Landmark Analysis Research Articles

Differential impacts of clinical, anatomical, and procedural factors on early and late mortality following open thoracoabdominal aortic repair: a retrospective observational study

BackgroundThe operative outcomes of thoracoabdominal aortic aneurysms (TAAAs) are challenged by high operative mortality and disabling complications. This study aimed to explore the baseline clinical, anatomical, and procedural risk factors that impact early and late outcomes following open repair of TAAAs.MethodsWe reviewed the medical records of 290 patients who underwent open repair of TAAAs between 1992 and 2020 at a tertiary referral center. Determinants of early mortality (within 30 days or in hospital) were analyzed using multivariable logistic regression models, while those of overall follow-up mortality were explored using multivariable Cox proportional hazards models and landmark analyses.ResultsThe rates of early mortality and spinal cord deficits were 13.1% and 11.0%, respectively, with Crawford extent II showing the highest rates. In the logistic regression models, older age (P < 0.001), high cardiopulmonary bypass (CPB) time (P < 0.001), and low surgical volume of the surgeon (P < 0.001) emerged as independent factors significantly associated with early mortality. During follow-up (median, 5.0 years; interquartile range, 1.1–7.6 years), 82 late deaths occurred (5.7%/patient-year). Cox proportional hazards models demonstrated that older age (P < 0.001) and low hemoglobin level (P = 0.032) were significant risk factors of overall mortality, while the landmark analyses revealed that the significant impacts of low surgical volume (P = 0.017), high CPB time (P = 0.002), and Crawford extent II (P = 0.017) on mortality only remained in the early postoperative period, without significant late impacts (all P > 0.05).ConclusionThere were differential temporal impacts of perioperative risk variables on mortality in open repair of TAAAs, with older age and low hemoglobin level having significant impacts throughout the postoperative period, and low surgical volume, high CPB time, and Crawford extent II having impacts in the early postoperative phase.

Combination therapy with immune checkpoint inhibitors and denosumab improves clinical outcomes in non-small cell lung cancer with bone metastases

BackgroundThe concomitant use of denosumab and immune checkpoint inhibitor (ICI) treatment may have synergistic effects and enhance antitumor activity; however, this has not been fully evaluated. This study aimed to evaluate the clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastases receiving combination therapy and to identify the best combination regimen. MethodsEighty-six NSCLC patients with bone metastases who received ICI treatment were enrolled in this study. The patients were divided into two groups; a denosumab combination group (D + ICI group; n = 47) and a non-combination group (non-D + ICI group; n = 39). The response rate (RR) for bone metastases, disease control rate (DCR), overall survival (OS), real world progression-free survival (rwPFS), and the incidence of immune-related adverse events (irAEs) were evaluated. Additionally, the time when denosumab treatment should commence and concomitant treatment duration were evaluated. ResultsThe D + ICI group showed significantly better RR (40.4 % vs. 20.5 %, p = 0.01), DCR (67.3 % vs. 38.7 %, p = 0.02), OS (14.2 vs. 8.6 months, p = 0.02), and rwPFS (7.4 vs. 3.6 months, p < 0.01) than the non-D + ICI group; however, incidence of irAEs showed no difference (29.7 % vs. 12.8 %, p = 0.07). Although clinical outcomes did not differ regardless of whether denosumab was initiated before or after ICI treatment, the group that received concomitant denosumab for more than four months had significantly better RR (46.2 % vs. 17.4 %, p = 0.03), OS (20.3 vs. 3.8 months, p < 0.01), and rwPFS (10.9 vs. 2.8 months, p < 0.01) than the group that received concomitant denosumab for less than four months. However, the landmark analysis showed no significant differences in OS (20.4 vs. 12.7 months, p = 0.11) and rwPFS (22.8 vs. 11.2 months, p = 0.21), and the results of denosumab duration were influenced by long-term survivors. ConclusionDenosumab showed favorable synergistic effects with ICI treatment and may significantly improve the response to bone metastasis and prognosis without increasing the incidence of irAEs.

The effect of dialysis modality on annual mortality: A prospective cohort study

Despite numerous studies on the effect of each dialysis modality on mortality, the issue remains controversial. We investigated the hazard rate of mortality in patients with incident end-stage renal disease (ESRD) concerning initial dialysis modality (hemodialysis vs. peritoneal dialysis). Using a nationwide, multicenter, prospective cohort in South Korea, we studied 2207 patients, of which 1647 (74.6%) underwent hemodialysis. We employed the weighted Fine and Gray model over the follow-up period using inverse probability of treatment and censoring weighting. Landmark analysis was used for identifying the changing effect of dialysis modality on individuals who remained event-free at each landmark point. No significant difference in hazard rate was observed overall. However, the peritoneal dialysis group had a significantly higher hazard rate than the hemodialysis group among patients under 65 years after 4- and 5- year follow-up. A similar pattern was observed among those with diabetes mellitus. Landmark analysis also showed the higher hazard rate for peritoneal dialysis at 2 years for the education-others group and at 3 years for the married group. These findings may inform dialysis modality decisions, suggesting a preference for hemodialysis in young patients with diabetes, especially for follow-ups longer than 3 years.

Incidence of checkpoint inhibitor-associated inflammatory arthritis, immunomodulation and mortality in cancer patients on immunotherapy: a retrospective cohort study.

Immune checkpoint inhibitor (ICI) associated inflammatory arthritis (ICI-IA) occurs in 4-6% of ICI-treated patients based on one observational study. We identified cases of ICI-IA using administrative claims to study its incidence and characteristics at the population level. We used the Medicare 5% sample to identify patients initiating ICIs. Cancer patients were identified by having ≥ 2 ICD-9/10-CM diagnosis codes from an oncologist for lung cancer, melanoma, or renal/urothelial cancer. ICI-IA was defined as having two Medicare claims ≥ 30 days apart with combinations of ICD-9/10-CM diagnosis codes that favored specificity. ICI-IA was identified in patients with a musculoskeletal diagnosis after ICI initiation, who had i.) no inflammatory arthritis or inflammatory rheumatic disease before ICI initiation ever, and ii) no musculoskeletal complaint in the one year prior to ICI. We examined DMARD utilization and visits to rheumatology in patients with ICI-IA. Landmark analysis and a time varying Cox proportional hazards model for overall survival was constructed. The incidence of ICI-IA was 7.2 (6.1-8.4) per 100 patient years. Patients with ICI-IA were mean (SD) age 73.5(7.0) years, 48% women, 91% white. Median(IQR) time from ICI initiation to first ICI-IA diagnosis was 124(56, 252) days. Only 24(16%) received care from a rheumatologist, and 24(16%) were prescribed a DMARD (46% by a rheumatologist). The HR for mortality in patients with ICI-IA was 0.86 (95% CI 0.59-1.26, p= 0.45). The incidence of ICI-IA identified in claims data is similar to that reported in observational studies, however, few patients are treated with a DMARD or see a rheumatologist. There was no difference in overall survival between ICI-treated patients with and without ICI-IA.

Long-Term Outcomes of Tricuspid Valve Replacement With Mechanical Versus Tissue Valves: Meta-Analysis of Reconstructed Time-to-Event Data

Tricuspid valve replacement (TVR) with mechanical versus tissue valves remains a controversial subject. To evaluate the long-term effects of types of valves on patient-relevant outcomes, we performed a systematic review with meta-analysis of reconstructed time-to-event data of studies published by March 15, 2024 (according to referred the Reporting Items for Systematic Reviews and Meta-analyses guidelines). A total of 21 studies met our eligibility criteria and included 7,166 patients (mechanical: 2,495 patients, 34.8%). Patients who underwent mechanical TVR had a lower risk of death than those who received a tissue valve (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.70 to 0.84, p <0.001). Mechanical TVR was associated with lifetime gain, as evidenced by the restricted mean survival time, which was 2.2 years longer in patients who underwent TVR with mechanical valves (12.4 vs 10.2 years, p <0.001). Our landmark analysis for reoperations revealed the following: from the time point 0 to 7 years, we found no difference in the risk of reoperation between mechanical and tissues valves (HR 0.98, 95% CI 0.60 to 1.61, p = 0.946); however, from the time point 7 years onward, we found that mechanical TVR had a lower risk of reoperation in the follow-up (HR 0.24, 95% CI 0.08 to 0.72, p = 0.001). The meta-regression analysis demonstrated a modulating effect of atrial fibrillation on the association between mechanical valves and mortality; the HRs for all-cause death tended to decrease in the presence of populations with a larger proportion of atrial fibrillation (p = 0.018). In conclusion, our results suggest that TVR with mechanical valves, whenever considered clinically reasonable and accepted by patients as an option, can offer a better long-term survival and lower risk of reoperation in the long run.

Long-term impact of type 2 diabetes onset on dementia incidence rate among New Zealanders with impaired glucose tolerance: A tapered-matched landmark analysis over 25 years.

We aimed to investigate the association between the onset of type 2 diabetes (T2D) and dementia incidence rates (IR) in the population with impaired glucose tolerance (IGT) identified in primary care in New Zealand (NZ) over 25 years. Tapered matching and landmark analysis (accounting for immortal bias) were used to control for potential effects of known confounders. The association between T2D onset and 5- and 10-year IR of dementia was estimated by weighted Cox models. The onset of T2D was significantly associated with the 10-year IR of dementia, especially in the socioeconomically deprived, those of non-NZ European ethnicity, those currently smoking, and patients with higher metabolic measures. Our findings suggest that the onset of T2D is a significant risk factor for dementia in individuals with IGT. Dementia screening and structured diabetes prevention are vital in the population with IGT, particularly those from deprived or ethnic minority backgrounds. Increased dementia incidence rate links with T2D onset in people with IGT. Significant incidence varied by ethnicity, socioeconomic status, and health factors. Results emphasize the diabetes manage and socioeconomic factors on dementia risk. Secondary analysis highlights the key role of vascular health in dementia prevention.

Major cardiovascular events in long-term multiple myeloma survivors: a Korean case–control study (the CAREMM-2105 study)

PurposeDespite improvements in multiple myeloma (MM) survival rates, data on cardiovascular outcomes in long-term survivors remain lacking.MethodsThis retrospective case–control study utilized the Korean National Health Insurance Service database (2009–2020) to compare the incidence of cardiovascular disease (CVD) between patients with MM and a matched control group, focusing on long-term (> 5 years) survivors. A preliminary case cohort (n = 15,402 patients with MM) and a matched control cohort (n = 123,216 patients without MM) were established based on birth year and sex. Following 1:1 propensity score matching, the final matched cohorts each comprised 15,402 participants.ResultsThe case and control cohorts were comparable in mean age (66.2 ± 11.5 years vs. 66.1 ± 11.3 years), sex, age distribution, and comorbidities. By the 8-year follow-up, the cumulative incidence of CV events (12.5% vs. 22.1%) and CVD risk were significantly lower in the case cohort. The 5-year landmark analysis revealed significant differences in CVD incidence between the cohorts (7.8% [case cohort] vs. 9.8% [control cohort]), with variations across age groups and sex, highlighting a significantly higher CVD risk among patients aged < 50 years in the case cohort (P < 0.001).ConclusionsThese findings underscore the need for vigilant CVD monitoring in MM long-term survivors, particularly those aged < 50 years at first diagnosis.Implication for Cancer SurvivorsThis study highlights the importance of integrating cardiovascular monitoring and risk management into long-term care for MM survivors, with a focus on younger patients and personalized interventions.

Long term results of a randomized phase III study of nimotuzumab in combination with concurrent radiotherapy and cisplatin versus radiotherapy and cisplatin alone, in locally advanced squamous cell carcinoma of the head and neck.

LBA6092 Background: The addition of nimotuzumab to weekly cisplatin as a radiosensitizer had improved progression-free survival (PFS) in a phase 3 study in locally advanced head and neck squamous cell carcinoma (LA HNSCC). However, whether it leads to an improvement in long-term OS is unknown. Hence this analysis was performed to evaluate the efficacy (in terms of OS) and late-term adverse events of the addition of nimotuzumab to concurrent chemoradiation in LA HNSCC. Methods: This was an open-label, investigator-initiated, phase 3 randomized trial conducted from 2012 - 2018. 536 adult patients with LA HNSCC, fit for radical chemoradiation were randomly assigned. Primary sites in the nasopharynx, salivary gland, nasal cavity, and paranasal sinus were excluded. Randomized 1:1 to either radical radiotherapy (66-70 Gy) with concurrent weekly cisplatin (30 mg/m2) (CRT) or the same schedule of chemoradiation with weekly nimotuzumab (200 mg) (NCRT). The primary endpoint was a 10-year OS; the key secondary endpoint was late adverse events. Intent to treat analysis was performed. OS was defined as the time from randomization till death. Kaplan Meier method will be used for the estimation of OS. Landmark analysis was performed to compare 10 OS between the 2 arms. COX proportional hazard model will be used for the calculation of hazard ratio (HR). The adverse events between the 2 arms were compared using a Fisher's test. A p-value of 0.05 will be considered as significant. Results: The median follow-up was 8.86 years (95% CI 8.59-9.16). The primary site of the primary was the oropharynx (269,50.2%) and only 24 cases were HPV positive. The 10-year OS was 22.5% (95% CI 16.7-28.8) versus 33.5% (95% CI 27.6-39.4) in the CRT and NCRT arm respectively (Hazard ratio=0.811; 95%CI 0.664-0.995, P=0.044). The median OS was 2.78 years (95% CI 2.31-3.69) versus 3.69 years (95% CI 2.90-4.49) in the CRT and NCRT arm respectively (P value by log-rank test=0.04). The median OS in HPV negative oropharynx was 1.8 years (95% CI 1.51-2.09) versus 2.48 years (95% CI 1.79-3.16) in the CRT and NCRT arm respectively (P value by log-rank test=0.02; HR 0.724 95%CI 0.546-0.959). Long-term adverse events were captured in 380 patients. There was no statistically significant difference in late-term adverse events between the 2 arms and will be presented at the conference. Conclusions: The addition of nimotuzumab to weekly cisplatin leads to improvement in long-term overall survival in locally advanced HNSCC without any additional increase in late-term adverse events. These results are largely applicable in HPV-negative patients. Clinical trial information: CTRI/2014/09/004980 .

Long term results of phase 3 randomized study evaluating the addition of low dose nivolumab to palliative chemotherapy in head and neck cancer.

LBA6054 Background: The addition of low-dose nivolumab to metronomic chemotherapy (MC) improved 1-year overall survival in relapsed and refractory head and neck squamous cell carcinoma (HNSCC). However, sustained benefit over the long term is an important aspect of immunotherapy and it has never been studied in a prospective randomized study for low-dose nivolumab. Methods: This was an open-label randomized phase 3 superiority study. Adult patients (age= or &gt;18 years), ECOG PS (0-1), relapsed -recurrent or newly diagnosed advanced HNSCC, and normal organ functions were eligible. Patients were randomly assigned 1:1 to oral metronomic chemotherapy consisting of methotrexate 9 mg/m2 weekly, celecoxib 200 mg twice daily, and erlotinib 150 mg daily, with (TMC-I) or without (TMC) with intravenous nivolumab 20 mg flat dose once-every-3-weeks. Systemic therapy was continued till the development of intolerable side effects or progression of disease. The primary endpoint was overall survival (OS). Landmark analysis was performed to compare OS between 2 arms. Results: The median follow-up was 32.5 months (95% CI 29.6-32.7). The 1 year, 2 year and 2.5 year OS were 20% (95%CI 11.9-29.7) versus 35.5% (95%CI 25-46.2) {Hazard ratio (HR)= 0.6534, 95%CI 0.4473 -0.956: P=0.028}, 5.3% (95%CI 1.7-12.3) versus 18.4 %(95%CI 10.7-27.8) {HR= 0.6318, 95%CI 0.4476 -0.8919: P=0.009} and 5.3% (95%CI 1.7-12.3) versus 17.1 % (95%CI 9.66.-26.3) {HR= 0.6379, 95%CI 0.4524 -0.8993: P=0.01} in the TMC and the TMC-I arms respectively. The benefit of the addition of nivolumab was independent of other factors like age, gender, ECOG PS, Site of malignancy, time to failure, PDL1 score, and previous exposure to platinum (Table). Conclusions: The addition of low-dose nivolumab to triple metronomic chemotherapy leads to a tripling of OS thus suggesting that even low-dose nivolumab has sustainable benefits. The benefit observed is irrespective of known prognostic factors in HNSCC. Clinical trial information: CTRI/2020/11/028953 . [Table: see text]

Impact of Graft-Versus-Host Disease on Relapse and Nonrelapse Mortality Following Posttransplant Cyclophosphamide-Based Transplantation

Following conventional graft-versus-host disease (GVHD) prophylaxis, the development of acute and/or chronic GVHD is associated with lower relapse rates. However, the effects of GVHD on relapse and non-relapse mortality following post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis have not been well studied. To this end, we analyzed the impact of acute and chronic GVHD following PTCy-based haploidentical donor transplantation (HIDT). The analysis included 335 consecutive HIDT recipients transplanted at a single institution between 2005 and 2021. Landmark analysis (LA) and time-dependent multivariable analysis (MVA) were utilized to study the impact of GVHD development on transplant outcome. Landmarks were defined as Day +100 for acute GVHD and one-year for chronic GVHD. Recipient characteristics included a median age of 50 (19-80) years, most commonly transplanted for acute leukemia[/MDS [242]. PBSC was the graft source in 81%, and regimen intensity was myeloablative in 49%. Median follow-up was 65 (23-207) months. In landmark analysis, development of grade 3 to 4 acute GVHD (versus 0-1) was associated with inferior 3-year overall survival (OS 47% versus 64%, P = .041), due to higher NRM (25% versus 10%, P = .013). In contrast, development of grade 2 acute GVHD had no significant effect on NRM or survival. When restricted to acute leukemia/MDS patients, development of grade II acute GVHD was associated with improved OS (79% versus 58%, P = .027) and a trend towards lower relapse (24% versus 36%, P = .08). Development of moderate-to-severe chronic GVHD resulted in significantly higher NRM (15% versus 4%, P = .010), but had no impact on relapse, DFS or OS. In Cox multivariate analysis (MVA), grade 3 to 4 acute GVHD and moderate-to-severe chronic GVHD were both associated with significantly higher NRM (HR 3.38, P < .001 and HR3.35, P < .001, respectively). In addition, grade 3 to 4 acute GVHD predicted worse OS (HR 1.80, P = .007) and DFS (HR 1.55, P = .041). In contrast, relapse was not impacted by acute or chronic GVHD in MVA. Grade 2 acute GVHD was not associated with transplant outcome in MVA. In summary, both grade 3 to 4 acute and moderate-to-severe chronic GVHD were associated with higher NRM after PTCy-based HIDT, without an effect on relapse risk. Methods of early identification of such patients in order to augment GVHD prophylaxis are clearly needed.

Glofitamab monotherapy in patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL): Updated analysis from a phase I/II study.

7008 Background: Glofitamab, a bispecific antibody with a novel 2:1 (CD20:CD3) format, engages and redirects T cells to eliminate malignant B cells. In a Phase I/II study (NCT03075696), fixed-duration glofitamab monotherapy showed high, durable complete responses (CR) and manageable safety in patients (pts) with heavily pretreated R/R MCL (Phillips et al. ASH 2022). We report updated efficacy and safety data for pts with R/R MCL. Methods: Pts received obinutuzumab pretreatment (Gpt; 1000mg or 2000mg) 7 days before their first glofitamab dose. Glofitamab step-up dosing was given on Cycle (C) 1 Day (D) 8 (2.5mg) and D15 (10mg), and target dose (16mg or 30mg) from C2D1 to C12 as a fixed-duration therapy. Efficacy endpoints were CR, overall response rate (ORR), duration of CR (DOCR), duration of response (DOR) and progression-free survival (PFS). Post-hoc PFS and overall survival (OS) landmark analyses were performed in pts with a CR at end of treatment (EOT). Results: As of Sept 4, 2023, 61 pts were enrolled; 60 received study treatment (1000mg Gpt, n=16; 2000mg Gpt, n=44). Median number of prior lines of therapy was 2 (range: 1–5); 73.3% were refractory to the last line of prior therapy. Median duration of glofitamab therapy was 7.4 months; median number of cycles was 12. Of the 31 pts (51.7%) who received prior Bruton’s tyrosine kinase inhibitor (BTKi) therapy, 29 (93.5%) were BTKi refractory; median number of prior lines of therapy was 3 (range: 1–5); 90.0% were refractory to the last line of prior therapy. At a median PFS follow-up of 17.2 months, ORR and CR rate were 85.0% and 78.3%, respectively. Median DOCR was 15.4 months; the majority of CRs (28/47; 59.6%) were ongoing at data cut-off. Of 19 pts with a CR, 9 had disease progression and 10 died (fatal adverse event [AE], n=8; COVID, n=7; septic shock, n=1). Estimated 12-month DOCR and DOR rates were 71.0% and 66.6%, respectively. Median PFS was 16.8 months. Landmark analyses indicated that most pts with a CR at EOT were alive and progression free 15 months post-EOT (OS rate, 72.7%; PFS rate, 59.2%). Observed efficacy data were consistent across both Gpt cohorts. In post-BTKi pts after a median PFS follow-up of 26.1 months, ORR and CR rate were 74.2% and 71.0%, respectively. Median DOCR was 12.6 months; median PFS was 8.6 months. No new safety signals were observed. Cytokine release syndrome (CRS) remained the most common AE (42/60, 70.0%; Grade 1/2, 58.3%) and was lower in the 2000mg (63.6%) vs the 1000mg (87.5%) Gpt cohort. Glofitamab monotherapy (2000mg Gpt) is currently under investigation in the Phase III GLOBRYTE study (NCT06084936). Conclusions: Fixed-duration glofitamab continues to demonstrate compelling response rates that are maintained beyond EOT, with long-term durability observed in heavily pretreated pts with R/R MCL, including pts with prior BTKi therapy. The safety profile was manageable and CRS mainly low grade. Clinical trial information: NCT03075696 .

Association between treatment (tx) response and PFS and OS in R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL): A 12-month landmark (LM) meta-analysis.

7047 Background: Despite advances in tx for CLL/SLL, CRs are rarely observed after tx in the R/R setting, thus impacting long-term outcomes. We evaluated the association between response after tx and survival outcomes in patients (pt) with R/R CLL/SLL. Methods: Adults with R/R CLL/SLL and ≥ 1 prior line of therapy (LOT) from 6 clinical trials (initiated after 01/01/2012 and completed before 12/31/2022) were sourced from the Medidata Enterprise Data Store. Cox models adjusted for potential prognostic factors were used to assess pt-level associations between achieving and maintaining a CR or CR with incomplete bone marrow recovery (CRi) by 12 mo after start of tx (LM date) and PFS and OS. In separate LM analyses (LMA), associations between achieving and maintaining CR/CRi, PR/nodular PR (nPR) by LM, or non-CR/non-PR (ie, those not achieving or maintaining CR/CRi or PR/nPR or not evaluated by LM), and PFS and OS were assessed. Results: Of 1604 pts (CLL, 97.7%; SLL, 2.3%; age ≥ 65 y, 61.8%; male, 66.6%; ECOG PS 0–1/2, 93.2%/6.8%; median [IQR] follow-up, 3.4 y [2.2–4.1]; median [IQR] LOT, 2 [1–3]; study tx, BTKi [40.4%], BCL2i [40.1%], anti-CD20 mAb [12.5%], and PI3Ki [9.9%]), 15.1% and 61.7% achieved a best overall response of CR/CRi and PR/nPR, respectively (ORR, 76.8%); 6.8% of pts had no response recorded in follow-up. A total of 1178 pts without progression, death, or censoring before LM were included in PFS LMA. Median (95% CI) PFS from LM was 64.4 mo (61.7–not reached [NR]) for CR/CRi, 43.3 mo (38.8–54.7) for PR/nPR, and 23.9 mo (18.3–50.6) for non-CR/non-PR. Pts who achieved and maintained CR/CRi had significantly longer PFS versus both non-CR/CRi and PR/nPR pts, with adjusted HR of 0.62 ( P = 0.01) and 0.64 ( P = 0.02), respectively (Table). For OS LMA, 1404 pts without death or censoring before LM were included. Median (95% CI) OS from LM was NR for CR/CRi and PR/nPR groups and 62.9 mo (51.2–NR) for non-CR/non-PR. At 24 mo from LM, 90% (85%–95%) CR/CRi, 87% (84%–89%) PR/nPR, and 72% (67%–77%) non-CR/non-PR pts were still alive. CR/CRi pts or PR/nPR pts had significantly longer PFS and OS versus non-CR/non-PR pts. Conclusions: We demonstrated that achieving and maintaining CR/CRi by 12 mo after start of tx was associated with significantly improved PFS versus achieving and maintaining PR/nPR, which was also better than not achieving/maintaining any response. These findings support the potential utility of durable CR/CRi as an informative early endpoint for assessing the value of tx in pts with R/R CLL/SLL. Adjusted HR (95% CI) [Table: see text]

Circulating tumor DNA (ctDNA) kinetics in colorectal cancer (CRC) treated with curative intent in the VICTORI study with an ultrasensitive MRD assay.

e15625 Background: Detection of molecular residual disease (MRD) with ctDNA is highly prognostic for recurrence in CRC. However, many cancers still recur without detectable ctDNA and increased lead time before clinical recurrence may create a window of opportunity to intervene. Here we apply an ultra-sensitive assay, NeXT Personal, to profile patients in the VICTORI study, a prospective cohort of patients with CRC managed with curative-intent treatment. Methods: To date, the first 33 patients with CRC have undergone panel creation. NeXT Personal was employed to construct personalized liquid biopsy panels for each patient with up to ~1,800 single nucleotide variants (SNV) identified via whole-genome sequencing. For each patient, plasma is collected before curative intervention (baseline), every 2 weeks for 2 months (MRD window), and every 3 months for up to 3 years (surveillance). VICTORI will enroll &gt; 175 patients and include a health economics analysis. Results: Of 33 patients enrolled to date, 25 (76%) are stage I-III and 8 are stage IV treated with curative interventions. 18 colon cancers and 15 rectal cancers are included. Pre-operative baseline sensitivity was 90.6% (29/32; 1 patient excluded as pCR at the time of baseline blood draw). Of the MRD- patients at baseline, 2 had prior neoadjuvant treatment and 1 was stage 1. Preliminary results (median 7.2 month follow-up; 5 recurrences) show 80% (4/5) of recurrences are MRD+ at the 4-week landmark and 50% (2/4; 1 missing sample) were MRD+ at the 2-week landmark. In 75% (3/4) stage II-III recurrences, the first MRD+ detection was in the ultra-low range of &lt; 100 PPM ( &lt; 0.01% tumor fraction). MRD detection at week 4 and 8 trended towards poorer recurrence-free survival (RFS) with similar separation of patients (log rank p = 0.062 and p = 0.011, respectively). Conclusions: Preliminary results from our prospective study demonstrate strong rates of ctDNA detection at week 4 landmark analysis, potentially due to detection of very low levels of ctDNA with an ultra-sensitive MRD assay. The majority of the first detections for MRD were in the ultra-low ctDNA range, indicating the importance of high sensitivity MRD testing. [Table: see text]

Timing of EGFR or ALK inhibitor initiation and survival among patients with advanced NSCLC.

11148 Background: ALK or EGFR inhibitor is an ideal frontline treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring targetable alteration in ALK or EGFR. However, in the real-world setting, frontline treatment may be delayed or unideal. For such patients, the magnitude of survival benefit when initiating ALK or EGFR inhibitor at a much later timepoint remains unclear. Methods: We utilized a nationwide electronic health record-derived, deidentified database collected from diverse oncology practices across the United States to investigate the timeliness of preferred targeted therapy (PTT), defined as osimertinib, lorlatinib, alectinib or brigatinib. Individualized data obtained from patients with stage IV NSCLC at diagnosis treated with PTT during 2018 to 2023 were analyzed. Timing of PTT initiation was modeled as time-varying covariate. Results: Data from 3250 patients were analyzed: 2640 patients (81%) with EGFR mutation and 610 patients (19%) with ALK rearrangement. The median time to PTT was 7 weeks from diagnosis with 26.4% of patients started PTT within 1 month. Landmark analyses using timepoints ranging from 1 to 12 months after diagnosis showed that at all timepoints, patients who had started on PTT had a significantly better survival than those who had not (Table). In a multivariable analysis, time to PTT ≤ 1 month from diagnosis was an independent predictor of survival: HR 0.74 (95% CI: 0.62-0.89), p=0.002. Prolonged time to PTT was significantly associated with advanced age, positive smoking status and genomic class being ALK as compared to EGFR. Conclusions: In this population-based analysis, an initiation of PTT occurring as late as at least 1 year from diagnosis still resulted in a significant survival benefit, though the magnitude of benefit appeared decreased as time passed. [Table: see text]

Durable-polymer versus biodegradable-polymer drug-eluting stents in acute coronary syndromes: three-year outcomes of the HOST REDUCE POLYTECH RCT Trial.

Long-term follow-up is essential to evaluate the impact of polymer degradation in drug-eluting stents (DES). We aimed to compare durable-polymer DES (DP-DES) and biodegradable-polymer DES (BP-DES) during a 3-year follow-up to evaluate the entire period of polymer resolution (before, during, and after degradation). The HOST REDUCE POLYTECH RCT Trial was a randomised clinical trial enrolling patients with acute coronary syndrome (ACS) and comparing the efficacy and safety of DP-DES and BP-DES. The primary outcome was a patient-oriented composite outcome (POCO), and the key secondary outcome was a device-oriented composite outcome (DOCO). A total of 3,413 ACS patients were randomised to either the DP-DES (1,713 patients) or BP-DES (1,700 patients) group. During the 3-year follow-up, the risk of the POCO was similar between the DP-DES and BP-DES groups (14.8% vs 15.4%, hazard ratio [HR] 0.96, 95% confidence interval [CI]: 0.80-1.14; p=0.613). However, the risk of the DOCO was lower in the DP-DES group (6.0% vs 8.0%, HR 0.73, 95% CI: 0.57-0.95; p=0.020). In a landmark analysis, the lower risk of the DOCO for the DP-DES group was evident during the transition from the early to the late period after percutaneous coronary intervention (PCI) (from 8 to 16 months post-PCI; 1.8% vs 3.3%, HR 0.54, 95% CI: 0.34-0.84; p=0.007), which was mainly driven by a risk reduction of target lesion revascularisation. In ACS patients, DP-DES showed similar results to BP-DES regarding the POCO up to 3 years. For the DOCO, DP-DES were superior to BP-DES; this was due to the higher event rate during the period of polymer degradation.

T cell-mediated rejection and cancer risk in 579,905 organ transplant recipients.

10552 Background: Prolonged immunosuppression following organ transplant raises post-transplant malignancy (PTM) risk without affecting chronic rejection graft failure (CRGF) rates. Our study investigated if T cell responses during rejection could protect against cancer, whereas T cell suppression in PTM might prevent rejection. Methods: Data from 1987 to 2023 on adult first-time single-organ transplant recipients were collected from the UNOS-OPTN database, excluding those with a history of malignancy. Time-dependent Cox regression and landmark analyses (at 1, 2, 3, 5, 10, 15, and 20 years) were used to explore the link between rejection-induced graft failure (RGF) and PTM. Results: The study included 579,905 recipients (kidney 386,878, liver 108,390, heart 45,046, lung 37,643, pancreas 1,948), with a mean follow-up of 7.3 years. RGF occurred in 9.5% of recipients (kidney 12.1%, liver 1.8%, heart 3.9%, lung 12.0%, pancreas 10.2%; p&lt;0.001), with 2.1% experiencing acute rejection graft failure (ARGF) and 7.4%, CRGF. PTM occurred in 12.0% of recipients (kidney 9.9%, liver 12.4%. heart 20.9%, lung 22.6%, pancreas 11.3%; p&lt;0.001), including breast (0.5%), digestive (1.2%), genitourinary (1.7%), gynecologic (0.1%), head and neck (0.3%), hematologic (1.4%), musculoskeletal (0.1%), neurologic (0.0%), respiratory (1.1%), and skin/Kaposi sarcoma (6.4%). In recipients with RGF, PTM risk significantly decreased (HR 0.21 [0.19-0.24]; p&lt;0.001), with consistent trends observed across seven time landmarks (HR 0.20-0.07; p&lt;0.001). Both ARGF and CRGF were associated with lower PTM risk (HR 0.23 [0.18-0.29], 0.21 [0.19-0.24]; p&lt;0.001). In organ-specific analyses, kidney transplants showed similar outcomes for RGF, ARGF, and CRGF (HR 0.21-0.22; p&lt;0.001). Lung transplants exhibited significant risk reductions with RGF (HR 0.44 [0.22-0.89]; p=0.02) and CRGF (HR 0.47 [0.24-0.94]; p=0.03), with no significant results in other organs. All findings remained consistent even after excluding re-transplantations and deaths due to rejection. Excluding PTM-related deaths from PTM cases significantly lowered RGF risk (HR 0.69 [0.65-0.73]; p&lt;0.001), a trend that was consistent across all time landmarks (HR 0.51-0.80; p&lt;0.001). This inverse pattern was seen in kidney, liver, heart, and lung transplants (HR 0.90 [0.84-0.95], 0.21 [0.11-0.38], 0.21 [0.14-0.31], 0.18 [0.14-0.23]; p&lt;0.001) but not in pancreas transplants (HR 1.62 [0.69-3.77]; p=0.27). Conclusions: This study shows that rejection lowers cancer risk in kidney and lung transplants and that PTM reduces rejection risk in kidney, liver, heart, and lung transplants. Implementing enhanced cancer screening for those who have not experienced rejection may be considered. Further research is needed to elucidate the underlying T cell biology specific to each type of transplant.

Prognostic implications of PSA levels at 7 months in metastatic hormone-sensitive prostate cancer treated with enzalutamide: Landmark analysis of ENZAMET (ANZUP 1304).

5079 Background: ENZAMET (NCT02446405) showed that enzalutamide added to testosterone suppression (TS) with or without docetaxel improves overall survival (OS) compared with TS plus standard non-steroidal anti-androgen (NSAA) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We assessed PSA levels in ENZAMET participants at 7 months after randomization to determine correlations with OS. In CHAARTED, participants with mHSPC high volume disease (HV), 20% achieved PSA ≤ 0.2 with ADT (androgen deprivation therapy) alone versus 44% with low volume disease (LV) and for HV with ADT + Docetaxel, 36% achieved PSA ≤ 0.2 vs 64% with LV. Methods: Participants were included if they were followed for at least 7 months after randomization, and had availability of PSA and outcome data. Landmark analysis at 7 months used prognostic classifiers as previously identified in SWOG 9346 and CHAARTED of PSA ≤ 0.2 and &gt; 0.2 at 7 months after initiation of therapy. Results: The total number of ENZAMET participants (pts) with PSA at 7 months of ≤0.2ng/mL was 646 of 1125 (57%): 271/562 (48%) in the NSAA arm versus 375/563 (67%) in the ENZA arm. Five-year OS for TS + NSAA (±Doc) arm PSA ≤ 0.2 = 71% vs PSA &gt; 0.2 = 36% and for TS + ENZA (±Doc) arm PSA ≤ 0.2 = 74% vs PSA &gt; 0.2 = 43%. The % of pts with PSA levels at 7 months ≤0.2ng/mL and corresponding 5-year OS outcomes by key prognostic groups (HV vs LV) ± docetaxel is shown (Table). In comparison with CHAARTED in those with HV, 37% achieved PSA ≤ 0.2 with ADT alone versus 61% with LV which increased to 55% for HV and 79% for LV respectively with addition of enzalutamide. In those with HV treated with ADT + D 39% achieved PSA ≤ 0.2 vs 58% with LV increasing to 60% for HV and 74% for LV respectively with addition of enzalutamide. Conclusions: A PSA nadir of ≤0.2 at 7 months is associated with a longer OS regardless of treatment and prognostic group (HV vs LV). Enzalutamide increased the rate of achievement of PSA &lt;0.2 for all groups. Clinical trial information: NCT02446405 . [Table: see text]

Long term outcomes of patients with advanced/unresectable melanoma treated with immune checkpoint inhibitors.

e21518 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced/unresectable melanoma. There is a need for long term follow up of patients (pts) treated with ICIs in the real world to evaluate durability of response and facilitate follow-up care. Methods: Pts ≥ 18 years (y) old with advanced/unresectable melanoma who received ≥ 1 cycle of ICI at BC Cancer between 2012 and 2022 were identified using the BC Cancer Registry and pharmacy databases. Best overall response of complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) was obtained from CT and PET reports. Oligo-progression that was successfully treated with local therapy was not considered true progression. Results: In total 530 pts were identified. The median follow up for alive pts was 65 months (m) (range 1.4 – 150 m); the median age was 66 y (range 21 – 98). The majority were male (63%) and Caucasian (91%), with ECOG performance status 0 (38%) or 1 (48%). Primary tumour origin was cutaneous (n = 390, 74%), mucosal (n = 36, 7%), ocular (n = 47, 9%) or unknown (n = 57, 11%). BRAF V600 mutations (mut) were identified in 35% of pts (40% cutaneous/unknown). Pts either received PD-1 inhibitor alone (PD-1i) (n = 242, 46%), combination ipilimumab and nivolumab (ipi/nivo) (n = 136, 26%), ipilimumab alone (ipi) (n = 83, 16%) or sequential use of ipi and PD-1i (sequential) (n = 69, 13%). Overall survival (OS) was superior in cutaneous/unknown (5 y 34.5%) compared with mucosal (5 y 28%) and ocular (5 y 5%) primaries (p &lt; 0.001). Excluding ocular cases for the ensuing analyses, by treatment group (ipi/nivo, PD-1i, ipi, sequential) the 5 y OS was 43%, 36%, 37% and 10%, respectively (p &lt; 0.001). Pair-wise comparison of ipi/nivo vs PD-1i favored ipi/nivo (OS p = 0.059) despite a greater proportion of pts with M1d disease (24% vs 15%; p = 0.012). The benefit of ipi/nivo was more pronounced in pts &lt; 65 y (5 y OS 45% vs 36%; p = 0.07), but less clear in pts ≥ 65 y (5 y OS 40% vs 36%; p = 0.385). An OS benefit was observed with ipi/nivo in pts with BRAF wild-type disease (5 y 47.5% vs 33%, p = 0.018 (cutaneous/unknown only, p = 0.021) but not in patients with BRAFmut positive disease (5 y 38% vs 41.5%, p = 0.989). Those treated with ipi/nivo vs PD-1i had numerically higher rates of CR (37% vs 26%), though pts who achieved a CR with either ipi/nivo or PD-1i had a similar 5 y OS (88% vs 96%; p = 0.285). To minimize guarantee-time bias, a 1 y landmark analysis was performed for those treated with ipi/nivo and PD-1i, excluding pts that died during the first year. 5 y OS differed significantly by response (CR, PR, SD, PD) to both ipi/nivo (86%, 36.5%, 42%, 8%; p &lt; 0.001) and PD-1i (90.5%, 35%, 16%, 19%; p &lt; 0.001). Conclusions: Overall, pts treated with ipi/nivo have the best long-term outcomes. However, outcomes are similar in pts treated with PD-1i who have a CR. Further, in older pts and pts with BRAFmut positive disease the benefit of ipi/nivo over PD-1i is less clear.

The gut microbial characteristics and underlying mechanisms of patients with different clinical prognoses from immunotherapy by landmark analysis.

2606 Background: A subset of cancer patients could benefit long-termly from immune checkpoints inhibitors (ICIs), which was called smearing effect. Gut microbiota was widely found to be associated with the initial ICIs efficacy and immune-related adverse event (irAE). This study aimed to identify the baseline gut microbiota characteristics of long-benefit patients and explore the possible underlying mechanisms. Methods: Lung cancer patients initially treated with anti-PD-1/PD-L1 therapy were consecutively enrolled from May 2020 to September 2022. All patients were classified into Benefit group, Resistance group and Severe irAE group based on the long-term prognosis. The baseline gut microbiota characteristics were identified by metagenome sequencing. MelonnPan was used to predict the abundances of 79 metabolites. The sequences of autoantigen, lung cancer antigen and anticancer peptides (ACPs) from IEDB and CancerPPD databases were aligned against the scaftigs of fecal samples. Results: 54 patients were enrolled with 24 in Benefit group, 13 in Severe irAE group and 17 in Resistance group. The microorganism composition was significantly different between Benefit group and Resistance group ( P=0.03), while no difference between Benefit group and Severe irAE group ( P=0.93). The co-occurrence network showed the Benefit group patients had the most compact microbiota network. Metabolites prediction analyses showed the short chain fatty acids propionate ( P=0.005) and butyrate/isobutyrate ( P=0.03) were significantly enriched in Benefit group than Resistance group, wherein the acetyl-CoA pathway ( P=0.04) accounted for the largest proportion of butyrate-production ability difference. The beneficial species had more positive correlations with butyrate-producing enzymes ( P&lt;0.001). The microbiota of irAE patients had abundant aligned sequences with antigen epitopes of multiple autoimmune diseases. The total counts of systemic lupus erythematosus-related epitopes were significantly more enriched in patients with immune-related colitis ( P=0.04), especially FDNGRRGRPVTGP ( P=0.02) and IDNGRRGRPITGP ( P=0.02). Likewise, the microbiota of patients with good ICIs efficacy tended to have more abundant cancer-related antigen counts ( P=0.07) and ACPs counts ( P=0.06). Strain-level analysis revealed Escherichia coli and Faecalibacterium prausnitziishowed a centralized trend of genomic variations based on different clinical phenotypes. Conclusions: Long-term benefit patients had converging characteristics of gut microbiota, which coevoluted a compact microbial community with high butyrate-producing ability. The microbiota molecular mimicry of autoimmune and tumor antigen might contribute to irAE and ICIs efficacy. The strain-level genomic variations of specific species may also play a role in clinical phenotypes.

Associations of early adverse events with clinical outcomes in patients with NSCLC treated with EGFR tyrosine kinase inhibitors.

e20551 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) constitute the primary treatment modality for EGFR-mutant non-small cell lung cancer (NSCLC). While efficacious, EGFR TKIs are associated with adverse events (AEs) like dermatologic toxicities, diarrhea, and stomatitis. This study examined the prognostic implications of these on-target AEs in NSCLC patients receiving EGFR TKI therapy. Methods: A retrospective cohort study was conducted, encompassing advanced NSCLC patients treated with first-line EGFR TKIs within two distinct healthcare delivery systems in Taiwan between June 2011 and December 2019. Patients were stratified by TKI type, and those who had received AE reliever medications within 180 days prior to EGFR TKI initiation were excluded. We examined correlations between AEs and key endpoints: time to next treatment (TTNT) and overall survival (OS). To minimize immortal time bias, a landmark analysis at 60 days post-treatment initiation was utilized. On-target AEs were identified based on the issuance of at least two prescriptions for AE management on different dates within this period. Multivariable Cox proportional hazards models were utilized to evaluate the association between AEs and clinical endpoints, and a random-effects meta-analysis was performed to combine findings from both institutions. Results: Our analysis included 1,605 patients on gefitinib, 848 on erlotinib, and 1,236 on afatinib. Despite potential variations in AE reporting due to prescribing behaviors, the incidence of AE within the first 60 days of treatment was highest for afatinib, particularly with diarrhea (76.7%) and stomatitis (14.9%), followed by erlotinib with notable skin reactions (49.4%). Gefitinib showed the lowest incidence rates across all examined AEs. Of note, afatinib-treated patients who experienced diarrhea within the initial 60 days demonstrated a statistically significant extension in OS (HR 0.75, 95% CI 0.60-0.92). No significant prognostic link was found for other AEs in afatinib users or any AEs among users of gefitinib and erlotinib. Sensitivity analyses, incorporating modified AE definitions, corroborated these outcomes. Conclusions: Identifying AEs via prescription records for symptom relief poses methodological challenges and introduces uncertainty. Nevertheless, the occurrence of diarrhea within the first 60 days of therapy emerged as a significant predictor of enhanced OS in EGFR-mutant NSCLC patients receiving afatinib. This finding suggests a potential prognostic implication. The correlation was not evident in patients treated with first-line gefitinib or erlotinib.