Riechelmann, Rachel P.

632 Background: Paltusotine is an oral, nonpeptide, selective somatostatin receptor 2 agonist. In a phase 2 study, treatment with once-daily paltusotine reduced the frequency and severity of carcinoid syndrome (CS) symptoms and was well tolerated. The effect of paltusotine on biomarkers of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was further explored. Methods: This exploratory study, without formal power calculations, included an 8-week randomized treatment phase (completed) and a 102-week open-label extension phase (currently ongoing). The purpose was to evaluate safety, pharmacokinetics, and exploratory efficacy endpoints, including changes in biomarkers of paltusotine treatment. Enrolled patients were adults with a stable, documented grade 1 or 2 neuroendocrine tumor (NET) and CS. These patients were actively symptomatic and either untreated with somatostatin receptor ligand (SRL) therapy (average of ≥4 bowel movements [BMs] per day or >2 flushing episodes per day in ≥2 days over a 2-week period) or washed out of SRL therapy (symptoms previously controlled on SRL), with demonstrated symptom worsening after washout. Patients were randomized to once-daily paltusotine 40 mg or 80 mg; one optional uptitration (from 40 mg to 80 mg or 80 mg to 120 mg) was permitted. Blood samples for assessment of biomarkers (serum serotonin and plasma 5-HIAA) were collected longitudinally from screening to end of treatment. Upper limit of normal was prespecified as 541 ng/mL for serotonin and 22 ng/mL for 5-HIAA. This analysis focuses on changes in biomarker from baseline to the end of 8-week randomized treatment phase and after approximately one year (48 weeks). Results: Thirty-six patients (n=9 untreated; n=27 SRL washout) were randomized. Mean age was 60.8 years (range 35-83), and 52.8% were female. Nineteen patients had grade 1 NETs, and 17 had grade 2 NETs. As reported previously, treatment with once-daily, oral paltusotine was well tolerated and reduced the frequency and severity of CS symptoms, justifying further clinical development of the 80 mg dose. Mean serum serotonin decreased from 1553.0 ng/mL at baseline to 643.9 ng/mL at Week 8, and mean plasma 5-HIAA decreased from 245.1 ng/mL to 159.7 ng/mL. There was a trend of untreated patients achieving a greater reduction in comparison to washout patients. At 48-week follow-up, mean serum serotonin was stabilized at 791.50 ng/mL (n=20), and mean plasma 5-HIAA was stabilized at 190.45 ng/mL (n=20). Conclusions: Paltusotine significantly reduced serotonin and 5-HIAA levels, with effects maintained at 48 weeks. Biomarker reductions paralleled reductions in BM and flushing frequency. These findings support further investigation in the ongoing phase 3 study (CAREFNDR, NCT07087054). Clinical trial information: NCT05361668 .

662 Background: Alkylating-based chemotherapy (ALK) is one of the main treatments used in patients with advanced pancreatic neuroendocrine tumors (PanNETs). Its use has been associated with an increased risk of grade progression and acquisition of a hypermutator phenotype, associated with frequent alterations of the mismatch repair (MMR) genes. This suggests a potential benefit of immune checkpoint inhibitors (ICI) that are otherwise ineffective in ALK-naïve PanNETs, which are mostly hypomutated. We aimed to describe the efficacy of ICI in patients with advanced PanNET pretreated with ALK. Methods: We assembled an international retrospective cohort of patients with advanced PanNET who received at least one cycle of ICI, and who had previously received at least 3 months of ALK. Patients with poorly-differentiated neuroendocrine carcinoma were excluded. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was the objective response rate (ORR). The impact of tumor mutational burden (TMB, high being defined by >10 mut/Mb) and MMR alterations (mutations or IHC) was explored. Results: We included 39 patients (median age 58.7, male sex 62%). All PanNETs were progressive at baseline and presented a median of 3 (IQR, 2-4) metastatic sites. Tumors were predominantly classified as G2 (47%) or G3 (42%), with a median Ki-67 of 18.5% (IQR, 12-35). 23/27 patients with tumor tissue or ctDNA NGS testing had high TMB (median, 35 mut/Mb; IQR, 24-106) and 12/22 had MMR alterations. Patients had previously received an average of 14 cycles (IQR, 7-25) of ALK (temozolomide 78%, streptozotocin 18%, dacarbazine 4%), which had yielded objective response in 72% of cases. In addition, patients had received a median of 4 (IQR, 3-5) other treatments (including platinum drugs in 80% and PRRT in 51%). ICI mainly consisted in an anti-PDL1/PD1 + anti-CTLA4 combination (85%) or a monotherapy (15%), with a median of 3 (IQR, 2-8) cycles. The ORR was 18% and the disease control rate was 46%. Median PFS was 2.8 months (95% CI, 0.62-4.96) and 6-month PFS rate was 31%. 19% of patients had grade 3-4 toxicity. Patients with high TMB had higher ORR (30% vs. 0%, p=0.03) and longer median PFS (4.9 vs. 2.1 months, p=0.004) compared with patients with low/unknown TMB. Patients with altered MMR had higher ORR (42% vs. 7%, p=0.02) and longer median PFS (8.9 vs. 2.5 months, p=0.014) compared with patients with no/unknown MMR alterations. Conclusions: While ICI shows limited efficacy in unselected patients with advanced PanNETs pretreated with ALK, it may be an effective treatment option in case of high TMB and MMR alterations.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgement. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard-of-care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only). PURPOSE To provide evidence-based guidance for clinicians who treat patients with stage I-III anal cancer. METHODS A systematic review of the literature conducted by the Minnesota Evidence-based Practice Center provided the evidence base for this guideline. An ASCO Expert Panel reviewed this evidence and came to consensus on a set of evidence-based recommendations. RESULTS The systematic review contained three randomized controlled trials and three nonrandomized studies of interventions that were relevant to the guideline topic and informed the recommendations. RECOMMENDATIONS Mitomycin-C (MMC) with a fluoropyrimidine (fluorouracil [FU] or capecitabine) is recommended as the radiosensitizing component of chemoradiation (CRT) for anal cancer; the Expert Panel recognizes that capecitabine is often used as an orally administered alternative to FU and is currently being used in ongoing clinical trials. Cisplatin with FU is an additional chemotherapy combination that may be recommended as radiosensitizing chemotherapy. Because of the myelosuppression associated with MMC, the preferable regimen for patients with immunosuppression is cisplatin and FU. Cisplatin is not recommended for patients with renal dysfunction, significant neuropathy, or hearing loss, and there is no evidence to recommend substituting carboplatin for cisplatin. Dose and schedule options for recommended chemotherapy agents are included within the full text of the guideline. Routine induction chemotherapy before CRT and additional chemotherapy after CRT are not recommended for patients with localized anal cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Abstract Neuroendocrine neoplasms are a diverse group of neoplasms that can occur in various areas throughout the body. Well‐differentiated neuroendocrine tumors (NETs) most often arise in the gastrointestinal tract, termed gastroenteropancreatic neuroendocrine tumors (GEP‐NETs). Although GEP‐NETs are still uncommon, their incidence and prevalence have been steadily increasing over the past decades. The primary treatment for GEP‐NETs is surgery, which offers the best chance for a cure. However, because GEP‐NETs are often slow‐growing and do not cause symptoms until they have spread widely, curative surgery is not always an option. Significant advances have been made in systemic and locoregional treatment options in recent years, including peptide‐receptor radionuclide therapy with α and β emitters, somatostatin analogs, chemotherapy, and targeted molecular therapies.

Even though significant improvements in the treatment of colorectal cancer (CRC) have been made in recent years, survival rates for metastatic colorectal cancer (mCRC) are poor. Effective treatment options for metastatic colorectal cancer remain limited, and new therapeutic strategies are desperately needed. Several tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) that target angiogenesis, a critical process for facilitating tumor cell growth, invasion, and metastasis, are either approved or in clinical development for the treatment of mCRC. Many of these agents have shown efficacy in mCRC, both as single agents and in combination with standard chemotherapy regimens. However, there is a need for predictive markers of response to identify those patients most likely to benefit from antiangiogenic therapy, and, to date, no markers of this type have been validated in patients. Additionally, because antiangiogenic agents typically cause cytostatic as opposed to cytotoxic antitumor effects, it is important to determine the best strategies for evaluating therapeutic response in mCRC to ensure maximum clinical benefit. In this review, we summarize the efficacy and tolerability of approved and investigational antiangiogenic agents for the treatment of mCRC. We also discuss potential markers of response to antiangiogenic agents and how these markers, along with appropriate endpoint selection, can improve clinical trial design.