Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/low-dose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to 5 years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (N=83) or non-HCT (N=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95% confidence interval [CI]: 18.9-30.1) in the HCT and 15.6 months (95% CI: 10.4-20.8) in the non-HCT arm (P=0.022) due to a decrease in cumulative relapse incidence from 91.1% (95% CI: 80.7-100.0) after non-HCT to 37.8% (95% CI: 27.2-48.4) after HCT (P<0.0001). The secondary endpoints RM-OS up to 5 years was 27.8 months (95% CI:22.3-33.2) in the HCT as compared to 28.6 months (95% CI: 22.2-35.0) in the non-HCT arm; non-relapse mortality at 5 years was 33.4% (95% CI: 23.0-43.9) with HCT and 0% without. In older patients with AML in CR1 5-year RM-LFS is better with HCT than with non-HCT consolidation treatment. The long-term RM-LFS benefit did not translate into a better RM-OS during the study period.
OBJECTIVE:To evaluate the addition of immunotherapy and metastasis-directed stereotactic body radiotherapy (SBRT) to induction chemotherapy followed by definitive local therapy of the locoregional primary tumour in patients with synchronous oligometastatic non-small cell lung cancer (NSCLC). METHODS:CHESS is a prospective, international, multicentre, single-arm, phase II trial evaluating the efficacy and safety of combined chemotherapy (carboplatin plus paclitaxel), immune checkpoint inhibition (durvalumab) and metastasis-directed SBRT, followed by definitive radiotherapy or surgery of the primary tumour (if no disease progression at the 3-month restaging) and maintenance durvalumab for maximum one year in patients with synchronous oligometastatic NSCLC. The primary endpoint was one-year progression-free survival, aiming to an improvement from 25% to 50%. RESULTS:A total of 49 patients were enrolled from 11/2019 to 07/2022. Up to 05/2023, the median follow-up was 22 months. Of 47 patients starting treatment, 10 progressed and 2 died before restaging, while 35 proceeded to definitive therapy of the locoregional primary (11surgery, 24 radiotherapy). Among the first 42 evaluable patients, 14 (33%; ≥17 required) reached one year without progression, and the null hypothesis could not be rejected. The one-year overall survival rate for all patients was 74.9% (95% CI: 60.0%-84.9%). Treatment-related grade ≥ 3 adverse events were reported in 34% of patients, with no grade 5 event. CONCLUSION:The CHESS trial did not meet its primary endpoint. However, the favourable safety profile and promising overall survival provided the basis for further intensification of induction systemic therapy (addition of tremelimumab in a subsequent study cohort; CHESS-Cohort 2).
Importance:The Breast Cancer Index (BCI) previously identified premenopausal patients with tumors in which the ratio of expression of HOXB13 relative to IL17BR (hereafter, BCI [H/I]-low tumors) as likely to derive greatest benefit from ovarian function suppression (OFS)-containing adjuvant therapy in the Suppression of Ovarian Function Trial (SOFT) trial. Objectives:To assess BCI as a predictive biomarker of benefit from exemestane plus OFS vs tamoxifen plus OFS and to validate BCI as a prognostic biomarker for premenopausal patients. Design, Setting, and Participants:This prognostic study used a prospective-retrospective translational design within the Tamoxifen and Exemestane (TEXT) and SOFT trials (enrolled November 2003 to April 2011). Blinded BCI testing in all available tumor samples was completed in March 2024. Premenopausal women with hormone receptor-positive breast cancer randomized to tamoxifen plus OFS or exemestane plus OFS who had BCI assessed were included. Analysis occurred from March to August 2024. Exposure:5 years of adjuvant tamoxifen plus OFS or exemestane plus OFS. Main Outcomes and Measures:The primary outcomes were breast cancer-free interval (BCFI) for predictive analyses and distant recurrence-free interval (DRFI) for prognostic analyses after a median follow-up of 13 years in the TEXT cohort. Secondary objectives examined the predictive performance of BCI (H/I) in the combined TEXT and SOFT cohort overall and in prespecified clinical subgroups. Results:Of 1782 patients in the TEXT study, 1034 (58.0%) had BCI (H/I)-low tumors; 915 (51.3%) of patients had N0 disease and 1077 (60.4%) were younger than 45 years. Patients with BCI (H/I)-low tumors had a 6.6% absolute benefit in 12-year BCFI (HR, 0.61; 95% CI, 0.44-0.85) for exemestane plus OFS vs tamoxifen plus OFS, while those with BCI (H/I)-high tumors had a 6.3% absolute benefit (HR, 0.78; 95% CI, 0.57-1.07; P for interaction = .29). Results were consistent in the combined TEXT plus SOFT cohort (2896 patients) and adjusting for clinicopathological variables. Clinical subgroup analyses consistently showed benefit of exemestane plus OFS vs tamoxifen plus OFS for BCI (H/I)-low tumors, and more variable relative treatment effects among BCI (H/I)-high tumors, including by age. Post hoc exploratory time-varying estimates suggested the treatment × BCI associations may differ in years 0 to 5 vs greater than 5 years. BCI and BCI N+ as continuous indices were prognostic for distant recurrence in N0 (HR, 1.27; 95% CI, 1.11-1.44; P < .001) and N1 (HR, 1.58; 95% CI, 1.21-2.05; P < .001) cancers. The 12-year DRFI was 96.3%, 90.3%, and 84.9% for BCI low-, intermediate-, and high-risk N0 cancers, respectively. Conclusions and Relevance:In this study of premenopausal women with hormone receptor-positive breast cancer, BCI (H/I) status did not clearly predict greater benefit of adjuvant exemestane plus OFS vs tamoxifen plus OFS for women with BCI (H/I)-low tumors than for those with BCI (H/I)-high tumors; BCI continuous indices were reconfirmed as prognostic for premenopausal women. These findings support prior results of SOFT, which compared tamoxifen-alone vs OFS with either exemestane or tamoxifen, indicating premenopausal patients with BCI (H/I)-low tumors may benefit from more intensive endocrine therapy.
308 Background: NRG/RTOG 0126 and SAKK 09/10 were phase III randomized trials examining whether higher dose resulted in better response/outcomes in PCa patients following definitive and post-operative RT, respectively. RTOG 0126 showed a benefit for RT dose escalation (DE) from 70.2Gy to 79.2Gy though SAKK 09/10 did not show a benefit from 64Gy to 70Gy. We hypothesized that a previously developed 24-gene prostate cancer RT gene expression score (PORTOS) could distinguish patients who benefited from RT DE in both trials. Methods: PORTOS scores were calculated on biopsy samples in RTOG 0126 and prostatectomy samples in SAKK 09/10 as published. Since the original PORTOS cutoffs were in the post-op setting, we utilized tertile score groups in RTOG 0126, whereas the published PORTOS cutoffs were used for SAKK 09/10. The primary objective was to evaluate PORTOS as a predictive biomarker for the benefit of RT DE on biochemical failure (BF) via the Phoenix criteria in RTOG 0126 (N=215) and clinical progression-free survival (CFPS) in SAKK 09/10 (n=226). In addition, we also investigated clinical and molecular correlates of PORTOS in large real-world datasets of 31,107 prostate biopsy samples and 42,407 radical prostatectomy samples. Results: In RTOG 0126, in patients with lower tertile PORTOS scores, there was no difference in Phoenix BF (sHR 1.14 [0.54-2.40], P=0.73). However, for patients in the middle and higher tertile PORTOS score range, there was a significant benefit for RT DE for Phoenix BF (middle PORTOS: sHR 0.45 [0.22-0.90], P=0.02; higher PORTOS: sHR 0.30 [0.12-0.75], P=0.009). An interaction test indicated a significant difference in benefit for DE between higher and lower PORTOS groups (P=0.048). Similarly in the post-op SAKK 09/10 trial, only patients in the higher PORTOS score group benefited from RT DE (CPFS HR 0.19 [0.05-0.70]; P=0.01), with a significant biomarker-treatment interaction between lower vs. higher PORTOS and treatment arm (P=0.003). Interestingly, PORTOS was not consistently associated with clinicopathologic variables in either trial or in the large real-world biopsy or prostatectomy datasets. Biologically, in the real-world datasets, PORTOS was modestly associated with hypoxia signatures consistent with its role in radio-resistance, and strongly associated with immune signatures and molecular subtypes. Conclusions: In two phase III randomized trials, we have validated that PORTOS can identify patients who benefit as well as those that do not benefit from RT DE for localized PCa and provides the first randomized evidence for any biomarker to be able to predict RT dose response. PORTOS could be used to personalize radiation dose for patients with prostate cancer clinically, and allow selection of patients most likely to benefit from RT DE while sparing others from the potential increased risk of toxicity.
