Two-year Overall Survival Research Articles

Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis

Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p < 0.0001) and multivariate (HR = 0.311; p < 0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib’s pro-erythropoietic mechanism of action, and potentially informing treatment decision-making.

Abstract CT008: Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100

Abstract Introduction: Sotorasib, a first-in-class KRASG12C inhibitor, has been FDA-approved for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapies based on the Phase 1/2 global, single-arm CodeBreaK100 trial. We will report the longest follow-up for a KRASG12C inhibitor, including 2-year survival, safety, and genomic profiles associated with durable clinical benefit. Methods: Sotorasib was administered orally at 960 mg once daily to patients who progressed on prior therapies and had KRAS p.G12C-mutated locally advanced, metastatic NSCLC. Primary endpoint was objective response rate (ORR) assessed by central review. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. In an exploratory analysis, baseline tumor tissue and/or plasma samples were collected and analyzed for genomic alterations. Tumor samples were analyzed for PD-L1 levels to evaluate correlates with prolonged tumor response, defined as patients with PFS ≥ 12 months, in comparison with those with PFS ≤ 3 months. Results: In the first analysis of the combined Phase 1 and Phase 2 study (N=174), the median number of prior lines of therapy was 2.0 (range 1-4+). 90.2% received prior anti-PD1 or anti PD-L1 treatment; 82.8% received both prior platinum-based chemotherapy and anti-PD1/PD-L1. Updated ORR by central review was 40.7% (95% CI: 33.2, 48.4) and median DOR was 12.3 months (7.1, 14.6). Median PFS and OS was 6.3 months (95% CI: 5.3, 8.2) and 12.5 months (10.0, 17.8). One and two-year OS was 50.8% and 30.3%. Sotorasib was well-tolerated in the long-term with mild and manageable toxicities, and no new safety signals emerged. Prolonged tumor response was observed across PD-L1 expression, including in tumors with low PDL-1 expression and STK11 co-mutation that may derive less benefit from immunotherapy. Conclusions: In the longest follow-up of any KRASG12C inhibitor, sotorasib continued to demonstrate a favorable safety profile and durable efficacy, including a 2-year OS observed in 30% of patients. Current analyses continue to support long-term clinical benefit across subgroups in patients with KRAS p.G12C-mutated NSCLC, and additional biomarker data will be presented. Citation Format: Grace K. Dy, Ramaswamy Govindan, Vamsidhar Velcheti, Gerald S. Falchook, Antoine Italiano, Juergen Wolf, Adrian G. Sacher, Toshiaki Takahashi, Suresh S. Ramalingam, Christophe Dooms, Dong-Wan Kim, Alfredo Addeo, Jayesh Desai, Martin Schuler, Pascale Tomasini, Qui Tran, Simon Jones, Agnes Ang, Abraham Anderson, Antreas A. Hindoyan, David S. Hong, Bob T. Li. Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT008.

Incidence of chronic graft versus host disease using post-transplant cyclophosphamide in HLA-matched versus haploidentical donors.

e19044 Background: Allogeneic hematopoietic cell transplant (allo-HCT) is the only potential cure for many hematologic cancers. Graft-versus-host disease (GVHD) is a significant cause of mortality after allo-HCT. Post-transplant cyclophosphamide (PTCy) in haploidentical HCT (haplo-HCT) has yielded survival outcomes similar to those seen in HLA-matched allo-HCT. Single center studies have demonstrated lower rates of chronic GVHD with the use of PTCy in HLA-matched allo-HCT. In this single center study, we analyzed the outcomes of HLA-matched and haplo-HCT in patients (pts) who received PTCy for GVHD ppx. Methods: Pts who received allo-HCT from matched related (MRD), matched unrelated (MUD), and haploidentical donors (Haplo) from Jan 2016 to July 2021 were identified. Pts who did not receive PTCy were excluded. Pts were divided into two groups – MRD/MUD and Haplo. Primary endpoint was cumulative incidence of chronic GVHD. Secondary endpoints were cumulative incidence of relapse, non-relapse mortality (NRM), and overall survival (OS) at 2-years. Comparisons were made based on log-rank test and a model for subhazard function of a failure event of primary interest with p &lt; 0.05 used as cut-off point for statistical significance. Results: 62 pts (45 MRD/MUD,17 Haplo) were included. Baseline characteristics were similar. Median follow-up was 342 days post-transplant. Most had a diagnosis of AML (50%), high/very high DRI (48%), and received RIC (55%). Cumulative incidence of chronic GVHD was 11% overall (95% CI 5.8-21.3%); 6% for MRD/MUD and 27% for Haplo (p = 0.045). Cumulative incidence of relapse was 28% overall (95% CI 18-42%); 34% for MRD/MUD and 13% for Haplo (p = 0.09). Two-year OS was 55% overall (95% CI 39.1- 68.7%); 53% for MRD/MUD and 61% for Haplo (p = 0.043). There was no significant difference in incidence of grade 2-4 acute GVHD or NRM between groups. Conclusions: PTCy resulted in a significantly lower incidence of chronic GVHD in MRD/MUD group compared to Haplo group. Although cumulative incidence of relapse was not statistically different between groups, OS was worse in the MRD/MUD allo-HCT group after PTCy and most deaths were due to relapse.[Table: see text]

Characterization of clinical outcomes after shorter course hypofractionated and standard-course radiotherapy for stage I-III curatively-treated Merkel cell carcinoma

BackgroundLimited data exists regarding the efficacy of curative hypofractionated radiotherapy (hypo-RT) regimens compared to conventionally-fractionated radiotherapy (conv-RT) for Merkel cell carcinoma (MCC). MethodsA retrospective analysis of 241 patients diagnosed with non-metastatic MCC from 2005-2021 and who received RT at Dana-Farber/Brigham & Women’s Cancer Center. The primary outcome was cumulative incidence of in-field locoregional relapse using Gray’s test with competing risks of death and isolated out-of-field recurrence. Secondary outcomes included overall survival (OS) and MCC-specific survival using log-rank tests, and risk factors of recurrence using Cox-proportional hazards regression. ResultsThere were 50 (20.6 %) and 193 (79.4 %) courses of hypo-RT and conv-RT, respectively. The hypo-RT cohort was older (≥73 years at diagnosis: 78.0 % vs 41.5 %, p < 0.01), and received a lower equivalent total RT dose in 2 Gy per fraction (<50 Gy: 58.0 % vs 5.2 %, p < 0.01). Median follow-up was 65.1 months (range: 1.2–194.5) for conv-RT and 25.0 months (range: 1.6–131.3) for hypo-RT cohorts. Two-year cumulative incidence of in-field locoregional relapse was low in both groups (1.1 % conv-RT vs 4.1 % hypo-RT, p = 0.114). While two-year OS was lower for the hypo-RT group (62.6 % vs 84.4 %, p = 0.0008), two-year MCC-specific survival was similar (84.7 % vs 86.6 %, p = 0.743). On multivariable analysis, immunosuppression, clinical stage III disease, and lymphovascular invasion were associated with any-recurrence when controlling for sex, age, and hypo-RT. Conclusions and RelevanceThere was no difference in cumulative incidence of in-field locoregional relapse or MCC-specific survival between hypo-RT and conv-RT. Prospective studies are needed to confirm hypo-RT as an efficacious treatment option for MCC.

Prognostic value of node-to-primary tumor maximum standardized uptake value ratio in T1-4N1-3M0 non-small cell lung cancer patients treated with concurrent chemo-radiotherapy.

BackgroundThis study aimed to identify whether NTR is the independent risk factor for progression-free survival (PFS) and overall survival (OS) in patients treated with concurrent chemo-radiotherapy (cCRT).MethodsWe retrospectively studied 106 T1-4N1-3M0 non-small cell lung cancer patients treated with cCRT. The maximum standardized uptake value (SUVTumor) of the primary tumor and the metastatic lymph nodes (SUVLN) were measured. The prognostic significance of NTR for predicting PFS and OS was assessed. A multi-adjusted spline regression model was conducted to provide more precise estimates and examine the shape of the associations between NTR and the risk of progression.ResultsFrom 2012 to 2017, 106 eligible patients were analyzed. The median follow-up time was 15.3 months (3.5–44.6 months). We determined the maximizing area under the time-dependent receiver operating characteristic curve was at an NTR of 0.73 for predicting PFS. The two-year PFS was significantly lower in the high-NTR group (35.7% vs. 55.4%, P = 0.02) and two-year OS (43.4% vs. 61.1%, P = 0.03 was also significantly worse. Multivariable analysis revealed that only NTR was an independent prognostic factor for PFS (hazard ratio [HR]: 10.04, P < 0.001) and OS (HR: 4.19, P = 0.03). The restricted cubic spline regression model showed that NTR had a non-linear relationship with log relative risk for progression.ConclusionNTR was an independent risk factor for predicting PFS and OS in T1-4N1-3M0 non-small cell lung cancer patients treated with cCRT.

Application of transoral robotic surgery in treatment of oropharyngeal squamous cell carcinoma

Objective: To evaluate the therapeutic and prognostic outcomes of transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OSCC). Methods: A retrospective study of 99 OSCC patients treated with TORS in Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center between April 2017 and May 2021 was conducted. There were 84 males and 15 females, with an age range of 35-85 years. Patients' clinical characteristics, including clinical staging, HPV infection status, perioperative management and postoperative adjuvant treatment, were recorded. The overall survival (OS) and progression-free survival (PFS) were analyzed. The survival outcomes were analyzed with Kaplan-Meier method and Log-rank test. Results: The hospital stay of OSCC patients with TORS was (5.3±2.9) days and the average time of postoperative nasal feeding tube indwelling was (15.2±10.8) days. Among the 99 patients, 21 (21.2%) received tracheotomy and the average time of tracheotomy tube indwelling was (11.9±11.4) days. The two-year OS and PFS in patients with follow-up over two years were 94.0% and 87.7%, respectively and the three-year OS and PFS of patients with follow-up over three years were 94.0% and 78.9%, respectively. The two-year OS and PFS were respectively 97.4% and 88.9%, for patients with stages I-II and 86.8% and 88.9% for patients with stages III-IV. HPV-negative and HPV-positive patients had respectively two-year OS (100.0% vs. 91.5%) and PFS (88.9% vs. 87.2%). There was no significantly statistical difference in survival between patients with and without adjuvant radiotherapy after TORS (82.6% vs. 90.5%, HR=0.52, 95%CI: 0.12-2.23, P=0.400). Conclusions: TORS is more suitable for the treatment of patients with early (Ⅰ-Ⅱ) or HPV-positive oropharyngeal squamous cell carcinoma, and the recovery after TORS treatment is good.

Outcomes of relapsed/refractory diffuse large B-cell lymphoma and influence of chimaeric antigen receptor T trial eligibility criteria in second line-A population-based study of 736 patients.

SummarySeveral recently published trials investigate novel therapies for relapsed/refractory diffuse large B‐cell lymphoma (R/R DLBCL). To estimate the benefit of these therapies in the real‐world setting, comprehensive data on patients treated in clinical routine are needed. We report outcomes for 736 R/R DLBCL patients identified among all curatively treated DLBCL patients in Sweden in the period 2007–2014. Survival and associations with disease characteristics, second‐line treatment and fulfilment of chimaeric antigen receptor (CAR) T‐cell trial criteria were assessed. Median overall survival (OS) was 6.6 months (≤70 years 9.6 months, >70 years 4.9 months). Early relapse (≤12 months) was strongly associated with selection of less intensive treatment and poor survival. Among patients of at most 70 years of age, 63% started intensive second‐line treatment and 34% received autologous stem cell transplantation (ASCT). Two‐year OS among transplanted patients was 56% (early relapse ≤12 months 40%, late relapse >12 months 66%). A minority of patients 76 years (n = 178/506, 35%) fitted CAR T trial criteria. Median progression‐free survival (PFS) for patients with early relapse fitting trial criteria was 4.8 months. In conclusion, most R/R DLBCL manifest early and are often ineligible for or cannot complete intensive regimens resulting in dismal survival. Real‐world patients eligible for CAR T trials also did poorly, providing a benchmark for efficacy of novel therapies.

Clinical Outcomes of MRI-Guided Adaptive Brachytherapy for Each Fraction in Locally Advanced Cervical Cancer: A Single Institution Experience

PurposeThis study aims to evaluate clinical outcomes of MRI-guided adaptive brachytherapy (MR-IGABT) for each brachytherapy fraction in patients with locally advanced cervical cancer (LACC).Methods and MaterialsA retrospective analysis was performed on 97 consecutive patients with LACC treated with 44.0–50.4 Gy external beam radiotherapy (EBRT) ± concurrent platinum-containing chemotherapy followed by 4 × 7 Gy MR-IGABT between September 2014 and April 2019. Intracavitary (IC)/interstitial (IS)/hybrid intracavitary and interstitial (IC/IS) brachytherapy was used in MR-IGABT. Brachytherapy planning and dose reporting followed the GEC-ESTRO recommendations. Clinical outcomes including overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), local control (LC), and treatment-related toxicity evaluated by the RTOG criteria were analyzed. Kaplan–Meier and univariable and multivariable Cox regression analyses were used to analyze the prognostic factor.ResultsMedian follow-up was 21.1 months. Median dose to 90% (D90) of the high-risk clinical target volume (HR-CTV) was 91.7 Gy (range 76.7~107.2 Gy). Two-year OS, CSS, PFS, and LC were 83.5%, 84.1%, 71.1%, and 94.8%, respectively. Four patients (4.1%) suffered from grade 3 late gastrointestinal radiation toxicity, and no other grade 3 or greater radiation toxicity occurred. Initial HR-CTV was an independent factor of OS (p = 0.001, HR = 1.018/cm3), PFS (p = 0.012, HR = 1.012/cm3), and LC (p = 0.011, HR = 1.028/cm3). The HR-CTV D90 (p = 0.044, HR = 0.923/Gy) was an independent factor of PFS. Age was an independent factor of LC (p = 0.010, HR = 1.111/year).ConclusionFor patients with LACC, MR-IGABT was effective and safe. It showed favorable LC, OS, and minimal toxicity. Moreover, initial HR-CTV, HR-CTV D90, and age were significant prognostic factors.

Circulating tumour cells to drive the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer

BackgroundGuidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of nonmetastatic muscle-invasive bladder cancer (MIBC). NAC is, however, underutilized in practice because of its associated limited overall survival (OS) benefit and significant treatment-related toxicity. We hypothesized that the absence of circulating tumour cells (CTCs) identifies MIBC patients with such a favourable prognosis that NAC may be withheld.Patients and methodsThe CirGuidance study was an open-label, multicentre trial that included patients with clinical stage T2-T4aN0-N1M0 MIBC, scheduled for radical cystectomy. CTC-negative patients (no CTCs detectable using the CELLSEARCH system) underwent radical surgery without NAC; CTC-positive patients (≥1 detectable CTCs) were advised to receive NAC, followed by radical surgery. The primary endpoint was the 2-year OS in the CTC-negative group with a prespecified criterion for trial success of ≥75% (95% confidence interval (CI) ±5%).ResultsA total of 273 patients were enrolled. Median age was 69 years; median follow-up was 36 months. The primary endpoint of 2-year OS in the CTC-negative group was 69.5% (N = 203; 95% CI 62.6%-75.5%). Two-year OS was 58.2% in the CTC-positive group (N = 70; 95% CI 45.5%-68.9%). CTC-positive patients had a higher rate of cancer-related mortality [hazard ratio (HR) 1.61, 95% CI 1.05-2.45, P = 0.03] and disease relapse (HR 1.87, 95% CI 1.28-2.73, P = 0.001) than CTC-negative patients. Explorative analyses suggested that CTC-positive patients who had received NAC (n = 22) survived longer than CTC-positive patients who had not (n = 48).ConclusionThe absence of CTCs in MIBC patients was associated with improved cancer-related mortality and a lower risk of disease relapse after cystectomy; however, their absence alone does not justify to withhold NAC. Exploratory analyses suggested that CTC-positive MIBC patients might derive more benefit from NAC.Trial registrationNetherlands Trial Register NL3954; https://www.trialregister.nl/trial/3954

Final results of a multicenter prospective phase II clinical trial of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade upper tract urothelial carcinoma.

440 Background: Neoadjuvant chemotherapy (NAC) has proven survival benefits for invasive urothelial carcinoma of the bladder, yet its role in upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a phase II multicenter trial of NAC with gemcitabine and cisplatin (GC) in patients with high-risk UTUC prior to extirpative surgery to evaluate major outcomes of response, survival, and tolerability. Methods: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of GC prior to surgical resection and lymph node dissection. The primary study endpoint was pathologic response rate (defined as &lt; pT2N0). Patients with progressive disease prior or unable to proceed to surgery were considered treatment failures. Secondary endpoints included time to disease progression (PFS), overall survival (OS), and safety and tolerability. Results: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response, meeting the primary endpoint of the study. A complete response was noted in 11 patients (19%), defined as pT0N0. Forty patients (70%) tolerated all four cycles of GC, and all patients proceeded to surgery. The 90-day ≥ grade 3 surgical complication rate was 7.0%. With a median follow up of 42.3 months among survivors, six patients succumbed to disease. Two and five-year PFS were 76% (95% CI 66, 89) and 61% (95% CI 47, 78). Two and five-year OS were 93% (95% CI 86, 100) and 79% (95% CI 67, 94). Patients demonstrating pathologic response had improved PFS and OS compared to those who did not (two-year PFS 91% vs 52%, log-rank p &lt; 0.001, two-year OS 100% vs 80%, log-rank p &lt; 0.001). Conclusions: NAC for high-risk UTUC demonstrates outcomes of favorable pathologic response, is well tolerated requiring minimal delay to surgery without significant perioperative complication risk, and thus should be considered a new standard of care option for patients with high-risk UTUC. Better survival outcomes in patients with favorable pathologic features after NAC indicate a potential clinical benefit to this approach. Clinical trial information: NCT01261728.

Survival after stereotactic radiosurgery of recurrent glioblastomas in patients with radical resection of primary tumor

glioblastoma (GBM) is an aggressive tumor with high rate of recurrence and estimated survival of 15-18 months after diagnosis. Factors associated with longer survival of GBM patients are age &lt; 50 years, high performance status and radical resection of the primary tumor. The optimal treatment for recurrence/ progression of GBM has not yet been determined and remains a challenging issue. Stereotactic radiosurgery (SRS) is considered today as a therapeutic option for effective treatment of recurrent malignant gliomas. The aim of this retrospective study was to analyze the survival after SRS of the recurrent GBM in a cohort of 59 patients, which had a radical resection of the primary tumor. The cohort consisted of 59 patients (28 / 47.5% of women and 31 / 52.5% of men); the average age was 51 years (interval 24 - 81). SRS was performed by means of linear accelerator "Trilogy" (USA) (6 MeV) from 2014 to 2020 at the State Institution "Romodanov Neurosurgery Institute". In all cases, the diagnosis of grade 4 GBM according to the WHO classification was confirmed after neurosurgical procedures of the primary tumor. All 59 patients underwent the maximal safe removal of the primary tumor: in the vast majority of cases (54 / 91.5%) - in the perifocal area; in 5 / 8.5% of cases - subtotal. In all 59 cases, patients received adjuvant radiation therapy (total dose 60 Gy in 30 fractions); in 33 / 55.9% of cases radiotherapy was combined with concomitant alkylating chemotherapy (CHT) (Temozolomide 75 mg / m2). In 31 / 52.5% of patients, maintenance alkylating CHT was continued (Temozolomide 150-200 mg / m2). In most cases (51 / 86.4%) recurrent GBM (RGBM) was diagnosed by clinical and radiological signs; in 8 / 13.6% of patients - after repeated surgery. Overall survival (OS), recurrence/progression free survival (RFS) and survival after recurrence (SAR) represented the end-points of the study. The effect of the following quantitative and categorical factors (covariates) on the survival was studied: sex, age, performance status, combination of adjuvant RT with alkylating chemotherapy, neurosurgical procedures of RGBM, type of GBM recurrence, total dose of irradiation (BED11) and SRS dose (BED11), number of SRS fractions, volume of target in SRS, duration of RFS. The effect of RFS was studied in three independent groups: group I – RFS &lt; 10 months; group II – RFS from 10 to 20 months; group III – RFS &gt; 20 months. The survival was analyzed by Kaplan-Meier (KM) method. Log-rank test was used for analysis of the survival according to the binary predictors. The effect of several categorical factors on survival was analyzed by Pearson Chi-square test. The effect of the quantitative covariates on survival was studied by regression analysis in Cox proportional risk model. Hazard ratio was calculated with 95 % confidential intervals (CI). The analysis revealed the following. Median OS following SRS RGBM was 26.3 months (95 % CІ 17 – 45.5), median RFS was 12.9 months (95 % CІ 8.4 – 25.6), median SAR – 9.8 months (95 % CІ 6.7 – 24.4). Two-year OS in our study was 56 %. 6-month survival after SRS –77 %; one-year survival after SRS – 39 %, and two-year survival after SRS – 28 %. The significant impact of performance status (p = 0.00159), duration of recurrence-free period (p = 0.02711) and surgical resection of RGBM (р = 0.009391) on the OS was demonstrated. The best OS was shown for the patients with Karnofsky score 90, recurrence occurring after more than 20 months and previous surgical resection of RGBM. The effects of other factors on OS were not demonstrated. Such factors as age, sex, performance status, adjuvant RT with сoncomitant alkylating CHT, surgical resection of RGBM, type of recurrence, number of SRS fractions, BED11 in SRS RGBM, BED11 for overall courses of irradiation, SRS target volume demonstrated no effect on SAR. SRS is non-invasive method for RGBM treatment that allows for improving the survival without significant radiation toxicity. Primary biological properties of the tumor seem to be of priority in determining the survival of RGBM patients. Although irradiation of GBM is advantageous regarding the improvement of the survival, one could also speculate that re-irradiation of the recurrent malignant glioma triggers some changes in its biology neutralizing the potential effect of the survival factors that had predictive value before re-irradiation.

Abstract P2-08-21: Overall survival associated with BRCA or ATM mutation status in patients with metastatic triple-negative breast cancer: Findings from the PRIOR-2 study

Abstract Background: Many clinical guidelines recommend patients with metastatic triple-negative breast cancer (mTNBC) undergo mutational testing of genes involved in DNA damage repair response as a predictive marker of clinical benefit from recently approved targeted therapies. However, there is little known regarding the prognostic impact of BRCA1/2 or ATM mutation on the survival experience of mTNBC patients receiving contemporary routine care in the United States.Methods: In this retrospective cohort study, we identified patients aged ≥18 years with metastatic BC (≥2 BC diagnoses within 90 days and ≥1 diagnosis or ≥2 note mentions of metastatic disease) in Optum’s de-identified electronic health record (EHR) database (1/1/2013 - 6/30/2020; N=22.5M total lives). Index date was first diagnosis/note mention of metastatic disease; TN status was based on ER, PR and HER2 negative test results in the 1-year baseline through 90 days post-index. Patients were stratified by BRCA/ATM status and followed for up to 24 months from the start of treatment to assess overall survival (OS) using death information captured from the EHR and linked social security and obituary data. Differences in 2-year OS by BRCA/ATM status were evaluated using a Cox Proportional-Hazards model, adjusting for baseline demographics, comorbidities, clinical and prognostic factors.Results: Among 3,017 patients with mTNBC, 1,234 (40.9%) had evidence of being tested for BRCA/ATM: 394 (31.9%) had a BRCA/ATM mutation (POS), 487 (39.5%) were negative for a BRCA/ATM mutation (NEG), and 353 (28.6%) had unknown BRCA/ATM mutation status. Patients with a BRCA/ATM mutation had a mean age (SD) of 49.5 (12.9) years, while NEG patients had a mean age (SD) of 51.2 (12.1) years. Among POS patients, 22.1% had 2+ metastases at diagnosis, 11.4% had bone metastases, 5.6% had brain metastasis, 5.1% had liver metastasis, and 9.1% had lung metastasis. Among NEG patients, 18.5% had 2+ metastases at diagnosis, 9.4% had bone metastases, 5.7% had brain metastasis, 5.3% had liver metastasis, and 8.4% had lung metastasis. Of the 762 patients (338 POS; 424 NEG) with known stage at diagnosis, 40% of both POS and NEG patients presented at stage 3/4. Two-year OS rates were not significantly different by BRCA/ATM mutation status from start of treatment in the metastatic setting (POS: 79.3% vs NEG: 74.6%, p=0.30); unadjusted hazard ratio (HR) 1.28 (95% CI =0.81-2.03); adjusted HR 1.22 (95% CI 0.75-2.00). Conclusion: In this observational study of US patients with mTNBC, there was no statistically significant difference in 2-year OS rates between patients with or without BRCA/ATM mutation. OS at 2-years may have been overestimated in our sample due to the potential for unobserved death. Additional research is needed to evaluate the association between BRCA/ATM status and overall survival in different patient populations. Citation Format: Gboyega Adeboyeje, Maria Sierra, Amy Bartels, Michelle Field, Sumit Jhamb, Ami Buikema, Seongjung Joo. Overall survival associated with BRCA or ATM mutation status in patients with metastatic triple-negative breast cancer: Findings from the PRIOR-2 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-21.

Robot-Assisted Partial Cystectomy versus Open Partial Cystectomy for Patients with Urachal Cancer

Introduction: Localized urachal cancer (UrC) can be treated with an open partial cystectomy (OPC) with en bloc resection of the urachal remnant and umbilicus. Robot-assisted partial cystectomy (RAPC) is an alternative approach, of which its safety and efficacy for UrC remains to be determined. In the present study, we analyze these outcomes after RAPC, compared with OPC. Methods: We retrospectively evaluated 55 cN0M0 UrC patients who underwent RAPC (n = 8) or OPC (n = 47) between 1994 and 2020. Overall survival (OS) and recurrence-free survival (RFS) were assessed using Kaplan-Meier methods. Positive surgical margins (PSM), port-site recurrences (PSR) versus wound recurrences were compared. Complications were recorded using the Clavien-Dindo classification. Results: Median follow-up was 40 months (IQR 21–95). Two-year OS and RFS for RAPC were 73% (95% confidence intervals (CI); 56–89 months) and 60% (95% CI; 42–78 months), respectively, versus 90% (95% CI; 85–95 months) and 66% (95% CI; 59–73 months) for OPC. PSM rate was 13% in both groups. PSR occurred in 2/8 (25%) patients after RAPC. No wound recurrences occurred after OPC. Postoperative complications occurred in 2/8 (25%) patients after RAPC, versus 5/47 (11%) after OPC (p = 0.27). Conclusion: Both RAPC and OPC seem feasible surgical modalities to treat localized UrC with comparable survival. The PSR rate of 25% after RAPC should prompt us to be cautious to recommend RAPC as no such recurrences were seen using OPC.

Prognostic Value of Metabolic, Volumetric and Textural Parameters of Baseline [18F]FDG PET/CT in Early Triple-Negative Breast Cancer.

Simple SummaryThe aim of this study was to evaluate PET/CT parameters to determine different prognostic groups in TNBC, in order to select patients with a high risk of relapse, for whom therapeutic escalation can be considered. We have demonstrated that the MTV, TLG and entropy of the primary breast lesion could be of interest to predict the prognostic outcome of TNBC patients. (1) Background: triple-negative breast cancer (TNBC) remains a clinical and therapeutic challenge primarily affecting young women with poor prognosis. TNBC is currently treated as a single entity but presents a very diverse profile in terms of prognosis and response to treatment. Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose ([18F]FDG) is gaining importance for the staging of breast cancers. TNBCs often show high [18F]FDG uptake and some studies have suggested a prognostic value for metabolic and volumetric parameters, but no study to our knowledge has examined textural features in TNBC. The objective of this study was to evaluate the association between metabolic, volumetric and textural parameters measured at the initial [18F]FDG PET/CT and disease-free survival (DFS) and overall survival (OS) in patients with nonmetastatic TBNC. (2) Methods: all consecutive nonmetastatic TNBC patients who underwent a [18F]FDG PET/CT examination upon diagnosis between 2012 and 2018 were retrospectively included. The metabolic and volumetric parameters (SUVmax, SUVmean, SUVpeak, MTV, and TLG) and the textural features (entropy, homogeneity, SRE, LRE, LGZE, and HGZE) of the primary tumor were collected. (3) Results: 111 patients were enrolled (median follow-up: 53.6 months). In the univariate analysis, high TLG, MTV and entropy values of the primary tumor were associated with lower DFS (p = 0.008, p = 0.006 and p = 0.025, respectively) and lower OS (p = 0.002, p = 0.001 and p = 0.046, respectively). The discriminating thresholds for two-year DFS were calculated as 7.5 for MTV, 55.8 for TLG and 2.6 for entropy. The discriminating thresholds for two-year OS were calculated as 9.3 for MTV, 57.4 for TLG and 2.67 for entropy. In the multivariate analysis, lymph node involvement in PET/CT was associated with lower DFS (p = 0.036), and the high MTV of the primary tumor was correlated with lower OS (p = 0.014). (4) Conclusions: textural features associated with metabolic and volumetric parameters of baseline [18F]FDG PET/CT have a prognostic value for identifying high-relapse-risk groups in early TNBC patients.

Outcomes of Radiation Therapy Plus Immunotherapy in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System

PurposeWith the integration of immunotherapy (IO) agents in the management of metastatic renal cell carcinoma (mRCC), there has been interest in the combined use with radiation therapy (RT). However, real world data are limited. The purpose of this study was to evaluate outcomes in patients with mRCC receiving both RT and IO compared with IO alone. Methods and MaterialsData were collected from Canadian Kidney Cancer Information System from January 2011 to September 2019 across 14 academic centers. Patients with mRCC who received IO as first- or second-line therapy were included. RT was categorized as radical dose or palliative dose. Kaplan-Meier estimates were reported for overall survival (OS) and time to treatment failure. Cox proportional hazard models were used adjusted for age and International Metastatic RCC Database Consortium risk categories. ResultsIn total, 505 patients were included in the study: 179 received RT + IO and 326 received IO alone. Two-year OS for the RT + IO group was 55.0% compared with 66.4% in the IO alone cohort (adjusted hazard ratio [aHR], 1.38; P = .07). At 2 years, 12.2% of the RT + IO patients remained on therapy versus 30.9% in the IO alone group (aHR, 1.30; P = .02). For patients receiving first-line therapy, 2-year OS in the RT + IO group was 56.4% versus 78.4% in the IO alone arm, though this difference was not statistically significant (aHR, 1.23; P = .56). For patients receiving radical dose and palliative dose, 2-year OS was 57.0% and 53.9%, respectively (aHR, 0.86; P = .63). ConclusionsIn this descriptive analysis, more than one-third of patients with mRCC received RT and demonstrated inferior outcomes compared with IO alone. Potential explanations include greater presence of adverse metastatic sites in those receiving RT. Prospective clinical trials evaluating potential benefits of RT in an IO era remain an important need.

Volume of Disease as a Predictor for Clinical Outcomes in Patients With Melanoma Brain Metastases Treated With Stereotactic Radiosurgery and Immune Checkpoint Therapy.

Purpose/ObjectivesClinical trials of anti-Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein (CTLA-4) therapies have demonstrated a clinical benefit with low rates of neurologic adverse events in patients with melanoma brain metastases (MBMs). While the combined effect of these immunotherapies (ITs) and stereotactic radiosurgery (SRS) has yielded impressive results with regard to local control (LC) and overall survival (OS), it has also been associated with increased rates of radiation necrosis (RN) compared to historical series of SRS alone. We retrospectively reviewed patients treated with IT in combination with SRS to report on predictors of clinical outcomes.Materials and MethodsPatients were included if they had MBMs treated with SRS within 1 year of receiving anti-PD-1 and/or CTLA-4 therapy. Clinical outcomes including OS, LC, intracranial death (ID), and RN were correlated with type and timing of IT with SRS, radiation dose, total volume, and size and number of lesions treated.ResultsTwenty-nine patients with 171 MBMs were treated between May 2012 and May 2018. Patients had a median of 5 lesions treated (median volume of 6.5 cm3) over a median of 2 courses of SRS. The median dose was 21 Gy. Most patients were treated with ipilimumab (n = 13) or nivolumab-ipilimumab (n = 10). Most patients underwent SRS concurrently or within 3 months of receiving immunotherapy (n = 21). Two-year OS and LC were 54.4% and 85.5%, respectively. In addition, 14% of patients developed RN; however, only 4.7% of the total treated lesions developed RN. The median time to development of RN was 9.5 months. Patients with an aggregate tumor volume >6.5 cm3 were found to be at increased risk of ID (p = 0.05) and RN (p = 0.03). There was no difference in OS, ID, or RN with regard to type of IT, timing of SRS and IT, number of SRS courses, SRS dose, or number of cumulative lesions treated.ConclusionsIn our series, patients treated with SRS and IT for MBMs had excellent rates of OS and LC; however, patients with an aggregate tumor volume >6.5 cm3 were found to be at increased risk of ID and RN. Given the efficacy of combined anti-PD-1/CTLA-4 therapy for MBM management, further study of optimal selection criteria for the addition of SRS is warranted.

Upfront Chemotherapy Followed by Stereotactic Body Radiation Therapy with or without Surgery in Older Patients with Localized Pancreatic Cancer: A Single Institution Experience and Review of the Literature.

Objective: To report on clinical outcomes and toxicity in older (age ≥ 70 years) patients with localized pancreatic cancer treated with upfront chemotherapy followed by stereotactic body radiation therapy (SBRT) with or without surgery. Methods: Endpoints included overall survival (OS), local progression-free survival (LPFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and toxicity. Results: A total of 57 older patients were included in the study. Median OS was 19.6 months, with six-month, one-year, and two-year OS rates of 83.4, 66.5, and 42.4%. On MVA, resection status (HR: 0.30, 95% CI 0.12–0.91, p = 0.031) was associated with OS. Patients with surgically resected tumors had improved median OS (29.1 vs. 7.0 months, p < 0.001). On MVA, resection status (HR: 0.40, 95% CI 0.17–0.93, p = 0.034) was also associated with PFS. Patients with surgically resected tumors had improved median PFS (12.9 vs. 1.6 months, p < 0.001). There were 3/57 cases (5.3%) of late grade 3 radiation toxicity and 2/38 cases (5.3%) of Clavien-Dindo grade 3b toxicity in those who underwent resection. Conclusion: Multimodality therapy involving SBRT is safe and feasible in older patients with localized pancreatic cancer. Surgical resection was associated with improved clinical outcomes. As such, older patients who complete chemotherapy should not be excluded from aggressive local therapy when possible.

A Systematic Review and Meta-Analysis of Malignant Rhabdoid and Small Cell Undifferentiated Liver Tumors: A Rational for a Uniform Classification

Simple SummaryMalignant rhabdoid tumors of the liver are very rare pediatric liver tumors with a devastating prognosis. It is currently unclear which histological subtypes of pediatric liver tumors belong to this entity and how these tumors should be treated. In this systematic review with meta-analysis, we analyzed all reports on pediatric patients with malignant rhabdoid liver tumors, but also with so-called small cell undifferentiated liver tumors. This is another rare liver tumor subtype that has recently been regarded to belong to the entity of rhabdoid tumors by some authors. The main result of this study is that these two tumor subtypes show large overlap on several levels and even mixtures of both histological patterns have been documented. Our meta-analysis provides an evidence base for the recommendation to classify these two tumor subtypes as one entity. We showed that treatment of these tumors with hepatoblastoma directed chemotherapy is ineffective and that a therapy with chemotherapy regimens initially applied for soft tissue sarcoma is associated with a significantly better survival. This study represents the highest level of evidence available for these rare liver tumors.Background: Rhabdoid liver tumors in children are rare and have a devastating prognosis. Reliable diagnosis and targeted treatment approaches are urgently needed. Immunohistochemical and genetic studies suggest that tumors formerly classified as small cell undifferentiated hepatoblastoma (SCUD) belong to the entity of malignant rhabdoid tumors of the liver (MRTL), in contrast to hepatoblastomas with focal small cell histology (F-SCHB). This may have relevant implications on therapeutic approaches. However, studies with larger cohorts investigating the clinical relevance of the histological and genetic similarities for patients are lacking. Purpose: To analyze possible similarities and differences in patient characteristics, tumor biology, response to treatment, and clinical course of patients with MRTL, SCUD and F-SCHB. Applied therapeutic regimens and prognostic factors are investigated. Methods: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed for this PRISMA-compliant systematic review. All studies of patients with MRTL, SCUD and F-SCHB that provided individual patient data were included. Demographic, histological, and clinical characteristics of the three subgroups were compared. Overall survival (OS) was estimated with the Kaplan–Meier method and prognostic factors investigated in a multivariable Cox regression model. Protocol registered: PROSPERO 2021 CRD42021258760. Results: Fifty-six studies with a total of 118 patients were included. The two subgroups MRTL and SCUD did not differ significantly in baseline patient characteristics. However, heterogenous diagnostic and therapeutic algorithms were applied. Large histological and clinical overlap between SCUD and MRTL could be shown. Two-year OS was 22% for MRTL and 13% for SCUD, while it was significantly better in F-SCHD (86%). Chemotherapeutic regimens for hepatoblastoma proved to be ineffective for both SCUD and MRTL, but successful in F-SCHB. Soft tissue sarcoma chemotherapy was associated with significantly better survival for MRTL and SCUD, but was rarely applied in SCUD. Patients who did not undergo surgical tumor resection had a significantly higher risk of death. Conclusions: While F-SCHB is a subtype of HB, SCUD should be classified and treated as a type of MRTL. Surgical tumor resection in combination with intensive, multi-agent chemotherapy is the only chance for cure of these tumors. Targeted therapies are highly needed to improve prognosis. Currently, aggressive regimens including soft tissue sarcoma chemotherapy, extensive resection, radiotherapy or even liver transplantation are the only option for affected children.

Effect of systemic inflammation biomarkers on overall survival after lung cancer radiotherapy: a single-center large-cohort study

Introduction Recent studies suggest that immune-related cells can be recruited for anti-tumor functions as well as tumor progression and the interplay between systemic inflammation and local immune response may play a major role in the development and progression of various cancers including lung cancer. Inflammatory markers, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) can be used as surrogate biomarkers of host immune status. In this work, associations between neutrophils, lymphocytes, platelets, NLR, PLR, SII and overall survival (OS) are investigated in two cohorts of non-small cell lung cancer (NSCLC) patients treated with fractionated radiotherapy (RT) and stereotactic body radiation therapy (SBRT) and a cohort of small cell lung cancer (SCLC) patients treated with fractionated RT. Material and Methods Data from 2513 lung cancer patients were retrospectively analyzed. Baseline NLR, PLR, and SII (NLR × platelet count) were calculated from full blood test prior to RT initiation. Cox proportional hazards regression analyses were used to evaluate the association between systemic inflammation markers and known clinical factors with OS. Results The two-year OS was 42%, 63%, and 62% in the NSCLC fractionated RT, SBRT, and SCLC cohort. NLR (per 1 unit: hazard ratio [HR]: 1.04, p < 0.05) and SII (per 100 × 109/L: HR: 1.01, p < 0.05) remained the strongest independent factors of OS in multivariable Cox analyses, correcting for clinical factors in early-stage and locally advanced NSCLC and SCLC patients treated with RT. Discussion This single-center large-cohort study suggests that baseline NLR and SII are independent prognostic biomarkers associated with OS in locally advanced and early-stage NSCLC patients treated with either curative-intent fractionated RT or SBRT and SCLC patients treated with curative-intent fractionated RT. External validation is warranted to evaluate the utility of these biomarkers for patients’ stratification and adapting new treatment approaches.

Adjuvant Hepatic Arterial Infusion Pump Chemotherapy after Resection of Colorectal Liver Metastases; Surgical Complications, Toxicity, and Survival in a Prospective Study in the Netherlands

Background: Hepatic arterial infusion pump (HAIP) chemotherapy remains a promising treatment for patients with colorectal liver metastases (CRLM). The aim of this study was to investigate surgical complications, toxicity, and survival outcomes of patients who received adjuvant HAIP chemotherapy for CRLM. Methods: A single arm phase II study was performed in four centers. Patients with resectable CRLM without extrahepatic disease were eligible. An infusion pump was implanted after complete local treatment of CRLM followed by a maximum of 6 cycles of HAIP chemotherapy with floxuridine. Outcomes were 90 days pump-related major complications (Clavien Dindo grade ≥III), intra-arterial chemotherapy-related severe toxicity (CTCAE grade ≥III), and overall survival (OS). Results: Twenty-nine patients were included. Four patients (11.8%) had pump-related major complications, all requiring pump replacement; one for pump dysfunction, two for pump dislocation, and one for pump pocket infection. All patients started with HAIP chemotherapy. The median number of cycles was 5 (IQR 4-6), and the median cumulative dosage was 72% (IQR 55-85%). Ten patients (34%) required intra-arterial steroid treatment for biliary toxicity. Seven patients (24%) developed severe toxicity; five patients required stent-placement (three for biliary sclerosis/hyperbilirubinemia, two for persistent increase in liver enzymes without hyperbilirubinemia), one patient developed hepatic artery thrombosis, one patient required endoscopic extraction of an intrahepatic gallstone. Two-year OS was 93% (95%CI: 85-100%). Conclusion: Adjuvant HAIP chemotherapy for CRLM may result in major complications and severe toxicity; 1 in 7 patients required pump replacement and 1 in 6 patients required stent-placement for biliary sclerosis. Two-year OS was 93%.Tabled 1Patient and surgical characteristicsMedian [IQR] / n (%)Age at resection (years)57 [50-64]Clinical Risk Score (Fong score)2 [1-3]Preoperative systemic CTx9 (30)Major hepatectomy6 (21)Synchronous resection with primary CRC3 (10)Open ablation (with or without resection)11 (45)Surgery time (min)247 [204-300]Blood loss (mL)455 [187-762]Postoperative hospital stay (days)8 (6-9) Open table in a new tab