Citations

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor. Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 10 6 plaque-forming units (PFU)/mL in week 1, followed by 10 8 PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported. At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297 .

Abstract Background Producing scholarship in education is essential to the career development of a clinician-educator. Challenges to scholarly production include a lack of resources, time, expertise, and collaborators. Objective To develop communities of practice for education scholarship through an international society to increase community and academic productivity. Methods We developed multi-institutional scholarship pods within the American Thoracic Society through the creation of a working group (2017–2019). Pods met virtually, and meetings were goal focused to advance education scholarship within their area of interest. To understand the impact of these scholarship pods, we surveyed pod leaders and members in 2021 and analyzed the academic productivity of each pod via a survey of pod leaders and a review of the PubMed index. Results Nine pods were created, each with an assigned educational topic. The survey had a response rate of 76.6%. The perceived benefits were the opportunity to meet colleagues with similar interests at other institutions, production of scholarly work, and engagement in new experiences. The main challenges were difficulty finding times to meet because of competing clinical demands and aligning times among pod members. Regarding academic productivity, eight publications, four conference presentations, and one webinar/podcast were produced by six of the nine pods. Conclusion The development of communities of practice resulted in increased multi-site collaboration, with boosted academic productivity as well as an enhanced sense of belonging. Multiple challenges remain but can likely be overcome with accountability, early discussion of roles and expectations, and clear delegation of tasks and authorship.

Abstract Introduction: Colorectal cancer (CRC) is the second leading cause of cancer death in the United States (US). Primary care physicians (PCP) are critical towards a successful CRC screening program. However, the impact of availability of PCP on CRC-related mortality is not well studied. Materials and Methods: We extracted data on crude incidence and mortality rates of CRC among all 50 states and District of Columbia (D.C.) from the Center for Disease Control (CDC) WONDER database for the year 2019. Data on number of actively practicing PCPs in all 50 states and D.C. for the year 2020 were obtained from Association of American Medical Colleges (AAMC) State Physician Workforce Data Report. The correlation between the ratio of number of PCPs per CRC case with age-adjusted mortality rate (AAMR) for CRC was studied by state and within White and African American (AA) populations from 2017-2019. Pearson’s co-efficient was used to study correlations and T-test was used for comparing independent samples. Statistical analysis was performed using VassarStats. Results: The median AAMR for CRC from 2017-2019 in the US was 13.2 (IQR 11,15.4) per 100,000 population. AAMR for CRC was significantly higher among AA versus White populations (t=5.79, p<0.001). The national median PCP per CRC case ratio was 2.14 (IQR 1.46, 2.82). Higher state-wide PCP per CRC case ratio correlated with lower state CRC-related mortality (r=-0.36, p=0.011). PCP per CRC case ratio was significantly lower among AA as compared to White populations (t=-15.95, p<0.0001). Higher PCP per CRC case ratio correlated with lower CRC-related mortality among both White (r=-0.64, p<0.0001) and AA (r=-0.57, p=0.0002) populations. Using Fisher r-to-z transformation, we found no significant difference between the correlation of PCP per CRC case ratio with CRC-related mortality in White versus AA populations (z=-0.51, p=0.61). Conclusion: Results of this study suggest that greater availability of primary care physicians correlates with lower CRC-related mortality. AA have a significantly higher AAMR for CRC with a lower PCP per CRC case ratio. This may indicate a lower access to primary care among AA populations with CRC. Our results underscore the need to expand access to primary care among AA populations with the goal of minimizing disparities in CRC-related mortality. Citation Format: Udhayvir S. Grewal, Shiva J. Gaddam, Manik Aggarwal, Subhash C. Garikipati, Prabhat Kumar, Naomi Fei. Correlation of availability of primary care physicians and colorectal cancer-related mortality in the United States: Do racial disparities exist. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6488.

Abstract Purpose: Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking. Patients and Methods: We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

Introduction: Lewy body dementia (LBD) is common, yet under-recognized and under-researched. To plan studies with the highest impact, engagement of the community personally affected by these conditions is essential. Methods: A web-based survey of people living with LBD and current and former caregivers of people with LBD queried research priorities through forced ranking and exploration of burden of LBD symptoms. Specific caregiving needs in LBD and perceptions of research participation were also investigated. Results: Between April 7, 2021 and July 1, 2021, 984 responses were recorded. Top research priorities included disease-modifying therapies and improved disease detection and staging. People with LBD were interested in pathophysiology and more bothered by motor symptoms; caregivers were interested in risk factors and symptomatic therapies and more bothered by neuropsychiatric symptoms. Few available LBD treatments and resources were rated as helpful, and many valuable services were never received. Previous participation in LBD research was infrequent, but interest was high. Discussion: People with LBD and caregivers highlighted the need for research across all aspects of LBD, from pathophysiology and disease modification to prognosis, education, symptomatic treatments, and caregiver support. Funders should increase support for all aspects of LBD research to target the many needs identified by individuals and families living with LBD.

80 Background: Incidence of colorectal cancer (CRC) among adolescents and young adults (AYA) is increasing. A significant proportion of adolescents and young adults (AYA) with colorectal cancer (CRC) lack traceable genetic risk factors. We sought to study the impact of lifestyle-related risk factors on the incidence and mortality of CRC in these patients. Methods: We extracted data on crude incidence and mortality rates of CRC (reported per 100,000 population) for ages 15-39 years in all 50 U.S. states and District of Columbia from the Center for Disease Control (CDC) WONDER database (1999-2018). Data on risk factors such as obesity, physical activity, alcohol and tobacco abuse and nutrition were obtained from the Behavioral Risk Factor Surveillance System (BRFSS, 2020). Correlations were analyzed using Pearson’s co-efficient. p < 0.05 was considered statistically significant. Statistical analysis was performed using VassarStats. Results: Median crude incidence and mortality rates of CRC in AYA in the US from 1999-2018 were 3.8 (IQR 3.2, 4.4) and 0.7 (IQR 0.5,0.9) per 100,000 population respectively. States with higher age-adjusted prevalence of obesity per 100,000 had higher incidence (r = 0.36, p = 0.01) and mortality rates (r = 0.49, p = 0.0002) of CRC in AYA population. States with a higher age-adjusted prevalence of adherence to recommended weekly aerobic activity had lower incidence (r = -0.4515, p = 0.001) and mortality (r = -0.569, p < 0.0001) rates. While states with higher age-adjusted prevalence of tobacco abuse had higher incidence rate of CRC (r = 0.33, p = 0.02), there was no correlation with mortality rates (r = 0.24, p = 0.09). Higher prevalence of alcohol consumption was associated with decreased mortality rate (r = -0.44, p = 0.001), with no impact on incidence rate (r = -0.16, p = 0.26). States with lower daily consumption of fruits had higher incidence (r = 0.37, p = 0.01) and mortality rates (r = 0.59, p < 0.0001). No correlation of daily consumption of vegetables with incidence (r = -0.1516, p = 0.29) and mortality (r = 0.18, p = 0.22) rates was noted. Conclusions: In the current analysis, higher prevalence of obesity, lower rates of aerobic activity and lower daily consumption of fruits were strongly associated with increased incidence and mortality rates. The impact of tobacco abuse and alcohol consumption was more variable. Apart from improving access to genetic testing and counseling, efforts aimed at mitigating the rise of CRC incidence among AYA should also focus on traditional lifestyle-related risk factors.

Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status. This study assessed if MSI-H detected by a plasma-based circulating tumor DNA liquid biopsy test predicts robust response to ICI in patients with pancreatic ductal adenocarcinoma (PDAC). Retrospective analysis of patients with PDAC and MSI-H identified on Guardant360 from October 2018 to April 2021 was performed; clinical outcomes were submitted by treating providers. From 52 patients with PDAC +MSI-H, outcomes were available for 10 (19%) with a median age of 68 years (range: 56–82 years); the majority were male (80%) and had metastatic disease (80%). Nine of 10 patients were treated with ICI. Eight out of nine patients received single-agent pembrolizumab (8/9), while one received ipilimumab plus nivolumab. The overall response rate by Response Evaluation Criteria in Solid Tumors was 77% (7/9). The median progression-free survival and overall survival were not reached in this cohort. The median duration of treatment with ICI was 8 months (range: 1–24), and six out of seven responders continued to show response at the time of data cut-off after a median follow-up of 21 months (range: 11–33). Tissue-based MSI results were concordant with plasma-based G360 results in five of six patients (83%) who had tissue-based test results available, with G360 identifying one more patient with MSI-H than tissue testing. These results suggest that detecting MSI-H by a well-validated liquid biopsy test could predict a robust response to ICI in patients with PDAC. The use of liquid biopsy may expand the identification of PDAC patients with MSI-H tumors and enable treatment with ICI resulting in improved outcomes.

9573 Background: Mucosal melanoma is a rare, highly aggressive form of melanoma with extremely high recurrence rates, despite definitive surgical resection. Median RFS has been reported to be 5.4m, with RFS rates at 1 and 2 years of 10%, and 0%, respectively (Lian B, Si L, Cui C, et al. Phase II Randomized Trial Comparing High-Dose IFN-α2b with Temozolomide Plus Cisplatin as Systemic Adjuvant Therapy for Resected Mucosal Melanoma. Clinical Cancer Research 2013, 19(16):4488-4498). Currently there is no consensus on recommendations for adjuvant therapy. Data on the use of immune checkpoint inhibitors (ICI) adjuvantly is lacking. Methods: We performed a single arm, multicenter clinical trial using “flip dose” ipilimumab (1mg/kg q3w x4 cycles),and nivolumab (3 mg.kg q3w x4 cycles), then Nivolumab 480 mg q4w x 11 cycles to complete a year of adjuvant therapy. The primary endpoint was recurrence-free survival (RFS), and the study had 85% power to detect an improvement in RFS between 5.5 and 9.5 months using a one-sided log rank test. Participants must have had R0/R1 resection <90 days prior to registration, and no prior systemic therapy (adjuvant radiation allowed), ECOG 0/1, no uncontrolled significant autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From 9/17 to 8/21, 44 patients were approached at 6 centers. Of these 9 were ineligible, and 35 were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) had adjuvant radiation prior to enrollment. As of Dec 2021, 31 patients have completed the treatment phase. Of the 35 patients treated on study, 20 patients have recurred (7 local, 5 distant, 3 regional, 5 sites unconfirmed), 6 stopped therapy due to adverse effects, and 8 have died. The mean age of patients was 65.8 years and 21 (60.0%) were female. The primary site of disease was vulvovaginal N=12 (32.4%) patients, sinonasal N= 11 (29.7%), anorectal N= 9 (24.3%) and other site N= 5 (13.5%). Adjuvant radiation had been given in 7 pts. Driver mutations were rare, with only 3 (8.6%) patients having a KIT mutation, and one patient (2.9%) each having a NRAS or BRAF mutation. RFS rates at 1 and 2 years were 50% (95% CI 31-66%) and 37% (95% CI 19-55%), with OS rates at 1 and 2 years of 87% (95% CI 68-95%) and 68% (95% CI 46-83%). Median RFS was 10.3 m (95% CI5.7-25.8). Most common grade 3 adverse events were diarrhea (14%), hypertension (14%), hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip dose ipilimumab and nivolumab after resection is associated with outcomes improved over previously reported outcomes in the absence of therapy. Long term follow up is ongoing as are subgroup analyses and correlative studies. Clinical trial information: NCT03241186.