Propensity Score Weighting Using Overlap Weights: A New Method Applied to Regorafenib Clinical Data and a Cost-Effectiveness Analysis.

BACKGROUND: In situations of markedly different population characteristics and weak population overlap, inverse propensity score (PS) weights suffer from extreme values. The new propensity score weighting method using overlap weights (PSOW) overcomes this limitation by estimating the overlap population at the point of highest mutual overlap, thus may be preferred to other balancing methods (trimming, target, or inverse weights) in some situations. OBJECTIVES: To evaluate the performance of PSOW with regorafenib effectiveness data from previously treated patients with metastatic colorectal cancer based on the Czech national registry data (regorafenib) and a global phase 3 randomized clinical trial (RCT) (placebo). The second goal was to assess the cost-effectiveness of regorafenib versus placebo. METHODS: Individual data on progression-free survival (PFS)/overall survival (OS) were balanced via PSOW for age, sex, Eastern Cooperative Oncology Group performance status, number of treatment lines, metastatic colorectal cancer location, KRAS mutation, and time from metastases estimated using logistic regression. The weighted Kaplan-Meier PFS/OS curves were used in a 3-state partitioned survival model. The R code is provided. RESULTS: In comparison with target or inverse PS weights, PSOW showed remarkable performance measured by effective sample size and PS weight distribution or extreme weights despite the weak overlap between the registry and RCT. In the registry or RCT cohort, regorafenib provided better survival compared with the RCT. The new PSOW hazard ratio for OS was 0.53 (RCT: 0.79), which is conservative compared with inverse or target weights with a hazard ratio of 0.44 and 0.27, respectively. CONCLUSION: This is the first use of PSOW for clinical data and cost-effectiveness analysis. It is promising in cases of weak or small population overlap and makes pharmacoeconomic modeling, in such cases, feasible.

Prognostic Value of Neurotrophic Tyrosine Receptor Kinase Gene Fusions in Solid Tumors for Overall Survival: A Systematic Review and Meta-Analysis.

PURPOSE: Evidence suggests that neurotrophic tyrosine receptor kinase (NTRK) gene fusions in solid tumors are predictive biomarkers for targeted inhibition across a number of adult and pediatric tumor types. However, despite robust clinical response to tyrosine receptor kinase (TRK) inhibitors, the natural history and prognostic implications of NTRK fusions in solid tumors are poorly understood. It is important to evaluate their prognostic significance on survival to provide some context to the clinical effectiveness observed in clinical trials of TRK-targeted therapies. METHODS: A systematic literature review was conducted in Medline, Embase, Cochrane, and PubMed to identify studies comparing the overall survival (OS) of patients with NTRK fusion-positive (NTRK+) versus NTRK fusion-negative (NTRK-) tumors. Five retrospective matched case-control studies published before 11 August 2022 were assessed for inclusion, and three were selected for the meta-analysis (sample size: 69 NTRK+, 444 NTRK-). Risk of bias was assessed using the Risk of Bias Assessment tool for Non-randomized Studies tool. The pooled hazard ratio (HR) was estimated using a Bayesian random-effects model. RESULTS: In the meta-analysis, the median follow-up ranged from 2 to 14 years and the median OS was between 10.1 and 12.7 months (where reported). Comparing patients with tumors NTRK+ and NTRK-, the pooled HR estimate for OS was 1.51 (95% credible interval, 1.01 to 2.29). The patients analyzed had no previous or current exposure to TRK inhibitors. CONCLUSION: In patients not treated with TRK inhibitor therapies, those with NTRK+ solid tumors have a 50% increased risk of mortality within 10 years from diagnosis or the start of standard therapy compared with those with NTRK- status. Although this is the most robust estimate of the comparative survival rate to date, further studies are required to reduce uncertainty.

Survival Outcomes of Patients With Tropomyosin Receptor Kinase Fusion-Positive Cancer Receiving Larotrectinib Versus Standard of Care: A Matching-Adjusted Indirect Comparison Using Real-World Data.

PURPOSE: Larotrectinib, a highly specific tropomyosin receptor kinase (TRK) inhibitor, previously demonstrated high response rates in single-arm trials of patients with TRK fusion-positive cancer, but there are limited data on comparative effectiveness against standard-of-care (SoC) regimens used in routine health care practice, before widespread adoption of TRK inhibitors as SoC for TRK fusion-positive cancers. Matching-adjusted indirect comparison, a validated methodology that balances population characteristics to facilitate cross-trial comparisons, was used to compare the overall survival (OS) of larotrectinib versus non-TRK-inhibitor SoC. MATERIALS AND METHODS: Individual patient data from three larotrectinib trials (ClinicalTrials.gov identifiers: NCT02122913, NCT02637687, and NCT02576431) were compared with published aggregate real-world data from patients with locally advanced/metastatic TRK fusion-positive cancer identified in the Flatiron Health/Foundation Medicine database. OS was defined as the time from advanced/metastatic disease diagnosis to death. After matching population characteristics, the analyses included (1) a log-rank test of equality to test whether the two groups were similar before larotrectinib initiation; and (2) estimation of treatment effect of larotrectinib versus non-TRK-inhibitor SoC. These analyses are limited to prognostic variables available in real-world data. RESULTS: Eighty-five larotrectinib patients and 28 non-TRK-inhibitor SoC patients were included in the analyses. After matching, log-rank testing showed no difference in baseline characteristics between the two groups (P = .31). After matching, larotrectinib was associated with a 78% lower risk of death, compared with non-TRK-inhibitor SoC (adjusted hazard ratio, 0.22 [95% CI, 0.09 to 0.52]; P = .001); median OS was 39.7 months (95% CI: 16.4, NE [not estimable]) for larotrectinib and 10.2 months (95% CI: 7.2, 14.1) for SoC. CONCLUSION: Matching-adjusted indirect comparison analyses suggest longer OS with larotrectinib, compared with non-TRK-inhibitor SoC, in adult patients with TRK fusion-positive cancer.

Indirect Treatment Comparison of Larotrectinib versus Entrectinib in Treating Patients with TRK Gene Fusion Cancers.

Information regarding the comparative efficacy of first-generation receptor tyrosine kinase inhibitors is limited. This matching-adjusted indirect comparison (MAIC) evaluated differences in efficacy and safety across larotrectinib and entrectinib trials. Data from clinical trials for larotrectinib (LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431)) and entrectinib (ALKA-372-001 (EudraCT 2012-000148-88), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267)) were used. Adults (≥18 years) across trials were matched on available baseline characteristics. Outcomes evaluated included overall response rate (ORR), complete response (CR) rate, duration of response (DoR), overall survival (OS), progression-free survival (PFS), any serious treatment-related adverse events of grade ≥ 3 (TRAEs), and TRAEs leading to treatment discontinuation. The MAIC included 74 patients from entrectinib trials and 117 and 147 patients for the larotrectinib efficacy and safety populations, respectively. Post-matching, larotrectinib was associated with a significantly longer median duration of OS than entrectinib (p < 0.05) and a numerically longer median PFS (p = 0.07). ORR was similar for both agents (p = 0.63). The CR rate was higher (p < 0.05) and the DoR was longer for larotrectinib (p < 0.05). Safety outcomes were comparable and low for both treatments. Results were consistent in sensitivity analyses. These findings suggest favorable efficacy for larotrectinib and comparable safety profiles versus entrectinib in treating tropomyosin receptor kinase fusion cancer.

Impact of Disease Evolution on Efficacy Outcomes From Larotrectinib in Patients With Locally Advanced or Metastatic Tropomyosin Receptor Kinase Fusion-Positive Solid Tumors.

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions encode oncogenic, chimeric tropomyosin receptor kinase (TRK) proteins. Larotrectinib, an approved TRK inhibitor, is efficacious in locally advanced or metastatic (adv/met) TRK fusion cancer. We evaluated the time from initial diagnosis to locally advanced or metastatic disease and to initiation of larotrectinib treatment as well as larotrectinib impact on disease course. MATERIALS AND METHODS: Patients were grouped by prior lines of therapy (0, 1-2, and ≥ 3) and pre-larotrectinib duration of adv/met disease (short [< 3.5 months], medium [3.5 to < 15.7 months], and long [≥ 15.7 months]). Overall response rate (ORR), duration of response (DOR), and progression-free survival were assessed. RESULTS: One hundred sixty-four patients were evaluated. The median time from initial diagnosis to development of locally adv/met stage was 2.1 months; the duration of pre-larotrectinib adv/met disease was 7.3 months (n = 153). In patients with 0, 1-2, and ≥ 3 prior lines of therapy, the median time from diagnosis to adv/met stage was 0.9, 1.2, and 9.4 months, and 1.5, 5.8, and 29.0 months from adv/met disease to larotrectinib initiation, respectively. Clinical outcomes were independent of line of therapy (ORR: 86%, 63%, and 80%, respectively; median DOR: 27.6, not reached, and 32.9 months), and similar across subgroups of short, medium, and long duration of pre-larotrectinib adv/met disease status (ORR: 88%, 65%, and 69%, respectively; median DOR: not reached, 27.6, and 32.9 months). CONCLUSION: The short time from initial diagnosis to adv/met stage before larotrectinib suggests that NTRK gene fusion does not generally have a positive prognostic value. Patients on larotrectinib had high, sustained ORR, independent of number of prior therapies or duration of adv/met disease, suggesting that the effect of TRK inhibition in molecularly selected patients is independent of prior treatments or disease course.

Effect of Regorafenib in Delaying Definitive Deterioration in Health-Related Quality of Life in Patients with Advanced Cancer of Three Different Tumor Types.

PURPOSE: The efficacy and safety of regorafenib have been demonstrated in phase 3 trials for multiple tumor types, including metastatic colorectal cancer (mCRC) (CORRECT [NCT01103323]; CONCUR [NCT01584830]), advanced gastrointestinal stromal tumor (GIST) (GRID [NCT01271712]), and hepatocellular carcinoma (HCC) (RESORCE [NCT01774344]). The objective of this post hoc exploratory analysis was to explore the impact of regorafenib on delaying health-related quality of life (HRQOL) deterioration across these tumor types. PATIENTS AND METHODS: HRQOL data (assessed with EORTC QLQ-C30 and EQ-5D questionnaires) were pooled for all trials to determine time until definitive deterioration (TUDD), defined as the patient's first minimal clinically important deterioration in HRQOL score from baseline that does not resolve, using stratified Kaplan-Meier estimators and Cox proportional hazards models adjusted for relevant trial, cancer type, and baseline covariates. Additional analyses based on cancer type were conducted by pooling mCRC trials (CORRECT and CONCUR) and pooling the two mCRC trials with the HCC trial (RESORCE). RESULTS: A total of 1699 patients with HRQOL data were pooled across the four trials. The results showed that regorafenib significantly delayed TUDD compared with placebo across all three tumor types. Median time to deterioration across the five scales ranged from 16.3 to 24.1 weeks for regorafenib and 8.6 to 12.1 weeks for placebo. The results from the individual studies, the pooled mCRC trials, and the pooled mCRC and HCC trials were similar to the overall pooled results. CONCLUSION: A pooled analysis of four phase 3 trials demonstrated that regorafenib delayed a clinically relevant exploratory endpoint, defined as TUDD, compared with placebo across three different tumor types (mCRC, GIST, and HCC), which supports a novel benefit of the impact of regorafenib with respect to patients with these three types of cancers by allowing initial declines in HRQOL to resolve and patients the opportunity to continue treatment.