McWilliams, Robert R.

Abstract Background It is unclear whether results from recent trials of resectable pancreatic ductal adenocarcinoma (PDAC) are generalizable to older patients, who are underrepresented. We aimed to evaluate outcomes of surgery and of neoadjuvant and adjuvant therapy in older patients with resectable PDAC. Patients and Methods We included patients aged ≥65 years with upfront resectable PDAC from a prospectively maintained pancreatic cancer registry from 2007 to 2016. Patients were stratified into ages 65–75 and 75+ years. Overall survival (OS) was assessed in treatment comparisons: (A) surgery (n = 636) versus nonsurgical (n = 178), (B) neoadjuvant therapy (n = 139) versus upfront surgery (n = 497), and (C) adjuvant therapy (n = 379) versus surgery alone (n = 118). We compared neoadjuvant (n = 139) versus adjuvant therapy (n = 379) in an exploratory analysis. Results Nine hundred and three patients had a median age of 73.7 (range, 65–96.6) years. Median OS was 26.6 versus 11.9 months (adjusted hazard ratio [HRadj], 0.4; 95% confidence interval [CI], 0.31–0.52; p < .001) in Comparison A groups, 30.7 versus 25.8 months (HRadj, 0.69; 95% CI, 0.49–0.96; p = .03) in Comparison B groups, and 26.9 versus 17.4 months (HRadj, 0.62; 95% CI, 0.44–0.88; p = .008) in Comparison C groups, respectively. OS benefit in these treatment comparisons was present in age group 75+ with HRadj 0.24 (95% CI, 0.16–0.36; p < .001) in Comparison A and HRadj 0.52 (95% CI, 0.27–1; p = .049) in Comparison B, but not in Comparison C with HRadj 0.68 (95% CI, 0.43–1.08; p = .1). Statistically comparable median OS of patients who received neoadjuvant or adjuvant therapy stratified by age groups was observed. Conclusion Older patients with resectable PDAC who received surgery, neoadjuvant therapy, or adjuvant therapy appeared to have improved survival outcomes compared with those who did not receive such treatment. Implications for Practice Older patients with resectable pancreatic ductal adenocarcinoma (PDAC) in general are underrepresented in large clinical trials and less well studied in terms of the role of surgery, neoadjuvant therapy, and adjuvant therapy. This study collected data on older patients with resectable PDAC from a prospectively maintained single-institutional pancreatic cancer registry of a tertiary referral center from 2007 to 2016. It was found that, with multidisciplinary evaluation, older patients with resectable PDAC who received surgery, neoadjuvant therapy, or adjuvant therapy appeared to have improved survival outcomes compared with those who did not receive such treatment. These results are of substantial importance to practitioners who treat older patients, who are traditionally underrepresented in most clinical trials.

e22052 Background: Metastatic Uveal Melanoma (MUM) is a rare tumor with poor prognosis following development of liver metastasis. We hypothesized that patterns of metastasis in Uveal Melanoma correlate with clinical outcomes. Methods: We retrospectively reviewed patients with MUM at Mayo Clinic, Rochester from January 1999 to August 2019. Patients were stratified into two groups based on the pattern of hepatic and pulmonary metastasis at the time of diagnosis of metastatic disease: Group 1 (≤5 liver metastasis or lung metastasis) and Group 2 ( > 5 liver metastasis without lung metastasis). Baseline characteristics were compared between both groups. Survival analysis was performed using the Kaplan Meier method. Univariate and multivariate analysis were performed for Overall Survival (OS). Results: 147 patients were included in the study (n = 67 Group 1; n = 80 Group 2). In Group 1, 49/67 patients presented with ≤5 liver metastasis and 18/67 had lung metastasis without liver metastasis. Median OS for Group 1 was significantly longer than Group 2 (38 vs. 15 months; p < 0.0001) (Table). On univariate analysis, predictors for OS were: Pattern of Metastasis, ECOG PS > 0, Time to metastasis > 60 months, and Surgical metastatectomy. Pattern of Metastasis was an independent predictor for OS in a multivariate model that included these predictors (p = 0.0004). Group 1 patients were more likely to undergo surgical metastatectomy compared to group 2 (21.5% vs. 1.3%; p < 0.0001). Interestingly, the median time to metastasis from diagnosis of UM was significantly longer for Group 1 as compared to Group 2 (67 vs. 24.5 months; p < 0.0001). Conclusions: Limited (≤5) liver metastasis or lung metastasis (without liver metastasis) at diagnosis predict favorable clinical outcomes in MUM. The occurrence of such metastasis following a significantly longer time from primary diagnosis suggests the existence of a distinct sub-type of metastatic disease with relatively indolent behavior. [Table: see text]

e22020 Background: The combination of nab-paclitaxel (NP) and bevacizumab (BEV) in patients with MM has shown promising clinical activity. AB160 is a 160 nm nano-immunoconjugate of NP nanoparticles non-covalently coated with BEV for targeted delivery into high VEGF expressing tissues. Preclinical data showed that AB160 improved tumor targeting/ tumor inhibition more than NP followed by BEV. Methods: A 3+3 phase I trial was conducted in patients (pts) with MM who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. Dose level 1 (DL1) was 125 mg/m2 NP /50 mg/m2 BEV. Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT < 25,000, serum creatinine ≥ 2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Tumor evaluations (RECIST) were conducted every 8 weeks. Treatment continued until progression or intolerability. Results: 21 pts (11 ♀) aged 36-78 years old were enrolled. One of the first 3 pts on DL1 developed a G2 colonic perforation; this was considered a DLT. One of the next 3 pts on DL1 had a DLT: G4 neutropenia. Of the 3 pts on DL-1 (100 mg/m2 NP/40 mg/m2 BEV), 2 had no DLTs and 1 died of sepsis after C1D1 dose. Enrollment was suspended until an amendment modifying the eligibility criteria was approved by the IRB. The trial reopened. One of the 4 pts on DL-1 and 1 of the 5 pts on DL1 had a DLT: G3 pain and G3 fatigue, respectively. Enrollment ended after 2 of the 3 pts on DL2 (150 mg/m2 NP/ 60 mg/m2 BEV) developed G4 neutropenia. Thus, MTD is DL1. A median of 3 cycles was administered. Treatment ended due to progression (9), intolerability (9), refusal (2) and death (1). There were no objective tumor responses. Common G3-4 toxicities were: neutropenia (33%) and thromboembolic events (19%). Conclusions: AB160 was found to have insufficient clinical benefit in patients with previously treated MM to justify further development. However, parallel phase I testing in gynecologic cancers suggests clinical benefit (abstract #300225). Clinical trial information: NCT02020707.

Management of PD-1 blockade resistance in metastatic melanoma (MM) remains challenging. Immunotherapy or chemotherapy alone provides limited benefit in this setting. Chemo-immunotherapy (CIT) has demonstrated favorable efficacy and safety profiles in lung cancer. Our pre-clinical study showed that in MM patients who have failed PD-1 blockade, the addition of chemotherapy increases CX3CR1+ therapy-responsive CD8+ T-cells with enhanced anti-tumor activity, resulting in improved clinical response. Here, we examined the clinical outcomes of CIT in MM patients after PD-1 blockade failure and the treatment-related changes in CX3CR1+ therapy-responsive CD8+ T-cells. We reviewed MM patients seen between January 2012 and June 2018 who failed anti-PD-1-based therapy and received subsequent CIT, immune checkpoint inhibitors (ICI) or chemotherapy alone. Overall survival (OS), objective response rate (ORR), event-free survival (EFS), and toxicities were assessed. Among 60 patients, 33 received CIT upon disease progression on PD-1 blockade. At a median follow-up of 3.9 years, the CIT group had a median OS of 3.5 years [95% confidence interval (CI) 1.7–NR] vs. 1.8 years (95% CI 0.9–2; P = 0.002) for those who received subsequent ICI (n = 9) or chemotherapy alone (n = 18), with ORR of 59% vs. 15% (P = 0.0003), respectively. The median EFS was 7.6 months (95% CI 6–10) following CIT vs. 3.4 months (95% CI 2.8–4.1; P = 0.0005) following ICI or chemotherapy alone. Therapy-responsive CX3CR1+CD8+ T-cells showed dynamic increase with successful CIT. CIT showed favorable clinical outcomes and acceptable safety profile in PD-1 blockade-resistant patients. CX3CR1+CD8+ therapy-responsive T-cells can be potentially used for monitoring disease response to CIT.

Objectives: Survival benefit of combination over single-agent chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) was demonstrated in younger patients in clinical trials. The authors aimed to evaluate whether this survival benefit of combination chemotherapy is present in elderly patients with metastatic PDAC. Materials and Methods: The authors identified elderly patients (age 65 y or older) with stage IV PDAC and extracted available clinical information from a prospectively maintained institutional pancreatic cancer registry from 2007 to 2016. The primary endpoint was overall survival. Cox proportional hazards regression was used for multivariable survival analyses. Survival outcomes for the entire cohort and by age group I (elderly, 65 to 75 y) and age group II (very elderly, older than 75 y) were assessed. Results: A total of 606 patients were included with a median age of 73.8 years. Among them, 239 patients (39%) received combination chemotherapy and 152 patients (25.1%) received single-agent chemotherapy as first-line treatment. Combination chemotherapy was associated with significantly longer median overall survival compared with single-agent chemotherapy (10.9 vs. 7.5 mo, P<0.001) with hazard ratio 0.62 (95% confidence interval, 0.47-0.81; P=0.001) after adjusting for age, sex, comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status, and carbohydrate antigen 19-9 level. Analyses by age groups indicated that very elderly patients (age group II) benefited from combination chemotherapy compared with single-agent chemotherapy with hazard ratio 0.56 (95% confidence interval, 0.31-1; P=0.049), comparable with the age group I (P age-treatment interaction=0.81). Conclusion: Elderly patients, even those older than 75 years, with metastatic PDAC benefited from combination chemotherapy.

9016 Background: The MAP kinase (MAPK) pathway is of critical importance for keratinocyte proliferation and maturation and is essential for epidermal homeostasis. Occurrence of hyperproliferative skin lesions including keratoacanthomas (KA) and cuSCC are considered a class effect of BRAFi [Anforth 2012, Chu 2012, Mattei 2012]. These effects, as well as promotion of pre-existing RAS-driven malignancies, may be caused by paradoxical activation of the MAPK pathway downstream of BRAF in wild-type BRAF cells. As MEK inhibition blocks downstream MAPK signaling, it was hypothesized that addition of a MEKi to a BRAFi would abrogate these effects [Su, 2012]. Methods: This 4-part phase I/II study enrolled 365 BRAFV600E/Kmutated MM pts in Parts B-D. In part C, 162 pts (BRAFi and MEKi treatment-naïve, ≥ 18 yrs; ECOG PS <2; RECIST measurable disease) were randomized to D monotherapy 150mg BID (D mono) vs. the combination of D (150 mg BID) and T (1 mg or 2 mg QD). Primary endpoints included safety and efficacy. Occurrence of cuSCC (including KA) across three arms in Part C and secondary malignancies with D+T across all Parts are provided below. Results: The difference in incidence of cuSCC between D mono and the D+T (150/1) was statistically significant, whereas the difference in incidence between D mono and D+T (150/2) was not. The median time to onset of cuSCC was 30 days in D mono compared to 282 and 152 days with D+T (150/1 and 150/2, respectively). Of 365 pts who received D+T, 2 (<1%) cases of new cancers (colorectal and gliobastoma) and 2 (<1%) cases of new primary malignant melanoma were reported. Conclusions: These data support the experimental hypothesis that the occurrence of cuSCC (including KA) can be substantially reduced and delayed by the addition of a MEKi to BRAFi therapy. Clinical trial information: NCT01072175. [Table: see text]

9005 Background: Dual inhibition of the MAP kinase (MAPK) pathway with dabrafenib (D) and trametinib (T) in combination has demonstrated clinical benefit compared to D alone in a randomized Phase II trial in V600 BRAF-mutant MM pts, thus delaying the development of BRAFi resistance. Little is known about the efficacy of D + T after BRAFi resistance has been acquired. This analysis evaluates the ability of D + T combination to treat acquired resistance compared to the D + T combination as first-line treatment. Methods: These data from a phase I/II study include 1. BRAFi-resistant group: pts who received 150/2 D+T in Part B (n=26) and Part C (n=43) following progression on BRAFi monotherapy (mono); 2. BRAFi-naïve group: pts who received initial 150/2 D+T in Part B (n=24) and Part C (n=54). Results: Baseline characteristics (ECOG PS, M staging, LDH) were similar across all groups.In the Part B BRAFi-resistant group, 93% of pts previously received D or vemurafenib and all pts received D prior to D+T in Part C. In BRAFi-resistant group, prior best response of CR/PR (38%, 56%), SD (35%, 27%), PD (27%, 7%) was observed in Parts B and C respectively. In BRAFi-resistant group, the ORR and PFS with D+T was lower than initial D+T in BRAFi-naive group. Median duration of response (DoR) in BRAFi-resistant group cannot be calculated due to small no. of pts responding. Median DoR for BRAFi-naïve pts was 11.3 mo and 10.5 mo in Parts B and C respectively. In Part C, the 12-mo overall survival rates in BRAFi-naïve (150/2) pts was 79% vs 70% for pts initially on D mono, despite 80% pts crossing over to D+T combination. Conclusions: The clinical activity for 150/2 D+T combination is consistently superior in BRAFi-naive group vs BRAFi-resistant group in both Parts B and C. Dual MAPK blockade can delay clinical resistance to BRAF inhibition. However, once BRAFi resistance has occurred, the combination of BRAFi + MEKi is far less effective. Clinical trial information: NCT01072175. [Table: see text]

e14594 Background: PNETs are uncommon malignancies and little is known about risk their factors and association with other cancers. Our aim was to evaluate smoking, alcohol use, personal history of diabetes and a family history of PNET and other cancers as potential risk factors. Methods: PNET cases seen at Mayo Clinic Rochester from 2000 to 2011 were evaluated. Insulinoma and high-grade PNETs were excluded. Primary care patients served as controls and were matched (2:1 ratio) to cases on age, sex and region of residence. Cases and controls completed questionnaires at the time of evaluation. Categorical variables were compared with the chi-square test; continuous variables were compared using a two-sample t test. Results: 355 cases were evaluated, mean age was 56.6 years, 52% were males and 96% were White. Personal smoking history was not associated with PNETs (cases 51%, controls 47%, p=0.24). Ever-alcohol use was less common among cases (54% vs. 67%, p=0.001). 19% of cases reported a history of diabetes compared with 11% of controls (p<0.001). Cases were more likely than controls to report a family member with sarcoma (p=0.02), PNET (p=0.024), gall bladder cancer (p=0.024), ovarian cancer (p=0.04) and stomach cancer (p=0.01). Conclusions: Cases with PNETs were more likely than controls to report a history of diabetes and less likely to report alcohol use. There was no association with smoking. Several types of cancer were more commonly reported in family members of cases than controls.

4127 Background: Small bowel adenocarcinoma (SBA) is a rare tumor accounting for less than 2% of all GI tumors. The prognosis of advanced disease is poor. Benefits of adjuvant therapy following complete resection are uncertain. Methods: We retrospectively reviewed the records of 491 pts with primary SBA diagnosed at the Mayo Clinic from 1970–2005. Patients with ampullary and periampullary tumors were excluded. Results: 303 pts (62%) were male and the median age was 62 years. 280 (57%) of the tumors were located in the duodenum, 143 (29%) in the jejunum, 48 (10%) in the ileum and in 20 (9%) the location was not specified. Abdominal pain was the most common principal symptom occurring in 203 pts (43%), followed by anemia/GI bleeding in 104 pts (22%) and nausea/vomiting in 76 pts (16%). The most common histologic grading was 3, occurring in 224 pts (45%). 79 pts (16%) grade 4, 170 pts (35%) grade 2, with 7 (1.4%) grade 1. The TNM staging was as follows: 0: 3 (0.6%), I: 36 (7.3%), II: 133 (27.1%), III: 137 (27.9) and IV: 163 (33.2). In 18 pts (3.7%), data were insufficient for staging. The median survival for the entire cohort was 20.7 months, with 5 and 10 year survival 26% and 19% respectively. Increasing age (p < 0.0001), male sex (p = 0.026), advanced stage (p < 0.0001), grade 4 tumors (p = 0.005) and residual disease after surgery (p < 0.0001) were independently associated with shortened survival in a multivariate analysis. Neither adjuvant chemoradiation (n = 40) nor 5-FU based chemotherapy (n = 33) improved overall survival after complete resection, even after adjusting for age, sex, location, lymph node status and grade (RR 1.17, p = 0.45). This remained true for the subset of patients with resected duodenal tumors as well (RR 1.06, p = 0.83). The use of chemotherapy was associated with prolonged survival in patients with metastatic disease. The median survival and 1-year survival was 15.3 mos vs. 3.1 mos and 59% vs. 5.9% respectively (p < 0.0001), in this highly selected group. Conclusion: SBA is a rare tumor with a relatively poor prognosis. Complete resection of all disease offers the only chance of cure. The benefits of adjuvant therapy remain unknown, but chemotherapy in the metastatic setting may provide survival benefit. No significant financial relationships to disclose.

19561 Background: Diarrhea is a common side effect of chemotherapy (CT). At times, often unpredictably, patients develop profound diarrhea during CT. Though the clinical diagnosis of celiac disease (CD) is relatively rare, (1/ 2000), the serologic prevalence is much higher (1/ 133), suggesting a large number of undiagnosed cases. Latent CD may be unmasked by stressors, such as CT. We hypothesized that undiagnosed CD may account for some cases of severe diarrhea from CT. Methods: We performed a retrospective chart review at the Mayo Clinic (1980–2006) for patients with diagnoses of cancer and CD that received CT at our center. CD cases were confirmed by biopsy (n= 25) or serologic studies. Data analyzed included severe (grade ≥ 3,) diarrhea while on CT, site of primary cancer, diagnosis of CD prior to or after CT, and specific CT agents received. Results: We identified 27 patients with CD and cancer (12 lymphoma, 6 gastrointestinal, 2 leukemia, 2 breast, 1 brain, bladder, lung, uterine, sarcoma) who received CT at our center. Fifteen were diagnosed with CD prior to receiving CT and 12 after, with the former group presumably on a gluten-free diet. One patient was excluded for lack of clinical data. Five of remaining 14 patients (35%) managed for their CD prior to CT had diarrhea, though 4 of these 5 had only mild diarrhea (gr. 1). One patient suffered gr. 3 diarrhea, though was reported to be poorly compliant with his diet. Three patients received treatment with 5- fluorouracil (5FU), and 2 had gr. 1 diarrhea. Five of the 12 patients (42%) with celiac disease undiagnosed prior to CT were reported to have diarrhea during treatment (3 gr. 4; 2 gr. 1). Of those receiving 5FU, 3 out of 4 had severe (gr. 4) diarrhea. The small numbers of patients precluded meaningful statistical analysis. Conclusion: Patients with known CD compliant with a gluten-free diet tolerated CT well. However, in a subset of undiagnosed patients, severe diarrhea developed during CT, most notably with 5FU-based regimens. We propose that when patients have diarrhea disproportionate to other effects, CD should be considered. Also, in malignancies with a high incidence of CD such as lymphoma and small bowel cancer, underlying CD should be considered before CT is given. No significant financial relationships to disclose.