Supplemental Methods. Supplemental Table 1: Dose levels for irinotecan, 5-FU, leucovorin and nab-paclitaxel

Objectives Acceptance and commitment therapy (ACT) is a promising behavioural intervention to improve quality of life in patients with advanced cancer and their family caregivers. Little qualitative research has examined the effects of ACT in cancer populations. Thus, this qualitative study examined the perceived impact of ACT, including mindfulness practice and values-based action, on patients with advanced gastrointestinal (GI) cancer and their family caregivers. Methods Individual, semistructured qualitative interviews were conducted with 13 patients with stage IV GI cancer and 14 family caregivers following their participation in a six-session ACT intervention. Data were analysed using an immersion/crystallisation approach. Results Most participants identified benefits of ACT that facilitated their adjustment to cancer or caregiving. Patients and caregivers described several effects of mindfulness, including improved management of fatigue and other symptoms, improved emotion regulation skills and an ability to savour the present moment. Some participants reported misperceptions of the purpose of mindfulness, such as emptying the mind of thoughts or relaxing. In addition, engaging in actions based on personal values often led to patient empowerment (eg, renewed sense of purpose in life), improved caregiver self-care and better relationship quality between patients and caregivers. Conclusions Results raise hypotheses about potential mechanisms and outcomes of ACT interventions that warrant examination. Findings also suggest that enhancing education on mindfulness in ACT interventions may reduce conceptual misunderstandings. Finally, results suggest that a dyadic ACT intervention may improve relationship functioning between family members.

Supplementary Data from Epidermal Growth Factor Receptor Is Required for Colonic Tumor Promotion by Dietary Fat in the Azoxymethane/Dextran Sulfate Sodium Model: Roles of Transforming Growth Factor- and PTGS2

Patients with advanced gastrointestinal cancer often experience high symptom burden, which is associated with heightened distress in both patients and their family caregivers. Few interventions have been tested to jointly address patient and caregiver symptoms in advanced gastrointestinal cancer. In a randomized pilot trial, telephone-based, dyadic acceptance and commitment therapy (ACT) was found to be feasible in this population. The present secondary analyses examined the impact of this intervention on patient and caregiver physical and psychological symptoms. Patients and caregivers (N = 40 dyads) were recruited from clinics in Indianapolis, Indiana and randomized to either six weeks of telephone-based ACT or education/support, an attention control condition. Outcomes were assessed at baseline and at 2 weeks and 3 months post-intervention. Study group differences in outcomes were not statistically significant. However, when examining within-group change, only ACT patients experienced moderate reductions in pain severity and interference at 2 weeks post-intervention (effect size [ES]=-0.47; -0.51) as well as moderate reductions in depressive symptoms at 2 weeks (ES=-0.42) and 3 months (ES=-0.41) post-intervention. ACT caregivers experienced moderate reductions in sleep disturbance (ES=-0.56; -0.49) and cognitive concerns (ES=-0.61; -0.85) across follow-ups. Additionally, caregivers in both conditions experienced moderate reductions in fatigue (ES=-0.38 to -0.70) and anxiety (ES=-0.40 to -0.49) across follow-ups. Findings suggest that ACT may improve certain symptoms in dyads coping with advanced gastrointestinal cancer and warrant replication in a larger trial.

731 Background: The incidence of PDAC is on the rise and it is predicted to be the 2nd leading cause of cancer related mortality in the next decade. Most patients present with advanced disease at diagnoses with limited systemic treatment options. Fluoropyrimidines are active in PDAC. Lonsurf (L) is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Preclinical data demonstrate Lonsurf may have activity in 5-FU resistant malignancies. This phase I study combines Gem, nab-P, and L. Methods: Gem and nab-P are dosed on days 1 and 15 IV on a 28 day cycle. L (20-30mg/m2) is dosed twice daily on days 2-6 and 16-20 (table 1). Dose escalation is by 3+3 design. Key eligibility include pts with untreated locally advanced or metastatic PDAC, ECOG 0-1, and adequate hepatic and bone marrow function. Results: 14 pts (median age 62 yrs [range 43-74]) have been enrolled. Dose was initiated at DL1. The first 3 pts were treated without DLT. DL2 exceeded the MTD with 1 patient experiencing grade 3 infection (cholangitis). Dose expansion to 7 patients was completed at DL 1 with no further DLTs. The RP2D is Gem 800mg/m2, Nab-P 100mg/m2, and L 25mg/m2. Of the 10 patients with evaluable disease, 2 (20%) had PR and 7 (70%) had SD. Pts were on study a median of 14 months (range 4 -31+). Most common grade 3/4 AEs include fatigue (46%,) neutropenia (38%), anemia (31%) anorexia (15%), nausea (15%), vomiting (15%), abdominal pain (15%), hyperglycemia (15%). No grade 5 events occurred. Conclusions: The RP2D is Gem 800mg/m2, Nab-P 100mg/m2, and L 25mg/m2. This combination was well tolerated with expected toxicities of myelosuppression with prolonged responses seen. Clinical trial information: NCT04046887 . [Table: see text]

Supplementary Figure 1 from Epidermal Growth Factor Receptor Signaling Is Required for Microadenoma Formation in the Mouse Azoxymethane Model of Colonic Carcinogenesis

BACKGROUND:Fatigue interference with activities, mood, and cognition is one of the most prevalent and bothersome concerns of advanced gastrointestinal (GI) cancer patients. As fatigue interferes with patient functioning, family caregivers often report feeling burdened by increasing responsibilities. Evidence-based interventions jointly addressing cancer patient fatigue interference and caregiver burden are lacking. In pilot studies, acceptance and commitment therapy (ACT) has shown promise for addressing symptom-related suffering in cancer patients. The current pilot trial seeks to test a novel, dyadic ACT intervention for both advanced GI cancer patients with moderate-to-severe fatigue interference and their family caregivers with significant caregiving burden or distress.METHODS:A minimum of 40 patient-caregiver dyads will be randomly assigned to either the ACT intervention or an education/support control condition. Dyads in both conditions attend six weekly 50-min telephone sessions. Outcomes are assessed at baseline as well as 2 weeks and 3 months post-intervention. We will evaluate the feasibility, acceptability, and preliminary efficacy of ACT for improving patient fatigue interference and caregiver burden. Secondary outcomes include patient sleep interference and patient and caregiver engagement in daily activities, psychological flexibility, and quality of life. We will also explore the effects of ACT on patient and caregiver physical and mental health service use.DISCUSSION:Findings will inform a large-scale trial of intervention efficacy. Results will also lay the groundwork for further novel applications of ACT to symptom interference with functioning and caregiver burden in advanced cancer.TRIAL REGISTRATION:ClinicalTrials.gov , NCT04010227 . Registered 8 July 2019.

Few studies have examined the role of stereotactic body radiation (SBRT) after multiagent chemotherapy (ChT) in pancreatic ductal adenocarcinoma (PDAC). This was a prospective study of SBRT after ChT for PDAC.

e16764 Background: Both EGFR and the c-MET receptors are overexpressed in a majority of PDACs. Inhibition of both receptors simultaneously may be required for anti-tumor activity. Erlotinib, an EGFR inhibitor, has modest activity in metastatic PDAC and is approved by the FDA in combination with gemcitabine. Cabozantinib is a tyrosine kinase inhibitor targeting AXL, FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, TRKB, TYRO3, and VEGFR-1, -2, and -3. Preclinical data suggests that the addition of cabozantinib to erlotinib leads to tumor shrinkage and improvement in survival in a KPC PDAC mouse model compared to gemcitabine alone. This phase II study tests this hypothesis in patients with metastatic PDAC that co-express c-MET and EGFR. Methods: Key eligibility includes patients (pts) with metastatic PDAC with EGFR and c-MET overexpression (as determined by centrally tested IHC of 2+ or greater) that have progression on one prior chemotherapy regimen. Patients were treated with cabozantinib (40mg daily) and erlotinib (100mg daily) continuously. This dosing is based on previous combination data in NSCLC. This is a single arm two-stage phase II study with a primary endpoint of overall response rate. Secondary endpoints include of PFS, DCR and OS. Results: From October 2017 to October 2019, 43 pts were screened with 7 pts (median age 62 [range 51-76)] enrolled and treated on study. Pts had a median of 1 line of prior systemic chemotherapy. Most common reason for screen failure was due to lack of co-expression of c-MET and EGFR. EGFR IHC expression was +2 in 4 pts, +3 in 3 pts; c-MET IHC expression was +2 in 5 pts and +3 in 2 pts. Most common any-grade adverse events attributable to cabozantinib and erlotinib include: diarrhea (71%), AST increase (43%), fatigue (43%), nausea (43%), and rash (43%). Only one grade 3 event of fatigue occurred. All pts had clinical and/or radiographic progression within 1-2 months after initiating study therapy. Conclusions: The combination of cabozantinib and erlotinib was well tolerated with manageable toxicity. Due to lack of clinical responses, this study has been terminated due to futility. Clinical trial information: NCT03213626 .

436 Background: Neoadjuvant chemotherapy (NA CT) may improve surgical selection for resectable (R) PDAC, and margin negative resection in borderline resectable (BR) PDAC. Optimal duration of NA CT is unknown, as is the role of XRT with modern chemotherapy. We compared survival outcomes by duration of NA CT and NA CT + XRT. Methods: Patients with R or BR PDAC who underwent NA CT with or without XRT and followed by curative resection were included in this analysis. Data was extracted from an IRB approved pancreatic cancer database at Indiana University. Disease Free (DFS) and Overall (OS) survival were calculated from the surgery date and compared between: 1) < 3 v ≥ 3 months NA CT and 2) NA CT with/without XRT. Results: Between Summer 2008 and Summer 2018, 116 patients received NA CT with or without XRT and completed surgical resection. Median (range) age was 63 years (36, 84), stages were R=47%, BR=53%. Most patients received modified FOLFIRINOX or FOLFIRINOX (59 %), or gemcitabine/nab-paclitaxel (13%) and 24% received XRT. There were four (3 %) pathologic complete responders, all in the ≥ 3 mo NA CT + XRT group. Percent node positive was lower in NA CT + XRT versus NA CT only (median 0% vs 7.4%, p < 001), but did not differ by duration of NA CT. With a median (range) follow-up time of 13.7 mo (0.7, 83.0), median OS was 22.5 mo (19.5, 29.8) with < 3 mo NA CT versus 16.3 (12.2, 18.9) with ≥ 3 mo NA CT (p = 0.02) and was 22.6 mo (17.0, 82.9) with NA CT + XRT versus 19.5 (13.1, 22.5) in NA CT only (p = 0.03). There was no difference in DFS by duration of NA CT or XRT. Conclusions: In this study, patients who received a shorter course of chemotherapy and radiation had improved mOS when calculated from the surgery date. While this unexpected results could reflect selection bias of therapy, further analysis will account for tumor stage at diagnosis, perioperative complications and use propensity score adjustment to examine/adjust for possible treatment selection bias.

IMPORTANCE:Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune neurological disorder that is characterized by symmetrical progressive worsening or relapsing weakness and numbness of the limbs. There are no reliable diagnostic tests or definitive diagnostic criteria, and the diagnosis remains one of excluding other cases of polyneuropathy. Typical treatment for CIDP includes corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange. Little is known about CIDP as a treatment complication of immune checkpoint inhibitors (ipilimumab and nivolumab). This report will be helpful in increasing awareness and knowledge about this unique entity.OBSERVATIONS:We describe two cases of CIDP secondary to treatment with combined ipilimumab and nivolumab in patients with metastatic melanoma that were successfully treated with prednisone and IVIG. Conclusion and Relevance: This report illustrates that treatment with immune checkpoint inhibitors can lead to CIDP that can be successfully treated with complete resolution of symptoms. CIDP secondary to checkpoint inhibitors may have unique features such as low-grade lymphocytic pleocytosis on CSF evaluation as well as severe neuropathic pain as an early presenting symptom. Additionally, it is interesting to note that both patients presented in this report remained melanoma-free on follow-up more than 16 months later.

BackgroundOnly a few patients with pancreatic ductal adenocarcinoma (PDAC) recurring after curative resection and peri-operative (neoadjuvant and adjuvant) therapy are included in clinical trials of metastatic PDAC. As such, there is a paucity of data to guide treatment after relapse, and patients are treated similarly to those with de novo metastatic PDAC (mPDAC). We evaluated the patterns of chemotherapy use and over-all survival (OS) in patients with recurrent PDAC (rPDAC) following curative therapy.MethodsIn this retrospective study, the Indiana University pancreatic cancer database was used to identify patients with PDAC who underwent curative resection and subsequently developed recurrence. Demographics, tumor and treatment characteristics were collected. Patients were broadly divided into those who received chemotherapy for rPDAC and those who did not. Patients in the former category were further subdivided into those who received single agent therapy, any standard combination therapy (5-fluorouracil/irinotecan/oxaliplatin combination or gemcitabine/nab-paclitaxel) and those who received non-standard combinations. Survival analysis was performed by the Kaplan-Meier method. Log rank tests were used to determine differences in survival between treated rPDAC patients and those not treated. Cox regression analysis was employed to evaluate factors associated with OS.ResultsWe identified 435 patients with resected PDAC treated between 2008 and 2014. Two hundred and twenty-three patients (51.2%) were diagnosed with rPDAC. Of these, 140 patients (63%) received chemotherapy whereas 71 patients (32%) did not receive chemotherapy. The 74 patients (53%) who received any standard, approved multiagent combination regimen had a median OS of 14months compared to 8months for the 47 patents (34%) who received other non-standard combinations and the 19 (13%) who received single agent therapy (P=0.029). Multivariate cox regression analysis showed that margin negative resection, peri-operative therapy, radiotherapy and the use of any chemotherapy for rPDAC were associated with improved OS.ConclusionOur findings support the use of standard approved multi-agent therapy in rPDAC. Patients derive significant benefit from these standard combination therapies with median OS that is comparable to what is observed with treatment for de novo mPDAC.

Purpose: 5-Fluorouracil (5-FU)/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with UGT1A1 genotype–guided dosing of irinotecan. Patients and Methods: Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. UGT1A1 *1/*1, *1/*28, and *28/*28 patients received initial irinotecan doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2,400 mg/m2 over 46 hours, leucovorin 400 mg/m2, and nab-paclitaxel 125 mg/m2 were administered. Doses were deemed tolerable if the dose-limiting toxicity (DLT) rate during cycle 1 was ≤35% in each genotype group. DLTs were monitored using a sequential procedure. Results: Fifty patients enrolled, 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5 of 23 (22%) *1/*1 patients, 1 of 19 (5%) *1/*28 patients, and 0 of 7 *28/*28 patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks. Conclusions: FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Too few *28/*28 patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.

Sarcomas are an uncommon group of over 50 different individual histological malignancies arising from mesenchymal (non-epithelial or connective) tissues. Overall, they constitute 1% of human malignancies with an annual incidence rate of fewer than 5 patients per million. Sarcoma may arise from any mesenchymal cell lineages including fat, muscle, or other connective tissues. Due to the rarity of these groups of malignancies, many subtypes were, and still today, are managed as a single entity. This review focused on soft tissue sarcomas with an emphasis on how to integrate therapies for patients with this rare disorder. The role for surgical resection in cure and palliation as well as the relative benefits of adjuvant therapies such as chemotherapy and radiation therapy are discussed.

e16241 Background: 5-FU, IRI, and NP are active in GI cancers; the combination, FOLFIRABRAX, has not been evaluated. UGT1A1 clears SN-38, the active metabolite of IRI. UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. Dose adjustment in pts with this allele may be warranted. Primary endpoint: dose-limiting toxicity (DLT) rate of FOLFIRABRAX with genotype-guided dosing of IRI. Secondary endpoints include objective response rates (RR) in select GI cancers. Methods: Pts with previously untreated GI cancers and ECOG performance status 0/1 received FOLFIRABRAX with prophylactic pegfilgrastim Q14 days. CT scans were obtained Q8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 pts received initial IRI doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2400 mg/m2 over 46 hours (no bolus), leucovorin 400 mg/m2, and NP 125 mg/m2 were given IV Q14 days. DLT during cycle 1 was defined as Grade (Gr) 3/4 febrile neutropenia (FN), Gr 4 neutropenia ≥ 5 days, Gr 3/4 non-hematologic toxicity despite medical management, or treatment delay > 14 days due to toxicity. Doses were tolerable if DLT rate during cycle 1 was ≤ 35%. Enrollment of 17 pts per genotype allowed for an alpha level of 0.05 with 80% power under a sequential toxicity monitoring procedure, with 6 or fewer DLTs deemed tolerable. Results: 50 pts are evaluable for toxicity: 30 pancreatic cancer (PC), 9 biliary tract cancer (BTC), 6 gastroesophageal adenocarcinoma (GEA), 4 unknown GI primary, and 1 neuroendocrine. DLTs were observed in 5/23 (21.7%) *1/*1 pts, 1/20 (5%) *1/*28 pts, and 0/7 *28/*28 pts. DLTs were Gr 3 diarrhea (3 pts), Gr 3 nausea (2 pts), and Gr 3 FN (1 pt). RR is 12/39 (30.7%), with responses in PC (9/25 evaluable pts, 36%), GEA (3/6 pts, 50%), but not in BTC (0/8 pts). Ten pts continued therapy beyond 24 weeks. Conclusions: FOLFIRABRAX with genotype-guided dosing of IRI is tolerable in pts with advanced GI cancers and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Responses were observed in PC and GEA but not in BTC. Clinical trial information: NCT02333188.

TPS11628 Background: Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). Metformin has shown anti-cancer activity through its cellular (e.g., AMPK activation) and systemic effects (e.g., inhibition of IGF-1). We conducted a pilot study to test the hypothesis that metformin may potentiate mTOR inhibition by sirolimus. Methods: An open-label, randomized study was conducted in which eligible patients with advanced solid tumors were started on sirolimus (3mg daily) alone for the first 7 days. On day 8, patients were randomized to either receive metformin XL (500 mg daily) plus sirolimus (Arm A) or sirolimus alone (Arm B) for until day 21. From day 22 onwards, all patients recieved metformin XL plus sirolimus. The pharmacodynamic (PD) biomarkers were collected at baseline, day 8 and day 22 of cycle 1. The primary endpoint was to compare the change in PD biomarker phospho-p70S6K, using a two-sample t test (log ratio D22/D8 in arm A vs. arm B). The phospho-p70S6K was measured in peripheral blood T cells using Western blot. The secondary endpoints were to assess objective response rate (RECIST 1.1), toxicity (CTCAE V4.0) and changes in the serum levels of PD biomarkers: fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, leptin and adiponectin using two-sample t tests. Results: 24 patients were enrolled, at which time an interim futility analysis was conducted. 18 patients were evaluable for the primary endpoint (8 in arm A; 10 in arm B). The mean log ratios D22/D8 in phospho-p70S6K in arms A and B were -0.12 (SD = 0.13) and -0.16 (SD = 0.29), respectively (P = 0.64). Of the 17 pts evaluable for response, the best response was stable disease in 9 patients and progressive disease in 8 patients. There were no dose-limiting or unexpected toxicities. Of the 21 patients evaluable for serum PD biomarkers, there were no significant differences between arms A and B in fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-BP1, IGF-BP3, leptin and adiponectin (P > 0.05 for all). Conclusions: The addition of metformin to sirolimus, although well-tolerated, was not associated with significant changes in phospho-p70S6k and other PD biomarkers. Based on the results of the interim analysis, the trial was terminated. Clinical trial information: NCT02145559.

423 Background: 5-FU, IRI, and nab-paclitaxel (NP) are active in advanced GI cancers; the combination (FOLFIRABRAX) has not been evaluated. UGT1A1 clears SN-38, the active metabolite of IRI. UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. Dose adjustment in patients with this allele may be warranted. Primary objective: to determine the dose-limiting toxicity (DLT) rate of FOLFIRABRAX with genotype-guided dosing of IRI. Secondary objectives included determining objective response rates (ORR) in GI cancers. Methods: Pts with previously untreated GI cancers and ECOG performance status 0/1 received FOLFIRABRAX with prophylactic pegfilgrastim Q14 days. CT scans were obtained Q8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 patients (pts) received initial IRI doses of 180, 135, and 90mg/m2, respectively. 5-FU 2400mg/m2 over 46 hours (no bolus), leucovorin 400mg/m2, and NP 125mg/m2 were given IV Q14 days. DLT during cycle 1 was defined as Grade (Gr) 3/4 febrile neutropenia (FN), Gr 4 neutropenia ≥ 5 days, Gr 3/4 non-hematologic toxicity despite medical management, or treatment delay > 14 days due to toxicity. Doses were tolerable if DLT rate during cycle 1 was ≤ 35%. Enrollment of 17 pts per genotype would allow for an α level of 0.05 with 80% power under a sequential toxicity monitoring procedure, with 6 or fewer DLTs being tolerable. Results: 39 pts are evaluable for toxicity: 23 pancreatic cancer (PC), 6 gastroesophageal cancer (GE), 9 biliary tract cancer (BTC), 1 neuroendocrine. DLTs were observed in 4/20 (20%) *1/*1 pts, 1/15 (7%) *1/*28 pts, and 0/4 *28/*28 pts. DLTs were Gr 3 diarrhea (2 pts), Gr 3 nausea (2), and Gr 3 FN (1). ORR is 6/29 (21%), with responses in PC (3/17 evaluable pts, 18%) and GE (3/5 pts, 60%), but no responses in BTC (0/7 pts). Conclusions: FOLFIRABRAX with genotype-guided dosing of IRI is tolerable in pts with advanced GI cancers and UGT1A1*1*1 or UGT1A1*1*28 genotypes. There is activity in PC and GE but not in BTC. Accrual is ongoing to the 3 genotype cohorts to a goal of 51 pts. Study conducted by the University of Chicago Personalized Cancer Care Consortium Clinical trial information: NCT02333188.

e21599 Background: Prognostic role of BRAF mutation is not well-studied in malignant cutaneous melanoma. We conducted a large retrospective study using a state-wide database to assess the clinical characteristics and prognostic role of BRAF mutations. Methods: The Indiana Network for Patient Care (INPC) was used to identify patients diagnosed with malignant melanoma and who underwent BRAF testing between 1995-2016. The INPC represents the largest and longest tenured clinical data warehouse of the Indiana Health Information Exchange in the USA. Using natural language processing, we extracted the date of diagnosis, age, gender, race, Breslow thickness, ulceration, mitotic rate, stage, primary site, smoking, body mass index (BMI), LDH, BRAF status, date and cause of death. Chi-square or t-test was used for univariate analyses. Overall survival (OS) was estimated by Kaplan-Meier method. Logistic and Cox regression was used for multivariate analyses (adjusted for all variables except LDH and BMI). Results: Of 1971 study patients, 920 (46.7%) had BRAF mutation. On univariate analyses, male gender, non-Caucasian race, higher Breslow thickness ( > 1 mm), higher mitotic rate ( > 1/mm2), primary site, smoking and advanced stage (III and IV) were associated with BRAF mutation (p < 0.05). Multivariate logistic regression showed that the BRAF mutation is significantly (p < 0.05) associated with advanced stage (AOR 1.22, 95% CI [1.10-1.34]), male gender (1.15 [1.06-1.26]), presence of ulceration (1.22 [1.07-1.39]), higher Breslow thickness (1.03 [1.01-1.04]), higher mitotic rate (1.11 [1.01-1.22]), primary melanoma of trunk (0.85 [0.76-0.96]) and smoking (1.27 [1.17-1.39]). Kaplan-Meier analysis revealed that the BRAF mutant patients have significantly better OS as compared to BRAF wild-type patients (144 vs. 85 months; HR 0.72 [0.59-0.88], p = 0.001). However, BRAF mutation was not predictive of OS in multivariate Cox model (HR 1.28 [0.68-2.41], p = 0.43) unlike advanced stage, male gender and higher Breslow thickness. Conclusions: BRAF mutation in malignant cutaneous melanoma is associated with more aggressive clinical features however BRAF mutation is not an independent prognostic factor when adjusted for other prognostic variables.

TPS4157 Background: c-MET over-expression is associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC)(Kim JH, et al. Oncotarget. 2017;8(42):73098-104). It activates mitogenic signaling, and this may contribute to the limited clinical activity of erlotinib in metastatic PDAC, given the cross talk between EGFR and c-MET(Dulak AM, et al. Oncogene. 2011;30(33):3625-35). Preclinical data suggests that the addition of cabozantinib (a c-MET antagonist) to erlotinib improves anti-tumor activity. The combination in our lab resulted in significant tumor shrinkage, and improvement in survival in a KPC PDAC mouse model compared to treatment with gemcitabine alone. We designed this study to determine the activity of cabozantinib (Cabo) and erlotinib (Eelo) in a population of metastatic PDAC patients whose tumors co-overexpress EGFR and c-MET. Methods: This is an open-label, single arm, Phase II trial of the combination of cabozantinib and erlotinib in metastatic PDAC. Male and female patients > 18years with biopsy proven PDAC and radiologically measurable metastatic disease following progression after first line therapy are eligible. Patients must have tumor tissue available from a surgical resection or archived core biopsy. Only those whose tumors express at least 2+ EGFR and c-MET based on IHC will be allowed on study. ECOG PS2 and above, prior use of Cabo or Erlo, and symptomatic brain metastasis or brain metastasis requiring steroids will exclude patients from this study. Cabo will be administered at 40mg daily dose and Erlo at 100mg daily dose every 28 days without break. The study will be conducted at the Indiana University Simon Cancer Center. The primary objective is to demonstrate at least a 15% radiographic response rate for the combination in the selected population. Secondary objectives include assessment of safety and estimation of PFS, ORR and OS. Based on a Simon two stage design, we will enroll 37 patients in total. If there are no radiologic responses in the 11 patients tested in the first stage, the trial will be closed. The trial opened in November 2017, we have screened 4 patients and enrolled 1. ClinicalTrials.gov Identifier: NCT03213626