Ou, Fang-Shu

Background/Objectives: Results from a well-designed trial provide evidence to support approval of truly effective treatments or discontinuation of ineffective treatments. However, the information available at the time of trial design may be limited which may lead to underpowered trials. This work aims to evaluate the impact of design assumption misspecifications on the statistical power of randomized trials with survival outcomes. Methods: The impact of the design assumption misspecifications on statistical power of four different statistical methods was investigated in a simulation study. The methods include the log-rank test, MaxCombo test, the test of difference in survival probability, and test of difference in restricted mean survival time (RMST). The deviations considered include the survival rate in the control arm, the expected treatment effect in terms of magnitude and pattern, accrual rate, and drop-out rate. Results: Deviations in the control arm’s survival distribution have no impact on the power of the log-rank and MaxCombo tests but it affects the trial duration since trials designed with these tests require the total number of events to be met before the final analysis can be conducted. Misspecified treatment effect has similar effect on the statistical power of all four methods. When the proportional hazards assumption is misspecified, the RMST is more robust with a larger early treatment effect, while the survival probability and the MaxCombo tests are more robust with a larger late treatment effect and crossing hazards. Conclusions: Selecting the appropriate statistical tests to design a trial depends on the goal of the trial, the mechanism of action of the experimental treatment, the survival quantity of clinical interest, and the pattern of the expected treatment effect. The final design should be based on assumptions that are as accurate as possible, and the potential impacts of deviations from these assumptions on the trial’s statistical power should be carefully considered.

Abstract Background FGFR alterations are known to be driver alterations in several tumor types. We aimed to assess the efficacy of pemigatinib, an oral FGFR1-3 inhibitor, in patients with metastatic or unresectable colorectal cancer whose tumors harbored FGF/FGFR alterations. Patients and Methods The ACCRU-GI-1701 is a single-arm phase II trial which enrolled patients with previously treated FGF/FGFR-altered metastatic colorectal cancer to receive oral pemigatinib daily in 21-day cycles. The primary endpoint is objective response. Secondary endpoints include clinical benefit, progression-free survival, overall survival, quality of life, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04096417). Results Of the 14 patients included in the interim analysis, the objective response rate as well as clinical benefit rate were 0%. Given these results, the trial closed to enrollment after stage one due to futility. A total of 42.9% of patients had at least one grade 3 or higher AE, the most common being anemia and fatigue. Conclusion Pemigatinib monotherapy did not lead to objective responses in patients with chemorefractory metastatic colorectal cancer harboring FGF/FGFR alterations, although it was overall relatively well tolerated with no new safety signals. Notably, 93% (n = 13) of patients had only FGF/FGFR mutations and amplifications; one patient had an FGFR3-WHSC1 fusion at a low cfDNA percentage (0.02%).

Background and Aims: Screening for diseases can have psychological impacts, such as anxiety, and requires acceptability from the population to be effective. This study examined the perspectives on the benefits and harms of screening for metabolic dysfunction–associated steatotic liver disease (MASLD) among the general population to optimize screening practices. Approach and Results: A survey was sent to participants enrolled between 2020 and 2024 in a prospective MASLD screening study in Olmsted County, MN. The survey assessed participants' perceived anxiety, stigma, quality of life, preferred screening methods, financial concerns, and lifestyle impacts following screening and diagnosis. Of the 461 participants, 342 (74%) completed the survey. Overall, 14% of participants reported screening-related anxiety, and 14% were concerned about disclosing a potential MASLD diagnosis to others. Among those without a MASLD diagnosis, 99% felt reassured about their liver health, 48% reported an improved quality of life, and 25% made lifestyle changes pertaining to their diet, alcohol use, and physical activity. Of the 77 participants diagnosed with MASLD, 52% experienced some anxiety about their new diagnosis; however, 95% and 97% considered it important to receive an early MASLD diagnosis to mitigate the risk for cirrhosis and cardiovascular disease, respectively. Notably, 79% of diagnosed participants found the diagnosis beneficial in adopting healthier habits, with 30% achieving a >10% weight loss after screening. Conclusion: This population-based survey demonstrates that the perceived benefits of proactive MASLD screening, such as increased awareness, lifestyle changes, and early diagnosis, outweigh the harms. These findings highlight the importance of early screening through patient-centered protocols to improve health outcomes.

Abstract Background Atezolizumab plus bevacizumab (A/B) received FDA approval as the first-line therapy for patients with advanced hepatocellular carcinoma (HCC) in 2020. However, optimal subsequent treatment options are unclear. Here, we describe clinical outcomes of advanced HCC patients following first-line treatment with A/B. Patients and Methods We conducted a multi-site analysis of patients with HCC treated with first-line A/B between January 2018 and December 2022 at Mayo Clinic. This study cohort included all patients receiving second-line systemic therapy after A/B. Median overall survival (OS) and time-to-treatment discontinuation (TTD) were estimated using the Kaplan-Meier method. Child Pugh (CP) scores are also described at diagnosis, prior to first line, and prior to second-line therapy. Results Of the 342 patients who received A/B, 107 (31.3%) received second-line treatments including anti-VEGF therapy or immune checkpoint inhibitor (ICI) and were included in the final analysis. Median OS for all patients was 11.1 months from initiation of second-line therapy. Median OS was 10.7 months (95% CI: 7.2-12.8) and 15.7 months (95%CI: 6.8-NE) for those receiving anti-VEGF inhibitors and ICI ( P = .50). Median TTD for second-line therapies was 2.4 months (95% CI: 1.7-3.3) and 2.6 months (95% CI: 1.5-5.1) for anti-VEGF inhibitors and ICI, respectively (P = .87). In multivariate analyses, CP was significantly associated with survival. Conclusion Following first-line A/B treatment, there is no statistically significant difference in survival between ICI and anti-VEGF therapy, nor in time to treatment discontinuation. CP score remains an important prognostic tool.

Abstract Background A plant-based diet is associated with better survival among patients with nonmetastatic colorectal cancer (CRC), but its association in metastatic CRC is unknown. Methods Using an National Cancer Institute–sponsored trial (CALGB/SWOG 80405), we included 1284 patients who completed validated food frequency questionnaires at the initiation of metastatic CRC treatment. We calculated 3 indices: overall plant-based diet index (PDI), which emphasized consumption of all plant foods while reducing animal food intake; healthful plant-based diet index (hPDI), which emphasized consumption of healthful plant foods such as whole grains, fruits, and vegetables; and unhealthful plant-based diet index (uPDI), which emphasized consumption of less healthful plant foods such as fruit juices, refined grains, and sugar-sweetened beverages. We estimated the associations of 3 indices (quintiles) with overall survival (OS) and progression-free survival (PFS) using multivariable Cox proportional hazards regression. Results We observed 1100 deaths and 1204 progression events (median follow-up = 6.1 years). Compared with the lowest quintile, patients in the highest quintile of PDI had significantly better survival (hazard ratio [HR] for OS = 0.76 [0.62-0.94], Ptrend = .004; PFS = 0.81 [0.66-0.99], Ptrend = .09). Similar findings were observed for hPDI (HR for OS = 0.81 [0.65-1.01], Ptrend = .053; PFS = 0.80 [0.65-0.98], Ptrend = .04), whereas uPDI was not associated with worse survival (HR for OS = 1.16 [0.94-1.43], Ptrend = .21; PFS = 1.12 [0.92-1.36], Ptrend = .42). Conclusions Our study suggests that a plant-based diet, especially when rich in healthful plant foods, is associated with better survival among patients with metastatic CRC. The cause of survival benefits warrants further investigation.

A clinical trial represents a large commitment from all individuals involved and a huge financial obligation given its high cost; therefore, it is wise to make the most of all collected data by learning as much as possible. A multistate model is a generalized framework to describe longitudinal events; multistate hazards models can treat multiple intermediate/final clinical endpoints as outcomes and estimate the impact of covariates simultaneously. Proportional hazards models are fitted (one per transition), which can be used to calculate the absolute risks, that is, the probability of being in a state at a given time, the expected number of visits to a state, and the expected amount of time spent in a state. Three publicly available clinical trial datasets, colon, myeloid, and rhDNase, in the survival package in R were used to showcase the utility of multistate hazards models. In the colon dataset, a very well-known and well-used dataset, we found that the levamisole+fluorouracil treatment extended time in the recurrence-free state more than it extended overall survival, which resulted in less time in the recurrence state, an example of the classic “compression of morbidity.” In the myeloid dataset, we found that complete response (CR) is durable, patients who received treatment B have longer sojourn time in CR than patients who received treatment A, while the mutation status does not impact the transition rate to CR but is highly influential on the sojourn time in CR. We also found that more patients in treatment A received transplants without CR, and more patients in treatment B received transplants after CR. In addition, the mutation status is highly influential on the CR to transplant transition rate. The observations that we made on these three datasets would not be possible without multistate models. We want to encourage readers to spend more time to look deeper into clinical trial data. It has a lot more to offer than a simple yes/no answer if only we, the statisticians, are willing to look for it.

PURPOSE Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. MATERIALS AND METHODS Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. RESULTS Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes ( DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CONCLUSION CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.

PURPOSE The phase III Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial found no difference in overall survival (OS) in patients with metastatic colorectal cancer receiving first-line chemotherapy in combination with either bevacizumab or cetuximab. We investigated the potential prognostic and predictive value of HER2 amplification and gene expression using next-generation sequencing (NGS) and NanoString data. PATIENTS AND METHODS Primary tumor DNA from 559 patients was profiled for HER2 amplification by NGS (FoundationOne CDx). Tumor tissue from 925 patients was tested for NanoString gene expression using an 800-gene panel. OS and progression-free survival (PFS) were the time-to-event end points. RESULTS High HER2 expression (dichotomized at median) was associated with longer PFS (11.6 v 10 months, P = .012) and OS (32 v 25.3 months, P = .033), independent of treatment. An OS benefit for cetuximab versus bevacizumab was observed in the high HER2 expression group ( P = .02), whereas a worse PFS for cetuximab was seen in the low-expression group ( P = .019). When modeled as a continuous variable, increased HER2 expression was associated with longer OS (hazard ratio [HR], 0.83 [95% CI, 0.75 to 0.93]; adjusted P = .0007) and PFS (HR, 0.82 [95% CI, 0.74 to 0.91]; adjusted P = .0002), reaching a plateau effect after the median. In patients with HER2 expression lower than median, treatment with cetuximab was associated with worse PFS (HR, 1.38 [95% CI, 1.12 to 1.71]; adjusted P = .0027) and OS (HR, 1.28 [95% CI, 1.02 to 1.59]; adjusted P = .03) compared with that with bevacizumab. A significant interaction between HER2 expression and the treatment arm was observed for OS ( P intx = .017), PFS ( P intx = .048), and objective response rate ( P intx = .001). CONCLUSION HER2 gene expression was prognostic and predictive in CALGB/SWOG 80405. HER2 tumor expression may inform treatment selection for patients with low HER2 favoring bevacizumab- versus cetuximab-based therapies.

PURPOSE CALGB (Alliance)/SWOG 80405 was a randomized phase III trial that in first-line patients with metastatic colorectal cancer (mCRC) treated with bevacizumab or cetuximab with chemotherapy. We aimed to discover novel mutated genes associated with prognosis and differential response to therapy with the biologics. METHODS Primary tumor DNA from 548 patients was sequenced using FoundationOne. The effect of mutated genes and mutations on overall survival (OS) was tested adjusting for microsatellite instability status, BRAF V600E, all RAS mutations, arm, sex, and age. RESULTS The median number (lower-upper quartile) of mutated genes was 5 (3-7), 5 (3-6) in microsatellite stable and 12.5 (4.5-32) in microsatellite instability-high tumors. Mutated KRAS and APC were more frequent in Black (53% and 85%) than White (27% and 65%, respectively) patients while BRAF V600E was less frequent in Black (5%) than White (14%) patients. The median OS in patients with BRAF non-V600E (2.2% of patients) was 31.9 months (95% CI, 15.1 to not applicable [NA]) similar to that of BRAF wild-type (WT) patients (31.2 months [95% CI, 29.0 to 33.9]). Mutated LRP1B (10.7% of patients) was associated with improved OS compared with WT LRP1B (hazard ratio, 0.57 [95% CI, 0.40 to 0.80]). RNF43 (5.6% of patients) interacted with treatment arms as, in the cetuximab arm, patients with mutated RNF43 had a median OS of 11.5 (95% CI, 10.8 to NA) months compared with 30.1 (95% CI, 24.9 to 35.3) months in patients with WT RNF43, whereas in the bevacizumab arm, patients with mutated RNF43 had a median OS of 25.0 (95% CI, 14.2 to NA) months compared with 31.3 (95% CI, 29.0 to 34.3) months in patients with WT RNF43. CONCLUSION These results can provide new tools to predict patient outcome and improve therapeutic decisions and trial participation in patient minorities. The molecular alterations identified in this study may direct biomarker-driven studies.