BACKGROUND:S0221 investigated weekly vs every 2 weeks dosing of doxorubicin (A) and cyclophosphamide (C) followed by paclitaxel in patients with high-risk early breast cancer. After an interim analysis, random assignment to the 2 AC arms was stopped for futility, and the trial was modified to study only the paclitaxel schedules. METHODS:Between December 2003 and November 2010, a total of 2716 patients were randomly assigned in a 2 × 2 factorial design to 15 weeks of weekly A and daily C vs 6 cycles of every 2 weeks AC; and weekly paclitaxel for 12 weeks vs 6 cycles of every 2 weeks paclitaxel. Between January 2011 and January 2012, an additional 578 patients were assigned to 4 cycles of every 2 weeks AC and randomly assigned to weekly vs every 2 weeks paclitaxel. Updated survival was assessed using log-rank tests and Cox regression models. We compared outcomes by breast cancer subtype as well. RESULTS:At a median follow-up of 12.1 years, there were no statistically significant differences among the 4 treatment arms in disease-free survival (DFS) (P = .91) or overall survival (P = .34) in the original protocol. Among the 578 patients assigned AC for 4 cycles and randomly assigned to paclitaxel weekly vs every 2 weeks paclitaxel, there were no overall differences in DFS (P = .32) or overall survival (P = .42). CONCLUSION:As there were no statistically significant outcome differences in DFS or overall survival between the studied schedules of AC and paclitaxel with extended follow-up in the original or revised protocol, either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference.

LBA509 Background: NRG-BR003 is a phase III, randomized trial evaluating whether the addition of carboplatin (carbo) to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide (AC) followed by paclitaxel (P) will improve invasive disease-free survival (IDFS) compared to AC followed by P when administered to patients (pts) with operable node-positive or high-risk node-negative triple-negative breast cancer (TNBC). Methods: Eligible pts had operable node-positive or high-risk node-negative TNBC and were randomized to receive dose-dense (DD) AC every 2 weeks for 4 cycles followed by weekly P (80 mg/m2) for 12 doses or the same regimen with carbo AUC of 5 IV every 3 weeks for 4 cycles. Stratification factors were number of positive nodes (0, 1-3, 4-9, 10+) and BRCA mutation status (positive; negative; or unknown). The study was designed to detect a hazard ratio (HR) in IDFS at 0.67 with the addition of carbo. The stratified log-rank test was used for the primary analysis. Secondary endpoints include DRFI, OS, BCFS, and RFI. Results: 769 pts were randomized to control arm (n=385) and carbo arm (n=384) from June 2015 to May 2022. Patient characteristics include age >50 (66%), primary tumors >2 cm (70%), node-positive (69%), and g BRCA pathogenic variants (9%). Delivery of AC was balanced between arms and P delivery was not compromised by co-administration of carbo with a mean of 11.3 doses (sd=2.1) of P with a relative total dose intensity (RTDI) at 0.97 in the control arm and 11.0 doses (sd=2.3) and a RTDI at 0.95 in the carbo arm. At data cutoff (2/28/25), median follow-up was 79.4 mos. IDFS events were reported in 92 pts (23.9%) in the control group and 76 (19.8%) in the carbo group. The stratified log-rank test p-value was 0.097, not meeting the prespecified significance of 0.049; the HR was 0.77 (95% CI, 0.57-1.05). The 5-year IDFS (95% CI) was 77.8% (73.7%-82.2%) vs 82.9% (79.2%-86.9%), respectively. HR was similar across patient subgroups, including germline BRCA and nodal status. Grade ≥3 treatment-related AE rates were 51.1% in the control group and 72.9% in the carbo group. Grade 5 events were 0.8% vs 0.8%, respectively. Conclusions: The addition of carbo to P following DD AC for adjuvant therapy of node-positive or high-risk node-negative TNBC did not result in a statistically significant improvement in IDFS, DRFI, or OS. However, it increased grade ≥3 treatment-related AE rates. Although not meeting criteria for efficacy across the entire study population, results support planned translational research to identify subsets of pts who may benefit from carbo. Clinical trial information: NCT02488967 . Secondary efficacy results of DRFI and OS. End Points Treatment 5-year Event-free Rate (95% CI) HR (95% CI) DRFI AC → P 84.4% (80.7-88.2) 1 AC → P+Carbo 88.7% (85.5-92.0) 0.74 (0.50-1.10) OS AC → P 84.4% (80.8-88.3) 1 AC → P+Carbo 87.7% (84.4-91.2) 0.81 (0.56-1.16)

Background: While the landscape of metastatic breast cancer treatment has evolved over the years with incorporation of targeted agents and antibody drug conjugates, chemotherapy continues to be the mainstay of adjuvant treatment for high-risk early breast cancer. S0221 was a previously reported phase III randomized trial performed by the North American Breast Cancer Intergroup (now known as the National Clinical Trials Network [NCTN]) investigating alternative dosing schedules of chemotherapy for early breast cancer. Methods: S0221 investigated weekly (arms 2 and 4) doxorubicin (A)/cyclophosphamide (C) + granulocyte colony stimulating factor (GCSF; filgrastim or pegfilgrastim) versus (vs.) every 2 weeks (Q2W) (arms 1 and 3) schedule AC, followed by paclitaxel (P) given Q2W or weekly for 12 weeks as post-operative adjuvant therapy in node-positive or high-risk node-negative breast cancer. Weekly AC was given as doxorubicin 24mg/m2 IV once per week and cyclophosphamide 60mg/m2 orally once per day with GCSF. Between December 2003 and November 2010, 2716 patients were randomized in a 2x2 factorial design to: 1) 15 weeks of weekly AC vs. 6 cycles of Q2W AC and 2) P weekly vs. P Q2W with GCSF support and this accounted for arms 1-4. After enrollment of 2716 patients, randomization to the two AC arms was stopped for futility and the trial was modified to study only the P schedules. Between January 2011 and January 2012, an additional 578 patients were assigned to 4 cycles of Q2W AC and randomized to P weekly vs. Q2W accounting for arms 5-6. Here, we present updated survival outcomes of four arms on the original protocol and report, for the first time, analysis of 578 patients from two additional arms on the revised protocol. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 12.1 years, among the patients treated in the original protocol, there were no significant differences among the four treatment arms for disease free survival [DFS] (p=0.91) or overall survival [OS] (p=0.34). When stratified by disease subtype, the human epidermal receptor-2 (HER2) positive cohort had the highest 10-year DFS rate (77.7%) compared to HR-positive/HER2-negative (70.6%) or HR-negative/HER2-negative (70.3%) cohorts (p value = 0.0005). The HER2-positive cohort also had a superior 10-year OS rate of 82.3% compared to HR-positive/HER2-negative (78.1%) or HR-negative/HER2-negative (74.9%) cohorts (p=0.0044). Among the 578 patients assigned AC for 4 cycles and randomized to P weekly vs. Q2W P, there were no overall differences in DFS (p=0.32) or OS (p=0.42). There was no difference in 10-year DFS rate between original (71.3%) or revised (74.4%) protocol (HR 0.80; 95% CI 0.75-1.05). Patients were also stratified in terms of sex (23 men enrolled) and race (379 Blacks enrolled). While women have superior DFS and OS compared to men, due to small number of men and wide CI, these data should be interpreted with caution. Black patients had worse DFS and OS (10-year DFS rate of 64.2% vs. 72.8%; 10-year OS rate of 70.4% vs. 79.0%) compared to non-Blacks. In terms of toxicity, cardiac toxicity profile was more favorable in arms 2 and 4 (0.5-0.7%) that used weekly AC compared to the other four arms that incorporated AC Q2W (1.1-3.3%). There was more skin toxicity with weekly AC schedule with 15.7-16.1% events compared to 2.4-4.0% events in the other four arms. There was no difference in infectious risk or changes in metabolic profile but there were more neurological AEs, and more pain with arms that used Q2W paclitaxel compared to weekly paclitaxel. Conclusion: As there were no significant outcome differences in DFS or OS between the studied schedules with extended follow-up in the original cohort or in the additional 578 patients treated on the revised protocol, either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference rather than efficacy. Citation Format: Azka Ali, William E Barlow, Halle CF Moore, Timothy J Hobday, Claudine Isaacs, Muhammad Salim, Jonathan K Cho, Kristine J Rinn, Kathy S Albain, Helen K Chew, Gary V Burton, Timothy D Moore, Gordan Srkalovic, Bradley A McGregor, Lawrence E Flaherty, Danika. Long-Term Follow-up and updated analysis from S0221, Comparing Alternative Dose-Schedules of Adjuvant Anthracycline/Taxane Therapy in High-Risk Early Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr RF1-04.

e21574 Background: Access to routine cancer care during COVID-19 pandemic was greatly affected. The impact of this on melanoma care is unknown. Breslow thickness (BT) was seen to decrease and then increase during and post-COVID-19 lockdown in Italy. Here, we aim to study the impact of COVID-19 lockdown on melanoma care in the United States. Methods: Patients diagnosed with cutaneous melanoma (CM) pre (September 15th 2019-March 14th 2020), during (March 15th-June 14th 2020), and post-lockdown (June 15th-December 14th 2020) were retrospectively studied using Metropolitan Detroit Cancer Surveillance System (MDCSS) database. Patients without an identifiable primary lesion, or with ocular, mucosal, or acral melanoma were excluded. Demographic and clinical characteristics were reviewed. The primary endpoint was median BT during and post vs pre-lockdown. Fisher's exact and Kruskal-Wallis tests were performed for categorical and continuous variables, respectively, to compare groups. Interaction in subgroup analyses was assessed using likelihood ratio tests. Linear regression analyses were performed with Box-Cox transformed BT. Cox proportional hazards regression analyses were performed for overall survival. Covariates for multivariable analysis were selected using LASSO-based penalized regression models. Results: 802 patients were included (pre N = 347, during N = 87, post N = 368). Patients diagnosed with CM post-lockdown were younger (age < 50 years pre = 14%, during = 13%, post = 23%). More patients diagnosed pre-lockdown carried government-issued insurance (pre = 48%, during = 39%, post = 38%). No difference (diff) in median BT was seen between periods (median = 0.6mm for pre, during, and pos). Married status was associated with a lower BT vs unmarried (diff = -0.19, 95% CI -0.36 to -0.014, p = 0.034) and higher census tract poverty level was associated with a higher BT (5%-10% diff = 0.17, 95% CI 0.004 to 0.33, p = 0.045; 10%-100% diff = 0.27, 95% CI 0.093 to 0.45, p = 0.003) vs 0-5% poverty on univariable analysis. Male gender was associated with a lower BT on multivariable analysis (diff = -0.12, 95% CI -0.20 to -0.04, p = 0.005) and lower risk of death on univariable analysis (HR = 0.50, 95% CI 0.31 to 0.82, p = 0.006). Conclusions: We found no difference in median BT during and post- vs pre-lockdown. We also identified at-risk populations (female, unmarried, and living in greater poverty areas) who could benefit from proactive melanoma care. Time to surgery from initial diagnosis during and post vs pre-lockdown would be of interest to study further.

BackgroundCell cycle inhibition is an established therapeutic approach for some cancers. A multicenter, single-arm, phase 2 trial ( identifier NCT00937937) of the cyclin-dependent kinase inhibitor SCH 727965 (NSC 747135; dinaciclib) was conducted in patients with metastatic melanoma to determine its clinical activity.MethodsPatients with metastatic melanoma of cutaneous or mucosal origin were eligible if they had zero to one previous treatments, a Zubrod performance status of 0-1, and adequate organ function. SCH 727965 50 mg/m2 was given intravenously every 3 weeks until progression. Co-primary end points were 1-year overall survival (OS) and 6-month progression-free survival (PFS).ResultsSeventy-two patients were enrolled from July 1, 2009, to November 1, 2010, at 24 institutions. Sixty-eight percent of patients had M1c disease, and 43% had elevated lactate dehydrogenase levels. Twenty-eight patients (39%) experienced grade 4 adverse events, including 20 cases of neutropenia. Sixty-seven patients were evaluable for response. There was a response in zero of 67 patients (95% confidence interval [CI], 0%-5%), and stable disease was observed in 21%. The estimated median PFS was 1.4 months (95% CI, 1.4-1.5 months), and the 6-month PFS rate was 6% (2%-13%). The median OS was 8.2 months (95% CI, 5.5-10.5 months), and the 1-year OS rate was 38% (95% CI, 26%-49%).ConclusionsThis multicenter, US National Cancer Institute Cancer Therapy Evaluation Program-sponsored trial of SCH 727965 was conducted at a time when the current generation of effective therapies for melanoma were not available. Although the null hypothesis of 1-year OS was rejected, the minimal PFS impact and substantive toxicity indicated that this regimen lacks justification for further investigation as a single agent. A multicenter, US National Cancer Institute Cancer Therapy Evaluation Program-sponsored, single-arm, phase 2 trial (ClinicalTrials.gov identifier NCT00937937) of the cyclin-dependent kinase inhibitor SCH 727965 (NSC 747135, dinaciclib) was conducted in patients with metastatic melanoma to determine its clinical activity. Dinaciclib failed to demonstrate sufficient clinical activity to justify its further investigation as a single agent.

Background Metastatic human epidermal growth receptor II (HER2) negative breast cancer remains incurable. Our phase I study showed that anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) may be effective against HER2-tumors. This phase II trial evaluates the efficacy and immune responses of HER2 BATs given to patients with metastatic HER2-estrogen and/or progesterone receptor positive (HR+) and triple negative breast cancer (TNBC) as immune consolidation after chemotherapy. The primary objective of this study was to increase the traditional median time to progression after failure of first-line therapy of 2–4 months with the secondary endpoints of increasing overall survival (OS) and immune responses.Methods HER2- metastatic breast cancer (MBC) patients received 3 weekly infusions of HER2 BATs and a boost after 12 weeks.Results This phase II study included 24 HER2-HR+ and 8 TNBC patients who received a mean of 3.75 and 2.4 lines of prior chemotherapy, respectively. Eight of 32 evaluable patients were stable at 4 months after the first infusion. There were no dose limiting toxicities. Tumor markers decreased in 13 of 23 (56.5%) patients who had tumor markers. The median OS was 13.1 (95% CI 8.6 to 17.4), 15.2 (95% CI 8.6 to 19.8), and 12.3 (95% CI 2.1 to 17.8) months for the entire group, HER2-HR+, and TNBC patients, respectively. Median OS for patients with chemotherapy-sensitive and chemotherapy-resistant disease after chemotherapy was 14.6 (9.6–21.8) and 8.6 (3.3–17.3) months, respectively. There were statistically significant increases in interferon-γ immunospots, Th1 cytokines, Th2 cytokines, and chemokines after HER2 BATs infusions.Conclusions In heavily pretreated HER2-patients, immune consolidation with HER2 BATs after chemotherapy appears to increase the proportion of patients who were stable at 4 months and the median OS for both groups as well as increased adaptive and innate antitumor responses. Future studies combining HER2 BATs with checkpoint inhibitors or other immunomodulators may improve clinical outcomes.

Combination immunotherapy with sequential administration may enhance metastatic melanoma (MM) patients with long-term disease control. High Dose Aldesleukin/Recombinant Interleukin-2 (HD rIL-2) and ipilimumab (IPI) offer complementary mechanisms against MM. This phase IV study assessed the sequenced use of HD rIL-2 and IPI in MM patients. Eligible Stage IV MM patients were randomized to treatment with either two courses of HD rIL-2(600,000 IU/kg) followed by four doses of IPI 3 mg/kg or vice-versa. The primary objective was to compare one-year overall survival (OS) with historical control (46%, Hodi et al., NEJM 2010). Secondary objectives were 1-year progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) profile. Evaluable Population (EP) included patients who received at least 50% of planned treatment with each drug. Thirteen and 16 patients were randomized to receive HD rIL-2 first, and IPI first, respectively. One-year OS rate was 75% for intention to treat population. Eighteen patients were included in EP, 8 in HD rIL-2, 10 in IPI first arm. In EP, 1-year OS, PFS and ORR rates were 87%, 68%, and 50%, respectively. The frequency of AEs was similar in both arms with 13 patients experiencing Grade 3 or higher AEs, 3 resulting in the end of study participation. There was one HD rIL-2-related death, from cerebral hemorrhage due to thrombocytopenia. In this study with small sample size, HD rIL-2 and IPI were safe to administer sequentially in MM patients and showed more than additive effects. 1-year OS was superior to that of IPI alone from historical studies.

Background The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood. Patients and methods E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034). Results Occurrence of grades 1–2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1–2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1–2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1–2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1–2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3–4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3–4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1–2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found. Conclusions Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3–4 irAEs.

PURPOSE:Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI. PATIENTS AND METHODS:E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI. RESULTS:Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti-programmed death 1 use in the HDI arm versus ipi3 and ipi10 (P ≤ .001). CONCLUSION:Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.

Background: Brain metastases are a significant cause of mortality and morbidity for patients with melanoma. We hypothesize that the development of brain metastases may be explained by molecular heterogeneity between primary cutaneous melanoma (PCM) or extracranial (ECM) and brain (MBM) melanoma metastases. Materials and Methods: We compared next-generation sequencing, tumor mutational burden (TMB), and immunohistochemical staining for PD-L1 expression, among 132 MBM, 745 PCM, and 1190 ECM. Results: The most common genetic alterations among MBM included: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Four genes were found with higher frequency among MBM compared to PCM or ECM: BRAF (52.4% v 40.4% v 40.9%), SETD2 (11.9% v 1.9% v 3.9%), PBRM1 (7.5% v 1.6% v 2.6%), and DICER1 (4.4% v 0.6% v 0.4%). MBM showed higher TMB (p = .04) and higher PD-L1 expression (p = .002), compared to PCM. PD-L1 expression was slightly higher among MBM compared to ECM (p = .042), but there was no difference between TMB (p = .21). Conclusions: Our findings suggest a unique molecular profile for MBM, including higher rates of BRAF mutations, higher TMB and higher PD-L1 expression, and also implicate chromatin remodeling in the pathogenesis of MBM.

Background Sex differences in tumor immunity and response to immunotherapy were shown in murine models and descriptive analyses from recent clinical trials. Female sex hormones have been implicated in melanoma development and response to systemic therapy. We hypothesized a gender difference in response to adjuvant immunotherapy with ipilimumab (3 or 10 mg/kg; ipi3 or ipi10) versus high dose IFNα (HDI) as tested in the E1609 trial. Methods E1609 demonstrated significant overall survival (OS) benefit with ipi3 versus HDI.1 We investigated treatment efficacy between ipi and HDI in the subgroups by sex (female, male), age (< 55 or ≥55), stage at study entry (IIIB, IIIC, M1a/1b), ECOG performance status (PS 0, 1), ulceration (yes, no), primary tumor (known, unknown), number of lymph nodes involved (0, 1, 2–3, 4+). Forest plots were created to compare OS and RFS with ipi3 vs. HDI and ipi10 vs. HDI using the concurrently randomized ITT populations. For the estimated HRs, 95% confidence intervals were created for all subgroups. Results The subgroups of female, stage IIIC, PS=1, ulcerated, in-transit without lymph node involvement demonstrated significant improvement in overall survival (OS) and/or relapse free survival (RFS) with ipi3 versus HDI as summarized in table 1. Female sex was significant for both OS and RFS and was further explored. In investigating RFS with ipi3 versus HDI, a multivariate Cox regression model including sex, treatment and interaction term of sex*treatment, indicated a significant interaction between sex and treatment (P = 0.026). Including sex, PS (0 vs. 1), age (<55 vs. 55+), ulceration (yes vs. no), stage (IIIB, IIIC, M1a, M1b), treatment and interaction term of sex*treatment, indicated a significant interaction between sex and treatment (P = 0.024). While similar trends were seen, no significant interactions between sex and treatment effect were found in the OS multivariate analysis or in the comparison of ipi10 versus HDI. When exploring age, in the univariate analyses in the ipi3 versus HDI comparison older women appeared to drive most of the difference (age ≥55: OS, P=0.02 and RFS, P=0.08; differences non-significant for women <55). Table 1. Conclusions Female sex was independently associated with RFS adjuvant immunotherapeutic benefit from ipi3, supporting a potentially important role for female related factors in the immune response against melanoma, and these warrant further investigation. Trial Registration NCT01274338 Ethics Approval The study protocol was approved by the institutional review board (IRB) of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. This study was monitored by the ECOG-ACRIN DataSafety Monitoring Committee and the NCI. Consent All patients provided IRB-approved written informed consent. Reference Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567–575. PMID: 31880964.

60 Background: E1609 evaluated adjuvant ipilimumab at 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus high-dose interferon-α (HDI). In-depth analysis of irAEs and the use of immunosuppressants and hormone replacement may provide important lessons for management and future research. Methods: E1609 enrolled 1670 adult pts with resected cutaneous melanoma (AJCC7 IIIB, IIIC, M1a, M1b); Table. We investigated the characteristics of irAEs, corticosteroid, immunosuppressant and hormone use on the ipi arms and association with outcome. Stratified log-rank test was used and since most irAEs were observed within 3 months of initiating ipi, a 3-month landmark adjustment analysis was conducted. Results: The rates of corticosteroid, immunosuppressant and hormone use by treatment are summarized in Table and none had a significant association with RFS or OS. Significant association between occurrence of grade 1-4 irAEs (vs. no AE) and RFS was observed [5-year RFS: 0.49, 95% CI: (0.45, 0.52) compared to 0.41, 95% CI: (0.31, 0.50); landmark p=0.010]. Occurrence of grade 1-2 irAEs appeared to have a stronger association with RFS [5-years RFS: 0.52, 95% CI: (0.47, 0.56) compared to 0.41, 95% CI: (0.31,0.50) with no AE; p=0.006] and a trend towards improved OS [5-year OS: 0.75, 95%CI:( 0.71, 0.79) compared to 0.67, 95% CI: (0.56, 0.75) with no AE; p=0.064]. Among specific irAEs, rash was most significantly associated with RFS (p = 0.004 and 0.002) and OS (p = 0.007 and 0.003) for grade 1-4 and grade 1-2, respectively, followed by endocrinopathies, and weaker associations seen with other AEs. Conclusions: Adjuvant therapy with ipi is associated with significant irAEs that appear to be related to the immune mechanism of action. Corticosteroids and immunosuppressants were not shown to negatively affect the clinical outcomes. Predictors of irAE risk and understanding the underlying mechanisms are a major gap and are currently actively being investigated. Clinical trial information: NCT01274338. [Table: see text]

9504 Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3; HR 0.78, 95.6% RCI (.61, 1.00); p = 0.044. The prespecified efficacy boundary was crossed. For RFS, HR 0.85, 99.4% CI (.66, 1.09), p = 0.065. In the 2nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS [HR 0.88, 95.6% CI (.69, 1.12)] and RFS [HR 0.84, 99.4% CI (.65, 1.09)] in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. Clinical trial information: NCT01274338.

9565 Background: Nearly 50% of metastatic melanoma patients develop brain metastases, warranting further investigation into the biology of this event. Methods: We analyzed 132 MBM and 745 CM submitted to Caris Life Sciences from 2015-2018, using next generation sequencing of a 44 or 592 cancer-related gene panel, tumor mutational burden (TMB), and PD-L1 expression by IHC. Genomic alterations (GA), including somatic mutations or CNA, were reported. High TMB (TMB-H) was defined as ≥17 mut/Mb. Comparison of molecular profiles, including cancer-related genes and recurrently altered pathways, between tumor sites and by genomic subgroup (BRAF, NRAS, KIT, NF1), was performed using Fisher’s exact test. Results: Among 132 MBM, 72.7% were male, with median age 62 yo (range 25-83). The most common GAs among MBM were: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Compared to CM, MBM were more often TMB-H (53.7% v 38%, p = .025), with higher PD-L1 expression, using both a ≥1% (54.4% v 35.6%, p = .002) and ≥5% cut-off (32.9% v 15.9%, p = .0006). MBM showed higher rates of GAs among: SETD2 (11.9% v 1.9%, p = .0008), BRAF (52.4% v 35.6%, p = .017), PBRM1 (7.5% v 1.6%, p = .018), KRAS (4% v 1%, p = .026), CCND1 (2.9% v 0%, p = .03), and DICER1 (4.4% v 0.6%, p = .04), compared to CM. Alterations of the MAPK (87.9% v 77.8%, p = .015) and SWI/SNF (22.1% v 11.6%, p = .036) pathway were more frequent in MBM, than CM. When analyzed by genomic subgroup, BRAF+ MBM had more GAs involving the PI3K pathway (20% v 5.1%, p = .027), compared to BRAF WT MBM. NRAS+ MBM had higher PD-L1 expression at the ≥1% cutoff (66.7% v 38.6%, p = .05), but not ≥5%, compared to NRAS WT MBM. NF1+ MBM had more GAs involving the SWI/SNF (60% v 11.6%, p = .003) pathway, as opposed to NF1 WT MBM. No significant associations were seen between KIT status, TMB, PD-L1 or other pathways among MBM. Conclusions: In this cross-sectional study, MBM demonstrated higher PD-L1 expression and were more often TMB-H, compared to CM. MBM also featured more GAs involving BRAF and the MAPK pathway. We identified two novel genes, PBRM1 and SETD2, as well as recurrent alterations of the SWI/SNF pathway, supporting future studies of chromatin remodeling pathways in MBM.

Background: Data on the characteristics of patients who are likely to experience adverse events, both immune-related and non-immune-related, from programmed cell death-1 (PD1) inhibitors are limited. Patients and Methods: Data from patients who received ≥1 dose of single-agent PD1 inhibitor between August 3, 2011 and August 31, 2016 were obtained from our Institution's pharmacy database. AEs were graded using Common Terminology Criteria for Adverse Events version 4. Results: One hundred and eighty-two patients received at least one dose of single-agent PD1 inhibitor prior to data cut-off. After excluding 14 patients with uncommon malignancies, the total number of patients were 168. The median age was 63 (range=24-92) years. There were 87 (52%) cases of non-small cell lung cancer (NSCLC), 35 (21%) of renal cell carcinoma (RCC), 12 (7%) of melanoma, 18 (11%) of Hodgkin's lymphomas, eight (5%) of head and neck squamous cell carcinoma (HNSCC) and eight (5%) of small cell lung cancer. Considering grade 2 or more AEs, 30 (18%) patients had kidney injury, 34 (20%) hypothyroidism, 36 (21%) transaminitis, 20 (12%) pneumonitis, and 18 (11%) colitis. Patients with RCC had higher odds of experiencing grade 2 or more kidney injury than patients with other primary tumor types (adjusted p=0.025), whereas patients with Hodgkin's lymphoma and HNSCC had higher odds of grade 2 hypothyroidism (adjusted p=0.005). Patients with NSCLC had higher risk of death with pneumonitis than those whose primary cancer was not NSCLC (adjusted p=0.005). Discussion: The increased odds of patients with Hodgkin's lymphoma and HNSCC experiencing grade 2 or more hypothyroidism may be related to previous radiation exposure. Most patients with RCC had undergone nephrectomy, making them more susceptible to acute kidney injury. When pneumonitis occurred in patients with primary NSCLC, the overall survival was significantly worse. The duration of PD1 therapy was significantly associated with onset of pneumonitis (p=0.007). Conclusion: The site of primary tumor or metastasis may help predict the most common AEs in patients treated with PD1 inhibitors.

1080 Background: This study presents a phase II cell therapy trial in 32 women with metastatic or locally advanced HER2- breast cancer (BrCa) who received infusions of anti-CD3 x anti-HER2 bispecific antibody armed activated T cells (BATs). This phase II study (NCT 01022138) was conducted to determine if BATs infusions could improve time to progression (TTP) and overall survival (OS), as well as to confirm the toxicity profile of BATs. Methods: The phase II included 32 patients with a median of 4 lines of therapy (7 TNBC and 25 HR/PR+ HER2- patients) with an average age of 52.5 years (range 28-75 years). Twenty-one patients had ≥3 lines of prior therapy and 11 patients had 1-2 lines. Peripheral blood mononuclear cells (PBMC) were stimulated with anti-CD3 antibody and expanded in IL-2, armed with HER2Bi, and aliquoted for the clinical trial. Patients received oncologist’s choice of chemotherapy (4 cycles/4 months) followed by 3 infusions of BATs given once per week for 3 weeks and a boost given 12 weeks after the 3rd infusion. Results: Fifteen of 32 (ORR of 46.8%) who had received any cells had stable disease (SD) at 1 month after the last infusion, and 8 of 15 (25%) had SD > 4 months. For patients who completed 3 or 4 infusions (17-83 x 109 BATs), 8 of 31 patients had TTP > 4 months. One patient completed 2 infusions (17 x 109 BATs). There were no dose limiting toxicities (DLTs). Tumor markers decreased in 13 of 23 (56.5%) patients with evaluable markers. The median OS was 13.8, 16.5, and 12.4 months for all, ER/PR+, and TNBC, respectively. OS for all patients with chemosensitive (chemoS) and chemoresistant (chemoR) disease was 14.6 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in HER2- ER/PR+ patients was 16.5 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in TNBC patients was 12.4 and 22.6 months, respectively (NS). The median TTP for all, HER2- ER/PR+, and TNBC patients was 2.7, 2.9, and 1.4 months, respectively. Increases in serum IL-2 and IL-12 were associated with BATs infusions. Conclusions: Targeting HER2- tumors was safe. There were trends toward improved survival in patients who were HER2-/ER/PR+ TNBC, patients who were chemoS, was associated with increased TTP and OS in all groups, and was associated with decreased tumor markers in those who received 4 infusions. Immune studies showed evidence for induction of adaptive immunity directed at breast cancer antigens. Targeting metastatic HER2- BrCa with BATs shows promise. Clinical trial information: NCT 01022138.

Background Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes. Methods Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment naïve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7–18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1–5 and days 15–19. The primary objective was to assess complete responses (CR) at 10 weeks ±3 (assessment 1) and 26 weeks ±3 (assessment 2) from the start of HD IL-2. Results Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3–24) for both cohorts combined, and 27% (95% CI 8–55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure. Conclusions Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone. Trial registration NCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188

521 Background: S0221 investigated weekly vs q 2 week dosing of doxorubicin/cyclophosphamide (AC) and paclitaxel (P) in patients (pts) with high risk early breast cancer as previously reported (JCO 33:58-64, 2015). After enrollment of 2716 pts randomization to the two AC arms was stopped for futility and an additional 578 pts received 4 cycles of q 2 week AC and were randomized to P weekly (Pw) or P q 2 weeks (P2). We report updated results of the original trial design and the first report of the 578 pts treated with AC x 4 and Pw x 12 or P2 x 6. Methods: Between December 2003 and November 2010, 2716 pts were randomized in a 2x2 factorial design to 1) 15 weeks of weekly AC (A 24 mg/m2/week and C 60 mg/m2/day po) vs 6 cycles of q 2 week AC (A 60 mg/m2 and C 600 mg/m2) and 2) Pw (paclitaxel 80 mg/m2/week x 12) vs P2 (paclitaxel 175 mg/m2 q 2 weeks x 6), with growth factor support as previously described. After study amendment 578 patients received 4 cycles of q 2 week AC followed by Pw or P2. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 8.5 years, among the pts treated in the original protocol, there were no significant differences among the four treatments for DFS (p=0.21) or OS (p=0.08). The triple-negative subset had worse DFS (P<0.001) than the HER2-positive or ER/PR+/HER2- subsets, with 5 year DFS of 75% vs 83% and 84%, respectively. While we previously found in the triple negative subset that the arm using q 2 weeks for both AC and paclitaxel was marginally superior, the differences among the arms are no longer significant for DFS (p=0.12) or OS (p=0.11). Among the 578 pts assigned ACx4 and randomized to Pw v P2 there were no overall differences in DFS (p=0.70) or OS (p=0.63) after 4.4 years median follow-up. Conclusions: There were no significant differences in DFS or OS between any of the schedules with extended follow-up in the original cohort and no difference in outcome by paclitaxel schedule for the 578 additional patients in the revised protocol. Either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference rather than efficacy. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc. Clinical trial information: NCT00070564.

The incidence of CNS progression in patients with high‐risk regional melanoma (stages IIIAN2a‐IIIC) is not well characterized. Data from the S0008 trial provided an opportunity to examine the role of CNS progression in treatment failure and survival. All patients were surgically staged. Following wide excision and full regional lymphadenectomy, patients were randomized to receive adjuvant biochemotherapy (BCT) or high‐dose interferon alfa‐2B (HDI). CNS progression was retrospectively identified from data forms. Survival was measured from date of CNS progression. A total of 402 eligible patients were included in the analysis (BCT: 199, HDI: 203). Median follow‐up (if alive) was over 7 years (range: 1 month to 11 years). The site of initial progression was identifiable in 80% of relapsing patients. CNS progression was a component of systemic melanoma relapse in 59/402 patients (15% overall). In 34/402 patients (9%) CNS progression represented the initial site of treatment failure. CNS progression was a component of initial progression in 27% of all patients whose melanoma relapsed (59/221). The risk of CNS progression was highest within 3 years of randomization. The difference in CNS progression rates between treatment arms was not significant (BCT = 25, HDI = 34, P = 0.24). Lymph node macrometastases strongly associated with CNS progression (P = 0.001), while ulceration and head and neck primaries were not significant predictors. This retrospective analysis of the S0008 trial identified a high brain metastasis rate (15%) in regionally advanced melanoma patients. Further studies are needed to establish whether screening plus earlier treatment would improve survival following CNS progression.