Kaplan-Meier Overall Survival Research Articles

Lutetium-177–PSMA-617 experience in Appalachian patients with advanced prostate cancer at West Virginia University Health Science Center.

e17045 Background: Lutetium Lu-177 vipivotide tetraxetan (Lu-177) allowed for improved biochemical and radiographic response rate with relatively low toxicity for metastatic castration-resistant prostate cancer (PC) after multiple lines of therapy. In the 2021 VISION study (DOI: 10.1056/NEJMoa2107322), Lu-177 was reported to have a median overall survival (OS) of 15.3 months in patients (pts) with advanced prostate cancer (PC). We reviewed the result with Lu-177 for the treatment of advanced PC at a rural tertiary academic center at West Virginia University Health Science Center (WVU-HSC). Methods: All PC pts receiving one or more doses of Lu-177 at WVU-HSC were retrospectively reviewed. Pts were followed until death or the last clinic visit. All pts were established patients at WVU-HSC for management of the advanced PC between July 2022 and February 2024. Data was tabulated with descriptive statistics and median survival was calculated from Kaplan-Meier method. Results: Over an eighteen months period 34 pts received 126 doses of Lu-177. 26 pts were referred from outside the WVU-HSC specifically for Lu-177. Demographics from data collection showed predominantly Caucasian pts (91% Caucasian). The time from the initial PC diagnosis to the first dose of Lu-177 was a median of 67 months (range: 10 months-367 months). The median age at the first dose of Lu-177 was 65 years (range: 45-80). 18 patients (53%) remain alive as of Feb 2024. 14 pts (41%) completed 6 cycles of Lu-177 and 11 pts (32%) remain alive. The Kaplan-Meier median OS for these 34 pts starting from the first cycle of Lu-177 was 10 months. Conclusions: A 2022 estimated cost for Lu-177 was $42,500 per dose (excludes administration) so “payors” may have been charged more than $5,000,000 for the Lu-177 for these patients. Lu-177 may be of more benefit earlier in the PC disease spectrum, or perhaps pre-treatment PSMA imaging can better target patients who will benefit from Lu-177. Our observed median OS of 10 months did not match the 15.3 reported in the VISION study (DOI: 10.1056/NEJMoa2107322). Further data evaluation and collection are warranted from different communities to investigate the differences observed in the survival data reported in the literature and observed in the clinic setting. [Table: see text]

Treatment outcomes and survival of patients with breast cancer aged 75 and older: A comparative study using propensity score-adjusted analysis.

e13763 Background: With an aging society, the incidence of breast cancer among elderly patients is expected to rise. We aimed to explore treatment outcomes in breast cancer patients aged 75 and older at our institution. The lack of consensus on whether adjuvant therapy for elderly breast cancer patients should mimic that for younger patients prompted our investigation. Methods: We conducted a comparative study using data from 1553 breast cancer surgery cases (stage 0-3) treated between April 2007 and August 2021. Patients were divided into two groups: those aged 75 and older (n=184) and those aged 74 and younger (n=1369). Variables investigated included mean age, tumor size, stage, and subtype; surgical procedures and adjuvant therapies; overall survival (OS); and OS in the 75 and older group, considering the presence or absence of hormone therapy, and propensity score-adjusted OS. Results: Comparing the group aged 74 and younger with the group aged 75 and older revealed: Mean age: (55.5 years vs. 79.6 years), tumor size: (2.4 cm vs. 2.3 cm), stage (0/1/2/3) (%): (7.3/43.1/44.1/4/6 vs. 7.6/43.4/43.4/5.7), subtype (Luminal A/Luminal B/TN/HER2) (%): (60.0/16.7/11.3/7.9 vs. 63.5/10.7/15.7/5.7). Except for age, no significant differences were observed. Mastectomy (%): 45.9 vs. 50.8, axillary lymph node dissection (%): 33 vs. 22.3, adjuvant therapy (%): 93.2 vs. 65.7, adjuvant hormone therapy (%): 90 vs. 68, adjuvant chemotherapy (%): 68 vs. 14. The group aged 75 and older received significantly less adjuvant hormone therapy and chemotherapy. Kaplan-Meier 10-year OS rates: 90.3% vs. 77.5%, showing a trend toward lower survival in the group aged 75 and older, albeit not statistically significant. No significant differences were found in overall survival rates by subtype. In the group aged 75 and older, hormone therapy was omitted in 44.6% and administered in 55.4%, resulting in a significant difference in 10-year OS rates (63.5% vs. 84.7%). Following propensity score adjustment for age, stage, and subtype, the hormone therapy-free group exhibited a higher 10-year OS rate of 100%, in contrast to 84.7% in the hormone therapy group. Conclusions: Breast cancer cases in patients aged 75 and older show similar biological characteristics to those aged 74 and younger. The absence of adjuvant therapy does not impact OS, even though elderly patients aged 75 and older are less likely to receive adjuvant hormone therapy and chemotherapy.

Density of tumor-infiltrating NK and Treg cells is associated with 5 years progression-free and overall survival in resected lung adenocarcinoma

Surgical resection of pulmonary adenocarcinoma is considered to be curative but progression-free survival (PFS) has remained highly variable. Antitumor immune response may be important, however, the prognostic significance of tumor-infiltrating natural killer (NK) and regulatory T (Treg) lymphocytes is uncertain. Resected pulmonary adenocarcinoma tissues (n = 115) were studied by immunohistochemical detection of NKp46 and FoxP3 positivity to identify NK and Treg cells, respectively. Association of cell densities with clinicopathological features and progression-free survival (PFS) as well as overall survival (OS) were analyzed with a follow-up time of 60 months. Both types of immune cells were accumulated predominantly in tumor stroma. NK cell density showed association with female gender, non-smoking and KRAS wild-type status. According to Kaplan-Meier analysis, PFS and OS proved to be longer in patients with high NK or Treg cell densities (p = 0.0293 and p = 0.0375 for PFS, p = 0.0310 and p = 0.0448 for OS, respectively). Evaluating the prognostic effect of the combination of NK and Treg cell density values revealed that PFS and OS were significantly longer in NKhigh/Treghigh cases compared to the other groups combined (p = 0.0223 and p = 0.0325, respectively). Multivariate Cox regression analysis indicated that high NK cell density was independent predictor of longer PFS while high NK and high Treg cell densities both proved significant predictors of longer OS. The NKhigh/Treghigh combination also proved to be an independent prognostic factor for both PFS and OS. In conclusion, NK and Treg cells can be components of the innate and adaptive immune response at action against progression of pulmonary adenocarcinoma.

Comparing survival in trial- versus routine-care advanced urothelial cancer patients on immune checkpoint blockade.

Although recent trials involving first-line immune checkpoint inhibitors have expanded treatment options for patients with advanced urothelial carcinoma (aUC) who are ineligible for standard cisplatin-based chemotherapy, there exists limited evidence for whether trial efficacy translates into real-world effectiveness for patients seen in routine care. This retrospective cohort study compares differences in overall survival (OS) between KEYNOTE-052 trial participants and routine-care patients receiving first-line pembrolizumab monotherapy. A routine-care patient cohort was constructed from the Flatiron Health database using trial eligibility criteria and was weighted to balance EHR and trial patient characteristics using matching-adjusted indirect comparisons. The routine-care cohort was older, more likely to be female, and more often cisplatin-ineligible due to renal dysfunction. ECOG performance status was comparable between the cohorts. Median OS was 9 months (95% CI 7-16) in the weighted routine-care cohort and 11.3 months (9.7-13.1) in the trial cohort. No significant differences between the Kaplan-Meier OS curves were detected (p = 0.76). Survival probabilities were similar between the weighted routine-care and trial cohorts at 12-, 24-, and 36- months (0.45 vs. 0.47, 0.31 vs. 0.31, 0.26 vs. 0.23, respectively). Notably, routine care patients had modestly lower survival at 3 months compared to trial participants (0.69 vs. 0.83, respectively). Our results provide reassurance that cisplatin-ineligible aUC patients receiving first-line immunotherapy in routine care experience similar benefits to those observed in trial patients.

Risk Models for Predicting the Recurrence and Survival in Patients With Hepatocellular Carcinoma Undergoing Radio-Frequency Ablation

Background: Hepatocellular carcinoma (HCC) patients have a poor prognosis after radio-frequency ablation (RFA), and investigating the risk factors affecting RFA and establishing predictive models are important for improving the prognosis of HCC patients. Methods: Patients with HCC undergoing RFA in Shenzhen People’s Hospital between January 2011 and December 2021 were included in this study. Using the screened independent influences on recurrence and survival, predictive models were constructed and validated, and the predictive models were then used to classify patients into different risk categories and assess the prognosis of different categories. Results: Cox regression model indicated that cirrhosis (hazard ratio [HR] = 1.65), alpha-fetoprotein (AFP) ⩾400 ng/mL (HR = 2.03), tumor number (multiple) (HR = 2.11), tumor diameter ⩾20 mm (HR = 2.30), and platelets (PLT) ⩾ 244 (109/L) (HR = 2.37) were independent influences for recurrence of patients after RFA. On the contrary, AFP ⩾400 ng/mL (HR = 2.48), tumor number (multiple) (HR = 2.52), tumor diameter ⩾20 mm (HR = 2.25), PLT ⩾244 (109/L) (HR = 2.36), and hemoglobin (HGB) ⩾120 (g/L) (HR = 0.34) were regarded as independent influences for survival. The concordance index (C-index) of the nomograms for predicting disease-free survival (DFS) and overall survival (OS) was 0.727 (95% confidence interval [CI] = 0.770-0.684) and 0.770 (95% CI = 0.821-7.190), respectively. The prognostic performance of the nomograms was significantly better than other staging systems by analysis of the time-dependent C-index and decision curves. Each patient was scored using nomograms and influencing factors, and patients were categorized into low-, intermediate-, and high-risk groups based on their scores. In the Kaplan-Meier survival curve, DFS and OS were significantly better in the low-risk group than in the intermediate- and high-risk groups. Conclusions: The 2 prediction models created in this work can effectively predict the recurrence and survival rates of HCC patients following RFA.

Augmentation of Real-World Mortality Data in the Electronic Medical Record: Assessing the Impact on Overall Survival Estimates in Multiple Myeloma

Introduction: Utilization of real-world data (RWD) has progressively grown as a valuable supplement to randomized clinical trials in the context of drug development. Overall survival (OS) is a critical measure for assessing treatment effectiveness. Nevertheless, due to the frequent incompleteness in mortality data in the real world, there is a potential for overestimating OS. RWD has facilitated substantial research on multiple myeloma (MM), the second most prevalent hematologic malignancy. Given the paramount importance of OS as a clinical outcome in hematology and oncology settings, ensuring the completeness of mortality data is of utmost significance. The purpose of this study was to assess how different types of RWD mortality data sources affect OS estimates among patients with MM. Methods: This retrospective study included patients aged ≥18 years with initial diagnosis of MM between January 1, 2011, and December 31, 2022. Excluded populations consisted of those with an initial diagnosis of one or more primary malignancies other than MM, non-melanoma skin cancer, and/or cervical carcinoma in situ, and follow-up time <30 days. The study population was derived from ConcertAI real-world electronic medical record (EMR)-based oncology data (ConcertAI RWD360 dataset), representing approximately 7.6 million cancer patients from community and academic oncology practices throughout the United States. Death information is available as captured in the EMR as well as through patient-level linkage from external sources including the Social Security Death Index (SSDI), obituary, and open claims. Patients were categorized based on their source of death date. One composite death date based on the hierarchical order of availability from EMR, SSDI, obituary, and open claims was generated. OS was defined from the time of initial diagnosis date of MM to date of death. Patients were censored at the last recorded clinical activity date. Kaplan-Meier (KM) methods and Log-Rank tests were used to estimate OS across different mortality source categories. Results: The study population included 49,541 patients (53.1% male, 61.0% white) with a median age of 68 years (range: 18, 88) at initial MM diagnosis. Median follow-up from diagnosis to death or censored date was 2.4 years (range: 0.1, 12.5). Distribution of deceased patients by year of diagnosis was similar between the four sources. The number and percentage of patients with death event and date in each source were: 12,599 (25.4%) from obituary, 11,734 (23.7%) from EMR, 5,453 (11.0%) from SSDI, and 4,972 (10.0%) from open claims. Upon hierarchical integration of death date from the individual sources, 19,909 (40.2%) patients had an event. Figure 1 and Table 1 present the KM OS results by the death sources. Conclusion: This study evaluated the completeness of death date from multiple sources and its impact on OS estimates for an EMR-selected MM patient population. Among the sources evaluated, EMR and obituary had the highest level of death information captured relative to SSDI and open claims. Highest completion of death date was achieved when EMR death date was integrated with external data from obituary, SSDI, and open claims, resulting in OS estimates that are consistent with previous knowledge on MM prognosis. Completeness in capture of mortality data is essential to generate reliable estimates of OS in real-world studies, and integration of death information from multiple sources is critical in achieving this augmentation.

Demographics and Survival Outcomes of Burkitt Lymphoma in the US: A Hospital-Based Study from the National Cancer Database with Focus on Hispanics

BACKGROUND: Burkitt lymphoma (BL) is an aggressive B cell non-Hodgkin lymphoma primarily caused by MYC gene deregulation on chromosome 8 ( BloodPMID: 33171490). In the US, both sporadic and immunodeficiency-associated variants of BL are common, and their treatment and prognosis are generally similar ( BloodPMID: 15265787). BL is typically diagnosed at a median age of 30. However, the underrepresentation of Hispanics (HI) in previous studies has led to an incomplete and inaccurate representation of this population. ( J Clin OncolPMID: 9704731) To address this knowledge gap, a comprehensive nationwide study is underway to investigate the demographic, clinical, and survival outcomes of HI and non-Hispanic (NH) patients with BL. METHODS: Data from BL patients in the US (reported to NCDB between 2004 and 2019) were analyzed. Demographics, treatments, and overall survival (OS) were compared across ethnic groups. Kaplan-Meier and Cox regression analyses OS between HI and NH. Multivariate analysis and propensity score matching adjusted for age, stage, co-morbidity score, insurance status, facility type, and great circle distance. RESULTS: Among the 11,015 BL patients analyzed, 12% were HI and 84% were NH. Most were male (HI 76%, NH 74%) and diagnosed before age 65 (83% vs.72%). HI patients were younger (mean 47 years) than NH patients (mean 52 years) (p-value <0.001). Both groups were predominantly white (HI 90%, NH 82%), and stage IV was the most common (HI 52%, NH 52%). HI patients had a higher comorbidity burden (22%) with Charlson-Deyo Scores ≥2 compared to NH patients (16%) (p-value <0.001). Both groups had more government-sponsored insurance (HI: 42%, NH: 42%), but HI had a significantly higher uninsured percentage (16%) compared to NH (5.4%) (p<0.001). Regarding Census Median Income (2008-2012) HI's most prevalent bracket was $35,000 - $45,999 (27%), while NH's was $46,000+ (42%). HI had more median incomes below $30,000 (24%) than NH (13%) (p<0.001). HI patients had a shorter median distance to the reporting hospital (7.5 miles) compared to NH patients (11.5 miles) (p<0.001). In survival analysis, HI had higher 2, 5, and 10-year survival rates (64%, 60%, and 53%, respectively) compared to NH (69%, 54%, and 47%, respectively). The median survival time (MS) was 11.4 years for HI and 7.7 years for NH, favoring HI (p=0.003). Independently, on multivariate analysis, private insurance type was associated with higher OS (HR 0.69, CI 0.59-0.80, p<0,01). Interestingly, the propensity-matched analysis showed a significant MS difference between HI vs NH (6.22 vs. 2.77 years). CONCLUSION: The survival analysis conducted in this study revealed a significant and noteworthy difference in favor of HI patients with BL, despite their lower insurance coverage and income compared to NH patients. This finding could be attributed to their younger age at diagnosis, although both groups had similar burdens of comorbidities. Additionally, for both cohorts, private insurance type emerged as a significant prognostic factor in the multivariate analysis. These findings highlight the impact of ethnic and economic variations on oncological outcomes in BL for HI. This prompts further exploration of potential protective factors, unique disease characteristics, or access to improved treatments in this population. Understanding the underlying reasons for these differences could pave the way for targeted interventions and improved care for patients from diverse ethnic and economic backgrounds.

Prognostic Value of Measurable Residual Disease in High-Risk Myelodysplastic Syndromes with Intensive Chemotherapy Treatment: Analysis of HOVON-SAKK Studies

Diagnosis of myelodysplastic syndromes (MDS) and accurate risk assessment to tailor treatment remains challenging. High-risk MDS (hrMDS) patients who are fit enough may benefit from intensive chemotherapy followed by post-remission consolidation. The HOVON-SAKK (HO) acute myeloid leukemia (AML) trials, designed to test novel drug combinations with an intensive treatment regimen, included hrMDS patients (RAEB and RAEB-T). Since these HO-trials have been executed with large patient cohorts for many years, they offer the unique possibility to study the outcome, risk classification, and relevance of measurable residual disease (MRD) in hrMDS. A pooled database is available from HOVON-SAKK of patients who were treated with intensive chemotherapy (studies containing MDS patients with IPSS ≥ 1.5 HO42A, HO81, HO92, HO102, and IPSS-R > 4.5 HO103, HO132). The database contained 3268 patients; 11% (364/3268) were hrMDS scored according to IPSS and IPPS-R. Three-year overall survival (OS) for hrMDS was 32% (standard error; SE 2%) compared to AML 46% (SE 1%). In total, 1074 AML and 75 hrMDS had reached complete remission (CR/CRi) and received a second induction cycle (C2). MRD after C2 based on multiparameter flow cytometry (Cloos et al., 2018, J. Vis.) with a cut-off of ≥0.1% for MRD positivity was assessed to evaluate the MRD status. We observed a trend of a higher MRD positivity rate for MDS compared to AML patients (MDS vs. AML: 32% (23/73) vs. 22% (232/1064), P = 0.055). Kaplan-Meier OS analysis showed a significant prognostic value of MRD in MDS, but not in the cumulative incidence of relapse (CIR) (log-rank test 0.011, Gray's test P = 0.124). Since the MDS classification has been changed, we re-classified MDS based on the ICC 2022 classification into AML, AML/MDS, and MDS. We reclassified 3035 patients at diagnosis, including 2605 AML, 258 MDS/AML, and 172 MDS. The three-year OS was 47% (SE 1%) for AML, 29% (SE 3%) for MDS/AML, and 33% (SE 4%) for MDS. After C2, 2215 patients had reached CR/CRi. A total of 1074 patients containing 984 AML, 57 AML/MDS, and 33 high-risk MDS patients with CR/CRi after C2, with a suitable bone marrow sample, were included in the MRD analysis. Most patients were treated according to HO132 (40-48%). As expected, MDS patients were older (median age, range; 60, 32-74), had lower bone marrow blast counts, and were predominantly of adverse risk. A trend of a higher proportion of MRD positivity after C2 was observed in the MDS group (33%; 11/33) as compared to AML (22%; 215/984) or MDS/AML (18%; 10/57). Three-year OS was 61% for AML (SE 1.6%), 42% (SE 6.6%), and 49% (8.7%) for AML/MDS and MDS, respectively (Figure 1A). Kaplan-Meier OS analysis and CIR showed a significant prognostic value of MRD for MDS (log-rank test P<0.001, Gray's test P = 0.015) and AML ( P<0.001; P<0.001) but not for MDS/AML patients ( P = 0.5, P = 0.342)(Figure 1B). Remarkably, the three-year OS of MRDpos in MDS was 18% (SE 12%) compared to MRDpos in AML 40% (SE 16%). The limitation of this study is the relatively small number of MDS patients according to the new ICC 2022 guidelines. In summary, MRD detection in the HOVON-SAKK trials shows the potential of MRD as a prognostic value in MDS patients treated on intensive induction regimens with a clinically validated and standardized assay.

Indirect Treatment Comparison of First-Line CDK4/6-Inhibitors in Post-Menopausal Patients with HR+/HER2- Metastatic Breast Cancer.

Background: CDK4/6-inhibitors have demonstrated similar efficacy and are considered an effective first-line endocrine treatment of patients with hormone-receptor positive (HR+)/human-epidermal-growth-factor-receptor-2 negative (HER2-) metastatic breast cancer (MBC) in the endpoint of progression-free survival (PFS). Amongst these, palbociclib was first to achieve regulatory approval, followed subsequently by ribociclib and abemaciclib. However, recent updates of overall survival (OS) showed inconsistencies in the OS benefit for palbociclib compared with the other two CDK4/6-inhibitors. With the lack of head-to-head comparison studies, our study sought to compare indirect survival outcomes between CDK4/6-inhibitors in this setting using a novel reconstructive algorithm. Methods: Phase III randomized trials comparing first-line aromatase inhibitor with/without a CDK4/6-inhibitor in post-menopausal patients with HR+/HER2- MBC were identified through systemic review and literature search of online archives of published manuscripts and conference proceedings. A graphical reconstructive algorithm was utilized to retrieve time-to-event data from reported Kaplan-Meier OS and PFS plots to allow for comparison of survival outcomes. Survival analyses were conducted with Cox proportional-hazards model with a shared-frailty term. Results: Three randomized phase III trials-PALOMA-2, MONALEESA-2 and MONARCH-3-comprising 1827 patients were included. Indirect pairwise comparisons of all CDK4/6-inhibitors showed no significant PFS differences (all p > 0.05). Likewise, indirect treatment comparison between ribociclib vs. palbociclib (one-stage: HR = 0.903, 95%-CI: 0.746-1.094, p = 0.297), abemaciclib vs. palbociclib (one-stage: HR = 0.843, 95%-CI: 0.690-1.030, p = 0.094) and abemaciclib vs. ribociclib (one-stage: HR = 0.933, 95%-CI: 0.753-1.157, p = 0.528) failed to demonstrate a significant OS difference. Conclusions: Findings from this indirect treatment comparison suggest no significant PFS or OS differences between CDK4/6-inhibitors in post-menopausal patients with HR+/HER2- MBC.

Stereotactic radiosurgery and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors, or conventional chemotherapy for the management of melanoma brain metastases

BackgroundImmunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies. MethodsPatients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. Comparisons between groups were made for overall survival (OS), distant MBM control, local MBM, systemic progression-free survival (sPFS), and neurotoxicity. ResultsIn total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 and 2020 were identified. On MVA, treatment with anti-PD1+anti-CTLA-4, anti-PD-1, and BRAF/MEK-i improved distant intracranial control over conventional chemotherapy. No significant differences were noted in local control (LC) between groups (p = 0.78). Kaplan–Meier OS at 12 months for anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, and conventional chemotherapy was 68%, 59%, 45%, 62%, 21%, and 15%, respectively (p = <0.0001). The sPFS rates at 12 months were 57%, 53%, 42%, 45%, 14%, and 6% (p = <0.0001). No significant differences were noted in rates of radiation necrosis (p = 0.93). ConclusionsThis is among the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in OS, distant MBM control, and sPFS by systemic therapy. No differences in LC or radiation necrosis risk were noted.

LMAP-15 INTRACRANIAL RADIOTHERAPY WITH TUCATINIB FOR BRAIN METASTASIS FROM HER2-POSITIVE BREAST CANCER: A SINGLE-INSTITUTION SERIES

Abstract BACKGROUND Tucatinib, a HER-2 TKI, has demonstrated intracranial efficacy in the HER2CLIMB study. Treatment of brain metastases frequently includes stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT); however, HER2CLIMB did not detail outcomes with RT. METHODS Patients who received tucatinib at our institution from 2020-2022 were identified. Patients who had brain metastases and received intracranial RT within 6 months of receiving tucatinib were included. Patients with history of prior leptomeningeal disease (LMD) were excluded. The Kaplan-Meier (KM) method was used to estimate intracranial failure (ICF), overall survival (OS), and local control (LC). Adverse events and details regarding symptomatic radionecrosis were collected. RESULTS Between 2020 and 2022, 50 patients were treated with tucatinib. Forty patients had diagnosed brain metastasis and received intracranial RT. Median age at tucatinib start was 51 years (range: 33-83). All patients were HER-2+, 47.5% were HR+. Fifty-four separate RT courses were delivered within 6 months of tucatinib, including 45 courses of stereotactic RT (83%) and 9 (17%) WBRT. Twenty-three patients (57.5%) underwent concurrent tucatinib and intracranial RT, defined as RT within 2 months of tucatinib initiation. Median follow up for surviving patients was 18.9 months. Fifteen patients (37%) died at the time of analysis. Median OS was 25.1 months with 24-month KM OS of 52%. Median time to ICF was 12.5 months with 24-month KM ICF of 48%. At the time of ICF, 7 patients (17.5%) developed LMD. In total, 132 discrete lesions were treated with SRS. Ten lesions (7.5%) underwent local failure, with 24-month KM LC of 82%. Three patients (9.1%) undergoing SRS developed symptomatic radionecrosis; all completely resolved with dexamethasone. DISCUSSION In this first series reporting outcomes with RT and tucatinib, no evidence of excess toxicity was noted. Intracranial control appears favorable compared to previous reports. Concurrent RT with tucatinib should be assessed prospectively.

P.104 Grade 3 meningioma survival, recurrence and functional outcomes in an international multicenter cohort

Background: Meningiomas are the most common intracranial tumor, graded from 1 (benign) to 3 (malignant). The aim of this study was to identify clinical features associated with overall survival (OS), progression-free survival (PFS) and functional status for malignant meningiomas. Methods: Demographic, clinical and histopathological data from grade 3 intracranial meningioma cases were identified in the clinical databases from seven sites in North America and Europe from 1991-2022. Summary statistics and Kaplan-Meier OS and PFS curves were generated. Results: We identified 108 patients, with a median age 65 years (IQR: 52, 72) and 53.7% were female. Median OS was 109 months (95% CIs: 88, 227), and 5-year OS rate was 65% (95% CIs: 56, 76). Median PFS was 38 months (95% CIs: 24, 56) and 5-year PFS rate was 37% (95% CIs: 28, 49). OS and PFS were significantly lower in patients aged ≥65 years. Median preoperative KPS score was 80 (IQR: 70, 90), postoperatively KPS was 90 (IQR: 70, 98) and 1-year follow-up KPS was 70 (IQR: 50, 80). Conclusions: This study provides robust survival, recurrence and functional data for grade 3 meningiomas in North America and Europe over a 30-year period.

Evaluating novel imaging-based mathematical modeling prediction of immunotherapy response by individual melanoma brain metastasis and patient prognosis.

e14013 Background: Ipilimumab/Nivolumab (Ipi/Nivo) significantly transformed outcomes for patients with melanoma brain metastases (MBM), however inter- and intra-patient responses can vary widely. The purpose of this study is to develop and calibrate an imaging-based mathematical model to predict lesion-specific immune response to Ipi/Nivo in patients with MBM to guide early local treatments such as radiotherapy and evaluate the prognostic value of identifying treatment resistant lesions. Methods: Baseline and follow-up 3D T1-W contrast MRIs of patients who solely received Ipi/Nivo after diagnosis with MBM were used to segment individual brain metastases and track serial volumetric data for each lesion to develop a mechanistic model (eq 1). After applying appropriate assumptions to our model, tumor burden ( ρ), intrinsic lesion growth rate ( α 0), Ipi/Nivo-induced kill rate ( μ) and immune response strength ( Λ) were quantified for each lesion. Growth rate shortly after the start of treatment ( α 1 ) was calculated using the short-term model solution (eq 2). dρ/dt= (α0- μ+μ.Λ).ρ - μ.Λ.ρ2 (eq 1) ρ(t)≈eα1.t (eq 2) Change in BM volume between baseline and last follow-up was used to classify each lesion as either ‘responder’ or ‘non-responder’; these were compared with the Wilcoxon-rank-sum test. The highest α1 value for any one BM within a patient tumor was evaluated for its potential to sort patient overall survival (OS). Because the median survival was not reached for this cohort, we determined the α1 threshold of 0.005 to sort patients using an optimization routine that generates the maximum AUC to separate the cohort into 2 groups on an ROC curve. Kaplan-Meier (KM) curves were compared between these 2 groups. Results: In 23 patients, we evaluated 61 lesions. At the lesion level, model parameters representing μ and Λ were significantly different between responder and non-responder lesions (p-values &lt;0.0001 and 0.0004, respectively). The highest α1value for any one BM within a patient tumor was used to sort patient overall survival (OS) into prognostically ‘favorable’ or ‘unfavorable’ groups based on patient survival to ±1,200 days. In this limited cohort, OS KM curves by most aggressive lesion for favorable (α1 &lt; 0.005) vs. unfavorable (α1 &gt; 0.005) were not significant by log-rank test (p = 0.3263). Conclusions: In this limited cohort, we demonstrate feasibility to leverage serial conventional imaging and tumor volumetric data to calibrate a mechanistic model to predict per-lesion treatment response of MBM to Ipi/Nivo. Although the p-value between groups was found to be insignificant when predicting survival using α1, this is likely because of the small number of patients included in this study (n=23). Furthermore, when taken together with the notable AUC (=0.7917) observed in the ROC curve, this promising result supports further investigation in a larger cohort.

UNMET NEED IN RELAPSED/REFRACTORY (R/R) MANTLE CELL LYMPHOMA (MCL) POST‐BRUTON TYROSINE KINASE INHIBITOR (BTKI): A SYSTEMATIC LITERATURE REVIEW AND META‐ANALYSIS

Background: Most patients with MCL, a rare B-cell non-Hodgkin lymphoma, will relapse or become refractory to treatment. While the introduction of BTKis has been transformative, options for patients who fail to respond or whose disease progresses on BTKis remain limited and largely palliative in nature. We sought to characterize and quantify the unmet clinical need of patients with R/R MCL in the post-BTKi setting. Methods: MEDLINE, Embase, and CENTRAL were systematically searched to October 2022—supplemented with hand searches of select conferences—to identify studies reporting overall survival (OS), progression-free survival (PFS), and/or response outcomes of patients receiving non-CAR-T treatments or brexucabtagene autoleucel (brexu-cel) in the post-BTKi setting. Random effects bivariate meta-analyses of OS/PFS were conducted based on studies with published Kaplan-Meier (KM) curves from which individual patient data could be estimated. Response outcomes, based on the best response achieved, were meta-analyzed using a generalized linear mixed model. Outcomes were evaluated separately for patients treated with non-CAR-T and brexu-cel. Results: Twenty-six studies (23 observational; 3 trials), reporting the outcomes of 1845 patients treated from 2005 to 2022, were included, where patients were initially enrolled for treatment with a BTKi (12 studies) or for treatment post-BTKi (14 studies). The non-CAR-T interventions varied, with most studies reporting outcomes from cohorts of patients receiving a variety of interventions. Across the included studies, most patients were male (65-94%) and older, with the median age varying from 63 to 77 years. OS and PFS KM curves were published in 10 and 3 studies, respectively, for non-CAR-T outcomes. The pooled median OS/PFS for these patients was 9.1 and 7.6 months, respectively (Table 1). The pooled objective response rate (ORR) and percentage of patients achieving a complete response (CR) were 45% and 23%, respectively. The median OS/PFS of patients who received brexu-cel was 32.1 and 14.9 months, based on 5 and 6 studies with KM curves, respectively, with ORR/CR rates of 89% and 74%. Analyses were not sensitive to different survival distributions or fixed/random effects models. Conclusions: Treatment options in the post-BTKi setting are heterogeneous and a significant unmet clinical need persists. Though longer follow-up is needed for survival outcomes, treatment with brexu-cel is emerging as a promising option in this difficult-to-treat setting. The research was funded by: This study was funded by Kite, a Gilead company. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies Conflicts of interests pertinent to the abstract M. Dreyling Consultant or advisory role Astra Zeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche Research funding: Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche Educational grants: Janssen, Roche Other remuneration: Astra Zeneca, Gilead/Kite, Janssen, Lilly, Novartis, Roche B. Shah Consultant or advisory role Pepromene Bio; Takeda Honoraria: Kite/Gilead; BMS; Novartis; Amgen; Pfizer; Beigene; Adaptive; Century Therapeutics; Autolus Research funding: Kite; Servier; Jazz Pharma Educational grants: Kite/Gilead; Takeda Other remuneration: Chair, NCCN Adult ALL subcommittee J. Wu Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead; Amgen; Abbott; AbbVie; Avid; Curis; Viracta T. Itani Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead Sciences M. J. Zoratti Research funding: RainCity Analytics has received funds from for-profit healthcare companies for research S. Kanters Research funding: RainCity Analytics has received funds from for-profit healthcare companies for research S. W. Wade Consultant or advisory role Kite Pharma; Amgen; Allergan/Abbvie; Johnson & Johnson W. Peng Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead J. Castaigne Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead I. Kloos Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead Sciences M. Wang Consultant or advisory role AbbVie; Acerta Pharma; ADC Therapeutics America; Amphista Therapeutics Limited; AstraZeneca; Be Biopharma; BeiGene; BioInvent; Deciphera; DTRM Biopharma (Cayman) Limited; Genentech; InnoCare; Janssen; Kite Pharma; Leukemia & Lymphoma Society; Lilly; Merck; Miltenyi Biomedicine; Milken Institute; Oncternal; Parexel; Pepromene Bio; Pharmacyclics; VelosBio Honoraria: AbbVie; Acerta Pharma; AstraZeneca; Bantam Pharmaceutical; BeiGene; BioInvent; Bristol Myers Squibb; CAHON; Dava Oncology; Eastern Virginia Medical School; Genmab; i3Health; IDEOlogy Health; Janssen; Kite Pharma; Leukemia & Lymphoma Society; Medscape; Meeting Minds Experts; MD Education ; MJH Life Sciences; Merck; Moffit Cancer Center; Nurix; Oncology Specialty Group; OncLive; Pharmacyclics; Physicians Education Resources (PER); Practice Point Communications (PPC); Studio ER Congressi Research funding: Acerta Pharma; AstraZeneca; BeiGene; BioInvent; Celgene; Genmab; Genentech; Innocare; Janssen; Juno Therapeutics; Kite Pharma; Lilly; Loxo Oncology; Molecular Templates; Oncternal; Pharmacyclics; VelosBio; Vincerx

Indirect treatment comparison of first-line CDK4/6-inhibitors in post-menopausal patients with HR+/HER2- metastatic breast cancer.

1071 Background: In phase III studies, the CDK4/6-inhibitors palbociclib, ribociclib, and abemaciclib all have demonstrated similar clinical efficacy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) with regards to the primary endpoint of progression-free survival (PFS). However, the lack of overall survival (OS) benefit in the PALOMA-2 study is inconsistent with the OS benefit seen with the other two CDK4/6-inhibitors. This study sought to elucidate indirect treatment survival outcomes between CDK4/6-inhibitors in this setting. Methods: Phase III randomized controlled trials comparing first-line aromatase inhibitor with or without a CDK4/6-inhibitor in post-menopausal patients with HR+/HER2- MBC. A graphical reconstructive algorithm was utilized to retrieve patient level time-to-event data from reported Kaplan-Meier OS and PFS curves. Survival analyses were conducted with Cox proportional hazards model with a shared-frailty term incorporated to account for inter-study differences. Two-stage indirect treatment comparison model was conducted as a sensitivity analysis. Results: Three randomized phase III trials – PALOMA-2, MONALEESA-2 and MONARCH-3 – comprising 1,827 patients were included. Indirect pairwise comparison of all CDK4/6-inhibitor showed no significant PFS differences across one-stage and two-stage models (all p&gt;0.05). Likewise, indirect treatment comparison between ribociclib vs palbociclib (one-stage: HR=0.903, 95%-CI: 0.746-1.094, p=0.297), abemaciclib vs palbociclib (one-stage: HR=0.843, 95%-CI: 0.690-1.030, p=0.094) and abemaciclib vs ribociclib (one-stage: HR=0.933, 95%-CI: 0.753-1.157, p=0.528) failed to demonstrate a significant OS difference. Conclusions: Findings from this indirect treatment comparison suggest no significant PFS or OS differences between CDK4/6-inhibitor agents when combined with an aromatase inhibitor in post-menopausal patients with HR+/HER- MBC. [Table: see text]

Role of consolidative thoracic and prophylactic cranial radiation in extensive stage small cell lung cancer in chemo-immunotherapy era.

8595 Background: The role of consolidative thoracic and prophylactic brain radiation in extensive stage small cell lung cancer patients is controversial. We investigated the factors associated with the use of any radiation therapy (RT) and whether Radiation has a benefit to overall survival (OS) in the total patient group and whether this benefit is the same if Chemotherapy (CT) only is used, or chemo-immunotherapy (CT-IO) is used. Methods: The NCDB database was queried from years 2017-2019. Patients receiving systemic therapy- STX (CT or CT-IO) had to have at least 6 months of follow-up and have no brain metastases at diagnosis. All RT patients had to receive upfront systemic therapy, were treated 2 to 6 months from diagnosis, and if treated to the brain received 25Gy in 10 fractions only. Multi-variate analyses (MVA) were used to determine factors associated with OS and selection for any radiation. Propensity matching for factors affecting OS were used to generate Kaplan-Meier OS curves. Log-rank tests were used to determine differences in Kaplan Meier survival curves for the effects of RT on OS. Results: The total number of patients receiving RT or systemic therapy alone as well as their median follow-ups(months(mn) were (981, 33.02mn) and (8909, 30.59mn). The median time to the start of STX and RT were 22days and 135 days respectively. MVA noted that RT had a greater effect on OS (Thoracic, Brain, Both – HRs = 0.78, 0.75, and 0.68) than other interventions including IO (HR 0.87) and palliative care without RT (HR 1.07). Selection for radiation depended significantly upon factors affecting OS(HR) including liver metastases (0.59), females (1.21), age/10yr(0.78) and Charlson co-morbidity index of &gt; 3(0.66), but did not depend upon insurance status, race, or county income/high school graduation rates. Propensity score matched OS curves noted the same effects of RT on OS whether CT or CT-IO was given. The lowest HRs were noted when both thoracic and brain RT were given (see table). Conclusions: The patient with extensive stage small cell lung cancer who reach candidacy and receive RT may have a significant improvement in OS compared to the patients treated only with CT or CT-IO. Combined thoracic and prophylactic brain RT seems to be better than either one alone. The impact of radiation whether given to one or two sites may be more beneficial than immunotherapy added to chemotherapy. [Table: see text]

Efficacy of immune checkpoint inhibition in metastatic uveal melanoma: a systematic review and meta-analysis.

Metastatic uveal melanoma (mUM) has historically been associated with short survival and limited effective treatments. Immune checkpoint inhibitors (ICIs) have been trialed in mUM; however, robust conclusions regarding their efficacy are difficult to draw given small study sizes and heterogeneous patient populations. Five databases were searched using a combination of 'ICI' and 'mUM' headings, and data on patient demographics, objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) were extracted. Pooled ORR was calculated using a random effects model and the inverse variance method. Available Kaplan-Meier OS and PFS curves were used to construct summary OS and PFS plots, from which median values were derived. Pooled ORR was 9.2% overall (95% CI 7.2-11.8) [4.1% for anti-CTLA4 (95% CI 2.1-7.7), 7.1% for anti-PD(L)1 (95% CI 4.5-10.9) and 13.5% for anti-CTLA4 plus anti-PD1 (95% CI 10.0-18.0)]. Median OS was 11.5 months overall (95% CI 9.5-13.8) [8.0 months for anti-CTLA4 (95% CI 5.5-9.9), 11.7 months for anti-PD(L)1 (95% CI 9.0-14.0) and 16.0 months for ipilimumab plus anti-PD1 (95% CI 11.5-17.7) ( P < 0.001)]. Median PFS was 3.0 months overall (95% CI 2.9-3.1). ICIs have limited efficacy in mUM and a recommendation for their use must consider the balance of benefit and risk for individual patients if no other options are available. Further biomarker profiling studies may be helpful in assessing which patients will benefit from ICIs, in particular the addition of ipilimumab to anti-PD1 therapy.

Chemoradiation for muscle-invasive bladder cancer using 5-fluorouracil versus capecitabine: A nationwide cohort study

Background and purposeOral capecitabine and intravenous 5-fluorouracil (5-FU) are both used as a radiosensitizer in chemoradiotherapy (CRT). A capecitabine-based regimen is more convenient for both patients and healthcare professionals. Since large comparative studies are lacking, we compared toxicity, overall survival (OS) and disease-free survival (DFS) between both CRT-regimens in patients with muscle-invasive bladder cancer (MIBC). Materials and methodsAll patients diagnosed with non-metastatic MIBC between November 2017-November 2019 were consecutively included in the BlaZIB study. Data on patient, tumor, treatment characteristics and toxicity were prospectively collected from the medical files. From this cohort, all patients with cT2-4aN0-2/xM0/x, treated with capecitabine or 5-FU-based CRT were included in the current study. Toxicity in both groups was compared using Fisher-exact tests. Propensity score-based inverse probability treatment weighting (IPTW) was applied to correct for baseline differences between groups. IPTW-adjusted Kaplan-Meier OS and DFS curves were compared using log-rank tests. ResultsOf the 222 included patients, 111 (50%) were treated with 5-FU and 111 (50%) with capecitabine. Curative CRT was completed according to treatment plan in 77% of patients in the capecitabine-based group and 62% of the 5-FU group (p = 0.06). Adverse events (14 vs 21%, p = 0.29), 2-year OS (73% vs 61%, p = 0.07) and 2-year DFS (56% vs 50%, p = 0.50) did not differ significantly between groups. ConclusionsChemoradiotherapy with capecitabine and MMC is associated with a similar toxicity profile compared to 5-FU plus MMC and no difference in survival was found. Capecitabine-based CRT, as a more patient-friendly schedule, may be considered as an alternative to a 5-FU-based regimen.

The ability of magnetic resonance imaging to predict lymph node metastases and the risk of recurrence in rectal cancer.

This study aimed to examine the diagnostic accuracy and prognostic value of magnetic resonance imaging (MRI) detected lymph nodes in rectal cancer. We evaluated 806 rectal cancer patients consecutively operated on between 2015 and 2018 at Helsinki University Hospital. In total, 485 patients met the inclusion criteria of presenting with stage I-III disease and were intended for curative treatment at the time of diagnosis. The effect of MRI-detected clinical lymph node status (cN) on cumulative overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) was calculated using the Kaplan-Meier analysis. Negative predictive value (NPV) of MRI-lymphnode negativity was 74.8%. Positive predictive value of lymph node metastasis was only 48.6%. In the Kaplan-Meier survival analysis, OS (p = 0.989), DSS (p = 0.911), and DFS (p = 0.109) did not significantly differ according to MRI nodal status. However, cumulative disease-free survival significantly (p < 0.001) differed according to the histopathological lymph node metastasis status (pN). MRI detected lymph node positivity appears insufficiently precise and cannot predict disease recurrence or survival. Therefore, it should not serve as an independent risk factor when considering neoadjuvant treatment options for rectal cancer patients.

An indirect assessment of individual-level association between disease-free survival (DFS) and overall survival (OS) for resectable esophageal or gastroesophageal junction cancer (EC/GEJC): A pooled analysis of randomized controlled trials (RCTs) by an illness-death model.

369 Background: Validation of intermediate endpoints such as DFS as surrogates for overall survival (OS) in RCTs at individual-level remains as a challenge due to difficulty of collection of individual-level patient data. This study explores the individual-level correlation between DFS and OS indirectly using reconstructed Kaplan-Meier (KM) curves from the RCTs assessing therapies for (neo)adjuvant and perioperative treatment of EC/GEJC. Methods: An illness-death model previously validated in estimating individual-level association between DFS and OS for four correlation meta-analyses, two of which were published by the GASTRIC group, in early and late stage treatment of gastric cancer was employed. Reconstructed DFS and OS data from 25 RCTs published between 1994 - 2020 was pooled separately for each arm and each endpoint. Pooled data was analyzed to estimate the correlation between DFS and OS, as measured by Pearson’s r, Spearman’s rho, and Kendall’s tau. Predictive accuracy of the approach was evaluated by comparing its OS and restricted mean survival time (RMST) predictions to their counterparts obtained from the reported OS data from the RCTs. Sensitivity of correlation measures were assessed with respect to pre-specified variations in pre-recurrence death probability, post-recurrence mortality rate, and choice of the survival model used to extrapolate reported DFS curves from the RCTs. Results: Across all RCTs, the primary cancers covered were EC (n=13), EC/GEJC(n=9), GEJC (n=2) and GEJC/gastric cancer (n=1). According to the histology, 10 RCTs studied only squamous cell carcinoma (SCC) and 9 RCTs studied only adenocarcinoma (AC) of the disease, whereas the remaining 6 RCTs included varying mixtures of SCC and AC patients. The follow-up duration ranged between 27 and 72 months across RCTs. Comparator and intervention arms of the pooled data had 2499 and 2490 patients, respectively. Predicted Pearson’s r, Spearman’s rho, Kendall’s tau were 0.67, 0.79, and 0.70, respectively with negligibly narrow 95% CIs. Across both arms of the pooled data, on average, predicted OS curves laid within the 95% CIs of the pooled OS KM-curves 92% of the time. Average deviation between the RMSTs under the model-predicted OS curves and pooled OS KM curves was 2%. In sensitivity analyses, the ranges for r, r, and t were (0.56-0.88), (0.69-0.89), and (0.61-0.80), respectively. Conclusions: Results indicate moderate-to-strong correlation between DFS and OS in early-stage treatment of EC/GEJC providing supportive evidence for the validation of DFS as a surrogate for OS. Our approach mitigates the lack of patient level data in endpoint correlation assessment but may be prone to changes in the predicted value of pre-recurrence death probability.