Duma, Narjust

Abstract Background Immune-related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti-programmed cell death protein 1 (PD-1) therapy. Materials and Methods All patients with metastatic melanoma and non-small cell lung cancer (NSCLC) treated with anti-PD-1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan-Meier method and log-rank test was used for time-to-event analysis. Results In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression-free-survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. Conclusion Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. Implications for Practice The results of this study suggest that women may be at a higher risk for immune-related adverse events (irAEs) compared with men when treated with anti-programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow-up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment-related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.

Abstract Background: Multiple myeloma (MM) accounts for approximately 1% of all cancers and 10% of hematologic malignancies in the United States (U.S.). MM occurs in all races, but the incidence in African Americans is two to three times higher than in non-Hispanic whites. MM is also slightly more frequent in men than women (1.4:1). Many clinical trials lack appropriate representation of specific patient populations, limiting the generalizability of the evidence obtained. Therefore, we determined the representation of ethnic minorities, the elderly, and women in MM clinical trials. Methods: Enrollment data from all therapeutic trials reported as completed in clinicaltrial.gov from 2000 to 2016 were analyzed. Clinical trials including other hematologic malignancies and with recruitment outside of the U.S. were excluded. Enrollment fraction (EF) was defined as the number of enrollees divided by the 2013 SEER database MM complete prevalence. Chi-square test was used to estimate differences in categorical data. Results: Out of 177 MM clinical trials (CT), 78 (44%) reported ethnicity with a total of 12,055 enrollees. Regarding enrollees' ethnic composition, 84% were non-Hispanic White (NHW), 8.6% African American (AA), 2.8% Asian, 1.8% Hispanic, and 0.1% Native American/Alaskan Indian. Out of those 78 CT, 52 (66%) were phase II, 15 (19%) phase III, and 11 (14%) phase I. Most of the results were published from 2012 to 2016 (74%). Forty-six (59%) trials were sponsored by industry, 7 (9%) by NCI, and 25 (32%) were investigator initiated. Participation in CT varied significantly across ethnic groups, NHW were more likely to be enrolled in CT (EF of 0.23) than AA (EF of 0.08, p < 0.0001) and Hispanics (EF of 0.05, p< 0.0001). Males had a higher recruitment rate than females (58% vs. 42%), but this could be explained by the higher incidence of MM in males. Enrollees' median age was 62 years. Younger patients (< 65 years) were more likely to be enrolled in CT than the elderly (66% vs. 34%, p<0.0001). Industry-sponsored trials were less likely to recruit AA compared with investigator-initiated trials (7.6% vs. 12%, p<0.01). Conclusions: Despite the higher incidence of MM in African Americans and the elderly, the former only represented 8.6% of the study participants and 66% of these were less than 65 years of age; therefore, we are lacking data in the tolerability of these new agents in our aging MM population. We also observed that industry studies were less likely to recruit AA patients. Collaborations between investigators, sponsors, and the community are necessary to increase our minority and elderly patients' access to clinical trials. Citation Format: Narjust Duma, Miguel Gonzalez Velez, Jesus Vera-Aguilera, Richardo Parrondo, Veronica Mariotti, Jonas Paludo, Yucai Wang, Ronald Go, Alex Adjei. Diversity in multiple myeloma clinical trials [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A27.

Abstract Background: Despite the importance of diversity while studying new drugs, many cancer clinical trials (CT) lack appropriate representation of specific patient populations, limiting the generalizability of the evidence obtained. Therefore, we determined the representation of ethnic minorities, the elderly, and women in cancer CT. Methods: Enrollment data from all therapeutic trials reported as completed in clinicaltrial.gov from 2003 to 2016 were analyzed. CT in rare cancers (< 1% incidence) or with recruitment outside of the United States were excluded. Enrollment fraction (EF) was defined as the number of enrollees divided by the 2013 Surveillance Epidemiology and End Results (SEER) database cancer prevalence. Results: Out of 1,012 CT, 310 (31%) reported ethnicity with a total of 55,689 enrollees. 46,431 (83%) enrollees were non-Hispanic white, 3,270 (6%) African American, 2,982 (5.3%) Asian, 1,484 (2.6%) Hispanic, and 1,332 (2.4%) were classified as other. Participation in CT varied significantly across ethnic groups; non-Hispanic whites were more likely to be enrolled in CT (EF of 1.2%) than African Americans (EF of 0.7%, p <0.001) and Hispanics (EF of 0.4%, p <0.001). A decrease in African American (6% vs. 9.2%) and Hispanic (2.6% vs. 3.1%) enrollment was observed when compared with historical data from 1996 to 2002. Asians were well represented and their recruitment doubled over the past 14 years (2% vs. 5.3%). Hispanics were less represented in breast and prostate cancer CT, only contributing to 3% and 1.5% of the study population. African Americans were less represented in lung (5.4%) and renal cell carcinoma (3%) trials. Enrollees' median age was 60 years with 64% of patients <65 years of age. Younger patients (<65 years) were more likely to be enrolled in CT than the elderly (64% vs. 36%, p < 0.001). Lower recruitment of female patients was observed in CT for melanoma (35%), lung (39%), and pancreatic cancer (40%). Conclusions: African Americans, Hispanics, and the elderly were less likely to be enrolled in CT. Comparing with historical data, we observed a decrease in minorities' recruitment over the past 14 years. This change could be attributed to the increased complexity of CT and mandatory molecular testing as many minorities lack access to institutions with genetic-testing capacity. Future trials should take extra measures to recruit participants who adequately represent the U.S. cancer population. Citation Format: Narjust Duma, Jesus Vera-Aguilera, Yucai Wang, Jonas Paludo, Konstantinos Leventakos, Aaron Mansfield, Alex Adjei. Representation of minorities, the elderly, and women in over 1000 clinical trials [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A26.

594 Background: Given the heterogeneity of gastrointestinal cancers (GICs), molecular profiling is becoming part of the standard of care for many solid tumors. The aim of this study was to evaluate the molecular profile of patients (pts) with GICs using a multiplatform profiling tool and to assess how the pattern of detected molecular alterations could guide clinical decision-making in these tumors. Methods: We retrospectively analyzed samples of 85 pts with GICs via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) in order to evaluate clinically relevant genomic alterations (CRGAs) and clinically relevant biomarker expression (CRBs) in GICs. Results: A total of 85 pts with GICs were analyzed. 45 (53 %) were males and 40 (47%) were females. Tumors were colorectal 43 (51%), pancreatic 11 (13%) esophageal 11 (13%) gastric 8 (9%), hepatobiliary 8 (11%), anal canal 3 (4%), and small intestine 1 (1%). 80 cases (94%) had adequate sample for profiling. CRGAs were identified in 71 cases (89%) with a median of 3 CRGAs in the cohort. The most commonly detected CRGAs were TP53 45 (56%), APC 35 (44%), KRAS 32 (40%), ATM 14 (18%) and PTEN 5 (6%). The median number of CRBs was 9 and high expression levels were seen of mismatch repair biomarkers (MLH1, MSH2, MSH6, PMS2) in 45 (56%), TOPO1 in 44 (55%), PTEN in 27 (34%), TOP2A in 20 (25%), ERCC1 in 19 (24%), and both TS and TUBB3 in 17 (21%). Based on actionable CRGAs and CRBs, 94% of pts matched at least one FDA approved treatment with proven clinical benefit, with a median of 4 available therapies per pt. In addition, there was a median of 189 chemotherapy and 64 targeted therapy clinical trial opportunities available for these pts given the molecular blueprint of their GICs. Conclusions: Multiplatform molecular profiling identified a high frequency of actionable CRGAs and CRBs in GIC pts. This approach has the potential to aid in clinical decision-making by providing a stratification of beneficial therapeutic alternatives individualized to the molecular framework of tumor. Larger prospective studies are warranted to further investigate the impact of profiling guided treatment decisions on patient outcomes.

Abstract Background Early phase clinical trials evaluate the safety and efficacy of new treatments. The exclusion/inclusion criteria in these trials are usually rigorous and may exclude many patients seen in clinical practice. Our objective was to study the comorbidities limiting the participation of patients with breast, colorectal, or lung cancer in clinical trials. Materials and Methods We queried ClinicalTrials.gov on December 31, 2016. We reviewed the eligibility criteria of 1,103 trials. Logistic regression analyses were completed, and exclusion was studied as a binary variable. Results Out of 1,103 trials, 70 trials (6%) excluded patients >75 years of age, and 45% made no reference to age. Eighty-six percent of trials placed restrictions on patients with history of prior malignancies. Regarding central nervous system (CNS) metastasis, 416 trials (38%) excluded all patients with CNS metastasis, and 373 (34%) only allowed asymptomatic CNS metastasis. Regarding chronic viral infections, 347 trials (31%) excluded all patients with human immunodeficiency virus, and 228 trials (21%) excluded all patients with hepatitis B or C infection. On univariate analysis, chemotherapy trials were more likely to exclude patients with CNS metastasis and history of other malignancies than targeted therapy trials. Multivariate analysis demonstrated that industry-sponsored trials had higher odds of excluding patients with compromised liver function. Conclusion Many clinical trials excluded large segments of the population of patients with cancer. Frequent exclusion criteria included patients with CNS metastasis, history of prior malignancies, and chronic viral infections. The criteria for participation in some clinical trials may be overly restrictive and limit enrollment. Implications for Practice The results of this study revealed that most early phase clinic trials contain strict exclusion criteria, potentially excluding the patients who may be more likely to represent the population treated in clinical settings, leaving patients susceptible to unintended harm from inappropriate generalization of trial results. Careful liberalization of the inclusion/exclusion criteria in clinical trials will allow investigators to understand the benefits and drawbacks of the experimental drug for a broader population, and possibly improve recruitment of patients with cancer into clinical trials.

A 70-year-old female presented with a three-year history of evolving macroglossia causing dysphagia and dysarthria, with proximal muscle weakness. Given the classic physical finding of macroglossia, the patient underwent extensive evaluation for amyloidosis which proved to be negative apart from a bone marrow biopsy which stained positive for transthyretin without amino acid sequence abnormality, thus giving wild-type transthyretin amyloidosis. Since the wild-type transthyretin amyloidosis could not entirely explain her clinical presentation and evaluation, further studies were conducted in a sequential manner, thus leading to a diagnosis of Pompe disease explaining her presenting signs and symptoms including her macroglossia. Through this fascinating case, we attempt to highlight the approach for the diagnoses of two rare diseases in a patient by emphasizing the importance of having a broad differential diagnosis when presented with findings which may have been thought as pathognomonic for certain diseases.

e21038 Background: Several studies of advanced melanoma patients suggest that combining therapies that target tumor mechanisms of immune evasion with activation of normal immune cell functionality may provide optimal benefits for patients. The synthetic parasite derived GK1 peptide in combination with anti-PD-L1 showed significant longer survival (34 days) compared to GK1 or Anti-PD-L1 alone (23-27 days) in a murine melanoma model (p < 0.05). This means an increase survival increased in 47.82% in the mice treated with GK-1 + anti-PD-L1, 21.7% treated with GK-1, and 6.08% treated with anti-PD-L1. Methods: To elucidate the potential mechanism by which this combination treatment exerts its anti-melanoma effects, C57BL/6 mice were injected with B16-F10-luc2 cells and separated according to treatments in four groups: control, GK-1, anti-PD-L1 and GK-1/anti-PDL-1.Blood samples were collected at day 0, 14, and at euthanization or end of the experiment and monitored for serum cytokines using mice-specific V-PLEX Pro-inflammatory Panel. Results: On day 14, TNF-α levels in the Anti-PD-L1 and GK-1 therapy group was significantly lower compared to control mice. At sacrifice, the combined treatment group demonstrated significant decrease cytokine production in IL-6 and IL-10. Conclusions: The decreased cytokine levels observed in the GK-1/anti-PD-L1 group may explain the significant improved survival. GK-1 is a Th1 response inductor both in vitro and in vivo as it increases IFN-γ, IL-2 but not IL-4 and IL-10. It is noteworthy that when PD-L1 signaling is reduced in T cells these cells proliferate extensively in vitro and produce increased levels of IFN-γ and IL-17, suggesting an enhanced pro-inflammatory phenotype. It has been established that cytokines of Th2 response such as IL-4 and IL-5 and IL-6, have tumor-promoting activity. The anti-melanoma effect of the GK-1/anti-PD-L1 combination observed in the present study could be mediated by decreasing the pro-tumor Th2 response. These results provide novel alternative pathways and potential targets to enhance the clinical effect of the PD-1/PD-L1 blockade pathway.

e19525 Background: Rearrangements of the immunoglobulin heavy chain (IGH) on chromosome 14 are identified by FISH in about 15-20% of patients (pts) with newly diagnosed multiple myeloma (MM). Historically there is variation on the significance on prognosis of these rearrangements: typically, t(4;14), t(14;16) and t(14;20) have high risk (HR), and t(11;14) have standard risk (SR). A recent study (Kaufman et al, Leukemia. 2016 30:633-9) suggests that t(11;14) may confer a worse prognosis We report the prognostic significance of t(11;14) in a single-institution MM cohort. Methods: 87 pts with t(11;14) by CD 138 selected FISH at diagnosis were identified, pts without symptomatic MM were excluded. Cox regression was used for statistical analysis. Progression free survival (PFS), and overall survivals (OS) from diagnosis and post autologous stem cell transplant (ASCT) were analyzed by Kaplan-Meier. Results: Median age at diagnosis was 62 years, 45 pts (52%) were male, and 24 pts (27%) had ISS 3. All pts received either a proteasome inhibitor or an immunomodulatory agent, and 42 (48%) received triplet treatment as induction. Sixty-nine (79%) pts had ASCT, and overall response rate (ORR, partial response or better) post ASCT was 73%. For pts with HR FISH (defined as t(14;16), p53 del, 1q21 gain or 1p del) compared to SR FISH, the ORR post ASCT was 70% vs 77% (p = 0.67). OS from diagnosis was 93% at 3 years, 74% at 4 years and 51% at 5 years. Seven patients (8%) developed plasma cell leukemia, and there was no association between HR and SR FISH (p = 0.66). In multivariate analysis, ISS stage was an independent risk factor for mortality; pts with stage 3 had 7.3 times (CI: 1.16-36.4) and 5.7 times (CI: 1.63-20.0) the risk of mortality than pts with stage 1 and 2. Having an ASCT reduced mortality by 87% (CI: 0.04-0.41). Conclusions: Despite the use of novel therapies the OS at 5 years of our pts with MM was not significantly improved compared to SEER data from 1992-2013 (51% vs 48.5%). Pts with t(11;14) who had ASCT had increased survival compared to those who did not. Our results suggest that t(11;14) may confer a worse prognosis. Further prospective studies evaluating the risk of t(11;14) are warranted.

8044 Background: Racial disparities of FISH abnormalities in multiple myeloma (MM) have been well described in whites (W) but partially described in minorities (M) (Paulus et al, ASH 2016, 4432). We aimed to explore racial-based differences of FISH abnormalities using the largest cohort of m to date. Methods: CD-138 selected FISH was done on 799 consecutive patients (pts). Pts without symptomatic MM, and biopsy >6 months after diagnosis were excluded. The abnormalities evaluated included standard and intermediate risk: IGH rearrangements (IGH r), t(4;14), t(11;14), and high risk: t(14;20), t(14;16), del13q, del 17p, 1q21. Chi-square was used for statistical analysis. Due to smaller numbers, all m (Hispanic (H), Black (B), Asian (A) and Other (O)) were included into the same group for statistical analysis. Results: 482 pts were eligible, 343 (71%) were W, 52 (10%) H, 50 (10%) B, 19 (3%) A, and 18 (3%) O. Median age was 65 years, 54% were male, and 26% ISS stage 3. There were no were no statistically significant differences in FISH abnormalities between the m (Table1). Overall W had more abnormalities in IGH r, t(4;14), t(11;14), t(14:20), 1q21 gain compared to M. Most notably W had more IGH r (39% vs 28%; p=0.019) and t(11;14) (20% vs 12%; p=0.024). There were no statistically significant differences between W and m in the high risk FISH abnormalities. Conclusions: We had significant differences in FISH compared to M. W had more IGH r and t(11;14) than M, and there was no difference in high risk FISH abnormalities between W and M. This study confirms the biological racial disparities that exist in minorities with MM. Further studies with more inclusion of minorities are needed to elucidate these disparities and its effects on risk stratification and outcomes. [Table: see text]