Real-World Data of Off-Label Drug Use in Patients with Actionable Genomic Alterations on Next-Generation Sequencing

We analyzed the outcomes of patients in our institution treated with off-label drugs targeting actionable genomic alteration based on next-generation sequencing when clinical trials were not available. Our study endpoint was objective tumor response or stable disease at 16 weeks or later after treatment initiation. Sixteen patients were included in this study, 8 were treated with immune checkpoint inhibitors targeting PD-L1 or TP53 mutations and 8 with other drugs. Tumors were analyzed based on PD-L1 expression, TP53 mutation, MSI, TMB, MMR status, and other targetable alterations. Of the 16 patients in the intention-to-treat group, no patients had an objective response after 16 weeks. Eleven patients met the primary study endpoint with stable disease, 8 in the immune checkpoint inhibitors group and 3 in the non-immune checkpoint inhibitors group. Using the log-rank test, the p-value for the difference between groups was 0.008. In this study with off-label drugs, immune checkpoint inhibitors targeting TP53 mutations or PD-L1 expression were superior to the other drugs. This suggests the possibility of off-label use of anti-cancer drugs based on next-generation sequencing to be beneficial for advanced cancer patients without other therapeutic options.

Gemcitabine Maintenance Therapy in Patients With Metastasized Soft Tissue Sarcomas

BackgroundMetastasized soft-tissue sarcomas still pose a significant therapeutic challenge given the limited efficacy of currently available multimodal treatment strategies. Recent progress in molecular characterization of sarcoma subtypes has enabled successful personalized therapy approaches in a minority of selected patients with targetable mutations. However, in the majority of patients with refractory soft tissue sarcomas, long-term survival remains poor.MethodsWe report on three adult patients with various soft tissue sarcomas subjected to Gemcitabine maintenance therapy. Tumor entities included leiomyosarcoma of the pancreas (patient 1), undifferentiated pleomorphic sarcoma of the right femur (patient 2), and peri-aortic leiomyosarcoma (patient 3). Metastatic sites encompassed liver, lung, and bones. All patients received Gemcitabine maintenance therapy until disease progression following prior salvage chemotherapy with Docetaxel and Gemcitabine. Patients were treated outside of clinical trials. Response assessment was based on radiological imaging.ResultsIn response to salvage chemotherapy with Docetaxel and Gemcitabine, one patient exhibited a partial remission, and two patients showed stable disease. Patient 1 exhibited stable disease for 6 months during Gemcitabine maintenance therapy before suffering rapid progression of hepatic metastases. Patient 2 underwent 21 months of Gemcitabine maintenance therapy, which was discontinued after progressive pulmonary metastases were detected. Patient 3 is still being treated with Gemcitabine maintenance therapy. Remarkably, owing to significant chemotherapy-associated hematotoxicity, the dose of Gemcitabine dose was reduced by two-thirds. Nevertheless, stable disease with constant pulmonary metastases has been maintained in this patient for 14 months.ConclusionsGemcitabine maintenance therapy following prior Docetaxel and Gemcitabine chemotherapy is manageable and reveals potential benefits for patients with aggressive metastasized soft tissue sarcomas. Prospective trials evaluating Gemcitabine maintenance therapy are encouraged.

Neoadjuvant therapy bridging patients with hepatocellular cancer waiting for liver transplant

Introduction. Liver transplant (LT) is a widely accepted treatment for hepatocellular carcinoma (HCC). The role of neoadjuvant (NAT) is still under debate.The aim of the work is to assess the effect of NAT on relapse-free survival (RFS) and overall survival (OS) in patients with HCC who underwent LT.Methods and materials. 63 patients diagnosed with HCC were observed at Blokhin National Medical Research Center of Oncology from October 2010 to January 2020. Of these, 28 patients did not receive any type of treatment before transplantation, 35 patients received various types of NAT. Two groups had similar patient and tumour characteristics at baseline. A significant number of patients with decompensated cirrhosis were observed in the non-NAT group (n = 14; 50%), while no patients with CP-C liver cirrhosis were observed in the NAT group (n = 0; 0%; p = 0.000). The average wait for a liver transplant was 10.3 months in the NAT group and 6.8 months in the NAT-free group (p = 0.561).Results. In the bridging subgroup, the tumour progression was detected in 29% of patients, stable disease in 47% of patients, partial response was achieved in 14% of patients, complete tumour response was observed in 5%. For 5% of patients, it was not possible to estimate the effect of the therapy due to the lack of appropriate data archives. In the subgroup of downstaging therapy, the tumour progression was detected in 23% of patients, stable disease in 41% of patients, a partial response was achieved in 12% of patients, a complete tumour response was observed in 6%. The treatment allowed the Milan criteria to be fulfilled in 18% of patients.Conclusion. There was no difference in overall survival (OS) or disease-free survival (DFS) between the NAT and control groups.

Frequency and burden of potentially treatable symptoms in glioma patients with stable disease: a classical and a network approach

Background: Glioma patients experience a multitude of symptoms, impacting health-related quality of life. We aimed to assess frequency and burden of patient-reported symptoms in glioma patients with stable disease and whether patients would consider treatment. We also explored how symptoms co-occur and interact within a network.Methods: Patients rated frequency and burden and whether they would consider treatment of seventeen symptoms. Correlations between frequency, burden, and considering treatment were evaluated with Kendall’s Tau correlation coefficients. Partial correlations between symptom frequency scores were visualized as a symptom network.Results: Fifty-two glioma patients with stable disease were included (31 grade II/III, 21 grade IV tumors). The top five symptoms were fatigue, memory problems, reduced physical fitness, concentration problems, and drowsiness. Fatigue had the highest median frequency, 4.5 with an interquartile range of 2.5, on a seven-point Likert scale. More than 50% of patients experienced three or more symptoms simultaneously. In a network, symptoms seem to cluster together in a Fatigue, Cognition and Anxiety cluster. Overall, about one-third of patients would consider treatment for at least one symptom. Considering treatment correlated only moderately with frequency and burden (range of correlations 0.24-0.57 and 0.28-0.61, respectively).Conclusion: Glioma patients with stable disease often experience multiple co-occurring symptoms with a high symptom burden. Despite the high prevalence of symptoms, the inclination to undergo treatment was relatively low. The most frequent and burdensome symptoms and the way they are interrelated and cluster together could serve as a roadmap for future research on symptom management and treatment.

Bisphosphonates for the Treatment of Calcinosis Cutis—A Retrospective Single-Center Study

(1) Background: Calcinosis cutis is a frequent symptom of autoimmune connective tissue diseases leading to pain, transcutaneous expulsion of calcified material and bacterial superinfection. There is a high need for new therapeutic options as no standardized treatment algorithm is established. While case reports indicate beneficial effects of bisphosphonates, standardized evaluation of treatment effects is missing. (2) Methods: In this retrospective analysis we evaluate the effects of intravenous pamidronate, a second-generation bisphosphonate, in seven patients with calcinosis cutis using consecutive clinical pictures, radiological examinations and patient’s subjective evaluation. (3) Results: 5/6 patients reported a reduction of pain, improvement of general condition and cessation of calcinosis progression. Regression of skin lesions was detectable in clinical pictures of 2/6 patients, while 1/6 patients had stable disease. Radiological examination revealed improvement or stable disease in 3/5 patients. Fever was the most common side effect. One out of seven patients developed osteonecrosis of the jaw. (4) Conclusions: Bisphosphonates appear to have beneficial effects in a subgroup of calcinosis cutis patients. While patient’s subjective evaluation was mainly positive, objective assessments showed improvement in approximately half of the cases. With regard to potential severe side effects, a careful risk-benefit evaluation is necessary before treatment initiation.

Therapy of Angiosarcoma with Thalidomide and Lenalidomide

Angiosarcoma is an uncommon malignancy with a poor prognosis. Systemic therapy options for patients with metastatic disease generally have limited effectiveness. In this case study, a 73-year-old male with metastatic angiosarcoma who previously declined chemotherapy and developed progressive disease after checkpoint inhibitor immunotherapy elected to try thalidomide based on 6 case reports describing its effectiveness. Thalidomide resulted in stable disease for 9 months, but due to severe neuropathy as a side effect, lenalidomide was then substituted for thalidomide. The patient continued to have stable disease on lenalidomide for an additional 16 months and ongoing. This is the first case study to report on effective treatment of angiosarcoma with lenalidomide. Further investigation of lenalidomide in the management of angiosarcoma is warranted.

Role of Mir-192-5p during Response to Azacitidine and Lenalidomide Therapy in Myelodysplastic Syndromes

Background and Rationale. miRNAs are small non-coding RNAs that regulate gene expression by acting on the epigenetic machinery and are themselves controlled by epigenetic mechanisms. The expression of miRNAs is linked to cancer development and miRNA profiles are studied as new prognostic factors or therapeutic new perspectives (Jiang X et al. Nat Commun 2016). High-risk MDS are now treated with hypomethylating agents, like Azacitidine (AZA), alone or in combination with other drugs, such as Lenalidomide (LEN). Recent data showed that the concurrent acquisition of specific point mutations on PI3KCD, PLCG2 and AKT3 genes is associated with loss of response to AZA+LEN therapy (Follo MY et al. Leukemia 2019). Inositide signalling regulated by Phospholipase C (PLC) and PI3K/AKT is indeed involved in epigenetic processes and in MDS progression to AML, through the regulation of proliferation, differentiation and apoptosis. Patients and Methods. This study included 26 high-risk MDS patients treated with AZA (75 mg/m2/day, days 1-5, sc) and LEN (10 mg/day, days 1-21 or 8-21, orally) every 4 weeks. Patients showing complete remission (CR), partial remission (PR), any hematologic improvement (HI) or marrow CR+HI following IWG response criteria were considered as responders, while patients showing stable disease or disease progression were considered as non-responders. miRNAs expression was assessed using an Affymetrix miRNA 4.0 array on patients' cells extracted at baseline and during the therapy, at the 4th (T4) and 8th (T8) cycle of therapy. Results were then validated by Real-Time PCR and miRNA targets were studied by dual Luciferase assay. Real-Time PCR was also used to examine the expression of PLC genes. Results. All patients included in this study were considered evaluable for response. According to the revised IWG criteria (14), the overall response rate (ORR) was 76.9% (20/26 cases): CR (5/26, 19.2%), PR (1/26, 3.8%), marrow CR (mCR, 2/26, 7.7%), HI (6/26, 23.1%), mCR+HI (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. For our analyses, we considered 10 patients as responders (R, showing response within T4 and maintaining it at T8), 10 losing response (LR, showing response within T4 and losing it at T8) and 6 non-responders (NR, never showing a response). Paired analysis between R and NR patients showed a statistically significant up-regulation of miR-192-5p and miR-21-5p between T0 and T4, as well as a down-regulation of miR-224-5p between T4 and T8, hinting at a relevant role for these miRNAs during AZA+LEN response. Real-Time PCR analyses confirmed the modulation of miR-192-5p and an altered expression of PLC genes during AZA+LEN therapy in all patients' subgroups, as well as an involvement of BCL-2 (possible target of miR-192-5p) that was also proven in vitro by dual Luciferase assays. Furthermore, as miR-192-5p expression seemed to be correlated with response, we performed Kaplan-Meier analyses and found out an association between high levels of miR-192-5p at T4 and OS (p=0.08) or LFS (p=0.04) in our MDS cases. More interestingly, this correlation was stronger (p=0.03) in R, as compared with LR and NR. Conclusions. This study shows that AZA+LEN therapy in MDS affects the expression of miR-192-5p, whose high level at T4 is associated with higher OS and LFS in responder patients. Moreover, we showed that miR-192-5p specifically targets and inhibits BCL-2, hinting at a regulation of MDS proliferation and apoptosis. Additional studies, to be performed in a larger cohort of MDS patients, are needed to confirm these data, as well as better understand the molecular mechanisms and the prognostic relevance of miR-192-5p in AZA+LEN therapy. Disclosures Cavo: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Novartis: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Finelli: Celgene BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy; Novartis: Consultancy, Speakers Bureau.

Immune Profiles of Myeloma Tumor Microenvironment May Predict Sensitivity or Resistance to Elotuzumab

Background: Elotuzumab (ELO), an immunobiologic therapy targeting SLAMF7/CD319, is effective in the treatment of multiple myeloma (MM) with clinical indications in relapsed/refractory disease in combination with lenalidomide or pomalidomide. ELO binds SLAMF7 on the surface of MM cells to increase immune recognition while also binding SLAMF7 on NK cells resulting in the activation of an effector cell population capable of readily killing via antibody-dependent cellular cytotoxicity (ADCC) mechanisms. ELO efficacy has also been linked to enhanced antibody-dependent cellular phagocytosis (ADCP). Given the dependence of ELO activity on immune elements of the tumor microenvironment (TME), we hypothesized that characterization of the immunologic constituents of the immune TME (iTME) would provide cues capable of predicting clinical efficacy. Methods: Nineteen patients were enrolled on a single-center clinical trial run at Moffitt Cancer Center comparing clinical activity of ELO in combination with low-dose (10mg) vs high-dose (25mg) lenalidomide and dexamethasone in patients with biochemical relapse while on lenalidomide maintenance after first line therapy. Bone marrow aspirate (BMA) and peripheral blood (PB) samples we collected at baseline, after completion of 2 treatment cycles, and at time of progression. Cells isolated from the BMA were analyzed by multiparameter flow cytometry (MPFC) using 4 panels; 3 panels characterized lymphocytes according to maturation, activation and polarization (T H1, T H2, T H17 or T Reg) and a 4 th panel characterized myeloid elements. Data was acquired on a BD Symphony cytometer and analysis was performed using FlowJo software. Results: Patient samples were categorized according to initial therapeutic response. Responders (n=6) achieved >PR at best response, Progressors (n=5) were identified as patients whose disease markers increased >25% and Stable Disease (n=8) was identified as demonstrating <25% change in serologic disease markers. Here, we present a comparison of phenotypic profiles from the BM samples acquired at baseline before treatment initiation from patients classified as Responders or Progressors (patients demonstrating stable disease as best response were analyzed separately). Sample analysis by MPFC revealed distinct populations uniquely associated with responses as well as with treatment refractoriness. Principal component analysis (PCA) of the myeloid immune compartment shows 2 clusters representing distinct populations detectable only in Responders, while another large cluster, also expressing a granulocytic phenotype consistent with granulocytic myeloid suppressor cells, is prevalent in the Progressor patients but nearly absent from Responder patients, as might be predicted. Similarly, PCA identified monocyte/macrophage clusters uniquely associated with Responder or Progressor samples. Evaluation of lymphoid populations using 3 lymphoid panels also reveals distinctive clustering patters by PCA highlighting populations differentially associated with Responder or Progressor samples. Notably, while NK cells are present in all patient samples, there is a population of immature NK cells enriched in Responder patients that is largely absent from the Progressor population. Conclusion: Immune profiling of the myeloid and lymphoid components of the baseline BM iTME in MM prior to treatment with ELO reveals distinct patterns of cellular constitution associated with responsiveness or refractoriness to subsequent treatment. While NK cells are known to be important to the ELO mechanism of action, our data suggests that ELO activity is compromised in the absence of immature NK cells. This work suggests that measurable characteristics of the cellular components of the iTME may provide important cues to help predict ELO therapeutic efficacy. These observations will need to be confirmed in a larger data set. Disclosures Shain: Amgen Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Genzyme: Consultancy, Speakers Bureau; Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithLine, LLC: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm Therapeutics Inc.: Honoraria, Research Funding. Baz: BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding; Oncopeptides: Consultancy; GlaxoSmithKline: Consultancy, Honoraria; Merck: Research Funding. Nishihori: Novartis: Research Funding; Karyopharm: Research Funding.

Enasidenib (ENA) Is Effective in Patients with IDH2 Mutated Myelodysplastic Syndrome (MDS) : The Ideal Phase 2 Study By the GFM Group

Background : ENA is a selective inhibitor of IDH2 approved in the US for the treatment of patients with relapsed/refractory IDH2 mutated AML. Little is known on its efficacy in patients with IDH2m myelodysplastic syndromes. Here we report the preliminary results of a Phase 2 study evaluating the safety and efficacy of ENA in three different cohorts of MDS : Higher risk MDS having failed HMA (cohort A, n=29), untreated higher risk MDS without life threatening cytopenias (ie ANC < 500/mm3 or any recent severe infections and/or platelets below 30,000/mm3 and any bleeding symptom, cohort B, with the addition of AZA in non-Responders after 3 cycles, n=29) and lower risk MDS having failed ESA (cohort C, n=10). (ClinicalTrials.gov NCT03744390). Methods : Subjects enrolled in cohort A, B or C received continuous 28-day cycles of ENA - 100 mg PO QD. In cohort B, Azacitidine (75 mg/m2/d x 7 days, SC) was added to Enasidenib after 3 cycles, only in the absence of IWG 2006 response (absence of CR, PR or HI). The primary endpoint was Overall hematological response (including CR, PR,stable disease with HI according to IWG 2006). All patients who achieved CR, PR or HI were considered as responders and could continue treatment until loss of response. Secondary endpoints of the trial included safety,duration of response, EFS, Overall survival and translational project evaluating the role of biomarkers on response.We report interim results in the first 26 pts enrolled. Resul t s : At data cut off (6/15/2021), 45 pts were enrolled, including 26 who were evaluable for the primary endpoint. 11, 9 and 6 were enrolled in cohort A, B and C respectively. Median age was 75.5 years and 34.6% were female. WHO was MDS-MLD, MDS-RS-SLD, MDS-RS-MLD, MDS-EB1, MDS-EB2, CMML and AML (with 20-30% blast) in 1, 2, 3,4, 10, 2 and 4 pts, respectively. IPSS was low, intermediate 1, int 2 and high in 1, 7, 13, 5 resp. IPSS-R was low,intermediate, high and very high in 4, 8, 11, 3 resp. At data cut off, 10 pts were still on treatment. Most common reasons for discontinuing ENA were Treatment failure (7.7%), disease progression (23.1%), adverse events (7.7%) and death (3.8%). Three patients experienced a differentiation syndrome (1 in cohort A and 2 in cohort B) that resolved without sequelae. Other most common grade 3-4 AEs were nausea/diarrhea (n=4) and thrombocytopenia (n=5). Overall best response rate (ORR including CR, PR, and HI) was achieved in 11 pts (42 %), including 6 CR (55%), 2 PR (18%), 2 mCR with HI (18%), 1 Stable disease with HI (9%). ORR was achieved in 3 (27 %), 5 (56 %) and 3 (50%)in cohort A, B and C respectively. In cohort B, AZA wad added to ENA in 3 patients who were primarily resistant to ENA. Among them, 2/3 patients subsequently achieved a response. Moreover, CR was seen in 2, 1 and 3 in cohort A, B and C respectively. The 6 months response rate was 29.5 % [6 ;59], 53.1 % [11.7 ;83] and 50 % [7.7 ;82.9] in cohort A, B and C respectively. At the time of analysis, all responses but 2 were sustained. Responses were lower (p=0.27) among the 23 pts with IDH2 R140 (30.4%) as compared to the 3 with IDH2 R172 mutation (66.7%). With a median follow up of 8.6 months, the median OS was 17.3 months (figure 1). Six patients died during follow-up, including 4/11 in cohort A, 1/9 in cohort B and 1/6 in cohort C. The 6 months death rate observed was 8.2 % [0 ;18.4] and the 1-year OS was 55.4%, 100% and 80% in cohorts A, B and C, respectively. Four patients evolved to AML (2 and 2 in cohort A and B) with a 1y risk of AML of 19.3%. Conclusion : Results from the first 26 patients included in this study show that ENA has no limiting toxicity in patients with MDS and that it can provide responses in 42% of patients. These responses appear to be encouraging, especially in first-line (low and high risk) patients. An update of this study will be presented. Figure 1 Figure 1. Disclosures Ades: JAZZ: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding. Sebert: BMS: Consultancy; Abbvie: Consultancy. Stamatoulas Bastard: Pfizer: Other: Travel Support; Celgene: Membership on an entity's Board of Directors or advisory committees. Laribi: Novartis: Other: Personal Fees, Research Funding; AstraZeneca: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; Jansen: Research Funding; Le Mans Hospital: Research Funding; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Platzbecker: AbbVie: Honoraria; Takeda: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Geron: Honoraria; Novartis: Honoraria. Fenaux: Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. OffLabel Disclosure: enasidenib is not approved for MDS

NCOG-18. RELATIONSHIP BETWEEN RANO-PRO WORKING GROUP STANDARDIZED PRIORITY CONSTRUCTS AND DISEASE PROGRESSION AMONG MALIGNANT GLIOMA PATIENTS AS MEASURED THROUGH CLINICAL OUTCOMES ASSESSMENTS

Recognizing the importance of clinical outcomes assessments (COA), the RANO-PRO Working Group recommends inclusion of core symptoms/functions in clinical care/research for malignant glioma patients. This study evaluated the association between the recommended symptoms (pain, perceived cognition, seizures, aphasia, treatment-specific symptoms) and functions (physical: weakness, walking; and role/social: work, usual activities) and disease progression in these patients. MDASI-Brain Tumor and EQ-5D-3L scores, Karnofsky Performance Status (KPS), and Neurologic Function Score (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons. Our sample included 336 patients with malignant glioma; 82% white, 64% male, median age=52 (21-79). Imaging study revealed disease progression for 46% of patients. All symptoms except seizures and difficulty concentrating were worse in the group whose imaging showed disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (0.8 < difference < 1.8). Patients with disease progression were 4 times more likely to have a poor KPS (≤ 80) and worse NFS. Among patients with disease progression (n=112), all symptoms, except seizures, worsened from first assessment to time of progression. Up to 22% of patients reported worsening mobility, self-care, and usual activity; 46% and 35% had worsened KPS and NFS, respectively. Seven symptoms and functions were each individually reported by at least 10% of patients as having worsened the most. Worsening of symptoms and functions was not observed among patients with stable disease, except in difficulty understanding. Identified core symptoms/functions worsen at the time of progression demonstrating the relationship between priority constructs and a traditional tumor response measure while highlighting the importance of longitudinal collection of COA. The pattern of worsening was observed via both patient- and clinician-reported outcomes, emphasizing the utility of COA in clinical care and clinical trials.