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Abstract Approximately 90% of limited-stage Hodgkin lymphoma (HL) patients are projected to be cured with standard therapy, but many do not live their expected life span because of late treatment–related complications. New treatment paradigms are needed to reduce the use of radiation therapy (RT) as well as conventional chemotherapy drugs while improving upon current standard-of-care survival outcomes. In this phase 2 multicenter study, patients with non-bulky limited-stage HL received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by brentuximab vedotin (BV) consolidation. Forty-one patients were enrolled, and patient characteristics included median age of 29 years (range, 19 to 67 years), 58% were female, 45% had unfavorable disease, and 98% had stage II disease. Based on positron emission tomography (PET)–based risk stratification, patients received 2 to 6 cycles of ABVD followed by 6 cycles of BV. After ABVD followed by BV, 95% of evaluable patients (37 out of 39; 95% confidence interval [CI], 83%-99%) achieved PET-negative status. In the intent-to-treat patient population, the estimated 3-year progression-free survival (PFS) rate was 92%, and the overall survival (OS) rate was 97%, with a median follow-up of 47 months. All 37 patients who achieved negative PET status after BV consolidation effectively avoided RT and remain in remission with estimated 3-year PFS and OS rates of 100%. In conclusion, BV demonstrates encouraging clinical activity when it follows ABVD therapy in limited-stage HL. Early incorporation of BV may reduce the use of RT as well as conventional chemotherapy drugs while achieving favorable survival outcomes in risk-stratified patients with non-bulky limited-stage HL. This trial was registered at www.clinicaltrials.gov as #NCT01578967.

e19047 Background: Colorectal cancer is one of the leading causes of cancer deaths in the US. Area of residence affects survival in many cancers, though largely unknown in colorectal cancer. The purpose of this study is to evaluate disparities between the metropolitan, urban and rural populations and the impact on survival in colorectal cancer. Methods: Data was obtained from the National Cancer Database (NCDB) colon, rectosigmoid, and rectal data sets. Patients (pts) were categorized by area of residence: metropolitan (MA), urban (UA), or rural (RA). Gender, race, insurance status, income, marital status, and tumor related data was collected. Univariate and multivariate analyses were performed to evaluate variables affecting overall survival (OS). Results: A total of 973,139 pts, spanning 2004-2013 were included in the study, 83% MA, 15% UA, 2% RA. RA and UA pts were more likely to be white than MA pts (92.7 v 91.4% v 83%). RA and UA were more likely to have lower income, with slightly lesser amounts of women and pts with no comorbidities. Uninsured rates were similar (3.3%). On univariate analysis, OS was worse for RA (HR 1.10) and UA (1.06) pts, as compared with MA. On multivariate analysis, small differences persisted with worse OS for RA (HR 1.02, p = .043) and UA (HR 1.01, p = .003). Black (HR 1.14) and native American (HR 1.17) pts had worse outcomes, while Asian (HR 0.8) pts had improved OS. Women (HR 0.88) and pts with higher incomes ( > 46K or 63K) had improved OS (HR 0.88). Conclusions: This study identifies socio-demographic disparities in colorectal cancer outcomes. Pts from rural and urban areas had worse OS, even though the proportion of minority pts with poor outcomes was lower. The difference in OS for RA and UA remained statistically significant in multivariate analysis, though it was largely corrected when adjusting for influencing variables. Part of this difference may be due to economic disparities, as lower income was linked to worse OS. This can independently limit access to care, especially for geographically isolated individuals. Additional research efforts are needed in order for us to better understand the key issues facing and the optimal means to improve outcomes in at risk populations.

Introduction Limited stage disease accounts for 30-40% of Diffuse Large B-cell Lymphoma (DLBCL), with better overall survival than advanced stage disease, but with increased late relapses regardless of treatment strategy (Stephens 2016). Preferred treatment for these patients (pts) per NCCN guidelines is abbreviated R-CHOP followed by radiotherapy. Based on promising results of radioimmunotherapy consolidation in SWOG S0313 (Persky 2015), and of PET-directed experience by the BC Cancer Agency (Sehn 2011), we designed a National Clinical Trials Network (NCTN) PET-directed study to tailor therapy after 3 cycles of R-CHOP, to improve outcomes and decrease toxicities. Methods Pts had non-bulky (< 10 cm) stage I/II untreated DLBCL. Mediastinal, HIV-associated, testicular, central nervous system, and indolent lymphoma were excluded. Pts received standard R-CHOP therapy and had an interim PET scan on day 15-18 of cycle 3, which was centrally reviewed in real time. Pts with negative PET scan (Deauville 1-3, iPET-neg) proceeded with 1 additional cycle of R-CHOP. Pts with positive PET scan (Deauville 4-5, iPET-pos) initiated 36 Gy of involved field radiation therapy (IFRT), plus additional boost to FDG-avid area up to 9 Gy, within 5 weeks of 3rd cycle of R-CHOP. This was followed by ibritumomab tiuxetan (IFRT-Zevalin) 3-6 weeks after completing IFRT. Final PET scan was performed 12 weeks after treatment completion. Results The study completed accrual in June 2016. Safety, response, interim PET, and immunohistochemistry-based cell of origin (COO) and MYC/BCL2 analyses were presented previously (Persky 2017, Stephens 2017). Of 159 pts enrolled, 1 was upstaged by PET, and 26 pts were ineligible - due to incorrect histology (mostly concurrent indolent or follicular lymphoma grade 3B) (21), lack of diagnostic tissue submission for central pathology review (3), and bulky disease (2). In 132 eligible pts, median age was 62 years, 62% had stage I, 17% had B symptoms, 14% had elevated LDH, 43% had extranodal involvement, and 66% had exclusive involvement of the head and neck region. Stage modified IPI (smIPI, Miller 1998) was 0 in 27%, 1 in 42%, 2 in 28%, and 3 in 4% of the pts. COO by Lymph2Cx was assessable in 87 pts - 68% were GCB, 23% were ABC, and 9% were unclassifiable. Double protein expressers (MYC and BCL2, DPE) were 16%, while 4 (3%) pts had "double hit" lymphoma (DHL) - 2 with MYC/BCL2 and 2 with MYC/BCL6 rearrangements - none of which were DPE. Of 132 eligible pts, 128 had an interim PET scan centrally reviewed, of which 110 were iPET-neg. Only 18 were iPET-pos, 4 of them due to infection (Deauville X) which were treated as iPET-neg. Of 14 truly iPET-pos pts (11%), 2 refused radiation, and 12 pts received IFRT-Zevalin. Eight pts (67%) converted from PR to CR after IFRT-Zevalin and 4 (33%) had PR, for an overall CR of 92% and PR of 4% (with 4% unevaluable). With median follow up of 4.5 yrs (range 1.1 - 7.5 yrs), only 5 pts progressed and 2 died from lymphoma. Of 5 progressors, 3 received R-CHOP x 4, 1 was iPET-pos but declined radiation, and 1 went off treatment after 1 cycle of R-CHOP. Eleven pts died from non-lymphoma causes, including 1 pt from secondary AML (iPET-neg arm), and 1 of lung adenocarcinoma diagnosed upon iPET. S1001 5-yr PFS estimate is 87% and OS estimate is 90% (figure 1), with iPET-pos and iPET-neg pts having similar outcomes - PFS 86% vs. 88%, OS 93% vs. 91%, respectively. Five-yr PFS by smIPI was 97% for smIPI of 0, 86% for 1-2, and 30% for 3. GCB had 5-yr PFS of 95%, vs. 70% for ABC and 47% for unclassifiable. DPE pts had 5-yr PFS of 70, vs. 89% for non-DPE pts. All 4 DHL pts maintain remission. Conclusions S1001 is the largest US study of limited stage DLBCL in the rituximab era, with best NCTN results in this disease subset. Only 5 patients progressed and 2 died from lymphoma. Our study confirms the distinct biology of limited stage DLBCL, with predominance of GCB origin (68%), and head and neck location (66%). Due to small number of lymphoma events, no strong conclusions about prognostic ability of smIPI, COO, DPE, or DHL, could be made. S1001 demonstrated that 89% of pts maintained excellent outcomes after R-CHOP x 4 with PET-directed therapy. Only 11% of pts were iPET-pos and required radiation, but they also had excellent outcomes. Together with the FLYER trial in younger pts (Poeschel 2018), this NCTN trial establishes R-CHOP x 4 alone as the new standard approach to limited stage disease for majority of the pts. Disclosures Persky: Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy. Stephens:Acerta: Research Funding; Karyopharm: Research Funding; Gilead: Research Funding. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Bartlett:Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Genenetech: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy. Barr:Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Leonard:Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Sutro Biopharma: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Celgene: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Gilead: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy. Kahl:TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; BeiGene: Consultancy. Fisher:Celgene: Consultancy; AstraZeneca: Consultancy; Barclays: Honoraria; prIME: Honoraria. Rimsza:NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Smith:Portola Pharmaceuticals: Research Funding. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. OffLabel Disclosure: Ibritumomab tiuxetan in diffuse large B-cell lymphoma

Objectives: To longitudinally measure LV diastolic function in HIV-exposed but uninfected (HEU) children perinatally exposed to ART. Design: HEU children who were perinatally exposed to antiretroviral therapy (ART) may be at risk for adverse cardiac effects. We have previously reported that those children have decreased left ventricular (LV) mass, dimension, and septal thickness with increased contractility. Methods: Serial echocardiograms were obtained at specific times from birth to 48 months from two groups of HIV-uninfected children: 148 HIV-negative children who were perinatally exposed to ART and 130 non-ART-exposed HIV-unexposed healthy controls. The following LV diastolic indices were obtained: mitral valve early and late diastolic velocity (E and A), tissue Doppler-derived LV-free wall and septal early diastolic velocity (LV e′ and sep e′). Results: All echocardiographic indices were significantly different in ART-exposed children compared with ART-unexposed healthy controls. Both E and A were overall lower at all ages by 8.28 cm/s (P = 0.0002) and 13.46 cm/s (P < 0.0001) respectively. E/A ratio was higher by 0.27, 0.46, and 0.28 units at birth, 1 year and 2 years of age, respectively (all P ≤ 0.01). Moreover, LV e′ and sep e′ were overall lower at all ages by 0.84 cm/s (P = 0.01) and 0.47 cm/s (P = 0.02), respectively. Conclusion: Children who were exposed to ART in utero have subclinical yet significant differences in specific LV diastolic indices. Follow-up with serial echocardiograms are recommended in this population to further assess the potential cardiac toxicity of perinatal exposure to ART.

Background: The ABVD regimen containing doxorubicin, bleomycin, vinblastine, and dacarbazine is a common standard of care for the frontline treatment of advanced stage Hodgkin lymphoma (Santoro 1987; Duggan 2003) and is curative for the majority of patients; however, up to 30% of patients require a secondary therapy. Hodgkin Reed-Sternberg cells of classical HL (cHL) typically express CD30. In a pivotal phase 2 trial brentuximab vedotin (A, ADCETRIS®), comprised of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) induced an objective response rate (ORR) of 75% and complete response rate (CR) of 34% in highly treatment-refractory patients with cHL (Younes 2012). Methods: We conducted a phase 1, open-label, multicenter study to evaluate the safety and efficacy of A when administered in combination with standard therapy (ABVD) or the same regimen without bleomycin (AVD) (Younes 2013). Adult patients with newly diagnosed advanced stage (II bulky, II B, III or IV; 80% stage III or IV) received doses of 0.6, 0.9, or 1.2 mg/kg A with standard doses of ABVD or 1.2 mg/kg with AVD, depending on cohort assignment on Days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. Previously we reported that among patients assessable for response 95% of patients given ABVD+A achieved a CR, as did 96% of patients given AVD+A. None of 26 patients given AVD+A but 11 of 25 (44%) given ABVD+A experienced pulmonary toxicity, including 2 deaths, establishing that A cannot be safely combined with bleomycin. In this current study we provide the long term survival and safety data on patients enrolled in the phase 1 trial. Results: In total 51 patients were assigned to either ABVD+A (n=25) or AVD+A (n=26). 1 patient who withdrew from the trial during the first cycle of ABVD+A is excluded from this analysis and 1 patient who received 3 cycles of ABVD+A, then withdrew, then received 3 cycles of ABVD alone and 2 patients who died during treatment (pulmonary toxicity) are included (total n=50). Median follow-up from diagnosis for the 24 patients treated with ABVD+A is 41 months (range 9-51 months) and for the 26 patients treated with AVD+A, 31 months (range 9-35 months). All 26 patients treated with AVD+A have been followed longer than the longest time to relapse (7 months). 45 patients remain in first CR and 5 treatment failures have occurred: 4 in the ABVD+A cohort (2 toxic deaths; 2 relapses (9 and 23 months from diagnosis)) and 1 after AVD+A (7 months from diagnosis). 3y-failure-free survival (3y-FFS) is 83% and 96% for ABVD+A and AVD+A, respectively, and 3y-overall survival (3y-OS), is 92% and 100%. No additional toxic deaths have occurred in follow-up. Conclusions: These updated outcomes reflecting the impact of adding brentuximab vedotin (1.2 mg/kg) to standard doses of AVD for classical Hodgkin lymphoma, demonstrating 96% 3y-FFS and 100% 3y-OS with no major unexpected toxicity, strongly support the current large international trial comparing AVD-A (AVD+1.2mg/kg brentuximab vedotin) to standard ABVD (ECHELON-1, clinicaltrials.gov NCT01712490), which may identify a new, less toxic gold standard treatment for advanced stage classical Hodgkin lymphoma. Disclosures Connors: Seattle Genetics: Research Funding. Off Label Use: brentuximab vedotin in phase 1 trial. Ansell:Seattle Genetics: Research Funding. Park:Seattle Genetics: Research Funding; Millennium/Takeda: Research Funding. Fanale:Seattle Genetics: Research Funding. Younes:Seattle Genetics: Research Funding; Millennium/Takeda: Research Funding.

Abstract Abstract 955 Background: Hodgkin lymphoma (HL) is a lymphoid neoplasm defined by the presence of CD30-positive Hodgkin Reed-Sternberg (HRS) cells in a background of inflammatory cells. Frontline treatment is generally ABVD alone or in combination with other chemotherapy regimens or radiation. Although a standard ABVD regimen is curative for the majority of patients with advanced stage HL, up to 30% of patients will require a second-line therapy. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). In a phase 2 study, an objective response rate of 75% and multiple durable complete remissions (CRs) (34%) were obtained with single-agent brentuximab vedotin in highly treatment-refractory patients with HL. Methods: A phase 1, open-label, multicenter study is being conducted to evaluate the safety of brentuximab vedotin when administered in combination with standard therapy (ABVD) or a modified standard (AVD) (ClinicalTrials.gov #NCT01060904). Patients received doses of 0.6, 0.9, or 1.2 mg/kg brentuximab vedotin with standard doses of ABVD or 1.2 mg/kg brentuximab vedotin with AVD, depending upon cohort assignment. The combination regimens were administered on Days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. Each regimen evaluated a dose limiting toxicity (DLT) period, defined as any Cycle 1 toxicity requiring a delay of ≥7 days in standard ABVD or AVD therapy. Determination of antitumor activity is based on investigator assessment of objective response according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: Interim data are presented for the first 31 patients treated. Six patients received 0.6 mg/kg, 13 received 0.9 mg/kg, and 6 received 1.2 mg/kg with ABVD; 6 patients received 1.2 mg/kg with AVD. Baseline characteristics included: Stage IV, 55%; IPI score ≥4, 29%; male, 77%; median age, 35 years (range, 19–59). Combination treatment was generally well tolerated, with no DLT observed up to 1.2 mg/kg in either regimen. Overall, AEs reported in ≥45% of patients, regardless of severity, were nausea and neutropenia (77% each); peripheral sensory neuropathy (48%); and fatigue (45%). Infusion-related reactions occurred in 23% of patients. Grade 3/4 AEs observed in >10% of patients were neutropenia (74%), febrile neutropenia (16%), and anemia (13%). No Grade 5 events were observed. Overall, 6 patients discontinued combination treatment due to an AE. In the ABVD cohorts (n=25), AEs of pulmonary toxicity, dyspnea, and interstitial lung disease that could not be distinguished from bleomycin toxicity led to discontinuation of bleomycin in 7 patients. Five of these 7 patients continued treatment with AVD and brentuximab vedotin. All 10 patients who had a response assessment available after completion of frontline therapy achieved CR. Currently, an expansion cohort of approximately 20 patients is enrolling to explore 1.2 mg/kg brentuximab vedotin combined with AVD therapy. Conclusions: In this interim analysis of 31 patients with newly diagnosed HL, the maximum tolerated dose in combination with ABVD or AVD was not reached; no DLT was observed up to 1.2 mg/kg, the maximum planned dose. Brentuximab vedotin treatment was associated with manageable AEs; the most frequent AEs in the study were nausea and neutropenia. The safety profile observed thus far in this study suggests that brentuximab vedotin has potential for combination therapy with ABVD or AVD. Updated safety and response data will be presented at the meeting. Disclosures: Younes: Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau, Travel Expenses; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi-Aventis: Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; SBIO: Research Funding; Syndax: Research Funding; Celgene: Speakers Bureau; Gilead: Honoraria; Pharmacyclic: Honoraria. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Connors:Seattle Genetics, Inc.: Research Funding. Park:Seattle Genetics, Inc.: Research Funding. Hunder:Seattle Genetics, Inc.: Employment, Equity Ownership. Ansell:Seattle Genetics, Inc.: Research Funding.

Abstract Background: Treatment of Hodgkin lymphoma (HL) requires a careful balance between providing enough therapy to cure the disease and avoiding unnecessary treatment that could result in excessive long-term treatment-related complications. The preferred treatment option for limited stage non-bulky HL currently involves the use of combined chemotherapy and involved-field radiation therapy. Given the unclear overall survival advantage and the long-term side effects associated with consolidative radiation, the use of this modality remains one of the most controversial topics in the treatment of HL. Therefore, alternative consolidation approaches are worthy of exploration for treatment of limited stage non-bulky HL. Brentuximab vedotin has been associated with favorable response rates in patients with relapsed or refractory HL. We hypothesize that brentuximab vedotin may be safe and effective in eradicating residual disease after induction chemotherapy and may potentially replace radiation therapy for consolidation in patients with newly diagnosed limited stage non-bulky HL. Methods: In this phase 2 multicenter study, patients with non-bulky (< 7.5 cm) stage I or II HL are being enrolled to determine the efficacy and safety of brentuximab vedotin when administered for consolidation after a standard chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (ClinicalTrials.gov #NCT01578967). The primary objective of the study is to estimate the proportion of patients who achieve PET-negative disease (Deauville score of 2 or less) after induction chemotherapy followed by consolidation with brentuximab vedotin. Involved-field radiation is recommended only if the PET scan is positive at the completion of therapy with brentuximab vedotin. Patients received 2 to 6 cycles of ABVD based on their baseline risk factors and the interim PET scan result; patients with favorable disease with negative interim PET received 2 cycles, favorable disease with positive interim PET or unfavorable disease with negative interim PET received 4 cycles, and unfavorable disease with positive interim PET received 6 cycles of ABVD. Approximately 6 to 8 weeks after the induction chemotherapy, 1.8 mg/kg of brentuximab vedotin was given every 3 weeks for 6 cycles for consolidation. Results: Interim analysis was performed per protocol for futility and safety after 15 evaluable patients were enrolled since April 2012. Out of 15 evaluable patients, 8 patients have completed 6 cycles of brentuximab vedotin, and the remaining 7 patients are currently under active treatment. The median age was 28 years (range 19 – 58), and 7 patients (47%) presented with unfavorable disease defined by the presence of B symptoms, ESR > 50, or > 3 sites of disease. All patients had masses measuring less than 7.5 cm in diameter except one patient who requested an exception to the eligibility criteria for a conglomerate mediastinal mass measuring 10 cm. No grade 3 or above adverse events have been observed with brentuximab vedotin therapy. No grade 2 or above peripheral neuropathy or pulmonary toxicity has been reported. Ten out of 12 patients, who completed ABVD, achieved PET-negative disease after 2 cycles of ABVD, and all 7 patients who completed brentuximab vedotin achieved PET-negative disease and remain in remission with a median follow-up of 7.6 months (range 5.6 – 15). Thus far, none of the treated patients on this protocol required consolidative radiation therapy. Conclusion: In this interim analysis of 15 patients with newly diagnosed limited stage non-bulky HL, brentuximab vedotin as consolidation therapy demonstrates promising safety and clinical activity following ABVD. Enrollment is currently open with the target accrual of 40 patients to assess the feasibility of achieving PET-negative disease and thereby avoiding radiation therapy in at least 85% of patients who receive ABVD followed by brentuximab vedotin consolidation. Table: PET results in HL patients who received ABVD followed by BV Consolidation Interim-PET2 (n = 12) Post ABVD (n = 12) Post BV (n = 7) Deauville 1 0 1 4 Deauville 2 10 11 3 Deauville 3 2 0 0 Deauville ≥ 4 0 0 0 PET, positron emission tomography; HL, Hodgkin lymphoma; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; BV, brentuximab vedotin; Interim-PET-2, PET scan after 2 cycles of ABVD; Post ABVD, PET scan after 2 to 6 cycles of ABVD; Post BV, PET scan after 6 cycles of brentuximab vedotin Disclosures Park: Seattle Genetics: Research Funding; Teva: Research Funding; Janssen: Travel, Travel Other. Off Label Use: Brentuximab vedotin in previously untreated Hodgkin lymphoma patients.

Abstract Abstract 798 Hodgkin lymphoma (HL) is a lymphoid neoplasm associated with the presence of CD30-positive Hodgkin Reed-Sternberg cells in a background of inflammatory cells. The regimen containing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has become a common standard of care for the frontline treatment of HL. However, although ABVD is curative for the majority of patients with advanced stage HL, up to 30% of patients will require a salvage therapy. Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). This phase 1, open-label, multicenter study was conducted to evaluate the safety of brentuximab vedotin when administered in combination with standard therapy (ABVD) or a modified standard (AVD) (ClinicalTrials.gov NCT01060904). Patients received doses of 0.6, 0.9, or 1.2 mg/kg brentuximab vedotin with standard doses of ABVD or 1.2 mg/kg brentuximab vedotin with AVD, depending upon cohort assignment. The combination regimens were administered on Days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. Each regimen evaluated a dose limiting toxicity (DLT) period, defined as any Cycle 1 toxicity requiring a delay of ≥ 7 days in standard ABVD or AVD therapy. Determination of antitumor activity was based on investigator assessment of objective response according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). FDG-PET interpretation for Cycle 2 was performed by a central review per Deauville criteria with uptake above liver background considered positive. Data are presented for the 51 patients treated. Six patients received 0.6 mg/kg, 13 received 0.9 mg/kg, and 6 received 1.2 mg/kg with ABVD; 26 patients received 1.2 mg/kg with AVD. Overall, 37 patients were male (73%) and the median age of all patients was 33 years (range, 18–59). At baseline, 45% of all patients had Stage IV HL, 25% had an IPS score ≥4, and all patients with available ECOG status had a score of 0 or 1. No DLT was observed up to 1.2 mg/kg in either regimen. Common AEs (≥20 patients overall) noted in the ABVD and AVD cohorts, respectively, were nausea (76%, 77%), neutropenia (80%, 69%), peripheral sensory neuropathy (72%, 65%), vomiting (60%, 38%), fatigue (44%, 46%), and constipation (48%, 31%). Common ≥Grade 3 AEs (>10% of patients overall) observed in the ABVD and AVD cohorts, respectively, were neutropenia (80%, 65%), anemia (20%, 12%), febrile neutropenia (20%, 8%), and pulmonary toxicity (24%, 0%). In the ABVD cohorts, 11/25 (44%) patients had AEs of pulmonary toxicity, interstitial lung disease, or pneumonitis that led to discontinuation of bleomycin; 2 of these events led to death. Of these 11 patients, 7 completed treatment with AVD and brentuximab vedotin. In general, these events occurred between Cycles 3 and 6. No pulmonary toxicity was observed in the AVD cohort. The incidence of neuropathy was similar between the ABVD (72%) and AVD (73%) regimens; none of these events were ≥Grade 4 in severity. Overall, 7 patients discontinued brentuximab vedotin due to an AE (5 ABVD patients and 2 AVD patients). At Cycle 2, 48 patients were evaluated by FDG-PET by central review; of these, all 22 ABVD and 24/26 AVD patients were PET negative. Of the 51 patients treated, 4 withdrew consent or were lost to follow-up prior to end of treatment (EOT) assessments. The remaining 47 patients had a 96% objective response rate: 21/22 ABVD patients (95%) and 23/25 AVD patients (92%) achieved CR at the end of frontline therapy, 1 AVD patient had PR (with further workup ongoing), 1 ABVD patient died of AEs (hyponatremia and pulmonary toxicity) prior to EOT, and 1 AVD patient had PD. In patients with newly diagnosed HL, the maximum tolerated dose of brentuximab vedotin combined with ABVD or AVD was not reached; no DLT was observed up to 1.2 mg/kg every 2 weeks, the maximum planned dose. The safety profile observed confirmed that brentuximab vedotin can be safely combined with AVD; however, combination with a bleomycin-containing regimen is not recommended due to the incidence of pulmonary toxicity. The very high CR rate seen in this cohort of advanced-stage HL patients compares favorably with historical controls and warrants comparison with standard therapy. A phase 3 study comparing brentuximab vedotin combined with AVD versus ABVD alone is planned. Disclosures: Ansell: Seattle Genetics, Inc.: Research Funding; Celgene Corporation: Consultancy. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with brentuximab vedotin. Connors:Seattle Genetics, Inc.: Research Funding. Park:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Seattle Genetics, Inc.: Consultancy, Research Funding; Celgene: Honoraria; Novartis: Honoraria, Research Funding; Affimed: Research Funding; Gilead: Research Funding.

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.

Abstract Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.