Median Overall Survival Months Research Articles

Abstract 2502: Identification of poor responders to trastuzumab-deruxtecan with a multi-modal HER2-status predictor

Abstract Trastuzumab deruxtecan (TDXD) is approved for HER2 low or positive metastatic breast cancer. HER2-status is assessed through HER IHC and ERBB2 FISH assays. HER2-status has been shown to be correlated to RNA expression. This study aimed to assess if the addition of DNA to an RNA-based model can improve HER2-status prediction performance. Furthermore, to investigate the relationship between model score and outcomes for TDXD patients according to their overall survival (OS). Training and test sets of breast cancer samples were collected for HER2 status prediction (n = 1275, n = 397 respectively). HER2 status was reported positive: 11%, 12%, low: 61%, 60%, negative: 28%, 29% for each set respectively. HER2 testing and NGS were performed on samples with the same collection date. A TDXD discovery cohort of 284 patients included patients who received TDXD after RNA/DNA collection and had at least a 30-day follow-up. Metastatic disease was reported for 98% of the TDXD cohort. Receptor status was HR+/HER2- 39%, HR-/HER2- 17%, HR+/HER2+ 16%, HR-/HER2+ 9%, unknown 19%, and HER2-status was negative 11%, low 42%, and positive 27%, unknown 20%. OS was measured from medication start date. We trained a 12-gene linear model based on RNA expression and DNA copy number to predict HER2-positivity. The genes were selected by stepwise-selection on RNA and DNA features when predicting HER2-positivity using a random forest model. A baseline model consisting only of ERBB2 RNA expression was compared. Setting a HER2-positivity score threshold and allowing for an indeterminate group of 15% of the validation cohort, the RNA-DNA model achieved 91% PPA and 91% PPV in validation, whereas the RNA-only model achieved 83% PPA and 85% PPA. This indicates that the addition of DNA data improved the RNA-only HER2 predictor. The Concordance index of the RNA-DNA model score and OS for TDXD was 0.64. Characterizing this relationship, we partitioned the TDXD cohort to three equal sized sub-cohorts (33 1/3%) ordered by model score: low, intermediate, and high. Median OS in months for groups was: low 13.6, intermediate 18.5, and high 20.4. High-group patients had significantly better OS on TDXD compared to the low-group (HR = 0.39, log-rank p-value < 0.002). For patients with reported status, HER2-positivity rate in each group respectively was 6%, 16%, 85% (n=78), and HR-positivity in each group was 70%, 68%, 67% (n=156). Together, these findings indicate that HER2 status prediction improved by adding DNA to an RNA base predictor, and the predicted score was positively correlated with OS for TDXD. Citation Format: Kaveri Nadhamuni, Talal Ahmed, Mark Carty, Ben Terdich, Whitney L. Hensing, Timothy Taxter, Calvin Chao, Raphael Pelossof. Identification of poor responders to trastuzumab-deruxtecan with a multi-modal HER2-status predictor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2502.

3H-3000, AN FGFR2B-SPECIFIC MONOCLONAL ANTIBODY, SHOWS SUPERIOR TUMOR KILLING IN VIVO

Abstract Background and significance Fibroblast growth factor receptor 2b (FGFR2b), a splice isoform of FGFR2, is found to overexpress across multiple cancers types and promotes dysregulated tyrosine kinase activation, resulting in tumor cell proliferation and unchecked malignancy. Cohort studies reveal FGFR2b overexpression and/or amplification in Gastric cancer (~30.2%), squamous non-small cell lung cancer (~20.8%), and endometrial carcinoma (~40%). About 80–85% patients who have advanced HER2-negative gastro-esophageal cancer undergoes approximately 12-14 months of median overall survival (mOS). Thus, there is an urgent need for novel and effective molecular targeted agents. With the recent advancement of mechanistic studies, however, FGFR2b is becoming the optimal target of multiple modalities such as mAb, bispecifics, or antibody-drug conjugate. Bemarituzumab, a FGFR2b blocking antibody, developed by Five Prime clinically demonstrates the safety of FGFR2b target and exhibits preliminary efficacy in advanced GE/GEJ adenocarcinoma patients with overexpression of FGFR2 in at least 5% or 10% of tumor cells. 3H Pharmaceuticals developed a FGFR2b-specific mAb, 3H-3000, of high-affinity, differentiated epitope and enhanced ADCC effect for FGFR2b-overexpressing gastric cancer or other FGFR2b-associated cancer types. In the meantime, we will also explore the versatility of this mAb in other format and in the combination with small molecules that will bring about a wider therapeutic spectrum. Method and Result 3H-3000 is a humanized IgG1kappa antibody with a single digit nM affinity for FGFR2b and no binding to other FGFR2 isoforms. 3H-3000 shows potent proliferation-inhibitive effects on FGFR2b-overexpressing human tumor cells. In gastric cancer cell line SNU16, 3H-3000 can fully inhibit FGF7-induced phosphorylation of FGFR2b and SNU16 proliferation in vitro. On top of signaling blocking, we strongly believe efficacy of antibody-dependent cell cytotoxicity (ADCC) is another viable mechanism for growth factor-targeting therapy. Therefore, 3H-3000 was further engineered with a 20-fold ADCC enhancement which is validated through a CD16-F158 variant-based reporter system. In FGFR2b-overexpressing human gastric cancer SNU16 or OCUM-2M xenograft model, 3H-3000 was shown to inhibit tumor growth and even induce regression, which is rather unexpected given the relative low expression of FGFR2b on SNU16 and none of the competitors exhibit similar phenomenon. With potent efficacy of tumor inhibition and killing, and excellent biophysical characteristics and developability of 3H-3000, we expect to push the molecule to clinical development in the middle of 2024. Conclusion 3H-3000 is a potent FGFR2b blocker with well-defined ADCC efficacy enhancement. It demonstrates strong blocking activity of FGFR2 signaling, strikingly enhanced ADCC activity in vitro and potent efficacy of tumor inhibition in vivo. These data strongly support its clinical development in FGFR2b-overexpressing cancers. In parallel, 3H Pharmaceuticals are also developing FGFR2- selectively tyrosine kinase inhibitors targeting FGFR2 mutations or fusion. We propose a combination of small molecule FGFR2 inhibitors and mAb of FGFR2b specificity will significantly broaden the therapeutic spectrum of heterogenous tumors where mechanism is centered around FGFR2b alteration including mutation, fusion, and overexpression.

Inverse association of post-transplant malignancy and graft failure on survival outcome following double lung transplantation.

10629 Background: Graft failure (GF) and post-transplant malignancy (PTM) are common causes of death in lung transplantation. Immunosuppression to prevent graft failure is known to lead to de novo malignancies after solid organ transplantation. Here, we assess the relationship between graft failure and de novo malignancies after double lung transplantation (DLT). Methods: Data extracted from the Organ Procurement Transplantation Network (OPTN) registry were analyzed. DLT cases for non-cancerous diseases were selected. We evaluated the overall survival (OS) of recipients with or without PTM (PTM+ or PTM-), and that of recipients with or without GF (GF+ or GF-) after DLT. The association between GF and PTM was investigated. Results: Among 23,935 DLT recipients, there were 5,629 cases (23.5%) of PTM+ and 18,306 cases (76.5%) of PTM -, and 2,316 cases (9.7%) of GF+ and 21,619 cases (90.3%) of GF- following DLT. Among GF+ cases, the prevalence of acute, hyperacute, and chronic rejection after DLT was 1,962 cases (84.7%). The OS in recipients with GF+ was worse than that in recipients with GF- (p < 0.001). However, inversely, the OS in recipients with PTM+ was better than that of recipients with PTM- (p < 0.001). When patients were categorized into four categories by each factor (GF-, GF+, PTM+, PTM-), the GF rate was lower in recipients with PTM+ than in those with PTM- [GF+/PTM+ (n = 368, 1.5%) versus GF+/PTM- (n = 1,948, 8.1%)] (p < 0.001), and the PTM+ rate was higher in recipients with GF- than in those with GF+ [GF-/PTM+ (n = 5,261, 22.0%) versus GF+/PTM+ (n = 368, 1.5%)] (p < 0.001). And the GF-/PTM+ group showed the best prognosis with 97.3 months of median OS, and the GF+/PTM- group showed the worst prognosis with 36.8 months of median OS (p < 0.001). Conclusions: Recipients who developed PTM following DLT had longer OS compared with those who did not. And the GF rate was significantly lower in recipients with PTM compared to those without PTM. Further research is needed to investigate the underlying mechanism of the inverse association between PTM and GF in DLT recipients.

Update on the outcome of patients with metastatic prostate cancer in Kentucky: A Kentucky Cancer Registry (KCR) study.

e17121 Background: Overall survival (OS) of metastatic Prostate Cancer (mPC) in USA has improved by 3.6% during 2011–2016 compared to 2001–2005 (CDC, Oct 2020). Improvements in OS for mPC might reflect changes in clinical management, with approval of several new treatments. We aim to analyze if there is an improvement in OS of mPC in Kentucky between 2004-2011(T1) and 2012-2019(T2) and also analyze the impact of socioeconomic status as defined by Area Deprivation Index (ADI) on survival of mPC. Methods: All Kentucky male patients diagnosed between 2004 and 2019 who were > 20 years old at diagnosis with first primary of metastatic prostate adenocarcinoma were extracted from the Kentucky Cancer Registry (KCR) data. Basic demographics and survival outcomes were compared between two time periods - T1 vs T2 and by Appalachian status. Kaplan Meir (KM) and Multivariate Cox Regression (MCR) were used to examine OS. ADI is divided into three groups – bottom tertile (low deprivation-ADI 1-3, Gr 1), middle tertile (ADI 4-6, Gr 2), and top tertile (high deprivation-ADI 7-10, Gr 3). Results: A total of 2619 patients with mPC were included in this retrospective analysis, of which 69.3% were Non-Appalachian (Non-AP) and 30.7% were Appalachian (AP). Caucasians predominated in both time periods (89.2% vs 90%). T2 had a higher proportion of patients aged 50-74 years (72.5% vs 64.2%), and private insurance (31.4% vs 27.1%) compared to T1. T1 had more patients who were > 75 years (31.6% vs 24.8%), smokers (51.2% vs 47.4%), had medicare (59.6% vs 56.8%) and no insurance (4.2% vs 1.5%) compared to T2. KM showed improved OS in T2 (p < 0.0001). Non-AP had better OS compared to AP and improved more between T1 & T2. Median OS in months(95% CI) in T1 vs T2 for Non-AP was - 30(27-38) vs 58(53-69), p < 0.0001 & for AP was -34 (27-39) vs 44 (37-51), p = 0.0163. MCR showed that younger age, private insurance, being a nonsmoker, and receiving treatment, contributed to better OS. Gr 3 had higher proportion of African Americans (10.7% vs 6.5%), less private insurance (23.9% vs 39.7%) and more patients receiving no treatment (10.9% vs 7.5%) compared to Gr 1. AP Kentucky had more patients in Gr 3 (60.5% vs 39.5%) compared to Non-AP. KM showed OS had improved for all ADI groups in T2 vs T1. Within ADI groups, Gr 3 had significantly lower OS compared to Gr 1 & Gr 2 (p = 0.04) in T2. In T1, OS was not different within ADI groups. In MCR, race and ADI did not impact OS. Conclusions: OS has improved in mPC patients in Kentucky during 2012-2019, likely due to new treatments being available. There is improvement in OS in Appalachian Kentucky but numerically lower than Non-Appalachian, and worse OS in Gr 3 during 2012-2019 which could be partially due to differences in access to new treatments (or quality of care). Interestingly, race did not impact survival.

Safety, efficacy, and biomarker analysis of response to engineered tumor-infiltrating lymphocytes secreting anti-PD-1 antibody in recurrent glioblastoma: An open-label, two-arms, phase 1 study.

2042 Background: Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) is effective against solid tumors with convincing evidence. But T-cells infused were exhausted when they encountered PD-1-mediated immunosuppression in the microenvironment. Here, we generated a modified autologous TILs secreting antibody targeting PD-1 (PD1-TIL), and conducted a first-in-human, two arms, phase 1 study (NCT03347097) in recurrent glioblastoma who had a poor prognosis with estimated 6-9 months of median overall survival (OS). Methods: Patients were included to be treated with PD1-TIL or TIL cell products intravenously every one month following surgery. The primary endpoint was safety and feasibility. The secondary endpoints were disease control rate (DCR), OS, immunologic responses and biomarker analysis. The clinical response to cell therapy was assessed by MRI according to iRANO criteria. Here, patients with clinical benefit (CR, PR, and SD) were defined as responder. Results: A total of 21 consecutive patients (median age 45 years, range 20–64) received infusions of cell products (7 patients for PD1-TIL with 1 excluded, 14 patients for TIL with 2 excluded). 52% (11/21) and 29% (6/21) of 21 patients had methylated MGMT promoter and IDH1/2 mutant respectively. No significant differences in baseline characteristics between groups were found. Both of PD1-TIL and TIL infusions were well tolerated with no unexpected high-grade adverse events. Of 7 evaluable patients in PD1-TIL group, 1 had PR for more than 26 months, 2 had SD lasting for 7.7 months and 24 months, and 4 had PD after infusion. The DCR, 1-year and 2-years survival rates in PD1-TIL group were 43% (3/7), 86% (6/7) and 29% (2/7) respectively. In TIL group, 3 patients had SD and the others had PD. The DCR, 1-year and 2-years survival rates in TIL group were half of that in PD1-TIL group. Survival analysis showed that patients treated by PD1-TIL had extended OS than those received TIL (16.1 vs. 11.2 months, P = 0.047). Among 21 patients, clinical responders had significantly improved OS (30.9 vs. 10.7 months, P = 0.001) than non-responders. We also found a high capacity for engraftment and persistence of infused TILs in peripheral blood which could be detectable at 6 months after treatment. Existence of neoantigen-reactive T cell clonotypes in cell products may be important for responding because missing of missense mutations predicted to generate a neoantigen after cell therapy was a remarkable signature in responders. Responsive tumors were also associated with tumor microenvironment profiles. Conclusions: This first-in-human study establish the preliminary feasibility, safety and encouraging efficacy of PD1-antibody-secreting TILs, and may constitute a new treatment strategy by T-cell genetic engineering in glioblastoma. Clinical trial information: NCT03347097 .

Malnutrition risk at diagnosis and influence on survival in patients with solid tumors at a large academic cancer center.

6591 Background: Malnutrition is common in cancer patients and negatively impacts quality of life, tolerance to anti-cancer therapies and is associated with poor prognosis. It is, however, unclear if patient-reported malnutrition risk at initial diagnosis is related to overall survival (OS) in solid tumor oncology outpatients in the United States. Methods: A cohort of 3,562 patients who completed the malnutrition screening tool (MST), a validated assessment of malnutrition risk, at initial diagnosis of any stage solid tumor and had available survival data were analyzed. The primary objective was to evaluate the relationship of high malnutrition risk (≥2 of 5 = high risk for malnutrition, H-MST) to OS and was assessed using Kaplan Meier techniques and Cox proportional hazards models. Unadjusted analyses were performed, and adjusted multivariable analyses evaluated the impact of H-MST on OS controlling for key clinical baseline confounders. Results: The median age was 63 years (IQR: 54-71), with 62% females and 81% White. Most common cancer sites were breast (28%), gastrointestinal (GI, 21%), and thoracic (13%) and 80% were non-metastatic. Median follow up was 48.3 months. H-MST was associated with lower OS in the unadjusted model, median OS in months was 32.5 [H-MST] vs not reached in low MST [L-MST] (HR 3.3, 95% CI 2.9-3.7, p = < 0.001). Multivariable analysis confirmed that H-MST remained independently associated with OS when controlling for age, sex, cancer site, stage, BMI, and symptom scores. Landmark OS rates at 50 months were 60% [H-MST] vs. 69% [L-MST] (HR 1.51 95% CI 1.3-1.7, p = < 0.001). Adjusted subgroup analyses by cancer site showed the independent impact of H-MST was relatively similar across groups (Table). Conclusions: High malnutrition risk at initial diagnosis was independently associated with shorter survival across a large representative cohort of solid tumor oncology outpatients. The screening occurred before any anti-cancer therapy and it is noteworthy most had non-metastatic disease. These data highlight the need for systematic screening to identify patients at malnutrition risk who need additional assessment early during cancer. Further research on how to optimize allocation of limited nutrition resources for those with high malnutrition risk is needed. [Table: see text]

Epidemiology, treatment patterns, and clinical outcomes in de novo oligometastatic hormone-sensitive prostate cancer.

92 Background: Oligometastatic hormone-sensitive prostate cancer (omHSPC) represents an advanced prostate cancer subset where metastasis-directed therapy (MDT) and prostate radiation therapy (RT) may improve clinical response and outcomes; however, there is a lack of published data on the epidemiology, clinical outcomes, and current treatment patterns. As such, we conducted a study to better characterize de novo omHSPC in the United States Veterans Affairs Health Care System (VA). Methods: This observational retrospective cohort study utilized chart abstracted data from the VA electronic medical record, as well as data from the VA Corporate Data Warehouse, a central repository of VA patient medical records. We randomly selected 400 men diagnosed with de novo mHSPC from 1/2015-12/2020. omHSPC was defined as up to 5 bone, lymph node, and/or visceral (excluding liver) metastases in total, identified by conventional imaging (bone scan, CT, and/or MRI). We estimated prevalence, described treatment patterns and used Kaplan-Meier methods to estimate overall survival (OS) and time to castration resistance from date of mHSPC diagnosis. The log rank test was used to compare differences in outcomes between omHSPC and non-omHSPC groups. Results: Of the 400 men with de novo mHSPC, 76 (19%) had omHSPC by conventional imaging. Men with omHSPC and non-omHSPC were similar in age, race, Gleason grade group, comorbidities, and metastatic site (bone and lymph node being most common). Men with non-omHSPC had a higher median PSA at mHSPC diagnosis (147.0) than omHSPC (38.3). The percentage of men on first-line (1L) novel hormonal therapy (NHT) use (most commonly abiraterone or enzalutamide) was similar between groups in the 1L setting (22.4% (omHSPC) vs 20.4% (non-omHSPC)), but the percentage of men on a 1L chemotherapy regimen was lower in omHSPC (5.3%) vs. non-omHSPC (13.6%). Overall, there was a higher percentage of men treated with MDT or prostate RT in omHSPC (13.2%) vs non-omHSPC cases (2.5%). Median OS in months (mos) was higher in men with omHSPC (55.3 mos, 95% CI 35.9-79.0) vs. non-omHSPC (25.9 mos, 95% CI 20.5-31.7, p=0.002). Median time to castration resistance was also longer in omHSPC (not reached [NR], 95% CI 42.2-NR) vs. non-omHSPC (29.3 mos, 95% CI 23.7-36.1, p=0.0014). Conclusions: Our study provides real-world insight into the prevalence, treatment patterns and clinical outcomes for omHSPC using a nationally representative VA sample. Approximately 1 in 5 men with de novo mHSPC were oligometastatic, and OS in men with omHSPC was more than double that of non-omHSPC. Although more men with omHSPC compared to non-omHSPC received potential curative therapy, the percentage was still relatively low. Future studies are warranted as several clinical trials are investigating the potential for prolonged responses with aggressive, multimodal therapy inclusive of systemic and local therapies.

Impact of KRAS mutation variants on clinicopathological features and outcomes in patients with metastatic pancreatic adenocarcinoma.

749 Background: Most pancreatic ductal adenocarcinoma (PDAC) exhibit KRAS mutations. A subset of PDACs harbor KRAS wild-type (WT) and appear to carry better prognosis. Given the recent development of KRAS G12C inhibitors, it is imperative to better understand KRAS variants in contemporary cohorts. Herein, we characterized the prevalence of the different KRAS variants and its impact on clinicopathological features and outcomes. Methods: A retrospective review of patients with metastatic PDAC and a known KRAS mutation status who underwent next-generation sequencing (NGS) from liver biopsy was performed. Descriptive statistics analyzed the differences in clinicodemographic features by presence and type or absence of KRAS variants. Kaplan-Meier method was used to assess overall survival (OS). Cox regression was used to study the relationship between KRAS variants and OS when confounding factors were adjusted. Results: 50 pts with PDAC diagnosed at a single community-based institution between 2011-2018 were evaluated. Median age at diagnosis was 68 years (24-80 range), 68% were male, and 76% presented with metastases. Most (86%) tumors harbored KRAS mutations. The most frequent variants were G12V (44%), G12D (37%), G12R (9%), Q61R (5%), G12C (2%), Q61H (2%). Sex (p=0.03) and tumor differentiation (p=0.04) varied according to mutation status and KRAS variant subtype. However, no significant difference was observed in age, race, smoking status, location of primary, and performance status (PS) in KRAS variants. Overall, median OS in months was 8.9 (95% CI 6.7-14.3) for KRAS mutated patients and 11.2 (95% CI 2.1-33.5) for patients with WT. Among patients with KRAS mutations, median OS in months by variant was as following: G12V 9.6 (95%CI 6.6-17.2), G12D 8.4 (95%CI 3.9-15.4), G12R 8.2 (95%CI 1-20.8), and Q61R 11.8 (95%CI 1.3-22.3). However, these differences did not reach statistical significance (p=0.72). In multivariable analyses, female sex (HR 0.16, 95% CI 0.03-0.81, p=0.03) and no receipt of chemotherapy (38.5 95% CI 2.1-698.50, p=0.01) were significant predictors of death. KRAS mutation variant type was not an independent predictor of death. Conclusions: No significant difference was observed in metastatic PDAC with KRAS mutations compared to WT. However, numerical difference in OS were observed among the various KRAS mutation type. Hence, larger studies are needed to better define the effect of KRAS type on outcomes.

2,109 randomized oncology trials map continuous, meager improvements in progression-free and overall survival over 50 years

ObjectivesTo assess the patterns and time trends in overall survival and progression-free survival treatment effects across randomized controlled trials (RCTs) in oncology. Study Design and SettingA PubMed search for oncology network meta-analyses (NMAs) was carried (to September 30, 2021). Relevant hazard ratios were extracted for systemic treatments from RCTs in the NMAs. After removing duplicate results, relationships between treatment effects, year of publication, trial design, and other features were explored. ResultsFrom 241 oncology NMAs, 2,109 unique eligible RCTs provided analyzable data. On average, there was a 12%–14% reduction in hazard for overall survival and 27%–30% reduction for progression-free survival, with substantial heterogeneity across different malignancies. Correlation between overall survival and progression-free survival treatment effects was modest (r = 0.60, 95% confidence interval, 0.56–0.64). Over time, there was a suggestive trend of increased progression-free survival treatment effect, although overall survival treatment effects remained steady. Only one in five trials met criteria for clinically meaningful improvements in overall survival. Among 300 randomly selected trials, mean absolute improvement was 1.6 months for median progression-free survival and 1.4 months for median overall survival. ConclusionBroad patterns across the past 50 years of oncology research suggest continuous progress has been made, but few results meet clinically meaningful thresholds for overall survival improvement.

Nimotuzumab combined with gemcitabine versus gemcitabine in K-RAS wild-type locally advanced or metastatic pancreatic cancer: A prospective, randomized-controlled, double-blinded, multicenter, and phase III clinical trial.

LBA4011 Background: Pancreatic cancer is one of the most lethal malignancies diagnosed at an advanced stage, and current treatment regimens are ineffective, with only 6-8 months of median overall survival (mOS). The present study aims to assess the clinical efficacy and safety of nimotuzumab (anti-EGFR humanized monoclonal antibody) combined with gemcitabine in K-Ras wild-type patients with locally advanced or metastatic pancreatic cancer. Methods: Patients with locally advanced or metastatic pancreatic cancer were randomized to receive nimotuzumab (400 mg, every one week) followed by gemcitabine (1000 mg/m2 on days 1, 8, and 15, every four weeks), or placebo plus gemcitabine until progression or unacceptable toxicity. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Use restricted mean survival time (RMST)-Log function to analyze the survival benefits when the proportional hazards assumption is untrue. Results: A total of 92 Chinese patients were randomly assigned to the nimotuzumab- gemcitabine (n = 46) or placebo-gemcitabine group (n = 46). In the full analysis set (FAS, n = 82), the mOS was significantly longer in the nimotuzumab-gemcitabine group (10.9 vs. 8.5 months, p = 0.025 by RMST-Log test, hazard ratio [HR], 0.50, 95% Confidence Interval [CI], 0.06 to 0.94). The one-year survival rate was 43.6% in the nimotuzumab-gemicitabine group vs. 26.8% in the placebo-gemicitabine group, and 13.9% vs. 2.7% at three years. Subgroup analyses showed more survival benefit in patients without treatment of biliary obstruction (11.9 vs. 8.5 months, HR = 0.54, 95%CI 0.33-0.88, p = 0.037) and no surgical history (15.8 vs. 6.0 months, HR = 0.40, 95%CI 0.19-0.84). The median progression-free survival (mPFS) was 4.2 months in the nimotuzumab-gemicitabine group, as compared with 3.6 months in the placebo-gemicitabine group (HR = 0.56; 95% CI, 0.12 to 0.99; p = 0.013 ); Patients without treatment of biliary obstruction had significantly longer PFS (5.5 vs. 3.4 months; p = 0.008 ). No statistical difference in the ORR between the two groups ( p > 0.05). Nimotuzumab was safe and the incidence of adverse events in the nimotuzumab-gemicitabine group is similar to placbo-gemicitabine group. The most common grade 3 TRAEs in Nim-Gem group were neutropenia (11.1%), leukopenia (8.9%) and thrombocytopenia (6.7%). No grade 4 TRAEs. Conclusions: Nimotuzumab combined with gemcitabine increases OS and PFS in patients with K-Ras wild-type locally advanced or metastatic pancreatic cancer, particularly for those without treatment of biliary obstruction. The safety profile of nimotuzumab is similar to placebo. Clinical trial information: 02395016.

Outcomes of TP53‐mutated AML with evolving frontline therapies: Impact of allogeneic stem cell transplantation on survival

Outcomes of <scp><i>TP53</i></scp>‐mutated <scp>AML</scp> with evolving frontline therapies: Impact of allogeneic stem cell transplantation on survival

Impact of the Cancer and Aging Research Group score and treatment intensity on survival and toxicity outcomes in older adults with advanced noncolorectal gastrointestinal cancers.

Little is known regarding the predictive value of the Cancer and Aging Research Group (CARG) score, a validated chemotherapy toxicity prediction tool for older adults with cancer, for survival outcomes. This was a prospective observational study of patients ≥65 years old receiving first-line chemotherapy for advanced noncolorectal gastrointestinal cancer for which combination chemotherapy is the standard of care. Overall survival (OS), time to treatment failure (TTF), which was defined as the time from the start of first-line chemotherapy to the discontinuation of first-line chemotherapy for any reason, and toxicity were compared in 4 groups of patients: 1) non-high-risk (nHR) CARG score (<10) and standard-intensity therapy (ST), 2) nHR score and reduced-intensity therapy (RT), 3) high-risk (HR) CARG score (≥10) and ST, and 4) HR score and RT. Fifty patients (median age, 71 years) were enrolled. The median OS in months was 19.7 in nHR/ST (n = 19) group, 12.7 in nHR/RT (n = 9) group, 4.5 in HR/ST (n = 12) group, and 3.9 in HR/RT (n = 10) group (log-rank test, P = .005). The median TTF in months was 9.1 in nHR/ST group, 2.5 in nHR/RT group, 2.3 in HR/ST group, and 3.0 in HR/RT group (log-rank test, P = .04). The CARG-score category was prognostic of OS (HR, 3.04; 95% confidence interval [CI], 1.59-5.83, P = .001) and TTF (HR, 2.60; 95% CI, 1.31-5.20, P = .007). The incidence of grade 3-5 toxicity was 68% in nHR/ST group, 33% in nHR/RT group, 92% in HR/ST group, and 70% in HR/RT group (Fisher exact test, P = .048). Risk-adapted chemotherapy based on the CARG-score may improve treatment outcomes.

Bevacizumab in metastatic colorectal cancer in a real-life setting - toxicity profile, survival outcomes, and impact of tumor sidedness.

IntroductionTargeting angiogenesis in metastatic colorectal cancer (mCRC) using bevacizumab is a standard of care. The addition of this targeted biological agent to first-line infusional fluoropyrimidine-based chemotherapy was associated with superior overall survival (OS) in several randomized and controlled studies for CRC patients in the metastatic setting. However, access to this therapy in countries with limited resources is challenging. In Morocco, bevacizumab was introduced for this indication after considerable efforts of the Ministry of Health and Lalla Salma Foundation to support cancer patients with a limited income. In this report, the real-world efficacy and safety of the combination of bevacizumab with chemotherapy in mCRC are reported based on a retrospective cohort in Eastern Morocco.Material and methodsThe archives of the medical records of 98 mCRC patients treated with first-line bevacizumab at the Hassan II Regional Cancer Center (Oujda, Morocco) were sampled from 1st January 2014 to 31st December 2019 and analyzed using descriptive statistics, Kaplan-Meier estimation, and a multivariable Cox regression model for a time-to-event study.ResultsThe toxicity profile was dominated by grade I–II proteinuria (10%), bleeding events (10%), thromboembolic events (9%), grade I–III hypertension (3%), and other rare events such as delayed healing of the stoma, scar dehiscence, intestinal perforation, and heart failure deterioration. In terms of survival, median OS and progression-free survival in the whole cohort were 22 and 13 months respectively. Patients who benefited from a metastasectomy after bevacizumab treatment had 31 months of median OS as compared to 14 months in the matched cohort with non-resectable liver metastasis. Notably, we demonstrated that tumor sidedness is a predictive factor of OS [hazard ratio (HR) = 2.452; 95% CI: 1.434–4.191, p = 0.001]. Moreover, the median OS for patients who received between 10 and 20 or more than 20 bevacizumab administrations was 24 and 33 months respectively as compared to those who received less than 10 cures (17 months) (log rank p < 0.0001). These markedly improved outcomes were also confirmed in multivariate Cox regression. A highly significant association of bevacizumab use and OS was found after adjusting for covariates (HR = 0.518, 95% CI: 0.374–0.717; p < 0.0001).ConclusionsThe current study confirmed the important place of this therapeutic strategy in mCRC. Additional studies with prospective enrollment are awaited to validate these findings.

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the Management of Advanced Ovarian Cancer. A Literature Review

The rationale behind the use of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery is the association between pharmacological activity of chemotherapy delivered to the peritoneal cavity with the enhanced cytotoxic effect of hyperthermia. Data on the efficacy of HIPEC in the primary debulking surgery (PDS) setting are still controversial and limited by the small sample size of most of the studies, the inclusion of different treatment settings and chemotherapy regimens. Among the ongoing prospective trials, only the OVHIPEC-2 trial is investigating exclusively patients submitted to PDS ± HIPEC with cisplatin 100 mg/m22 and results are expected by 2026. On the interval debulking surgery (IDS) setting high quality data are coming from the result of the OVHIPEC-1 trial, which demonstrated a survival advantage of nearly 4 months in median progression-free survival (PFS) (14.2 months vs. 10.7 months; p = 0.003) and almost 12 months in median overall survival (OS) (45.7 months vs. 33.9 months; p = 0.02) for HIPEC treated patients (cisplatin 100 mg/m22) compared to no-HIPEC group, with comparable morbidity. However, due to some criticisms raised to the results of OVHIPEC-1 trial, the ESMO-ESGO guidelines recommended not to consider HIPEC as standard therapy until results from ongoing randomized control trials (RCTs) are provided. On the contrary, for the National Comprehensive cancer network (NCCN) guidelines HIPEC can be considered at the time of IDS. Similarly, data supporting the role of HIPEC in association with surgery in case of recurrent disease appear to be controversial in terms of patients and selection and intraperitoneal chemotherapy regimen. Indeed, despite the positive results coming from a prospective randomized trial, they appear to be biased by the inclusion of both platinum sensitive and resistant disease and the lack of information on PFS. Those results are in contrast with data coming from another prospective trial, which failed to demonstrate a survival gain of recurrent ovarian cancer patients treated with secondary cytoreductive surgery + HIPEC with carboplatin (800 mg/m22 for 90 min) compared to women submitted to cytoreduction only. Again, in this subgroup of patients data of ongoing RCTs are awaited to assess the impact on survival of HIPEC administration in case of recurrent disease.

Augmenting Real-World Data Through Modeling Key Clinical Trial Eligibility Criteria: An Example of Patients With Non-small-Cell Lung Cancer Treated With Pembrolizumab.

To compare and characterize baseline characteristics and overall survival (OS) differences by key oncology eligibility criteria for real-world patients from the Flatiron Health database with advanced non-small-cell lung cancer (NSCLC) who received pembrolizumab monotherapy. Real world data (RWD) were from the Flatiron Health advanced NSCLC database and include patients who initiated pembrolizumab monotherapy (first, second, or third line of therapy) by November 30, 2019. At the data cutoff (May 31, 2020), the median survival follow-up time was 8.4 months. Eligible patients satisfy the criteria of Eastern Cooperative Oncology Group performance status of 0/1 and laboratory values indicative of adequate organ function. RWD were analyzed for all patients and patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. Patients were divided into three categories: ineligible, eligible, and unknown (who satisfy all observed criteria, with at least one missing). An augmented population was also formed, which combines the latter two groups through a propensity-based adjustment. At the data cutoff, N = 3,877 patients with NSCLC received pembrolizumab monotherapy (1L = 2,682, 2L = 946, and 3L = 249). OS was consistently lower for the ineligible with similar survival for the eligible and augmented. Among all patients, the median OS in months (95% CI) was 8.2 (7.5 to 9.6), 16.3 (14.5 to 18.4), 16.4 (15.1 to 19.3), and 16.8 (15.6 to 18.5) for the ineligible (47%, n = 1,827), unknown (27%, n = 1,045), eligible (26%, n = 1,005), and augmented, respectively. The results were similar for patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. Real-world patients who received pembrolizumab monotherapy and meet key clinical eligibility criteria exhibited similar baseline characteristics and OS profiles as the unknown and augmented patient groups. Population augmentation is a feasible approach for improving the power of RWD analysis.

From 65 to 70 years old: what is the best approach in the treatment of glioblastoma?

Background: Glioblastoma (GBM) is the most common primary CNS tumor in adults. Between 65-70 years of age, treatment involves the best possible surgical removal followed by radiotherapy (RT), with or without temozolomide (TMZ). After assessing whether patients can tolerate TMZ, doubts regarding RT regimens persist in this age group. This study aimed to compare the overall survival (OS) in GBM patients aged 65-70 years, in two RT regimens with TMZ: Stupp (RT 60 Gy/30 fractions (fx)+TMZ) versus mini-Stupp (RT 40.05 Gy/15 fx+TMZ) and 2 regimens of RT without TMZ: 40 Gy/15 fx versus 25 Gy/5 fx.Methods: All GBM patients, 65-70 years, undergoing RT from 1 January 2014 to 31 December 2020 were retrieved and retrospectively evaluated. Patients were divided into 4 groups: group 1 was Stupp; group 2 was mini-Stupp; group 3 was 40,05 Gy/15 fx without TMZ; and group4 was 25 Gy/5 fx without TMZ.Results: Sixty patients were retrieved with median follow up of 12 months. In the analysis of groups 1 and 2, all variables were comparable (0.21&lt;p&lt;0.6). Median OS was 18 and 15 months, respectively, with no statistically significant difference (p=0.13). The OS at 2 years was 26% and 21% respectively, decreasing to 13% and 0% at 3 years.Analyzing groups 3 and 4, all variables were comparable (0.06&lt;p&lt;0.88). OS had no difference (p=0.5) with 7 months of median OS for both groups.Conclusions: From 65-70 years, if CHT is not viable, the 25 Gy/5 fx should be the standard. When CHT is possible, mini-Stupp appears to be equivalent to Stupp.

Treatment Patterns and Outcomes in Lenalidomide-Exposed Multiple Myeloma Patients in Real-World Settings: A Multi-Center Retrospective Study

BackgroundTreatment of multiple myeloma (MM) has changed significantly in recent years with the availability of novel agents including monoclonal antibodies (mAbs), proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) such as lenalidomide. Despite lenalidomide becoming a standard of care across all lines of myeloma therapy, the population of MM patients refractory to lenalidomide and their real-world clinical management has been poorly studied so far, especially outside the reality of interventional clinical trials (Moreau et. al. Blood Cancer J. 2019).With these considerations in mind, we have performed a retrospective study using two databases to better understand treatment patterns and outcomes of MM patients who were treated with lenalidomide and subsequently became refractory to it. This builds on work previously conducted at other data sources (Willenbacher et. al. EHA Library 2020).AimsThe objective of this study was to describe the treatment patterns and outcomes of MM patients exposed to lenalidomide, with a focus on refractory patients, as defined by IMWG (International Myeloma Working Group) consensus, in a real-world clinical setting.MethodsThe study utilised databases from two participating members of the IQVIA MM real world evidence network: University Hospital Frankfurt (Frankfurt) (Germany) and Portuguese Oncology Institute of Porto (IPO-Porto) (Portugal). Since the native format of databases from participating sites differs, key concepts were harmonised based on pre-agreed definitions. The study population included patients with an initial diagnosis of MM between 01/01/2012 and 31/12/2018 based on the IMWG criteria, were 18 years old or older at the time of diagnosis and received two or more cycles of lenalidomide treatment, alone or in combination, at any dose, excluding patients who only received lenalidomide as maintenance therapy. Patients were defined as refractory to lenalidomide treatment if they progressed on treatment or within 60 days following the end of lenalidomide treatment (excluding maintenance setting).Kaplan-Meier curves were produced to evaluate the time to next treatment (TTNT) and overall survival (OS) for lenalidomide exposed and lenalidomide refractory patients. TTNT was defined as the time between the start date of the line of lenalidomide therapy and the start date of the next line of therapy (LoT) or death due to any cause. OS was defined as the time between the start date of the line of lenalidomide therapy and death due to any cause.ResultsThe cohort included 55 and 42 MM lenalidomide-exposed patients from Germany and Portugal respectively. In Germany, 80% were initially exposed to the lenalidomide in LoT 1, whilst in Portugal 71% received initial lenalidomide treatment in LoT 3.In Portugal, following lenalidomide refractoriness, the majority (78%) of patients received chemotherapy and steroids only whilst in Germany a range of treatment types was observed (mAb-based 33%; PI-based 11%; PI/IMiD combo 11%; mAb/IMiD combo 11%; chemotherapy and steroids only 11%; other 22%).The median OS in months for lenalidomide-exposed refractory patients was 7 in Portugal and 31 in Germany; the median OS for non-refractory patients was 40 in Portugal and was not reached in Germany.The median TTNT in months for lenalidomide-exposed refractory patients was 4 in Portugal and 15 in Germany; the median TTNT for non-refractory patients was 14 in Portugal and 53 in Germany.ConclusionThe analysis of real-world data across two countries, showed heterogeneity in lenalidomide treatment patterns, with first exposure typically occurring in LoT 1 or 3. This has led to differences in the calculated TTNT and OS, and as such the results between the two countries cannot be directly compared. The OS from diagnosis for this cohort is being assessed and will provide an insight on the impact of different treatment pathways.Patients who became refractory to lenalidomide moved on to their next treatment much quicker after exposure vs patients who were not refractory to lenalidomide; similarly, patients who became refractory to lenalidomide had shorter OS than patients who were not refractory.Patients typically became refractory early in their treatment journey, indicating a growing population with unmet medical needs. [Display omitted] DisclosuresMetzler: GSK: Consultancy; Takeda: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy.

PD53-10 PREDICTING LIMITED SURVIVAL FOR PATIENTS WITH PENILE CANCER UNDERGOING INGUINAL LYMPH NODE DISSECTION

PD53-10 PREDICTING LIMITED SURVIVAL FOR PATIENTS WITH PENILE CANCER UNDERGOING INGUINAL LYMPH NODE DISSECTION

Effect of treatment sequence on mortality in advanced-stage endometrial cancer

<h3>Objectives:</h3> The aim of this study was to assess for an association between the sequence of surgical and systemic treatment and overall survival in patients with Stage IV endometrial cancer, as well as to identify prognostic factors for mortality. <h3>Methods:</h3> The National Cancer Database (NCDB) was queried for cases of endometrial cancer diagnosed between 2006 and 2015. These cases were further narrowed to include only International Classification of Diseases for Oncology (ICD-O) histologic codes of adenocarcinoma or endometrioid adenocarcinoma and FIGO stage IV disease. Exclusion criteria were: reference date prior to date of diagnosis; unknown treatment sequence; intraoperative chemotherapy use; and hormonal or immunotherapy as first-line systemic therapy or unknown hormonal or immunotherapy use. Three groups were defined according to sequence of administration of surgery and systemic therapy. Overall survival (OS) was compared by calculating hazard ratios for death via Cox regression analysis. The Incomplete Treatment (IT) group received surgery alone, systemic therapy alone, or no treatment. The Primary Surgery (PS) group received surgery before systemic therapy. The Interval Surgery (IS) group had neoadjuvant systemic therapy followed by surgery, with or without further systemic therapy after surgery. Subanalyses were performed to assess the impact of post-IS systemic therapy, age, ethnicity, insurance status, and Charlson-Deyo score on OS. Analysis was performed using STATA.16. <h3>Results:</h3> A total of 8,520 cases of FIGO Stage IV endometrial adenocarcinoma were identified using the criteria above. Median OS in months for each treatment sequence group was 7.2 for IT, 35.7 for PS, and 30.7 for IS. Regardless of treatment sequence, receiving both surgical and systemic therapy improved OS compared to receiving only one or neither treatment. The hazard ratio (HR) for death for PS compared to IT was 0.38 (95% CI 0.36-0.40) and for IS compared to IT was 0.41 (95% CI 0.36-0.47), p<0.0001 for both. There was no significant difference in survival for IS compared to PS (HR 1.10, 95% CI 0.96-1.24, p=0.18). Stratification of IS cases by administration of further systemic therapy after surgery yielded the same result. Patient groups with worse OS (p<0.0001 for all) included: age >50 years (HR 1.18, 95% CI 1.08-1.30), non-Hispanic Black compared to non-Hispanic White (HR 1.27, 95% CI 1.17-1.37), and presence of medical comorbidities reflected by Charlson-Deyo score of 1 or more. Patients with private insurance had better OS than uninsured patients (HR 0.80, 95% CI 0.71-0.90, p<0.0001) but the same was not true for government insurance. <h3>Conclusions:</h3> This retrospective survival analysis of NCDB data for FIGO Stage IV endometrial adenocarcinoma illustrated a benefit to receiving both systemic and surgical treatment over receiving only one or neither form of therapy. No difference in mortality was identified between primary surgery with adjuvant systemic therapy and neoadjuvant systemic therapy with interval surgery, even when accounting for additional chemotherapy after surgery. The decision whether to begin treatment with surgery or chemotherapy will thus depend on nuanced clinical factors specific to each patient. Patient factors associated with worse mortality included age >50 years, Non-Hispanic Black ethnicity, lack of insurance, and presence of medical comorbidities. These findings indicate a need to address the socioeconomic determinants of health contributing to these disparities in mortality.

PCN121 Estimating Prevalence in Oncology: The Development of a More Accurate Prevalence Formula

Estimating the prevalence of disease is an essential component to understanding disease burden, unmet need, and the potential budget impact of new treatments. Economic and epidemiologic models in oncology often calculate disease prevalence using median overall survival (OS). In this study, we propose an alternative approach that provides more accurate estimates of prevalence. A formula was developed from base principles to provide a reasonable estimate of prevalence for diseases of long duration but high mortality, such as cancer. Given the assumption that incidence is stable, prevalence can be calculated as incidence times the area under the survival curve. This is often simplified to incidence times average disease duration. In oncology, median OS is routinely substituted as average disease duration. We derived a more accurate formula, assuming a constant hazard for OS and a nonzero cure rate. The derived formula is prevalence ≈ 0.12*I*mOS*(1-0.5ˆ(Cm/mOS)) where I is annual incidence, mOS is median OS in months, and Cm is time until a patient is considered cured in months. Assuming Cm = 60 months, the formula predicts that true prevalence is up to 44% higher than estimated using the simplified approach of incidence times median duration of survival for diseases with median OS less than 12 months. Conversely, the formula predicts that true prevalence is at least 25% lower than current estimation methods for diseases with long median survival (e.g., more than 5 years). This formula provides a simple alternative approach for more accurate estimation of estimating disease prevalence. Given the essential role that prevalence estimates play in oncology models, this has the important implications for future health care decision-making.