Phase II-III Research Articles

Efficacy and Safety of Weekly Calcifediol Formulations (75 and 100 µg) in Subjects with Vitamin D Deficiency: A Phase II/III Randomised Trial

Background/Objective: Optimal vitamin D levels are required for bone health and proper functionality of the nervous, musculoskeletal and immune systems. The objective of this study was to assess the efficacy and safety profiles of new weekly calcifediol formulations with the potential to improve adherence and outcome. Methods: A Phase II-III, double-blind, randomized, multicentre trial (EudraCT 2020-001099-14 and NCT04735926). Subjects were randomized 2:2:1 to calcifediol 75 µg, 100 µg and placebo. 25(OH)D levels were measured at 4, 16, 24, 32 and 52 weeks. The main outcome was the percentage of subjects who achieved a response defined as 25(OH)D levels ≥20 ng/mL and/or ≥30 ng/mL at week 16. Results: 398 subjects (51.1 ± 15.96 years, 74.2% females, 98.7% Caucasian) with plasma 25(OH)D levels between 10 and 20 ng/mL were randomized. A total of 376 subjects completed 16 weeks of treatment, and 355 subjects completed the study. Six patients withdrew due to an adverse event, all unrelated to treatment. At week 16, 93.6% and 74.4% of subjects receiving calcifediol 75 µg achieved response levels of ≥20 ng/mL and ≥30 ng/mL, respectively. The calcifediol 100 µg group showed 98.7% and 89.9% of responders for ≥20 ng/mL and ≥30 ng/mL, respectively. Both calcifediol groups showed superiority over placebo at each response level at all time points analyzed (p < 0.0001). Calcifediol treatments increased 25(OH)D levels from baseline to week 24 and remained stable thereafter. The frequency of treatment-emergent adverse events was balanced between groups. Conclusions: New weekly calcifediol 75 and 100 µg formulations showed an effective and sustained response with a good long-term safety profile.

Bevacizumab Erlotinib Switch Maintenance in Chemo-Responsive Advanced Gallbladder and Cholangiocarcinoma (BEER BTC): A Multicenter, Open-Label, Randomized, Phase II Trial.

Patients with chemotherapy-responsive advanced biliary tract cancers (BTCs) are usually observed after 6 months of gemcitabine-based therapy. There is limited prospective evidence for maintenance strategies after chemotherapy. This investigator-initiated, open-label, randomized, integrated phase II-III study enrolled adult patients with advanced BTC from two cancer centers in India. Patients with histologically confirmed advanced biliary tract adenocarcinoma who had at least disease stabilization after 6 months of gemcitabine-based chemotherapy were randomly assigned (1:1) to either active surveillance or switch maintenance, which was a combination of bevacizumab 5 mg/kg intravenous once every 21 days plus erlotinib 100 mg once daily. Both arms were continued until disease progression, unacceptable toxicity, or patient decision to withdraw. The primary end point of the phase II component of the trial was investigator-evaluated progression-free survival. This trial is registered with Clinical Trials Registry of India (CTRI/2019/05/019323I). From May 2021 to November 2022, 98 patients were randomly assigned to active surveillance (n = 49) or bevacizumab-erlotinib (n = 49). A majority of patients had gallbladder cancer (80%). The median follow-up was 13.4 months. The median progression-free survival was 3.1 months (95% CI, 2.47 to 3.64) in the active surveillance group versus 5.3 months (95% CI, 3.53 to 7.04) in the bevacizumab-erlotinib group (hazard ratio, 0.51 [95% CI, 0.33 to 0·74]; P = .0013). The most common grade 3 class-specific adverse events associated with bevacizumab-erlotinib were acneiform rash 1 (2%) and oral stomatitis 1 (2%) with erlotinib and bleeding 1 (2%) with bevacizumab. The combination of bevacizumab and erlotinib as switch maintenance improves progression-free survival with an acceptable safety profile compared with active surveillance in patients with advanced BTCs in this phase II study. The trial moves on to the phase III component to evaluate improvement in overall survival.

Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A Systematic Review.

More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found. To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses. 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5%. The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.

Efficacy and safety of second-line immunotherapy in patients with advanced non-small cell lung cancer.

e20571 Background: Patients (Pts) with advanced non-small cell lung cancer (NSCLC) face limited treatment options. Immunotherapy (IO) has revolutionized the treatment of NSCLC in this setting. The objective of our study is to evaluate the efficacy and safety of atezolizumab (Az) in Pts with advanced NSCLC in the second-line setting following progression on platinum-based chemotherapy (CT) in the Huelva area. Additionally, we aim to compare the results with those obtained in the phase 2 POPLAR and phase 3 OAK clinical trials. Methods: This is a descriptive and observational study conducted on patients with advanced NSCLC who received second-line IO with atezolizumab 1200 mg/1680 mg every 3 or 4 weeks, from 2015 to 2023 in the Huelva area (Spain). SPSS Statistics 22 was used for data analysis. Results: 26 Pts were treated, median age 67 years and 88.5% men. ECOG PS 0-1 in 92.3%. According to smoking habits, 42.3% were ex-smokers and 38.5% were active smokers. Regarding histology, 53.8% were non-squamous. 73.1% were inicial stage IV and 23% were stage III. Depending on the expression of PDL-1, PDL-1 was &lt; 1% in 34.6% (9 Pts) of the sample, between 1-49% in 53.8% (14 Pt) and unknown in 3 Pts. 26.9% of patients achieved disease stability and 11.5% achieved partial response. The response has not been evaluated in 38.5% because these patients maintain treatment. The adverse effects (AE) suffered by patients treated with Az in the second line were 53.8% grade (G) 1- 2 and 7.7% G 3-4. The most frequent were asthenia (48%), pruritus and arthralgia in 15.4%, both cases, and skin toxicity in 11.5%. In the case of the 2 Pts with G 3-4 toxicity, they were due to autoimmune anemia and asthenia with subsequent to grade 1, so treatment did not have to be interrupted. The median progression-free survival (PFS) was 2.7 months (m) (95% CI 0-6.8) and the median overall survival (OS) was 5.2 m (95% CI 0.5- 9-9). In both cases the results were not statistically significant. According to PDL1, no statistically significant differences were found in the subgroup analysis. Conclusions: Based on our results and those of the Phase 2 POPLAR and Phase 3 OAK studies, we consider that Az has an acceptable safety profile, with fewer G 3-4 side effects compared to CT, so a lower percentage of Pts drop out the treatment. Although the PFS was similar to the phase II-III studies, the OS was lower, probably due to the percentage of Pts with rapid progression and patients currently continuing to receive treatment, being a limitation in our study along with the small sample size. Despite this, our results are encouraging regarding the benefit of IO in Pts. Therefore, we conclude that the use of IO in these Pts falls within good clinical practice, offering them a clearly effective therapy and thus avoiding treatments with greater toxicity such as CT.

Preliminary safety data of the PRODIGE 81-FFCD 2101-TRIPLET-HCC trial assessing the triple combination atezolizumab-bevacizumab-ipilimumab in patients (pts) treated in systemic therapy for hepatocellular carcinoma (HCC).

e16195 Background: TRIPLET-HCC is a French, multicentre, randomized 1:1, open-label phase II-III trial designed to evaluate efficacy and safety of the triple combination (Arm-A) by the addition of ipilimumab (1 mg/kg for the first 4 cycles) to atezolizumab/bevacizumab (Q3W), versus the double atezolizumab/bevacizumab combination (Arm-B) for HCC eligible to systemic therapy in first line setting. The primary objective of phase II is the objective response rate in Arm-A, and overall survival in Arm-A versus Arm-B in phase III. In phase II, the first 15 pts randomized in Arm-A were assessed for a safety-run in aim to detect a potential signal of overtoxicity after the first four cycles of triple therapy (induction phase), thus allowing or forbidding the continuation of the trial. Methods: The trial started on March 2023 the 9th. Adverse events (AE) and their imputability to treatment were reported in the eCRF by investigators. An independent data safety monitoring board (DSMB) was gathered 4 weeks after the last injection of ipilimumab of the 5th and the 15th patient randomized in Arm-A of phase II. The second DSMB meeting took place on November 2023 after extraction of data in November 2023 the 9th. These data are presented in the present abstract. Results: At the DSMB meeting date, 15 patients in Arm-A were analyzed for safety while 13 patients had been randomized in Arm-B and had reached at least 4 cycles of treatment. In Arm-A, 12 pts completed the first 4 cycles of triple therapy, 1 pt received 3 cycles (sepsis), 1 pt only 2 (prednisone &gt; 10 mg/day for grade-1 myocarditis which recovered), and 1 pt only 1 (sepsis and death). In Arm-B, 11 pts received the first 4 cycles of double therapy, 2 pts only 3 (anemia, lithiasic cholangitis). Three deaths occurred: 2 in Arm-A (1 possible related to immune-related (iR) hepatitis (not biopsy-proven) associated with sepsis, and 1 sudden death of unknow etiology), and one in Arm-B (tumor progression). Three pts in Arm-A (2 radiologic progressions, 1 death) and 1 pt in Arm-B (1 tumor progression with death) were withdrawn of the trial. Regarding grade-3/4 treatment-related adverse events (TRAE), 3 were reported in Arm-A (1 ASAT increase, 1 arterial hypertension, 1 colitis), and 2 in Arm-B (1 tumor bleeding, 1 arterial hypertension). Conclusions: The preliminary safety data from the TRIPLET-HCC trial suggest that the triple combination therapy is associated with a manageable safety profile, showing no unexpected signs of over toxicity. The DSMB's decision to continue the trial underscores the potential of this innovative therapeutic approach in improving outcomes for HCC patients. These findings support further investigation into the efficacy and long-term safety of the triple combination therapy in a broader patient population. Clinical trial information: NCT05665348 .

REPROGRAM-02: A phase II-III study evaluating an induction treatment with regorafenib and metronomic chemotherapy before the second line chemotherapy in metastatic colorectal cancer.

REPROGRAM-02: A phase II-III study evaluating an induction treatment with regorafenib and metronomic chemotherapy before the second line chemotherapy in metastatic colorectal cancer.

Abstract 678: Experimental therapy of triple negative breast cancer with next-generation of MDM2 inhibitors

Abstract Patients with triple-negative breast cancer (TNBC) typically experience minimal benefits from the existing hormonal or trastuzumab-based therapies, necessitating reliance on chemotherapy as the predominant treatment approach, which, unfortunately, is limited by insufficient efficacy, significant side effects, and the development of drug resistance. These issues highlight an urgent demand for the discovery and development of more effective and safer therapeutics for TNBC. Overexpression and amplification of the MDM2 oncogene frequently occur in TNBC, which is associated with invasive and high-grade/late-stage tumors, metastasis, and recurrence, and is an independent negative prognostic factor for TNBC patients. Extensive studies have indicated that MDM2 represents a novel molecular target for TNBC. Thus far, multiple strategies aiming at MDM2 inhibition have not succeeded in Phase II-III clinical trials, largely due to factors like inadequate efficacy, significant drug toxicity, and emergence of resistance. In addition, TNBC tumors commonly harbor mutant p53, and the existing MDM2 inhibitors that block p53-MDM2 binding and depend on wild-type p53 expression in the tumor to exert anticancer effects would have little or no clinical responses or even induce resistant clones by increasing MDM2 expression and its oncogenic activity. Therefore, there is a need for developing new-generation MDM2 inhibitors that are p53-independent. We recently discovered a novel class of MDM2 degraders, representing a paradigm shift in the strategy of targeting MDM2. One of these analogs, WW68, was identified as a potent and selective MDM2 inhibitor. Its in vitro and in vivo anti-breast cancer activities and underlying mechanisms of action were evaluated in breast cancer cell lines with various p53 backgrounds. Our results demonstrate that WW68 effectively induces MDM2 protein degradation. It selectively inhibits breast cancer cell growth, decreases cell proliferation, and induces G2/M phase arrest and apoptosis in breast cancer cells, regardless of p53 status. Notably, in clinically relevant TNBC PDX models, WW68 inhibited MDM2 and suppressed tumor growth without causing host toxicity. In conclusion, WW68 represents a new class of MDM2 inhibitor that exerts its anticancer activity through directly down-regulating MDM2, and may be developed as a novel anti-TNBC therapeutic agent. (Supported by NIH R01CA214019 and R01CA240447; and DoD W81XWH2010011) Citation Format: Wei Wang, Hao Chen, Yang Xie, Sayantap Datta, Wei Li, Ruiwen Zhang. Experimental therapy of triple negative breast cancer with next-generation of MDM2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 678.

P974 Incidence of Perianal Complications in Clinical Trials for Therapies for Moderate to Severe Inflammatory Bowel Disease

Abstract Background Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) with distinct clinical consequences. Distinct from patients with UC is that nearly 25% of patients with CD patients have or will develop perianal disease. Predictors for the development of new perianal disease or complications from existing perianal disease are not well described but such occurrences are included as adverse events (AEs) in clinical trials for IBD. We performed a systematic review and meta-analysis of perianal AEs in pivotal trials of therapies for IBD. Methods We conducted a search of PubMed, EMBASE, MEDLINE, Medline Plus, and CDSR library databases for registry and pivotal Phase II-III clinical trials of therapies for IBD. Safety data from clinicaltrials.gov was reviewed to identify incidence of perianal AEs using the terms "abscess" and "fistula." Reported perianal AEs included the following: anal abscess, fissure, fistula; perianal abscess, fistula; perineal abscess; perirectal and rectal abscess; subcutaneous (gluteal) abscess. Results Perianal AE incidence across all trials reviewed was 0.47% (91/19,327 patients). Perianal AEs were more likely to occur in patients with CD (0.77%, 70/9,046) than UC (0.20%, 21/10,281). Perianal AEs occurred more frequently in populations of drug-exposed patients than in patients exposed to placebo. In drug-exposed patients with UC, 0.22% (16/7,415) of patients experienced a perianal AE vs 0.17% (5/2,935) of patients exposed to placebo. In drug-exposed patients with CD, 0.76% (55/7,271) of patients experienced a perianal AE vs 0.61% (15/2,465) of patients exposed to placebo. The results are summarized in Table 1. Conclusion We found that perianal AEs occur in pivotal UC and CD clinical trials. Expectedly, the frequency of perianal AEs was higher in trials of CD than those for UC. However, the development of perianal AEs in trials of UC suggests that these patients may have been misclassified and have CD. Available data do not allow distinction between development of a perianal AE in a patient with known perianal disease or progression of undiagnosed clinical or subclinical perianal disease, nor does it allow for distinction in a patient not responding to the experimental agent. The finding that perianal AEs occurred more frequently with drug exposure than placebo may be due to fistula healing with consequential abscess formation or unique mechanistic effects that worsen perianal disease. These results highlight a probable rate of misclassification of patients with UC in pivotal trials, and suggest the possibility of subclinical perianal disease in some patients. Further clarification and study of these AEs and their implications are warranted.

Revisiting a (001)-oriented layered lead chloride templated by 1,2,4-triazolium: structural phase transitions, lattice dynamics and broadband photoluminescence.

This study revisits a (001)-oriented layered lead chloride templated by 1,2,4-triazolium, Tz2PbCl4, which recently has been an object of intense research but still suffers from gaps in characterization. Indeed, the divergent reports on the crystal structures of Tz2PbCl4 at various temperatures, devoid of independent verification of chiral phases through second harmonic generation (SHG), have led to an unresolved debate regarding the existence of a low-temperature phase transition (PT) and the noncentrosymmetric nature of the low-temperature phase. Now, by combining differential scanning calorimetry, single-crystal X-ray diffraction, dielectric, as well as linear and nonlinear optical spectroscopies on Tz2PbCl4, we reveal a sequence of reversible PTs at T1 = 361 K (phase I-II), T2 = 339 K (phase II-III), and T3 = 280 K (phase III-IV). No SHG activity could be registered for any of the four crystal phases, as checked by wide-temperature range SHG screening, supporting their centrosymmetry. The dipole relaxation processes indicate a decrease in activation energy with increasing temperature, from 0.60, 0.38, to 0.24 eV observed for phase IV (space group P21/c), phase III (Pnma), and phase II (Cmcm), respectively. This change is interpreted as a result of the diminishing strength of H-bonds as the system transforms from phase IV to III and subsequently to II. The weaker H-bonds facilitate the reorientation of Tz+ cations in the presence of an external electric field. The photoluminescence spectra of Tz2PbCl4 reveal an intriguing interplay of narrow and broadband emission, linked respectively to free excitons and excitons trapped on defects. Notably, as the temperature decreases from 300 K to 16 K, both the emission bands exhibit distinctive blue and red shifts, indicative of increased in-plane octahedral distortion. This dynamic behaviour transforms the photoluminescence of Tz2PbCl4 from greenish-blue at 300 K to yellowish-green at 13 K, enriching our understanding of 2D lead halide perovskites and highlighting the optoelectronic potential of Tz2PbCl4.

New approaches to the assessment and classification of patient's selection parameters for phase II-III clinical trials

Objective: to study the rate of enrollment of patients for inclusion in clinical trial according to various parameters and its change under the influence of internal factors, to develop new parameters and indicators that could be sensitive for assessing the effect of the this factors.Materials and methods: a retrospective analysis of phase II-III data from four phase II-III clinical trials in the field of oncology and hematology conducted from 2007 to 2017.Results: the rate of recruitment of patients, other parameters of recruitment of patients and their derivatives, which were influenced by internal factors, were studied.Conclusions: Patient recruitment is affected by internal factors. This impact can be multidirectional: can increase the number of patients or, conversely, reduce it. Knowing the direction of the influence of a certain factor, it is possible to predict the success of both the recruitment of patients and the success of the clinical trial in general.

GRECCAR 14 - a multicentric, randomized, phase II-III study evaluating the tailored management of locally advanced rectal carcinoma after a favourable response to induction chemotherapy: Study protocol.

Total neoadjuvant treatment (TNT) is becoming standard in patients with locally advanced rectal carcinoma (LARC). Preoperative chemoradiotherapy (CRT) has proven side effects on bowel and genitourinary function. An early tumoral response to induction chemotherapy demonstrates its high prognostic value. Tailored management could be used as an alternative to systematic CRT. The GRECCAR 14 trial will attempt to personalize treatment strategy according to the patient's early tumour response to intensive chemotherapy with the aim of achieving the best toxicity-efficiency ratio. GRECCAR 14 is a multicentric, randomized, two-arm, phase II-III noninferiority trial. Patients with mid or low LARC with a predictive circumferential resection margin ≤2 mm or T3c-d stage with extramural venous invasion will be included. Evaluation of the tumoral response will be performed after six courses of high-dose FOLFIRINOX chemotherapy. Good responders (GRs) will be defined by a 60% decrease in tumoral volume on magnetic resonance imaging. Patients will be randomized to CRT before surgery. The primary endpoints will be R0 resection for phase II and the 3-year disease-free survival (DFS) for phase III. Tailored management of LARC is becoming an exciting challenge for the modality of neoadjuvant treatment and for the type of surgery or its omission. Neoadjuvant FOLFIRINOX has established efficacy, with a significant increase in the 3-year DFS. Better control of systemic disease must be accompanied by the same locoregional control, with the lowest morbidity. Our previous GRECCAR 4 trial demonstrated the high value of the early tumoral response after induction chemotherapy and the long-term safety of tailored management for GRs. If GRECCAR 14 demonstrates the ability to tailor TNT for LARC, this could lead to changes in clinical practice.

PL04 Presentation Time: 2:15 PM: Bowel Function Evaluation After Radiotherapy Dose Escalation: Early Results from the Morpheus Randomized Phase II-III Trial

PL04 Presentation Time: 2:15 PM: Bowel Function Evaluation After Radiotherapy Dose Escalation: Early Results from the Morpheus Randomized Phase II-III Trial

Patterns of oral anticoagulant use and outcomes in Asian patients with atrial fibrillation: a post-hoc analysis from the GLORIA-AF Registry

Previous studies suggested potential ethnic differences in the management and outcomes of atrial fibrillation (AF). We aim to analyse oral anticoagulant (OAC) prescription, discontinuation, and risk of adverse outcomes in Asian patients with AF, using data from a global prospective cohort study. From the GLORIA-AF Registry Phase II-III (November 2011-December 2014 for Phase II, and January 2014-December 2016 for Phase III), we analysed patients according to their self-reported ethnicity (Asian vs. non-Asian), as well as according to Asian subgroups (Chinese, Japanese, Korean and other Asian). Logistic regression was used to analyse OAC prescription, while the risk of OAC discontinuation and adverse outcomes were analysed through Cox-regression model. Our primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACE). The original studies were registered with ClinicalTrials.gov, NCT01468701, NCT01671007, and NCT01937377. 34,421 patients were included (70.0±10.5 years, 45.1% females, 6900 (20.0%) Asian: 3829 (55.5%) Chinese, 814 (11.8%) Japanese, 1964 (28.5%) Korean and 293 (4.2%) other Asian). Most of the Asian patients were recruited in Asia (n=6701, 97.1%), while non-Asian patients were mainly recruited in Europe (n=15,449, 56.1%) and North America (n=8378, 30.4%). Compared to non-Asian individuals, prescription of OAC and non-vitamin K antagonist oral anticoagulant (NOAC) was lower in Asian patients (Odds Ratio [OR] and 95% Confidence Intervals (CI): 0.23 [0.22-0.25] and 0.66 [0.61-0.71], respectively), but higher in the Japanese subgroup. Asian ethnicity was also associated with higher risk of OAC discontinuation (Hazard Ratio [HR] and [95% CI]: 1.79 [1.67-1.92]), and lower risk of the primary composite outcome (HR [95% CI]: 0.86 [0.76-0.96]). Among the exploratory secondary outcomes, Asian ethnicity was associated with higher risks of thromboembolism and intracranial haemorrhage, and lower risk of major bleeding. Our results showed that Asian patients with AF showed suboptimal thromboembolic risk management and a specific risk profile of adverse outcomes; these differences may also reflect differences in country-specific factors. Ensuring integrated and appropriate treatment of these patients is crucial to improve their prognosis. The GLORIA-AF Registry was funded by Boehringer Ingelheim GmbH.

Tas-102 for Refractory Metastatic Colorectal Cancer: A Multicenter Retrospective Cohort Study.

Trifluridine/tipiracil (TAS-102) is an oral chemotherapy approved for the treatment of metastatic colorectal cancer. The efficacy and tolerability of TAS-102 were shown in phase II-III clinical trials and in several real-life studies. The elderly and other special subgroups are underrepresented in published literature. We conducted a retrospective multicenter study to assess the effectiveness and safety of TAS-102 in consecutive patients with pretreated mCRC. In particular, we estimated the effectiveness and safety of TAS-102 in elderly patients (aged ≥70, ≥75 and ≥80 years) and in special subgroups, e.g., patients with concomitant heart disease. One hundred and sixty patients were enrolled. In particular, 71 patients (44%) were 70 years of age or older, 50 (31%) were 75 years of age or older, and 23 (14%) were 80 years of age or older. 19 patients (12%) had a concomitant chronic heart disease, three (2%) patients were HIV positive, and one (<1%) patient had a DPYD gene polymorphism. In 115 (72%) cases TAS-102 was administered as a third-line treatment. The median overall survival (OS) in the overall population was 8 months (95% confidence interval [CI], 6-9), while the median progression-free survival (PFS) was 3 months (95% CI, 3-4). No significant age-related reduction in effectiveness was observed in the subpopulations of elderly patients included. The toxicity profile was acceptable in both the whole and subgroups' population. Our study confirms the effectiveness and safety of TAS-102 in patients with pretreated mCRC, suggesting a similar risk-benefit profile in the elderly.

Survival-inferred fragility index of FDA-approved cancer drugs using surrogate endpoints.

1573 Background: The survival-inferred fragility index (SIFI) quantifies the robustness of positive trials by estimating the number of changes in a survival analysis that would render the results insignificant. Here, we use a variation of SIFI (SIFI-median) in which the median patient is reassigned between study groups until significance is lost. Our goal was to study the robustness of oncology randomized controlled trials (RCTs) leading to drug approval by the FDA based on surrogate time-to-event endpoints. Methods: In this cross-sectional study, we identified phase II-III RCTs between 2010 and 2020. We reconstructed individual patient data from published Kaplan-Meier plots of surrogate time-to-event endpoints and calculated the SIFI-median, i.e., the minimum number of median survivor reassignments from the intervention group to the control group that would cause the loss of statistical significance. Results: A total of 101 studies comprising 60697 patients met the inclusion criteria. The most common surrogate endpoint was PFS 86 (85.1%), followed by DFS 7 (6.9%). The SIFI-median was 23 (interquartile range [IQR], 12 to 37) and the SIFI-median as a proportion of sample size was 5.3% (IQR, 2.7% to 8.1%). Forty-five studies (44.5%) had SIFI-median less than 5% of the total sample size which was often less than the number of censored patients during early follow-up. The SIFI-median was less than 1% of the total sample size in 10 studies (9.9%). Conclusions: Low fragility indices indicates that the statistical conclusions of clinical studies could be reversed with a small number of variations. The lack of statistical robustness in multiple FDA-approved drugs suggests higher uncertainty in their clinical benefit.

Venous and arterial thromboembolic risk of Janus kinase inhibitors: a systematic review with meta-analysis.

Preliminary data led licencing authorities to alert clinicians of an increased venous thrombotic risk associated to the use of Janus kinase (JAK) inhibitors (JAKi). We performed a systematic review to estimate the risk of venous and arterial thrombosis associated to JAKi for the treatment of immune-mediated inflammatory diseases (IMIDs). Randomized controlled trials (RCTs) on JAKi in patients with IMIDs were identified by the MEDLINE and EMBASE databases until October 2021. Risk of bias was assessed according to Cochrane criteria. The beta-binomial model was applied to calculate pooled odds ratio (OR) and corresponding 95% CI. The PROSPERO registration number is CRD42022324143. We have included one phase I, 21 phase II, three phase II-III and 36 phase III RCTs for a total of 19 443 patients in the JAKi group and 6354 in the control group. Thirty-one (unweighted rate 0.16%; 95% CI: 0.10, 0.21) events were reported in the JAKi group and 20 (unweighted rate 0.22%; 95% CI: 0.12, 0.32) in the control group in a mean follow-up of 16.8 weeks. IMID patients treated with JAKi did not have an increased thromboembolic risk compared with those treated with placebo (OR 0.82; 95% CI: 0.43, 1.56). No statistically different results were seen in subanalyses for each investigated IMID, drug and dosage. JAKi do not increase thromboembolic risk compared with placebo in IMID patients enrolled in selected RCTs.

Efficacy and safety of cabozantinib in metastatic renal cell carcinoma patients: Russian multicenter observational study

Purpose: an assessment of efficacy and safety of cabozantinib in unselected patients with metastatic renal cell carcinoma in the first and subsequent lines of therapy.Materials and methods. Russian multicenter observational study included 92 consecutive patients with morphologically verified metastatic renal cell carcinoma treated with cabozantinib (60 mg/d) in 16 Russian centers. Median age of the patients was 56 (19-79) years, a male-to-female ratio - 3:1. At the start of cabozantinib therapy 27.2 % of patients had ECOG PS 2. Most common histological type of kidney cancer was clear-cell RCC (90.2 %). Most patients were diagnosed with synchronous (71.7 %) multiple metastases (60.9 %). Previous nephrectomy was performed in 87.0 % of cases. Prognosis according to International Metastatic Renal Cancer Database Consortium (IMDC) score was assessed as favorable in 5.4 %, intermediate - in 58.7 % and poor - in 35.9 % patients. Cabozantinib as the first-line therapy was administered in 9 (9.8 %), following 1-5 lines of systemic treatment - in 83 (90.2 %) cases. Median follow-up was 11 (2.3-44.5) months.Results. In patients, receiving cabozantinib as the first-line therapy, objective response rate was 66.7 %, tumor control was reached in 100 % of cases. Median time to the objective response was 2.6 (1.9-3.6) months, median objective response duration - 13.2 (6.2-21.5) months. Median progression-free survival (PFS) and overall survival (OS) were not reached, 6- and 12-months PFS was 77.8 % and 77.8 %, 6- and 12-months OS - 88.9 % and 88.9 % respectively. Cabozantinib as the second and subsequent lines of therapy provided objective response rate of 34.9 %, tumor control rate - 97.6 %. Median time to the objective response was 2.5 (1.8-4.1) months, median objective response duration - 12.6 (5.5-27.3) months. Median PFS was not reached (6- and 12-months PFS - 92.5 % and 73.1 % respectively), median OS was 32.6 months (6- and 12-months OS - 97.4 % and 80.8 % respectively). Any adverse events (AE) developed in 88.8 %, AE grade III-IV - in 32.6 % of cases. Most frequent AE grade III-IV included arterial hypertension (18.5 %), diarrhea (6.5 %) and palmar-plantar erythrodysesthesia (6.5 %). Unacceptable toxicity demanded treatment cancellation in 2.2 %, therapy interruption - in 16.3 % and dose reduction - in 30.4 % of patients.Conclusion. Cabozantinib as the first and subsequent lines of therapy for metastatic renal cell carcinoma patients in the real world practice demonstrated high efficacy and better tolerability comparing with population assigned for cabozantinib monotherapy in the randomized phase II-III trials.

Optimal Time Point for Evaluation of Response to Pembrolizumab Treatment in Japanese Patients With Metastatic Urothelial Carcinoma.

The duration of pembrolizumab use in actual daily practice might be shorter than that in clinical trials because termination of pembrolizumab therapy is at the discretion of the physician. We retrospectively reviewed the response to pembrolizumab in Japanese patients with metastatic urothelial carcinoma (mUC) in relation to the time to response (TTR). The records of 165 patients treated with pembrolizumab for mUC were retrospectively analyzed. Response was evaluated at 2, 4, 6 and 8 months. TTR along with time to best response were analyzed. Phase II-III clinical trials were also reviewed to compare the TTR and time to best overall response. The median patient age was 70 years. The objective response rate in the total cohort was 27.1% (42 out of 155 patients). Median TTR was 2.4 months and the time to best response was 3.1 months. Radiological evaluation at each time point significantly predicted overall survival (OS). Considering the evaluation of response at 2, 4, 6 and 8 months, the response at later time points tended to predict OS better. Multivariate analysis showed that the evaluation of response at 8 months (hazard ratio=1.91, 95% confidence interval=1.16-3.16 months; p<0.01) and best response during the treatment (hazard ratio=1.69, 95% confidence interval=1.17-2.44; p<0.01) independently predicted improved OS. Given that response when evaluated at a later point during pembrolizumab treatment more favorably reflected improved survival than when assessed earlier, physicians may be encouraged to wait until at least the termination of pembrolizumab treatment to determine the best response.

Ipilimumab with atezolizumab-bevacizumab in patients with advanced hepatocellular carcinoma: The PRODIGE 81-FFCD 2101-TRIPLET-HCC trial.

A substantial proportion of patients with hepatocellular carcinoma have to face up, sooner or later, to systemic therapy. The current standards as first line systemic therapies are either atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF), or durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4). However, the median overall survival remains below 20 months, and a minority of patients become long-term survivors. Of interest in immune-oncology strategies for hepatocellular carcinoma, the objective response seems to be the most reliable surrogate marker of better overall survival. TRIPLET-HCC (NCT05665348) is a multicentre, randomised, open-label phase II-III trial designed to evaluate efficacy and safety of the triple combination by the addition of ipilimumab (anti-CTLA-4) to atezolizumab/bevacizumab, versus the double atezolizumab/bevacizumab combination. The main inclusion criteria are histologically proven BCLC-B/C HCC without previous systemic therapy. The primary objective of the phase II is the objective response rate in the triple arm, and OS in the triple versus double arms in the phase III. Secondary endpoints common to the phases II and III are the comparisons of progression-free survival, objective response rates, tolerance and quality of life. In addition, genetic and epigenetic studies from tissue and circulating DNA/RNA will be conducted to assess their prognostic or predictive value.

Maintenance strategies after anti–EGFR-based induction in RAS wild-type (wt) metastatic colorectal cancer (mCRC): A systematic review and Bayesian network meta-analysis.

148 Background: In RAS wt mCRC the use of maintenance therapy after induction with fluoropyrimidine (FP)-based cytotoxic therapy (CT) plus anti-EGFR agents is controversial. Herein, we conducted a systematic review and network meta-analysis to compare different maintenance strategies. Methods: PubMed, CENTRAL, Embase and oncological meeting websites were screened to identify eligible studies. Phase II-III randomized trials which enrolled patients with previously untreated RAS wt mCRC, who switched to a maintenance strategy after an induction of CT combined with an anti-EGFR agent were included. Maintenance strategies considered were: observation, single agent anti-EGFR or FP, FP + anti-EGFR, doublet CT + anti-EGFR. Outcomes were progression-free survival (PFS), overall survival (OS) and safety (grade 3-4 adverse events). Subgroup analyses were performed in BRAF wt patients and left sided tumors. The meta-analysis was conducted using a random-effects model. A Markov Chain Monte Carlo simulation was used to estimate the posterior distributions. Strategies were ranked using the surface under the cumulative ranking (SUCRA) probabilities. Risk of bias was assessed with Cochrane Risk of Bias Tool. Results: Overall, 4207 records were screened and 10 trials were included in the analysis. Cumulative risk of bias was low-moderate. Maintenance therapy with FP + anti-EGFR (HR 0.56, 95% CrI 0.36-0.88) and doublet CT + anti-EGFR (HR 0.68, 95% CrI 0.46-1.01), showed the greatest PFS benefit compared to observation. On SUCRA analysis, FU + anti-EGFR had the highest likelihood of improving PFS (96.3%), compared to doublet CT + anti-EGFR (73.5%) or EGFR monotherapy (48.0%). In terms of OS, compared to observation, maintenance therapy with doublet CT + anti-EGFR (HR 0.51, 95% CrI 0.19-1.28), FU + anti-EGFR (HR 0.59, 95% CrI 0.19-1.68) or anti-EGFR monotherapy (HR 0.56, 95% CrI 0.24-1.34) yielded similar results. On SUCRA analysis probabilities were 78.3% with doublet CT + anti-EGFR, 64.5% with FP + anti-EGFR and 63.4% with anti-EGFR monotherapy. FP + anti-EGFR confirmed to be the best option in terms of PFS in BRAF wt patients (SUCRA: 96.3%) and left sided tumors (SUCRA: 89.6%). OS results in BRAF wt patients were consistent with the primary analysis. In left sided tumors, the OS benefit of adding CT seems limited compared to EGFR monotherapy. The addition of CT to anti-EGFR agents resulted in an increase of toxicity while FP monotherapy plus anti-EGFR showed a favourable safety profile compared to doublet CT + anti-EGFR. Conclusions: FP + anti-EGFR should be considered the best maintenance option in RAS wt mCRC in terms of PFS. Taking into account the similar OS performance of the different strategies, EGFR monotherapy could be considered, especially in left-sided tumors. Doublet CT + anti-EGFR, despite being effective, is limited by toxicities.