Hálfdánarson, Þorvarður R.

Objectives Checkpoint inhibitors (CPIs) for low- and intermediate-grade neuroendocrine tumors (NETs) have been associated with limited efficacy; recent studies suggest CPIs may represent promising treatment for high-grade neuroendocrine neoplasms (NENs). Methods We examined 57 patients with NENs who were treated with CPIs to determine if NETs and neuroendocrine carcinomas (NECs) respond to immunotherapy. Results Patients with poorly differentiated NECs on CPI monotherapy had an objective response rate (ORR) of 0% and median progression-free survival (PFS) of 2.1 months (95% confidence interval [CI], 0.5–4.6). Patients with poorly differentiated NECs on dual CPI therapy had an ORR of 13% and PFS of 3.5 months (95% CI, 1.4–not reached [NR]). Patients with poorly differentiated NECs on CPI and cytotoxic therapy had an ORR of 36% with PFS of 4.2 months (95% CI, 1.6–NR). Well-differentiated grade 1 and 2 NETs on CPI monotherapy had an ORR of 25% with PFS NR. Well-differentiated grade 3 NETs had 0% ORR with a PFS of 2.9 months (95% CI, 1.4–4.2) on CPI monotherapy. Conclusions Checkpoint inhibitor therapy shows limited activity in patients with NENs. Future studies should identify biomarkers that can help identify patients who are likely responders to immunotherapy.

Background: The incidence and prevalence of neuroendocrine neoplasms (NENs) are rapidly rising. Epidemiologic trends have been reported for common NENs, but specific data for lung NENs are lacking. Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Associated population data were utilized to report the annual age-adjusted incidence and overall survival (OS) trends. Trends for large-cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC) were reported from 2000–2015, while those for typical carcinoid (TC) and small cell lung cancer (SCLC) were reported from 1988–2015. Results: We examined a total of 124,969 lung NENs [103,890—SCLC; 3303—LCNEC; 8146—TC; 656—AC; 8974—Other]. The age-adjusted incidence rate revealed a decline in SCLC from 8.6 in 1988 to 5.3 in 2015 per 100,000; while other NENs showed an increase: TC increased from 0.57 in 1988 to 0.77 in 2015, AC increased from 0.17 in 2001 to 0.22 in 2015, and LCNEC increased from 0.16 in 2000 to 0.41 in 2015. The 5-year OS rate among SCLC, LCNEC, AC, and TC patients was 5%, 17%, 64%, and 84%, respectively. On multivariable analyses, OS and disease-specific survival (DSS) varied significantly by stage, sex, histological type, insurance type, marital status, and race, with a better survival noted in earlier stages, females, married, insured, Hispanic and other races, and urban population. Similarly, TC and AC had better survival compared to SCLC and LCNEC. Conclusion: The incidence of lung NENs is rising, possibly in part because of advanced radiological techniques. However, the incidence of SCLCs is waning, likely because of declining smoking habits. Such population-based studies are essential for resource allocation and to prioritize future research directions.

Abstract Abstract Importance: The benefit of routine screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in patients with cancer before cancer-directed therapies is unclear. Herein, we characterize the outcomes of a cohort of cancer patients diagnosed with Coronavirus Disease 2019 (COVID-19) by routine screening in comparison with those diagnosed based on clinical suspicion or exposure history (non-routine screening). Objective: To describe and compare the outcomes of cancer patients diagnosed with COVID-19 on routine screening vs. non-routine screening at a multi-site tertiary cancer center. To identify risk factors for COVID-19-related hospital admission. Design: A multi-site prospective observational study was conducted between March 18 and July 31, 2020. Setting: Three major and 5 satellite campuses of the Mayo Clinic Cancer Center. Participants: Adult patients diagnosed with active cancer within the past five years and confirmed SARS-CoV-2 infection were included. Primary Outcomes and Measures: Clinical and laboratory data were assessed as independent variables. The primary outcome was COVID-19-related hospital admission. Secondary outcomes included intensive care unit (ICU) admissions and all-cause mortality. Results: Between March 18 and July 31, 2020, 5452 patients underwent routine screening in the outpatient setting, 44 (0.81%) were diagnosed with COVID-19. Routine screening detected additional 19 patients from inpatient and pre-procedural settings; 161 patients were diagnosed with COVID-19 based on non-routine screening. The median age of the entire cohort at diagnosis was 54 years, and 95 patients (42.2%) were female. COVID-19 related-hospitalization rate (17.5% vs. 26.7%, p=0.14), ICU admission (1.6% vs. 5.6%, p=0.19), and mortality (4.8% vs. 3.7%, p=0.72) were not significantly different between routine screening and non-routine screening groups. In the multivariable analysis, age ≥ 60 years (odds ratio: 4.4, p=0.023) and an absolute lymphocyte count ≤1.4 × 109/L (odds ratio: 9.2, p=0.002) were independent predictors of COVID-19-related hospital admission. Conclusions and Relevance: The COVID-19 positivity rate was low based on routine screening. Comparing the outcome with the non-routine screening cohort, there was no significant difference. These results led to an important practice change at our cancer center. We currently follow a testing strategy based on symptoms, exposure, risk factors, and clinical judgment. Citation Format: Zhuoer Xie, Antoine N. Saliba, Jithma Abeykoon, Umair Majeed, Daniel Almquist, Julia Wiedmeier-Nutor, Evandro Bezerra, Xavier Andrade-Gonzalez, Ashley Hickman, Karl Sorenson, Sagar Rakshit, Christopher Wee, Sri Tella, Anuhya Kommalapati, Nadine Abdallah, Joshua Pritchett, Mariza De Andrade, Dipesh Uprety, Andrew Badley, Joleen Hubbard, Naseema Gangat, Carrie A. Thompson, Thomas Witzig, Robert R. McWilliams, Konstantinos Leventakos, Thorvardur R. Halfdanarson. Outcomes of COVID-19 in patients with cancer: Results of a prospective observational comparison of routine screening strategy versus testing based on clinical suspicion [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr S06-03.

Background: Patient information is critical in shared decision-making and patient-centred management for neuroendocrine tumours (NETs). Most adults search the internet for health issues, with over half considering such information to be credible. Therefore, we evaluated the quality of online information on NETs. Methods: Searching for “Neuroendocrine Tumours”, the top 20 websites from Google and top 10 from Yahoo and Bing were identified. Open-access websites written in English were included. Websites indicated as advertisements or directed towards healthcare providers were excluded. Each website was evaluated using the JAMA benchmarks, DISCERN instrument, and the Health on the Internet (HONCode) seal by two independent reviewers. Results: We included 16 unique websites after removing duplicates. Four were education pages from healthcare institutions, 10 were Cancer Society pages, and 2 were general information pages. The average score for JAMA benchmarks was 2.3, with 19% of websites receiving the highest score of 4. Specifically, 31% met the benchmark for authorship, 69% for attribution, 94% for disclosure, and 44% for currency. The average score for the DISCERN instrument was 46.5, with no website achieving the maximum of 80 points. The HONCode seal was present in 3 out of 16 websites (18%). Conclusions: We identified major issues with the quality of online information for NETs using validated instruments. The majority of websites identified through common search engines are low-quality. Patients should be informed of the limited quality of online information on NETs. High-quality online information is needed to ensure that patients can avoid misinformation and actively participate in their care.

Abstract Introduction Recent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens. Materials and Methods This was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients’ demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression-free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR). Results Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum-etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96–16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months. Conclusion Among patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short-lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy. Implications for Practice High-grade well-differentiated neuroendocrine tumors (NET G3) are considered a different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.

402 Background: Pancreas cancer is an aggressive malignancy with limited therapeutic options. Nanoliposomal irinotecan (Nal-IRI) is a preferred second-line treatment, and current guidelines recommend its use in the absence of prior irinotecan. This study aimed to assess whether patients who had received regular irinotecan derive benefit from Nal-IRI. Methods: Medical records of metastatic pancreas cancer patients who had received regular irinotecan and then Nal-IRI were reviewed. The following information was extracted from each medical record: patient demographics, confirmation of a diagnosis of exocrine pancreas cancer, initial cancer stage, dates of administration of the drugs of interest, adverse events that occurred with Nal-IRI treatment, reasons for stopping regular irinotecan, and reasons for starting and stopping Nal-IRI. The primary endpoint was overall survival after the initiation of Nal-IRI (an a priori threshold of > 4 months defined success). Survival data were censored based on date of last follow up. Direct quotes from the medical record were documented to provide insight on prescribing Nal-IRI when guidelines advised the contrary. Results: Sixty four patients met eligibility criteria with a median age of 65 years (range: 36, 80 years). Prior to Nal-IRI, 61 patients had received FOLFIRINOX, and 3 FOLFIRI. Of these, 32 patients manifested progressive disease on regular irinotecan-based therapy. Nal-IRI was prescribed with a fluoropyrimidine; only one patient received monotherapy. At time of analysis, 54 patients had died. Median overall survival from initiation of Nal-IRI was 5.1 months (95% confidence interval (CI): 5.6, 4.3, months). An exploratory comparison, based on no cancer progression with regular irinotecan versus progression, showed improved survival with Nal-IRI in the former group: 6.1 months (95% CI: 9.3, 5.1 months) versus 4.3 months (95% CI: 4.8, 2.3 months); p=0.0006. Nal-IRI adverse events occurred as expected. Qualitative data illustrated several themes, including “limited treatment options,” which appeared to drive the decision to prescribe Nal-IRI. Conclusions: Nal-IRI might be considered in pancreas cancer patients who had received regular irinotecan, particularly in the absence of disease progression with the latter.

370 Background: Dual checkpoint inhibitor therapy with anti-PD-1 and ant-CTLA-4 therapy has shown promising results in patients with high-grade NENs, demonstrating varying response rates of 9 – 44%. More data are needed to evaluate the true response in a real-world cohort of patients. Methods: Retrospective study of all patients with high-grade neuroendocrine neoplasms treated at the Moffitt Cancer Center and Mayo Clinic between 9/2017 and 7/2020 who received combination therapy with ipilimumab and nivolumab. Primary endpoint was objective response rate. Results: 34 patients met eligibility criteria for evaluation. Patients had received an average of 2 lines of therapy prior to treatment with ipilimumab/nivolumab, including at least one cytotoxic chemotherapy regimen. 27 (79.4%) of patients had poorly differentiated NECs and 7 (20.6%) had well-differentiated high grade NETs. The most common primary site (10, 29.4%) was pancreas; other primary sites of disease included unknown primary (n = 9), colon (n = 5), uterus (n = 3), anorectum (n = 2), esophagus (n = 2), cervix (n = 1), stomach (n = 1), and small intestine (n = 1). 5 patients (14.7%) exhibited a best response of PR per RECIST 1.1 criteria, 9 (26.5%) SD, and 17 (50%) PD: 3 patients did not have a follow-up scan and discontinued treatment shortly after initiation due to clinical progression. ORR was 14.7% and DCR was 41.2%. Median PFS was 1 month (95% CI, 0.45 – 1.55); median OS from time of treatment initiation was 5.0 months (95% CI, 3.42 – 6.59) and median OS from diagnosis was 14.0 months (95% CI, 1.49 – 26.51). Median duration on treatment was 1 month (range 0 – 10 months). 26 patients discontinued treatment for progression, 4 patients for toxicity, and 4 remain on treatment at the time of data cut off. 12 patients (35%) experienced grade 3 and 4 treatment-emergent toxicities: liver transaminitis, elevated blood bilirubin, arthralgia, myalgia, peripheral sensory neuropathy, lower extremity edema, confusion, diarrhea, encephalopathy, acute kidney injury, rhabdomyolysis, myocarditis, and colitis. Conclusions: The ipilimumab and nivolumab regimen has modest activity in aggressive and heavily pretreated high-grade NENs who have progressed on prior cytotoxic chemotherapy. Use of this regimen may be considered in patients with particularly aggressive, refractory high-grade NENs.

239 Background: After trastuzumab (T) approval for advanced HER2-positive E/GEJ-AC, HER2 testing has increased in patients (pts) with resectable disease. Neoadjuvant carboplatin/paclitaxel chemoradiation (nCP-CRT) is a common therapy approach. We performed the largest evaluation, to our knowledge, of the prognostic impact of HER2 in E/GEJ-AC pts treated with nCP-CRT. Methods: We retrospectively reviewed medical records of all trimodality-eligible (T2+ or N+) pts with E/GEJ-AC who started nCP-CRT (usually 50.4 Gy) with planned surgery at Mayo Clinic (2014-2019). HER2 was tested using standard criteria for HER2 positivity (ie, immunohistochemistry 3+ or amplification by in situ hybridization). Clinicopathologic data and time to recurrence (TTR), disease free survival (DFS), overall survival (OS), survival after recurrence (SAR), and pathologic complete response (pCR – ie, no residual tumor in primary or nodes) were collected. Kaplan Meier and multivariate Cox analysis were used. Results: Of 161 consecutive eligible pts, HER2 status was available in 107 pts (HER2-positive n=26, HER2-negative n=81) of whom n=82 had surgery and n=19 had pCR. Most tumors were clinical T3 (80%) or N+ (81%), histologic grade 3 of 3 (62%). HER2 positivity was significantly associated with lower grade, but not with age, clinical T or N, or ECOG performance status (PS). A similar proportion of HER2-positive ( vs negative) pts had surgery. Among pts who had surgery, pCR rates were lower in HER2-positive ( vs negative) pts (11% [2/19] vs 27% [17/63]). After a median follow up of 23 mo, DFS and TTR were significantly shorter in HER2 positive ( vs negative) pts, independent of other pretreatment covariables (Table). Yet OS was comparable. Lung recurrence was enriched in HER2 positive ( vs negative) pts. Among pts with recurrence, SAR was longer in HER2-positive vs -negative pts. A total of 53% (10/19) of previously HER2-positive pts received T-based therapy after recurrence, and these pts were the drivers of favorable SAR (median 22 mo in n=10 HER2-positive pts who received T vs 11 mo in n=9 HER2-positive pts who did not receive T vs 11 mo in n=40 HER2-negative pts; P log-rank=.01). Conclusions: HER2 positivity ( vs negativity) is independently associated with shorter TTR and DFS, but more comparable OS. The adverse association of HER2 on tumor response and TTR may have been largely overcome through enhanced survival after recurrence, although OS data are maturing. These data may have implications for the design of endpoints in future curative-intent anti-HER2 trials. [Table: see text]

Objective In this study, we aimed to determine the cause of death (COD) after the diagnosis of neuroendocrine tumors (NET). Methods We used the Surveillance, Epidemiology and End Results (SEER) Program to review patients diagnosed with NET during 2000 to 2016. Patients were followed until death, and different CODs were determined. Results Of 94,399 patients with NETs, 40.9% died during the study period. During the first year of diagnosis, most deaths were from NETs (73%), followed by other cancers (11.2%) and cardiac diseases (4.6%). After more than 10 years, NET deaths decreased to 24.3%, whereas other cancers and cardiac disease became more common. Neuroendocrine tumors were responsible for 42.8%, 63.4%, and 81.2% of deaths in grade I, grade II, and grade III, respectively. For grade I localized NET, other cancers (22.2%) were the most common COD followed by NET (19.7%), whereas in grade 2 localized NET, NET was COD in 31.1% of cases followed by other cancers (22.4%). In metastatic disease, NET was the most common COD regardless of grade. Conclusions For low-grade localized NET, deaths were mostly secondary to non-NET causes. In contrast, NET is responsible for most of deaths in metastatic NET regardless of grade.