Abstract: Background Myelodysplastic syndromes (MDS) are a collection of hematopoietic disorders with widely variable prognoses and treatment options. Pathologic diagnosis can be challenging and misdiagnosis can impact patient therapy and outcome. How commonly misdiagnosis occurs, and the severity of diagnostic errors, is not known. Here, we report interim analyses of patients (pts) with cytopenia and suspected MDS from the NHLBI National MDS Natural History Study (https://thenationalmdsstudy.net ClinicalTrials.gov: NCT02775383) assessing MDS occurrence and rates of agreement on classification of MDS/MDS-related disorders by local and centralized review. Methods Pts with cytopenias and clinically suspected MDS were identified between 6/16 and 6/18 from 84 participating centers in this ongoing multi-Institutional Cooperative Group study, with a goal of recruiting 2000 MDS (WHO 2016 subcategories), MDS/MPN or low blast count acute myeloid leukemia (AML, 〈 30% blasts without core binding factor) and 500 cases with idiopathic cytopenia of undetermined significance (ICUS) from both NCI community oncology research program (NCORP) and lead academic participating sites. Centrally submitted clinical and pathologic data and bone marrow samples were analyzed by pathologists in the central laboratory & biorepository (CL/B) blinded to the original site's diagnosis, with a third-level review for cases with disagreement between the local and CL/B assignment. Disagreements in the 5 categories detailed in Figure 1 were considered clinically meaningful. Cases were assigned to longitudinal (MDS, MDS/MPN, ICUS, low blast count AML) versus cross-sectional (other cytopenias or cancers) cohorts after central classification based on clinical, pathologic, and cytogenetic features. Interrater-agreement was evaluated with the Kappa statistic. Results Of 375 pts for whom data and samples were submitted with completed classification, 88 (23%) had MDS, 15 (4%) MDS/MPN, 12 (3%) ICUS, 23 (8%) AML, and 237 (63%) other cytopenias (Figure 1). The median age of all pts was 71 years (range, 20-92), 44% were female, and median baseline blood counts and other baseline measures are in Figure 2. MDS pts had single lineage dysplasia (SLD, 0), SLD with ring sideroblasts (RS, 9 (10%)), multi-lineage dysplasia (MLD, 17 (19%)), MLD -RS (18 (20%)), excess blasts I (EB, 14 (16%)), EBII (19 (22%)), del(5q) (6 (7%)), and MDS-U (5(6%)). IPSS-R categories were defined in 51 of 88 MDS cases (58%): Very Low (27%), Low (43%), Intermediate (27%), High (16%), and Very High (14%). Overall site/central agreement on diagnosis occurred in 225 cases (60%) with inconsistency associated with recognized site coding errors resolved in 54 cases (14%) without 3rd party review. Seventy-eight others (21%) were referred to 3rd level review; confirmation of CL/B classification occurred in 49/78 cases (63%), agreement with site in 13/78 (17%), and a different diagnosis in 16/78 (21%). Clinically meaningful changes in diagnoses between local and central review occurred 26% of the time (Figure 1, n=97/375 kappa =.53 95% CI (.45, .61)). Site assigned MDS was changed to ICUS or other cytopenia in 35% (n=34/99); and to AML in 3% (n=3/99). For cases with site assignment to other causes of cytopenias (225 of 375 cases, 60%), central assignment identified ICUS in 3, MDS/MPN overlap in 8, AML in 2 and MDS in 22, totaling a change in diagnosis in 16%. Of note, 60% (15/25) of ICUS diagnosed locally were interpreted as reactive marrow or normal according to central review. Within MDS cases diagnosed locally, the greatest discrepancy was observed in the MDS-U classification, reported 31 times (31/99 31%) but confirmed in only 2 cases (6%), with 22 (71%) found to not have MDS. Across the study when compared to local assignment, central review changed the follow-up cohort assignment for 87 pts (23%). Conclusions In this well-characterized series of pts evaluated for MDS with bone marrow biopsy and paired site/central morphologic assessment, 40% of site diagnoses were changed at central review and site coding errors were common. In 26%, the changes were clinically meaningful, potentially affecting patient treatment and prognosis. In particular, site designation of MDS-U was an unreliable classification category, which could only partially be attributed to miscoding errors at the local site. Incorporating genomics data might help refine MDS diagnoses. Disclosures Bejar: Genoptix: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Honoraria; Modus Outcomes: Consultancy; Astex/Otsuka: Consultancy, Honoraria; AbbVie/Genentech: Consultancy, Honoraria; Foundation Medicine: Consultancy. Komrokji:Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Scott:Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy, Research Funding; Alexion: Consultancy. Gore:Celgene: Consultancy, Research Funding. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

Abstract: TPS4593 Background: Bone metastases are prevalent in approximately 30% of pts with advanced RCC. Pts with bone metastases have a worse prognosis compared to pts without bone metastases and are at risk of symptomatic skeletal events (SSEs). Cabozantinib, a multitargeted inhibitor of multiple kinases, including vascular endothelial growth factor (VEGF) receptor and MET, has improved survival in pts with metastatic RCC and has enhanced activity in bone. Ra-223, an alpha-emitting radioisotope with natural bone-seeking proclivity, has been shown to prolong survival in men with castration-resistant prostate cancer. We previously conducted a pilot study of Ra-223 with VEGF inhibition and demonstrated safety and declines in markers of bone formation and resorption with the combination (McKay et al, CCR 2018). Given that decreasing rates of SSEs and improving outcomes for pts with RCC with bone metastases are unmet needs in pts with RCC, we designed a randomized phase 2 study through the National Clinical Trials Network (NCTN) investigating cabozantinib with or without Ra-223 in patients with RCC with bone metastases. Methods: This is an open-label multicenter study. Eligible pts have metastatic RCC of any histology with ≥2 metastatic bone lesions untreated with prior radiation therapy and no more than 2 prior lines of systemic therapy. Pts with non-clear cell RCC are eligible and will be capped at 20% of the total accrual goal. Pts must have a Karnofsky performance status of ≥60%, have symptomatic bone pain defined as a prior SSE or need of analgesics, and be on osteoclast-targeted therapy unless otherwise contraindicated. Pts are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) Ra-223. Starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Ra-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, quality of life measures, and correlative analyses including liquid biopsy studies and tumor tissue analysis. The study has 90% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.025 significance. To ensure 191 evaluable patients, target accrual is 210 pts. This design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events (72 SSE events) have been observed. Final data analysis will occur when 143 events have been observed. The study was activated in December 2019 and accrual is currently ongoing throughout the NCTN. Clinical trial information: NCT04071223.

Abstract: Resistance to immune checkpoint inhibition (ICI) in advanced non–small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. METHODS In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity. RESULTS Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92] ; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14] ; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC. CONCLUSION This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.

Abstract: 9004 Background: Resistance to immune checkpoint inhibitor (ICI) therapy develops in most patients (pts) with advanced non-small cell lung cancer (NSCLC). Tumors that develop resistance to ICI constitute a major unmet need. Combined ICI and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types through immune modulation. We evaluated pembrolizumab and ramucirumab (P+R) in advanced, ICI-exposed NSCLC, under the aegis of Lung-MAP, a master protocol for pts with stage IV, previously treated NSCLC. Pt characteristics and treatment toxicities were presented at ASCO 2021. Methods: S1800A was a randomized phase II trial for pts ineligible for a biomarker-matched substudy with acquired resistance to ICI defined as previous ICI therapy for at least 84 days with progressive disease (PD) on or after therapy. Eligibility stipulated PD on prior platinum-based doublet therapy (sequential or in combination with ICI) and ECOG PS of 0-1. Pts were stratified by PD-L1 expression, histology, and intent to receive ramucirumab in the standard of care (SOC) arm and were randomized to P+R or SOC (investigator’s choice of docetaxel+R; docetaxel, pemetrexed, gemcitabine). With a goal of 144 total/130 eligible pts, the primary objective was to compare overall survival (OS) between the arms using a 1-sided 10% level log-rank test upon 90 deaths. Secondary endpoints included response, duration of response, investigator assessed-progression free survival and toxicity. Results: From May 17, 2019 to November 16, 2020, 166 pts were enrolled with 137 eligible (69 P+R; 68 SOC [45 +R, 23 w/o R]). Main causes for ineligibility were lack of PD on ICI or chemotherapy (6 SOC, 6 P+R), 〉 1 line of ICI (2 P+R), ICI discontinued due to toxicity (2 SOC), or lack of measurable disease (2 SOC, 1 P+R). OS was significantly improved with P+R (HR: 0.61 [0.38-0.97] , 1-sided p-value = 0.019; median [95% CI] OS of 15.0 (13.2-17) months (mo) for P+R and 11.6 (8.5-13.8) mo in SOC arm). Progression-free survival (PFS) was not different between the arms (HR: 0.86 [0.57-1.31] , 1-sided p-value=0.25; median PFS (95% CI) of 4.5 (4.0-6.9) mo for P+R and 5.2 (4.0-6.6) mo in SOC arm). ORR was not different between the arms (p=0.28). OS benefit for P+R was seen in most subgroups. Analysis of survival based on genomic alterations, tumor mutational burden and PD-L1 will be presented. Conclusions: Pembrolizumab + ramucirumab in pts with advanced NSCLC previously treated with chemotherapy and immunotherapy led to improved OS compared to SOC. Discordance of ORR and PFS from OS has been reported in prior ICI trials (Rittmeyer et al. Lancet 2017). This is the first trial in the 2nd line setting without a chemotherapy backbone to demonstrate a potential survival benefit compared to SOC regimens including docetaxel and ramucirumab using the Lung-MAP platform. Clinical trial information: NCT03971474.

Abstract: Immune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART). Patients and Methods: We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease & gt;6 months, and toxicity. Results: Thirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13–64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%–52%); median OS was 11 months (95% CI, 6–∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events. Conclusions: Ipilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease.

Abstract: Background: TAPUR is a phase II multi-basket study evaluating the anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations known to be drug targets. S is an oral multi-kinase inhibitor that inhibits Fms-like tyrosine kinase-3 (FLT-3) in biochemical and cellular assays. Results from mCRC pts each with FLT-3 amplification treated with S are reported. Methods: Simon’s optimal two stage design was used to test the null hypothesis of 15% response rate versus the alternative of 35%. Power and alpha were set at 85% and 10%, respectively. Response was assessed per RECIST v1.1. This design requires 10 pts in stage 1 and if & lt;2 pts have objective response (OR) or stable disease (SD) at 16 wks, the cohort is closed. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Genomic testing was performed using commercially available tests selected by sites. Treatment was determined according to protocol matching rules based on genomic inclusion criteria. Results: Ten pts were enrolled from November 2016 to April 2018. Pts received S at a dose of 50 mg orally once daily for four weeks followed by two weeks off. All pts had mCRC with FLT-3 amplification. All pts are included in the data analysis for demographics, safety, PFS and OS (Table 1). No ORs were observed and despite observation of 2 pts with SD at 16 wks, the cohort was closed after further examination revealed both pts with SD died due to disease progression shortly after the 16 wk evaluation. Grades 3-4 AEs at least possibly related to drug are required to be reported. A single grade 3 diarrhea was reported as possibly related to S. Conclusions: Monotherapy with S does not have sufficient clinical activity in mCRC pts with FLT-3 amplification for continued evaluation in this pt population. Other treatments should be considered for these pts, including treatments offered in clinical trials. Table 1:Baseline demographics, clinical characteristics and outcomes by cohortSunitinib targeting FLT-3Tumor TypemCRC (N=10)Median age, yrs (range)56 (41, 71)Male, %80ECOG Performance Status, %01230700Median PFS, wks (90% CI)10.1 (7.4, 15.9)Median OS, wks (90% CI)29.5 (15.7, 39.9)Drug-related AEs, grades 3-4 (% of pts)10 Citation Format: Ricardo H. Alvarez, Elizabeth Garrett-Mayer, Susan Halabi, Pam K. Mangat, Tareq Al Baghdadi, Eugene R. Ahn, Seungjean Chai, Andrew L. Rygiel, Kaitlyn R. Antonelli, Samiha Islam, Suanna S. Bruinooge, Richard L. Schilsky. Sunitinib (S) in patients (Pts) with metastatic colorectal cancer (mCRC) with FLT-3 alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT146.

Abstract: Introduction: Myelodysplastic syndromes (MDS) are a heterogenous group of blood disorders defined by peripheral cytopenia(s), bone marrow failure, morphological dysplasia, and risk of progression. To understand the genetic, epigenetic and biological factors associated with the initiation and progression of MDS, NHLBI created the National MDS Study (NCT02775383). This is a prospective cohort study conducted at 92 community hospitals and 29 academic centers enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasm (MPN) overlap syndrome. Eligible patients have yet to receive any therapy directed at their cytopenias. Previously untreated cytopenic participants underwent centralized histopathology and data review at the time of enrollment for assignment into distinct subcategories: MDS, MDS/MPN overlap, AML, and Other. Targeted exon sequencing of 96 genes was performed using marrow specimens from the first 300 consecutive individuals in the study. Here we report the genetic mutations for this cohort. Methods: NovaSeq 6000 was used for deep sequencing at a mean coverage of 1,286X and mean breadth (bases covered at ≥100X) of 99.8%. Reads were aligned against build GRCh38 using BWA-MEM, and VarScan2 was used to detect SNVs and INDELS. Variants were filtered for those with an allele base quality of 〉 25 in combination with rule-based and manual review criteria. Subjects in the Other category without an identified malignancy were considered clonal cytopenias of undetermined significance (CCUS) when a mutation or a clonal cytogenetic change was present. Fisher's exact and Wilcoxon rank sum tests in combination with Bonferroni correction were applied to compare groups. Results : A total of 350 putative nonsynonymous pathogenic variants in 36 genes with an allele frequency of 〉 .05 were identified across 150 patients (50%). At least one variant was noted in the following proportion of individuals: 61/72 (85%) with MDS, 13/13 (100%) with MDS/MPN, 15/17 (88%) with AML, and 61/198 (31%) in the Other category, of which 48 were CCUS and 13 were other cancers. Two CCUS patients only had a cytogenetic abnormality. Table 1 shows the distribution of variants in each subcategory of patients for the most commonly mutated genes in our cohort of 300 subjects. Mutations in these genes were enriched in specific groups: SF3B1, STAG2,TP53, and ASXL1 in MDS; TET2 in MDS/MPN; and IDH2 and TP53 in AML (one-sided p 〈 0.0012). None were enriched in the Other group. Within the CCUS subset, 21 genes were mutated, with 37 of 50 (74%) patients having a mutation in TET2, ASXL1, SRSF2, SF3B1, or DNMT3A. The heatmap presented in Figure 1 summarizes variants by subject and allele frequency. Pair-wise comparisons of baseline characteristics of subjects between MDS, MDS/MPN, AML, or CCUS groups revealed no significant differences for age or sex. The CCUS group had significantly higher hemoglobins than the MDS group with median hemoglobin levels of 11.35 and 9.40 g/dL, respectively (p 〈 0.0084). AML had significantly lower platelets compared to all other groups (median of 53 vs. 〉 110x109/L , respectively, p 〈 0.0084). All groups significantly differed in their median ANC with AML having the lowest (0.8x109/L), followed by MDS (1.5x109/L), CCUS (2.45x109/L), and MDS/MPN overlap (5.95x109/L) (p 〈 0.0084). There was no difference in the median number of variants per patient between groups or correlation with age (rs=0.11, p=0.18). The maximum variant allele frequency (maxVAF) per patient was highest in the MDS/MPN group (median = 0.42, range = 0.38-0.91) and lowest in the CCUS group (median = 0.37, range =0.06-0.98) with the MDS/MPN group having a significantly higher maxVAF compared to the MDS and the CCUS groups (p 〈 0.0084). The proportions of subjects with mutations was similar for those who had abnormal (92% [34/37]) and normal (91% [80/88] ) cytogenetics. Conclusions: Incorporation of gene-panel sequencing in the comprehensive evaluation of 300 adult cytopenic patients identified half of the cohort with potentially pathogenic variants. Ultimately, a diagnosis of CCUS was possible in 48 of 183 subjects (26%) not diagnosed with MDS, MDS/MPN overlap syndrome, AML, other cancers or clonal cytogenetics. This study continues to serially bank samples from patients with CCUS, in addition to MDS, MDS/MPN, and ICUS, with the goal to better understand the natural history of these diseases and their progression. Disclosures Lindsley: Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding. Bejar:Celgene: Consultancy; Takeda Pharmaceuticals: Research Funding; AbbVie/Genentech: Consultancy, Honoraria; Astex/Otsuka: Consultancy; Modus Outcomes: Consultancy; Daiichi-Sankyo: Consultancy. Al Baghdadi:Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Tracon: Equity Ownership; Epizyme: Equity Ownership; Bristol Myer Squibb: Consultancy, Honoraria; Sunesis: Equity Ownership; Portola: Equity Ownership; Heron therapeutics: Equity Ownership; Cardinal health: Consultancy, Honoraria; Bristol Myer Squibb: Equity Ownership; Celgene: Equity Ownership; Spectrum pharmaceutical: Equity Ownership; Astrazeneca: Equity Ownership; Seattle genetics: Equity Ownership; Roche: Consultancy, Honoraria. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Foran:Agios: Honoraria, Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Komrokji:DSI: Consultancy; Agios: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; pfizer: Consultancy; celgene: Consultancy; Incyte: Consultancy; JAZZ: Consultancy. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Starczynowski:Kurome Therapeutics: Consultancy. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.