Median Overall Survival For Pts Research Articles

Efficacy analysis of regorafenib combined with PD-1 inhibitors in elderly patients with metastatic colorectal cancer.

105 Background: Recently, an increasing number of patients (pts) with advanced colorectal cancer tend to receive regorafenib plus PD-1 inhibitors. However, there is a lack of information regarding real world effects of this therapeutic strategy, especially in elderly Chinese pts. We aimed to investigate the treatment patterns, clinical outcomes and prognostic factors of regorafenib plus PD-1 inhibitors therapy to Chinese elderly pts with advanced colorectal cancer. Methods: Retrospective analysis of a cohort of pts with advanced colorectal cancer received treatment of regorafenib combined with PD-1 inhibitors enrolled in our institution between January 2019 and January 2021. Among them, pts with 60 years or older were included in our final analysis. Overall survival (OS) and progression free survival (PFS) were estimated by Kaplan Meier curves, and other endpoints included objective response rate, prognostic factors. Results: At a median follow-up of 16.2 months, a total of 24 pts were enrolled in a real-world dataset from Henan Cancer Hospital. The median age was 68 years; 62.5% were female. The median OS and PFS were 15.03 months (95% CI 7.0-23.0) and 4.0 months (95% CI 1.8-6.2), respectively. 2/24 partial responses (PR) observed (ORR = 8.3%); Stable disease (SD) was obtained in 15/24. Disease control rate (PR plus SD) was therefore obtained in 17/24 (70.8%). When compared with PFS and OS in different initial daily doses group of regorafenib (such as ≤80, 120 or 160 mg), we concluded that there were no significantly difference between these groups. And similar results were found in final daily doses groups. However, it showed a trend toward better PFS in pts with ≥120 mg final daily doses group compared to <120 mg group (median PFS was 3.5 months in <120mg group versus 10.0 months in ≥120mg group). Median OS of pts for male gender demonstrated increasing trends compared with those female gender (20.2 months in males versus 13.2 months in females). Pts with previous treated with regorafenib had longer median OS than those without it (20.2 months versus 13.2 months). There were no obvious correlation for survival between pts only had liver metastasis and lung metastasis (P>0.05). No significant associations for survival could be seen in other tumor sites, K-RAS status, any kind of PD-1 inhibitors and whether previously treated with bevacizumab (P>0.05). Conclusions: This real-world dataset confirms that Chinese elderly pts with advanced colorectal cancer also can benefit from treatment of regorafenib combined with PD-1 inhibitors, similarly with this combination therapy strategies in all age pts. Furthermore, a longer survival time were obtained in pts with prior treated with regorafenib. The result also suggests that pts with ≥120mg final daily doses group had better PFS. However, further larger cohorts research should investigate whether the PFS advantage in high dose group could eventually lead to improved OS outcomes.

Treatment Patterns and Survival Outcomes of Patients with Acute Myeloid Leukemia Who Achieved Remission in the Connect ® Myeloid Disease Registry

Treatment Patterns and Survival Outcomes of Patients with Acute Myeloid Leukemia Who Achieved Remission in the Connect ® Myeloid Disease Registry

Outcome with Hypomethylating Agent and Venetoclax Combination in Patients with Chronic Myelomonocytic Leukemia

Outcome with Hypomethylating Agent and Venetoclax Combination in Patients with Chronic Myelomonocytic Leukemia

Azacytidine Treatment in Patients with Acute Myeloid Leukemia/High-Risk Myelodysplastic Syndrome: Day-Hospital Management Compared to Home Care Setting

Introduction Treatment with Hypometilating Agents (HMA) of unfit patients (pts) with Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic Syndromes (HR-MDS) is often difficult in the standard Day-Hospital (DH) setting, due to the number of hospital admissions required and the frail clinical conditions of pts. In the Viterbo province, accounting for 3612 Km 2 divided into 60 municipalities, is operative an Unit of Domiciliary Hematologic Care (UDHC) for clinical assistance to frail pts with hemopathies.Aims To evaluate the role of the UDHC compared to standard DH setting in the active frontline treatment with HMA +/- venetoclax (VTX) of pts with AML/HR-MDS.Methods All pts with newly diagnosed AML/HR-MDS unfit for intensive care and treated frontline with HMA from 1/2010 to 4/2021 were analysed.Results In this study period, 112 pts (62 AML/50 HR-MDS) received HMA (azacytidine in 105 cases and decitabine in 7 cases): six pts added VTX to HMA. As concern therapy management, 69 pts (61.6%) were treated in a standard DH setting and 43 (38.4%) were followed by UDHC: pts were allocated to DH or home care setting by responsible physician based on clinical conditions, comorbidities, caregiver availability and distance from hospital. The main features at baseline of HMA in the whole cohort and according to management are reported in the Table 1. Median interval from diagnosis to HMA initiation was 0.9 months (IQR 0.5 - 3.0). Median number of HMA cycles administered was 9 (IQR 4 - 16). The overall response rate (ORR), including complete response, partial response and hematologic improvement, was 43.7% (48/112 pts) in the whole cohort, without differences according to management [29/69 (42.0%) in DH vs 19/43 (44.1%) in home care, p=0.797]. Infections were also equally reported [46/69 pts (66.6%) in DH vs 31/43 (72.0%) in home care setting had at least 1 infection, p=0.362]. Median response duration of the whole cohort was 10.0 months (95%CI 5.7 - 14.2), without differences according to management [8.7 months (95%CI 7.0 - 10.3) in DH vs 13.0 months (95%CI 8.3 - 17.6) in home care, p=0.460]. Median Overall Survival (OS) of the whole cohort was 13.0 months (95%CI 9.7 - 16.2): median OS of pts treated in DH was 13.7 months (95%CI 9.9 - 17.4) compared to 13.0 months (95%CI 6.7 - 19.3) of pts managed by UDHC (p=0.753) (Figure 1).Conclusions Home care management of HMA for unfit AML/HR-MDS pts is feasible and effective, with results similar to those achievable in a standard DH setting: this approach is thus adequate to offer active therapies in a fraction of frail pts with AML/HR-MDS considered up to now ineligible. [Display omitted] DisclosuresLatagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria.

Azacitidine, Venetoclax and Pevonedistat As Frontline Therapy for Patients with Secondary Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy: Results from a Phase I/II Study

Azacitidine, Venetoclax and Pevonedistat As Frontline Therapy for Patients with Secondary Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy: Results from a Phase I/II Study

Definitive Radiation Therapy (dRT) for Hepatocellular Carcinoma (HCC) With Thrombus: Patient Selection to Maximize Therapeutic Ratio

<h3>Purpose/Objective(s)</h3> Tumor thrombus (TT) in HCC is a negative prognostic marker. dRT can provide durable tumor control with some risk of decompensation/death from RT liver injury. We sought to identify subsets of patients (pts) who stand to benefit most from RT. <h3>Materials/Methods</h3> The medical record of HCC pts with any thrombus receiving dRT (defined as prescribed dose of ≥50 Gy) between 2010 and 2019 was reviewed. TT was classified per Sarin (Gastroenterol 2019). We conducted univariate (UV)/multivariate (MV) Cox regressions for overall survival (OS), progression-free survival (PFS), and time-to-decompensation (TTD; liver decompensation with death as a competing risk). Variables with UV <i>P</i>-values < 0.20 were entered into the model which was then stepwise reduced with a stay criterion of <i>P</i> < 0.15. <h3>Results</h3> Select characteristics for the 61 identified pts are listed in the Table. With a median follow-up of 8.0 months (mo.), 37 pts had progressed (local - 9 (24%), regional - 26 (70%), and distant - 19 (51%)). Median PFS/OS were 5.7 mo. (IQR 2.8-14.2) and 8.8 mo. (IQR 4.3-21.0), respectively. Decompensation was observed in 36 pts (59%) with a median TTD of 6.8 mo. On UV OS analysis, ECOG performance status (PS) (2-3 vs. 0: HR 9.2, 95% CI 3.5-23.8, <i>P</i> < 0.0001; 1 vs. 0: HR 2.3, 95% CI 1.2-4.5, <i>P</i> = 0.02), albumin-bilirubin (ALBI) grade (G) 2-3 (HR 3.8, 95% CI 1.3-10.9 <i>P</i> = 0.01), and Child-Pugh score ≥B7 (HR 2.8, 95% CI 1.5-5.3, <i>P</i> = 0.001) were significant; gross tumor volume > 292cc (GTV_292; median) (HR 1.7, 95% CI 1.0-3.0, <i>P</i> = 0.06) trended towards significance. On MV OS analysis, only PS (2-3 vs. 0; HR 8.5, 95% CI 2.9-284.9, <i>P</i> < 0.0001; 1 vs. 0: HR 3.3, 95% CI 1.5-7.4, <i>P</i> = 0.004) and ALBI G2-3 (HR 3.7, 95% CI 1.2-11.2, <i>P</i> = 0.02) reached significance. Median OS for pts with TT, PS 0-1, and ALBI G1 was 19.6 mo. <h3>Conclusion</h3> In this retrospective analysis of HCC pts with thrombus, OS after dRT was significantly associated with PS and ALBI. While validation of these findings is needed, in pts with TT, those with PS 0-1 and ALBI G1 should be considered for dRT.

A Phase I/II Study of Selinexor (SEL) with Sorafenib in Patients (pts) with Relapsed and/or Refractory (R/R) FLT3 Mutated Acute Myeloid Leukemia (AML)

Background: Responses to FLT3-inhibitors are usually transient due to emergence of resistance through the acquisition of kinase domain point mutations and other non-mutational mechanisms. SEL is a potent first-in-class Selective Inhibitor of Nuclear Export/SINE™ that exerted marked cell killing of human and murine FLT3 -mutant AML cells, including those with ITD, D835Y, ITD+Y842C or ITD+F691L mutations by modulating the cdk inhibitor p27 and anti-apoptotic Mcl-1 (Zhang W et al, Blood 2015 126). The combination of SEL+sorafenib had synergistic pro-apoptotic effects in FLT3-mutated AML cells by suppressing phosphorylation levels of FLT3 and its downstream signaling mediators ERK/AKT, and by inducing myeloid differentiation in ITD and D835 mutated cell lines.Methods: We designed a phase I/II trial of SEL with sorafenib for FLT3-ITD and/or -D835 R/R AML pts. In phase I, the primary objectives were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and dose-limiting toxicity (DLT) of the combination. In phase II, primary objectives included the rate of complete remission (CR) + CR with incomplete count recovery (CRi) + partial response + >50% blast reduction within 3 months of therapy initiation. Secondary objectives were safety and overall survival (OS). SEL was given orally twice a week for 3-weeks on and 1-week off in 28-day cycles and sorafenib was given continuously at a dose of 400mg twice daily from cycle 1 day 1 of SEL. In phase I, SEL dose was de-escalated in “3+3” fashion starting at dose level 0 and going down if DLTs were exceeded (dose levels 0, -1, -2 = 80, 60, 40 mg, respectively). Once MTD was established, the phase II enrolled pts in 2 cohorts: prior FLT3-inhibitor failure (cohort 1) and FLT3-inhibitor naïve (cohort 2). PB or BM samples were collected at pre-dose (C1D1), 24 h (C1D2) and day 28 (C1D28) of cycle 1, and apoptosis induction was determined by measuring annexin V positivity with FACS.Results: Fourteen pts with a median age of 71 years (range, 24-81) were enrolled. All pts had baseline next generation sequencing for AML specific mutations (Figure 1A). The median number of prior therapies was 3 (range, 1-5) as follows: salvage (S) 1: n=1, S2: n=5, S3+: n=8. 11 (79%) pts had prior FLT3-inhibitors: 1 prior FLT3-inhibitor (n=9); 2 prior FLT3-inhibitors: n= (2). Three pts had prior SCT. Four pts were treated at dose level 0 (SEL 80mg) with DLTs in 2 (Grade (G) 3 sepsis, n=1; G3 mucositis, syncope, adrenal insufficiency, n=1). Three pts were subsequently treated at dose level -1 (SEL 60mg) with no DLTs and this was established as the MTD/RP2D. Seven pts were treated in expansion: 6 had prior FLT3-inhibitor therapy (cohort 1) and 1 had no prior FLT3-inhibitor (cohort 2).The median duration of treatment for all 14 pts was 28 days (range, 14-122) and therapy is ongoing in 1 pt. All pts are evaluable for response. CRp/CRi and >50% blast reduction as best responses were seen in 4/14 (29%) and 2/14 (14%) pts, respectively. All 6 responders had a prior FLT3 inhibitor yielding a response rate of 55% (6/11) pts with prior FLT3 inhibitor therapy. 3 pts with CRp/CRi (2 with FLT3-ITD and 1 with ITD+D835) achieved negative RT-PCR for FLT3. (Figure 1B). One pt in CRi was bridged to SCT and remains alive at 1 year. The most common G 3/4 adverse events irrespective of causality were bleeding (gastrointestinal, n=4; intracranial, n=1), febrile neutropenia (n=4), pneumonia (n=3) and syncope (n=2). The reasons for discontinuing study therapy were disease progression (n=9; 64%), toxicity (n=3; 21%) and SCT (n=1; 7%). The median OS for pts on study was 3.5 months (range, 0.9-15). Translational analysis showed that SEL+sorafenib induced apoptosis in 4 of 5 tested patients, especially in the BM samples (Figure 1C)Conclusions: The combination of SEL and sorafenib is safe with clinical activity and apoptosis induction in R/R FLT3+ AML. The benefit was especially encouraging in pts exposed to prior FLT3 inhibitors, with a response rate of 55% (6/11; including 2 CRi and 2 CRp). The RP2D is 60 mg twice weekly of SEL and the study is accruing (NCT01607892). [Display omitted] DisclosuresDaver:Kiromic: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy; Incyte Corporation: Honoraria, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Immunogen: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. DiNardo:Celgene: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Cortes:BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding.

Long-Term Outcomes in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Long-Term Outcomes in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Real World Data on Decitabine Treatment in 296 Patients with Acute Myeloid Leukemia: Outcome and Impact of TP53 Mutations

Real World Data on Decitabine Treatment in 296 Patients with Acute Myeloid Leukemia: Outcome and Impact of TP53 Mutations

Monitoring C-reactive protein facilitates early discontinuation of immune oncology without compromising outcomes in stage IV non-small cell lung cancer.

e21107 Background: C-Reactive Protein (CRP) is a non-specific inflammatory marker and reflects tissue destruction seen in metastatic cancer (ca). We have observed a tight correlation with CRP trends mirroring ca activity, hence it may prove to be a valuable marker to monitor response to Immuno-Oncology (IO) in non-small cell lung cancer (NSCLC) patients (pts). Once CRP levels stabilized, IO discontinuation was offered, and consenting pts were closely observed. This strategy resulted in shortened IO duration and impressive treatment-free progression-free survival (tf-PFS). We sought to examine the validity of this strategy using the rate of return to any form of ca therapy within 6 months after stopping IO. Methods: We analyzed all pts of a single provider since 2016 with stage IV NSCLC who had CRP checked while on IO, totaling 23 pts. We excluded pts who stopped IO for reasons besides stable CRP values (5 progressed on IO, 3 died while on IO, 1 had side effects, 1 stopped for a clinical trial, 1 opted to complete 2 years of IO, and 2 are still on IO). Of the remaining 10 patient cohort, all pts were males treated at the VA with ages between 56-75 years at diagnosis. 50% of the cohort had adenocarcinoma and 50% had squamous cell carcinoma. Results: Using the CRP trend to shorten the duration of IO resulted in durable drug-free holidays with none of the cohort returning to any form of ca therapy within 6 months and comparable rates of overall survival (OS) despite shorter IO duration. In KEYNOTE-042, the median OS for pts on the pembrolizumab arm was 16.7 months in the overall population and 20 months in the TPS ≥50% subgroup. Pts were treated for up to 35 months. In our cohort, median OS was 38 months, with all pts currently still alive, and median number of doses of IO was 9 cycles, or approximately 7 months. Our pts had ongoing progression free survival (PFS) after stopping treatment, which we report as tf-PFS. The median tf-PFS of our cohort was 23.5 months. Conclusions: In pts with stage IV NSCLC treated with IO, CRP appears promising as a marker to tailor IO therapy addressing tumor and clinical heterogeneity. Responding pts with stable CRP levels can be safely taken off IO. CRP should be monitored with stable values indicating continued PFS. tf-PFS rather than PFS may serve as a surrogate for cure and carries significant impact for pts financially, socially, and psychologically. [Table: see text]

Prognostic value of early imaging following CAR T-cell therapy in DLBCL.

e19559 Background: Chimeric antigen receptor T-cell (CART) therapies lead to durable disease control in patients (pts) with relapsed/refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL). We assessed the prognostic value of response on first staging scan, and whether pts with progression of disease (PD) convert to a response on second scan. Methods: We conducted a retrospective analysis of pts with R/R DLBCL treated with CART at our institute. Baseline characteristics were assessed at apheresis. We included staging scans (CT, PET-CT and MRI) that occurred up to 6 months (mos) after CART infusion. Responses were determined via the Lugano 2014 criteria. Overall survival (OS) was calculated from first scan to last follow-up. Kaplan Meier method and Cox model were used to correlate first scan result with OS. Results: Of the 118 pts who received CART, 111 pts had evaluable staging scans (7 passed prior to first scan). Of the 111 pts, median age was 61 years (range, 23-84), and median number of prior therapies was 3 (range, 1-7). 61 pts received tisagenlecleucel, and 50 pts received axicabtagene ciloleucel. 22% of pts had MYC rearrangement by FISH. The majority of pts were stage 3/4 (91%), with an IPI score ≥2 (82%). 32%, 66% and 2% of pts had a CT, PET-CT or MRI as their first scan respectively. After a median follow-up of 16.2 mos, median OS from first scan was not reached (NR) (95% CI, 17-NR). 37%, 5%, 32%, 25% of pts had PD, SD, PR, and CR on first scan respectively. Median time to first scan was 59 days (range, 13-115). Median OS for pts who had PD was 3 mos (95% CI 2-8), and the median OS for those who attained SD, PR or CR was NR (95% CI NR-NR). Accounting for statistically important factors on multivariate analysis, PD on first scan was an independent predictor of OS (p&lt;.001, HR 10.1 (95% CI 4.7-22)). We observed no evidence that pts with PD on first scan convert to a response on second scan without intervention. 26 of 41 pts who had PD did not start new treatment, 17 passed without follow-up scan, 1 is in follow-up, and 8 continued to show PD on subsequent scans. Conclusions: PD on first staging scan is a strong prognostic marker for survival for pts with R/R DLBCL who receive CART. There is no evidence to suggest conversion to a response will occur for patients who have PD. Performing staging scans at an earlier time-point has value, allowing for earlier treatment changes and goals of care conversations in this pt population.[Table: see text]

Contemporary outcomes for adults with AML requiring ICU admission.

7025 Background: Patients (pts) with AML frequently encounter life-threatening complications requiring transfer to an intensive care unit (ICU). Methods: Retrospective analysis of 145 adults with AML requiring ICU admission at our tertiary cancer center 2018-19. Use of life-sustaining therapies (LSTs) and overall survival (OS) were reported using descriptive statistics. Logistic regression was used to identify risk factors for in-hospital death. Results: Median age was 64 yrs (range 18-86). 47% of pts had an ECOG status of ≥ 2 with a median of at least 1 comorbidity (Table). 117 pts (81%) had active leukemia at admission. 68 pts (47%) had poor-risk cytogenetics (CG) and 32 (22%) had TP53-mutated disease. 61 (42%), 27 (19%) and 57 pts (39%) were receiving 1st, 2nd and ≥ 3rd line therapy. 33 (23%) and 70 pts (48%) were receiving intensive and lower-intensity chemotherapy, respectively, and 77 pts (53%) were concurrently on venetoclax. Most common indications for admission were sepsis (32%), respiratory failure (24%) and leukocytosis (12%); Table outlines additional ICU admission details. Median OS from the date of ICU admission was 2.0 months (mo) for the entire cohort and 6.9, 1.6 and 1.2 mo in pts with favorable-, intermediate- and poor-risk CG. Median OS of pts receiving frontline vs. ≥ 2nd line therapy was 4.2 vs. 1.4 mo (P&lt;0.001). Median OS in pts requiring 0-1 vs. 2-3 LSTs was 4.1 vs. 0.4 mo (P&lt;0.001). OS was not different by age, co-morbidity burden nor therapy intensity. In a multivariate analysis that included SOFA scores, only adverse CG (OR 0.35, P = 0.028), and need for intubation with mechanical ventilation (IMV; OR 0.19, P = 0.009) were associated with increased odds of in-hospital mortality. Conclusions: A substantial portion of pts with AML survive their ICU admission with sufficient functionality to return home and receive subsequent therapy. In contrast to general medical populations, age, co-morbidities, and SOFA scores were not independently predictive of in-hospital mortality. Disease CG risk and the need for IMV were the strongest predictors of ICU survival. This suggests that many pts with AML can benefit from ICU care.[Table: see text]

Survival benefit of nephrectomy prior to immunotherapy-based combinations in patients with metastatic renal cell carcinoma: An FDA pooled analysis.

4516 Background: Immunotherapy-based combination therapies (IO-X) are standard of care for metastatic RCC (mRCC) in the frontline setting. Limited data is available on the role of cytoreductive nephrectomy prior to IO-X in patients (pts) with mRCC (Bakouny, et al. GU ASCO 2020). We assessed the correlation between nephrectomy prior to IO-X and overall survival (OS) in pts with de novo mRCC. Methods: We pooled data from trials submitted for FDA review of a checkpoint inhibitor combination as first-line treatment for pts with mRCC. We only included trials with available data for stage at initial diagnosis (dx) to identify pts with stage IV disease at initial dx and to exclude those with nephrectomy in the non-metastatic setting. Kaplan-Meier method was used to estimate median OS in pts with de novo mRCC with and without nephrectomy prior to IO-X. Results: Five trials met inclusion criteria, all of which evaluated IO in combination with a kinase inhibitor. Data for stage at initial dx was available in 1708 pts who received IO-X. The majority of pts were male (72%) and White (80%). Among the 849 pts (50%) with stage IV RCC at initial dx, 523 pts (62%) had nephrectomy prior to IO-X. All pts had clear cell histology; Sarcomatoid differentiation was present in tumor pathology of 25% and 10% of pts with and without prior nephrectomy, respectively. Proportion of pts with favorable, intermediate and poor risk disease was 10%, 70% and 20%, respectively. OS appeared better in those with stage IV disease at dx who had prior nephrectomy compared to pts without nephrectomy (Hazard ratio (HR) = 0.53, 95% CI: 0.42, 0.68), even after adjusting for age and prognostic risk group (HR = 0.59, 95% CI: 0.46, 0.75) (see table). Conclusions: In this retrospective exploratory analysis, nephrectomy prior to IO-X in pts with new dx of stage IV RCC appeared to be associated with improved OS, even when controlling for age and prognostic risk group. The decision for nephrectomy is affected by factors such as medical comorbidities which could not be completely controlled. Results should be considered hypothesis generating.[Table: see text]

Computational features of tumor-infiltrating lymphocyte architecture of residual disease after chemotherapy on H&amp;E images as prognostic of overall and disease-free survival for triple-negative breast cancer.

584 Background: Approximately 30% of all breast cancers are characterized as triple-negative (TNBC). TNBC typically occurs in younger women and is associated with a poorer prognosis relative to other breast cancer subtypes. High levels of tumor-infiltrating lymphocytes (TILs) in residual disease after Neoadjuvant chemotherapy (NACT) have previously been shown to be associated with better prognosis in TNBC. In this work, we sought to evaluate the prognostic value of computationally derived measures of TIL spatial architecture in residual TNBC after NACT. Methods: H&amp;E-stained samples from 92 patients (pts) with TNBC (41 died, 45 had disease recurrence) and residual disease after NACT were retrospectively collected from 2 sites: Instituto Nacional de Enfermedades Neoplásicas (S1) and University Hospitals (S2). 45 pts (16 deaths, 23 recurrences) from S1 formed the training set and 47 pts (25 deaths, 22 recurrences) from S2 formed the independent validation cohort. Samples were digitized at 20x. Computerized algorithms automatically identified 2 types of nuclei (TILs and non-TILs) and built clusters for each nuclei type based on cell proximity. The spatial arrangement of these clusters was then quantified using network graph metrics. The top 5 features, determined by least absolute shrinkage and selection operator, were used to train a Cox regression model that assigned a risk of death and recurrence to each patient on the training set. The percentile 33 risk score was used as a threshold for stratifying pts on the validation set as either low or high risk. For comparison, we also employed a model based on TIL density alone. Survival analysis was used to evaluate the performance of both approaches on disease-free survival (DFS) and overall survival (OS). Results: Pts in S2 (n=47) identified as “high risk” by the model based on spatial architecture of residual TILs had a significantly shorter survival time. The median OS for pts at high risk was 25 months vs. 55 months for low-risk pts. The median DFS for pts at high risk was 32 months vs 51 months for low-risk pts. Univariable analysis showed this model was prognostic for both OS (Hazard Ratio (HR) = 2.57, 95% Confidence Interval (CI): 1.07-6.16, p=0.03) and DFS (HR=2.38, CI: 1.01-5.62, p=0.04). In contrast, the model based on TIL density was not prognostic for OS (HR=1.24, CI: 0.33-4.63, p=0.73) nor DFS (HR=1.19, CI: 0.32-4.34, p=0.78). Conclusions: A computerized image analysis model based on measurements of spatial arrangement of residual TILs and surrounding cells was found to be prognostic in TNBC pts who received NACT. This method appears to be more prognostic than TIL density alone. Additional multisite validation and multivariable analysis is needed to further establish the independent prognostic utility of TIL based image biomarkers in the post-NACT TNBC.

Clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) patients with underlying autoimmune disease (AID).

e16233 Background: Chronic inflammation from AID and the resultant immunosuppression from treatment increases the risk of various malignancies. Risk of PDAC is increased in patients (pts) with AID, however, there is paucity of cancer specific outcome data in these pts. We retrospectively reviewed the outcomes of pts with PDAC and AIDs to include Crohn’s disease (CD), ulcerative colitis (UC) and rheumatoid arthritis (RA). Methods: All pts aged 18 or older, diagnosed with PDAC in the setting of CD, UC and RA between January 2010 and December 2019 were included. Patients were identified using our institutional Clinical Research Data Warehouse (CRDW) and chart review. Clinical data was obtained by querying a cohort discovery tool (i2b2) from the CRDW with IRB approval. Pts with incomplete documentation were excluded. Descriptive statistics were used to report demographics. Overall survival (OS) was calculated from the time of diagnosis of PDAC to the date of death or last follow-up. Deaths from any cause were included in the survival analysis. OS and relapse free survival (RFS) were estimated using Kaplan-Meier methods. Results: We identified 51 pts who met inclusion criteria; 26 (51%) had RA, 15 (29.4%) had UC and 10 (19.6%) had CD. Median age at diagnosis of PDAC was 55.2 years, 49% were male (Table 1). Median duration from diagnosis of AID to PDAC for pts with CD, RA and UC was 173, 107 and 105 months, respectively. Metastatic disease at diagnosis was present in 19 (37.3%) of the 51 pts and 32 (62.7%) had localized disease (LD). Among the 17 pts with LD who underwent surgery, 6 (35.3%) experienced relapse with a median RFS of 14 months. The median OS of pts with LD who underwent surgery was 44 months compared to 8.25 months for those who did not. Among the 19 pts with metastatic disease at diagnosis, 0, 1, 2 &amp; 3 lines of chemotherapy was received by 4 (21.1%), 8 (78.9%), 3 (36.8%) and 2 (21.1%) of pts, respectively. Median OS of patients with metastatic disease at diagnosis was 8.9 months. Conclusions: The inflammatory milieu and immunosuppression associated with AID treatment may be responsible for the early onset of PDAC in these pts. Although our sample size is small, pts with AID and PDAC who complete all planned curative intent therapy appear to have excellent outcomes, emphasizing the importance of early diagnosis and perhaps routine screening in pts with AID. Receipt of chemotherapy and OS of pts with metastatic PDAC in the setting of AID does not appear to be significantly compromised despite their exclusion from several clinical trials. Demographics.[Table: see text]

CTONG1103: Final overall survival analysis of the randomized phase 2 trial of erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non–small cell lung cancer.

8502 Background: Median Overall survival (mOS) of stage IIIA resected NSCLC was 59.4 months (m) in CTONG 1104 adj gefitinib and 26.2m in SAKK neoadjuvant chemo trial. EMERGING-CTONG1103 showed neo-adjuvant/adjuvant erlotinib treatment significantly improved progression-free survival (PFS) vs standard doublet chemotherapy in patients (pts) with epidermal growth factor receptor ( EGFR) mutation-positive resectable stage IIIA (N2) non-small-cell lung cancer (NSCLC). Here, we present the final overall survival (OS) results from the study. Methods: This was a multicenter (17 centers in China) phase II randomized controlled trial of erlotinib（E）versus gemcitabine plus cisplatin (GC) as neoadjuvant/adjuvant therapy in pts with stage IIIA-N2 NSCLC with EGFR mutations in exon 19 or 21. From Dec 2011 to Dec. 2017, 386 pts sites were screened and 72 pts were randomly assigned to neoadjuvant/adjuvant E arm (N = 37) or GC arm(N = 35). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postoperative. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, downstaging rates of pathological lymph nodes, PFS, OS, safety, and tolerability. Data cut-off date was January, 29 2021. Results: With a median follow-up of 62.5 months, the median OS was 42.2months based on 47 (65.3%) events in ITT whole population. The mOS was 42.2m in E and 36.9m in GC (HR 0.83, 95%CI 0.47-1.47, p = 0.513). The 3-,5-year OS rate were 58.6%, 40.8% in E and 55.9%, 27.6% in GC respectively (p3-y = 0.819, p5-y = 0.252). All predefined subgroups including age, gender, EGFR mutation type had no significant difference in statistics between two arms. Subsequent treatments (ST) especially targeted therapy contributed most to OS (HR = 0.35,95% CI 0.18- 0.70). Median OS of pts receiving ST was 45.8m (n = 38), 34.6m in other treatment (n = 12), 24.6m in without ST (n = 15). For E mOS were 46.4 (n = 15; target therapy), 42.2m (n = 8; other) and 24.6m (n = 9; without, p = 0.021), for GC 42.6 (n = 23; target therapy), 30.1m (n = 4;other) and 24.6m(n = 6; without, p = 0.130). The RR was 53.3%, DCR 93.3%, mPFS 10.9m and mPPS 21.9m for patients with rechallenged EGFR TKI in E arm (n = 15). No novel unexpected SAE was observed during follow up. Conclusion: Erlotinib as neoadjuvant/adjuvant therapy for resected N2 NSCLC was feasibility and had a promising OS. The PFS survival advantage of E did not translate to OS difference in EMERGING trial (NCT01407822). Clinical trial information: NCT01407822.

Mucinous colorectal cancer: Disease characteristics, treatment outcomes and the impact of metastasectomy.

3586 Background: Mucinous colorectal cancer (CRC) differs from adenocarcinoma with regard to clinical and histological features and is reported to have inferior outcomes when compared to non-mucinous CRC. This study aims to evaluate the clinical features and outcomes of patients with mucinous CRC at our institution. Methods: Medical records of patients with CRC that were referred to medical oncology between September 1999 and September 2018 were retrospectively reviewed. Mucinous histology was defined as those containing &gt; 50% mucin identified on histology specimens. Statistical analysis was performed using Prism V9.0. Results: We identified 1,115 patients with CRC that were referred to medical oncology during this period. The tumours of 81 (7.3%) patients were classified as mucinous. Median age was 65 (28-94 years) and 45 (55.5%) were male. Forty-one patients (51%) had right sided tumours, 27 (33%) had left sided tumours and 13 (16%) had rectal tumours. Twenty-three (28.4%) had de novo metastatic disease. Eleven of 24 patients (46%) with stage II disease relapsed and 18 of 33 (55%) of those with stage III disease relapsed. Radiological surveillance identified 20/29 (69%) of relapsed disease, 5 (17%) were symptomatic and 4 (14%) had a rise in CEA. Median follow up for patients with stage II disease was 53 months and 3 year and 5-year disease free survival (DFS) was equal in both groups at 60.9%. For stage III disease 3- and 5-year DFS was 58.1% and 48.4% respectively with a median follow up of 43 months. In the metastatic setting, we observed no significant difference in overall survival (OS) between left and right sided tumours ( p = 0.550). Median OS for pts with stage IV mucinous CRC who received any treatment was 25 months. Metastasectomy was performed in 25/52 (48%) patients and was associated with a significant improvement in OS, 23 vs 51 months ( p &lt; 0.005, HR 0.4). Conclusions: Mucinous CRC has been associated with inferior responses to treatment and worse overall outcomes compared to non-mucinous histologies. Survival in advanced-stage disease in our cohort is higher than what has been reported in the literature. With an effective multi-disciplinary approach and the increasing use of metastasectomy as a treatment option, survival in the advanced disease setting may be comparable to non-mucinous CRC.

Familial pancreatic cancer (FPC) status as a clinical biomarker in patients receiving platinum-based systemic therapy: A case-control analysis.

430 Background: Familial pancreatic cancer (FPC) is broadly defined as kindreds with at least a pair of first-degree relatives with pancreatic ductal adenocarcinoma (PDA). The role of DNA damage response agents, including platinum has not been well studied in this patient population. Methods: In this retrospective analysis, treatment details and clinical outcomes were analyzed in pts with FPC with advanced, unresectable or recurrent disease enrolled in the Ontario Pancreatic Cancer Study database. The primary outcome, overall survival (OS) was calculated from the initial diagnosis of advanced disease until death. 179 non-FPC patients from the COMPASS trial [NCT02750657] served as a control cohort all of whom had full molecular profiling and family history documented. OS between pts that received platinum-based therapy, and those that did not was compared using multivariable Cox proportional hazards model adjusting for age, sex, diagnosis year and FPC status. Interaction between FPC status and platinum was evaluated. Results: A total of 205 FPC pts were identified, 71% of pts had full germline testing and 16 (8%) had germline pathogenic variants in BRCA1/2. 104 (51%) were female and 101 (49%) male. Median age was 63 years (20-93) and 58 (28%) received platinum-based chemotherapy. Within the control arm (n=179), 71 (40%) were female, and 108 (60%) male; the median age was 64 years (29-84) and 106 (59%) received platinum-based therapy. In univariable analysis, median OS in pts with FPC was 16.9 months compared to 9.6 months (HR 0.46 [95% CI 0.37-0.58]). FPC patients receiving platinum had a superior median OS of 19 months compared to 15.5 months without platinum. In a multivariable analysis, both FPC (HR 0.33 [95% CI 0.21-0.51]) and receipt of platinum HR 0.53 [95% CI 0.38-0.73]) were prognostic. No interaction was seen with FPC and receipt of platinum (p=0.15). Conclusions: FPC status is prognostic but not predictive of platinum response in this study. Further molecular profiling of this unique cohort of patients will provide insights into putative predisposing germline alterations, and novel treatment strategies.

Interrelation of 5q-Deletions and Mutations of TP53 in Patients with Myelodysplastic Syndromes and Complex Aberrations

Introduction: Cytogenetic changes occur in 50% of patients (pts) with Myelodysplastic Syndromes (MDS). Complex aberrations (cA, = 3 or more) are associated with a very poor outcome. In about 50% of the cases with cA aberrations of the TP53 locus are detectable. Those pts show an even worse outcome with a significantly shortened median overall survival (OS) compared to pts with wildtype TP53 (wtTP53). One of the most common cytogenetic aberrations in MDS is an interstitial deletion of the long arm of chromosome 5 (5q). As an isolated aberration, it is associated with a rather favorable prognosis. As part of a cA, 5q deletions however are assumed to even worsen the prognosis further. We wanted to find out in which prevalence 5q deletions and TP53 changes appear together and how those two factors in combination or not influence the OS of pts with MDS and cA. Methods: 218 pts with MDS or sAML and cA were identified and extensively characterized. 126 of them were diagnosed with MDS, 89 with sAML and 3 with CMML. Cytogenetic analysis by chromosome banding (CBA) and fluorescence in situ hybridization (FISH) of the TP53 locus on 17p as well as sequencing of TP53 either by Sanger or by Next Generation Sequencing was available for all pts. Multicolour FISH (mFISH) was available for 146 pts, SNP array analysis for 42 pts. The median number of cytogenetic aberrations was 8 (range 3-50). At the time of first diagnosis with cA the median age was 72 (range: 29-95). Median OS of the entire cohort was 10.7 months (95% CI: 8.0-16.4). Results: In 146 of 218 pts we found alterations of TP53: a single hit mutation in 32 pts, a single deletion in 22 pts, a combined mutation and deletion in 67 pts and more than 1 mutation in 25 pts. The OS of those 146 pts was 6.6 months compared to 22 months of the pts with wtTP53 (p-value &amp;lt;0.0001). In 161 of 218 pts we found deletions of 5q (del(5q)). The median OS of those pts was significantly shorter than those of pts without del(5q) (8.4 vs. 20 months, p-value 0.001). 130 of 218 pts both had a del(5q) and an alteration of TP53, 31 pts only had a del(5q) and wtTP53 and 16 pts showed different types of TP53 alterations without del(5q). The median OS of pts with TP53 multi hit status as defined by Bernard (Bernard et al., Nature Medicine 2020) was 6.6 months, 5.3 months in pts with single hit TP53 mutations and a del(5q) and 21.6 months in pts, with wtTP53 and del(5q) (p-value = 0.0025, figure 1). Conclusion: Mutations and/or deletions of TP53 show a strong association with del(5q). Both were frequent in our cohort of 218 pts with MDS and cA. There also was a large intersection of 130 pts with both del(5q) and TP53 alteration. The combination of both changes seems to further worsen the already poor prognosis of pts with MDS and cA. Our observation that those two factors appear together frequently supports the hypothesis that the presence of del(5q) may promote the acquisition of cA. This is in accordance with Hsu´s hypothesis that in small clones with a mono-allelic TP53 mutation a del(5q) may favor the loss of heterozygosity of TP53 which could in a next step lead to a higher complexity of cytogenetic aberrations (Hsu et al, 2019). It is remarkable that the presence of del(5q) in combination with a single hit status of TP53 confers the same bad prognosis compared to multi hit TP53 status (figure 1).We will continue analyzing pts with MDS and cA to examine the influence of different TP53 and 5q alterations on the prognosis, the disease progression and median OS of those pts with cA. Figure 1 Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

Response and Survival Outcomes with Hypomethylating Agents in Patients with Chronic Myelomonocytic Leukemia Based on Disease Phenotype and Risk Categories

Response and Survival Outcomes with Hypomethylating Agents in Patients with Chronic Myelomonocytic Leukemia Based on Disease Phenotype and Risk Categories