a survival plateau.

Background. Molnupiravir (MOL) and nirmatrelvir/ritonavir (NIR) were recently approved for the early treatment of COVID-19, but real-life data on tolerability, safety, and adverse events (AEs) are still scarce. Methods. We conducted a retrospective cohort study including all patients who were prescribed MOL and NIR at the Infectious Diseases Unit of Padua University Hospital, between January and May 2022. Demographic, clinical, and safety variables were recorded. Results. We included 909 patients, 48.3% males and 95.2% vaccinated against SARS-CoV-2. The median age was 73 (IQR: 62–82) years. MOL and NIR were prescribed in 407 (44.8%) and 502 (55.2%) patients, respectively. Overall, 124/909 (13.6%) patients experienced any AEs following antivirals intake: 98/124 (79%) patients reporting adverse events presented grade 1 AEs, 23/124 (18.5%) grade 2 AEs and 3 (2.5%) grade 3 AEs. Treatment discontinuation was recorded in 4.8% of patients. AEs were significantly higher in women, in patients treated with NIR compared to MOL and in people who were not vaccinated. Conclusions. In our real-life setting, AEs were higher than those reported by clinical trials, and were particularly associated with NIR use and with not being vaccinated. Further analyses are needed to better assess safety of oral antivirals and to define which patient’s profile may benefit most from MOL and NIR.

In metastatic triple-negative breast cancer (TNBC), the efficacy of immune checkpoint inhibitors (ICIs) in combination with chemotherapy has been demonstrated in randomized clinical trials (RCTs). Despite this, an indirect comparison is not yet available. Reconstruction of individual patient data from Kaplan-Meier curves allows the indirect comparison of different treatments. We analyzed six overall survival (OS) curves from three RCTs. In patients with ≥1% positivity, atezolizumab was found to determine a significantly better OS than pembrolizumab. As regards pembrolizumab, adopting a threshold of PD-L1 positivity ≥10% (as opposed to ≥1%) improved median survival to a remarkable extent (23.0 vs 15.5 months).

The restricted mean survival time (RMST) is a relatively new parameter proposed to improve the analysis of survival curves. As opposed to the median, the RMST has the advantage of capturing the overall shape of the survival curve, including the so-called "right tail." One limitation of RMST lies in the mathematical complexity of its calculation (model-dependent analysis). In the present report, we describe a model-independent method that simplifies the calculation of RMST. The estimation approach (trapezoidal rule) is the same as that commonly employed in pharmacokinetics. In the analysis of 6 survival curves, the performance of the model-independent method was virtually the same as that of model-dependent methods.

Programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) inhibitors are increasingly used in a variety of solid tumors. In patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer, their efficacy has been demonstrated in recently published phase-II trials. However, an indirect comparison of effectiveness between pembrolizumab, nivolumab, and nivolumab+ipilimumab is not yet available.After a standard literature search, we analyzed four overall survival (OS) curves from three phase-II trials. Individual patient data were reconstructed from each curve using a specific web-based technique (Shiny method). Indirect statistical comparisons were made based on hazard ratio (HR) and restricted mean survival time (RMST).Nivolumab+ipilumumab had a better HR compared with pembrolizumab (0.65, 95% confidence interval [CI], 0.43 to 1.002, p=0.051); the difference being close to statistical significance. In the analysis based on RMST, the combination of nivolumab+ipilimumab showed a significantly longer OS than pembrolizumab (improvement in RMST, 1.08 mos; 95%CI, 0.11 to 2.06; p=0.029). The other two pairwise differences in RMST (nivolumab vs. pembrolizumab and nivolumab+ ipilimumab vs. nivolumab) had a smaller magnitude (0.25 mos, 95%CI, -0.99 to 1.48, and 0.84 mos, 95%CI, -0.40 to 2.07, respectively) and were far from statistical significance.Our results favoring the combination of nivolumab+ipilimumab in metastatic colorectal cancer must be viewed with caution owing to the indirect nature of our statistical comparisons. With this limitation in mind, the magnitude of the incremental benefit for the above combination treatment was estimated to be around one month over a follow-up of 15 months.