• Advanced small intestine well-differentiated neuroendocrine tumors (WD-SiNET): A survey of practice on 3rd line treatment

  Lamarca, Angela; Cives, M.; de Mestier, L.; Crona, J.; Spada, F.; Oberg, K.; Pavel, M.; Alonso-Gordoa, T.; The Christie NHS Foundation Trust, Manchester, (2021)

  Introduction: Selection of third-line treatment after somatostatin analogues (SSA) and Peptide Receptor Radionuclide Therapy (PRRT) for WD-SiNETs remains challenging. Aim(s): Understand current practice and rationale for decision-making in the 3rd-line setting after SSA and PRRT. Materials and methods: An online survey (replies collected between 5/8/2020 and 21/9/2020) was built. Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored. Results: A total of 28 replies; medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from ENETS CoE (57.1%), who followed ENETS guidelines (82.1%). Overall, 3rd-line treatment for WD-SiNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%) or personal experience (22.2%). EVE was likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); irrespective of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was chosen if rapid progression (within 6 months) (WA 3.35/4), Ki-67 10-20% (WA 2.77/4), negative SSTR2 imaging (WA 2.65/4) or high tumor burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-FU (57.7%), FOLFOX (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4). Conclusion: Selection of 3rd line therapy is based on multiple factors mainly Ki-67, rate of progression, CS and tumor burden; decisions should be made within a multidisciplinary setting
• Systemic and intracranial efficacy of brigatinib vs.crizotinib: updated results from the ALTA-1L Trial

  Popat, S.; Kim, H. R.; Ahn, M. J.; Yang, J. C. H.; Han, J. Y.; Hochmair, M.; Lee, K. H.; Delmonte, A.; Campelo, M. R. G.; Kim, D. W.; et al. (2021)

  Background: At ALTA-1L (NCT02737501) first interim analysis (IA1), brigatinib demonstrated superior BIRC-assessed PFS and iPFS vs crizotinib. We report IA2 results, planned at w75% of 198 expected PFS events. Methods: Patients with TKI-naive advanced ALK+ NSCLC were randomized 1:1 to brigatinib 180 mg qd (7-day lead-in at 90 mg) or crizotinib 250 mg bid. Endpoints: Primary, BIRC-assessed PFS (RECIST v1.1); secondary included confirmed ORR and iORR, and iPFS (BIRC). Results: 275 patients were randomized (brigatinib/crizotinib, n¼137/ 138); median age, 58/60 years; prior chemotherapy, 26%/27%; baseline brain metastases (BIRC), 34%/36%; brain radiotherapy, 13%/ 14% (WBRT/SRS balanced across arms). At data cutoff (28 June 2019, median follow-up [brigatinib/crizotinib], 24.9/15.2 months, 150 PFS events): BIRC-assessed PFS HR, 0.49 (95% CI, 0.35e0.68, log-rank P<0.0001); brigatinib mPFS, 24.0 months (95% CI, 18.5eNE) vs crizotinib 11.0 months (9.2e12.9). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31e0.61, median 29.4 vs 9.2 months). OS was immature (total events: 33/37, brigatinib/crizotinib). In patients with baseline brain metastases, PFS HR was 0.25; data were less mature in brigatinib patients without brain metastases. Additional results in Table. Radiological overall disease progression occurred in (brigatinib vs crizotinib) 54 (39%) vs 74 (54%) patients (BIRC) and 50 (36%) vs 84 (61%) (investigator); of these, brain was first site of progression more frequently with crizotinib vs brigatinib: 31 (42%) vs 17 (31%) patients (BIRC); 22 (26%) vs 7 (14%) (investigator). Most common TEAEs grade 3: brigatinib: increased CPK (24.3%) and lipase (14.0%), hypertension (11.8%); crizotinib: increased ALT (10.2%), AST (6.6%), lipase (6.6%). Brigatinib significantly delayed median time to deterioration vs crizotinib for global health score/QoL (log-rank P¼0.0485), emotional and social functioning, fatigue, nausea and vomiting, appetite loss, constipation. Conclusions: Brigatinib demonstrated superior systemic and intracranial efficacy vs crizotinib in all patients with TKInaive ALK+ NSCLC and in patients with baseline brain metastases.
• Molecular profiling of well-differentiated neuroendocrine tumors: Role of ctDNA

  Lamarca, Angela; Frizziero, Melissa; Barriuso, Jorge; Kapacee, Zainul Abedin; Mansoor, Was; McNamara, Mairead G; Hubner, Richard A; Valle, Juan W; The Christie NHS Foundation Trust, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, (2021)

  Introduction: Tumor molecular profiling has proven relevant for the clinical management of cancer. Circulating tumor DNA (ctDNA) may be a useful surrogate of tumor tissue when this is insufficient for analysis. Aim(s): Aims: Rate of test failure, detection rate of pathological alterations (PAs) and impact on management. Materials and methods: Patients (pts) with well-differentiated neuroendocrine tumors (WdNETs) underwent ctDNA-based molecular profiling (FoundationLiquid®); non-WdNETs (paraganglioma, goblet cell or poorly differentiated neuroendocrine carcinoma) were used for comparison. Results: Fifteen pts with WdNET (18 ctDNA samples) included: 8 female (53.33%), median age 63.2 years (range 23.5-86.8). Primary: small bowel (8;53.3%); pancreas (5;33.3%); gastric (1;6.7%) and unknown primary (1;6.7%); grade (G)1 (n=5;33.3%); G2 (9;60.0%) and G3 (1;6.7%); median Ki-67: 5% (range 1-30). Thirty pts with non-WdNETs pts (34 ctDNA samples) were included. Five WdNETs samples (27.78%) failed analysis (vs 17.65% in non-WdNETs; p 0.395). Of 13 WdNET samples with successful ctDNA, PAs were detected in 6 (46.15%) (vs 82.14% in non-WdNETs; p 0.018). In WdNETs, PA rate was independent of anti-cancer systemic therapy (2/7;28.57% vs 4/6;66.67%; p 0.286) at time of ctDNA: 4, 1 and 1 samples had 1, 2 and 3 PAs, respectively; these were: CDKN2A mutation (m) (1 sample), CHEK2m (1), TP53m (2), FGFR2amplif (1), IDH2m (1), CTNNB1m (1), NF1m (1), PALB2m (1); nontargetable (0%) or impacted management (0%). There was a trend towards lower maximum mutant allele frequency (mMAF) in WdNETs (mean 0.33) vs non-WdNETs (mean 26.99); p 0.0584. Conclusion: Although feasible, ctDNA molecular profiling was of limited clinical utility for advanced WdNETs. Identification of PAs and mMAF seem higher in non-WdNETs.
• Incidence of brain metastases (BMs) and outcomes in patients (pts) with extrapulmonary neuroendocrine neoplasms (EP-NENs)

  Kapacee, Zainul Abedin; Dawod, Mohammed; Allison, Jennifer; Frizziero, Melissa; Chakrabarty, Bipasha; Manoharan, Prakash; McBain, Catherine A; Mansoor, Was; Lamarca, Angela; Hubner, Richard A; et al. (2021)

  Introduction: The incidence, management and outcomes of pts with EP-NENs and BMs are unclear. Aim(s): To investigate outcomes in pts with EP-NENs ± BMs. Materials and methods: A retrospective study of consecutive pts with EP-NENs and BMs treated at a single ENETS CoE was performed. Median (med) overall survival (OS)/survival from BM diagnosis were estimated (Kaplan Meier). Results: Between Aug 04-Feb 20, 730 pts with an EP-NEN diagnosis were identified: med age 64 yrs (15-90); 56% male, 67% had advanced disease (ADVD). In pts with ADVD, the primary NEN site were: small bowel 42%, pancreas 22%, unknown 14%, large bowel 10%, other 5%, stomach 4% and appendix <1%; 37%, 30% and 30% pts had grade (G)1, 2 and 3 EP-NENs respectively (no grading 3%). Med OS for pts with ADVD G1, 2 and 3 EP-NENs without BMs were 95.8 (95% C.I 77.0-177.1), 61.7 (95% C.I 50.1-124.4) and 11.3 (95% C.I 9.3-14.4) months (mo) respectively. 17 pts (2.3%) developed BMs; 2 at initial diagnosis, 15 metachronously; 5 pts (29%) had a solitary BM, 12 (71%) had multiple BMs. The primary sites of origin were: unknown 41%, oesophagus 18%, pancreas 17%, small bowel 12%, cervix 6% and bladder 6%; 6%, 24% and 70% had G1, G2 and G3 EP-NENs respectively. Most common presenting symptoms of pts with BMs were limb weakness and cognitive impairment. Pts with BMs received high dose steroids and best supportive care (35%), whole brain radiotherapy with steroids (29%), surgery (18%) and localised radiotherapy (6%). Med OS for pts with G1+2 EP-NENs and BMs was not reached. Med OS in pts with G3 EP-NENs and BMs was 9.0 mo (95% CI 6.0-12.1); med survival from BM diagnosis was 2.0 mo (95% CI 0.0-4.4). Conclusion: BMs in pts with EP-NENs are rare, predominant in G3 NENs, and have a poor prognosis. Improved therapeutic options are needed.
• Assessing the management of bone metastases in patients diagnosed with neuroendocrine neoplasms: Re-audit of clinical practice

  Garcia-Torralba, E; Lim, Kok Haw Jonathan; Barriuso, Jorge; McNamara, Mairead G; Hubner, Richard A; Mansoor, Was; Valle, Juan W; Lamarca, Angela; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, (2021)

  Introduction: There remains no global consensus on the optimal management of bone metastases in patients with neuroendocrine neoplasms (BM-NEN). Aim(s): To re-audit the clinical management of BM-NEN following the incorporation of institutional guidelines (TC-BM Guid) established in 2018 (PMID: 31639796). Materials and methods: Retrospective study of all patients with BM-NEN diagnosed from Jan-Dec 2019 following TC-BM Guid. Characteristics of BM-NEN and treatment received were evaluated against TC-BM Guid. Statistical analysis was performed using STATA v14. Results: Of 354 patients, 40 (11%) had BM (gastrointestinal: 53%, N=21; lung: 15%, N=6; unknown primary: 12%, N=5; other: 20%, N=8). BM were “widespread” in 80% (N=32). Compared to the cohort prior to TC-BM Guid implementation (2002-2018, N=85), incidence of symptoms (any), pain/hypercalcemia, and skeletal-related events were lower (45%, N=18 vs 78%, N=66; 40%, N=16 vs 64%, N=54; 13%, N=5 vs 20%, N=17, respectively). Use of analgesia for symptomatic BMs (80%, N=32 vs 44%, N=37) and use of bisphosphonates (33%, N=13 vs 22%, N=19) were higher. Use of radiotherapy and surgery were similar (23%, N=9 and 3%, N=1 respectively). The re-audit showed that management adhered to TC-BM Guid in the majority of patients (95%, N=38), including 4 patients who received best supportive care due to poor performance status (PS) and short prognosis (<3 months), which was not previously detailed in the guidelines. Conclusion: TC-BM Guid are deliverable, and current management of BM-NEN mostly adhered to these. Following this, TC-BM Guid were updated to reflect recommendations for symptomatic management only (best supportive care) for patients with poor PS/short life-expectancy.

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