Postoperative treatment with octreotide in patients with gastroesophageal cancer: An open-label phase 2 study

<p dir="ltr">Background: Gastroesophageal cancer (GEC) is notorious for causing extreme weight loss and symptoms contributing to weight loss are often the first sign of the disease. Malnutrition is not only associated with increased morbidity and mortality but does also impact on eligibility for multimodality treatment which might further deteriorate nutritional status and exacerbate weight loss. While nutrition is a key component in the standardized postoperative recovery protocol, nutritional route is not included due to lack of scientific evidence. At Karolinska University Hospital patients undergoing esophagectomy routinely receive a nutritional jejunostomy. Potential advantages of this approach were evaluated in study I. Quality of life measurements does not only assessing overall quality of life but also assess nutritional aspects. Study II assess effects of neoadjuvant treatment on Health-Related Quality of Life (HRQL) while study IV evaluates HRQL on time-to-surgery from neoadjuvant chemoradiotherapy (nCRT). Study III is a pilot-study for pharmacological treatment of nutritional issues in patients operated for GEC where HRQL serves as a secondary outcome.</p><p dir="ltr">Aim: The overall aim of this thesis was to investigate measures involved in the multimodal treatment of GEC to improve nutritional aspects and HRQL, enhancing understanding and treatment and ultimately contributing to reduce morbidity and mortality.</p><p dir="ltr">Method and results: Study I examined 1871 patients who underwent GEC surgery in Sweden between 2006 and 2017. Multivariable logistic regression showed that postoperative complications were more common in patients with a nutritional jejunostomy (39.0% vs. 44.4%, p=0.019). A sub-analysis demonstrated benefit of jejunostomy among patients with postoperative leakage (OR 0.19 for Clavien-Dindo score ≥ IIIb, range 0.04- 0.94). Study II evaluated the effects of neoadjuvant therapy vs. surgery alone in 361 patients undergoing curatively intended GEC surgery at Karolinska University Hospital between 2013 and 2020. Multivariable linear regression demonstrated less pain and fewer problems related to eating restrictions in patients assigned to neoadjuvant treatment (-11, p=0.004, - 12, p=0.005). Study III assessed safety and tolerability of Octreotide LAR depot, 10mg, administered intramuscularly at 7 days, 1 month and 2 months postoperatively. The study included 20 patients (10 gastrectomy, 10 esophagectomy) and was conducted from September 2021 to October 2023. Of the 20 participants, 19 (95%) completed the treatment. Mild to moderate adverse events were reported in 12 participants (60%). Two patients experienced serious adverse events, although none attributed to the exposure. Study IV was a secondary endpoint analysis within a multicenter randomized controlled trial, in which patients were randomized between standard time-to-surgery (4-6 weeks) and prolonged time-to-surgery (10-12 weeks). Among the 192 patients who completed at least one HRQL-questionnaire, 95 (49%) were assigned to the prolonged time-to-surgery. Preoperatively, after nCRT, patients in the prolonged time-to-surgery group reported better HRQL compared to those in the standard time-to-surgery group, but postoperatively no clinically significant differences were found.</p><p dir="ltr">Conclusions: The studies included in this thesis demonstrates beneficial use of selective jejunostomy and improved preoperative HRQL after neoadjuvant treatment compared to surgery alone. It demonstrates tolerability of Sandostatin LAR depot, which might potentially mitigate the undesired postoperative weight-loss in patients with GEC. Finally, the results demonstrates that postoperative HRQL is unaffected by time-to-surgery after esophagectomy for cancer.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Holmén A,</b> Hayami M, Szabo E, Rouvelas I, Agustsson T, Klevebro F. Nutritional jejunostomy in esophagectomy for cancer, a national register-based cohort study of associations with postoperative outcomes and survival. Langenbecks Arch Surg. 2021 Aug;406(5):1415-1423. <a href="https://doi.org/10.1007/s00423-020-02037-0" rel="noreferrer" target="_blank">https://doi.org/10.1007/s00423-020-02037-0</a></p><p dir="ltr">Il. Holmen A, Jebril W, Ida S, Agustsson T, Lampi M, Rouvelas I, Sunde B, Klevebro F. Effects of neoadjuvant therapy on health-related quality of life for patients with gastroesophageal cancer. Eur J Surg Oncol. 2023 Nov;49(11):107008. <a href="https://doi.org/1016/j.ejso.2023.107008" rel="noreferrer" target="_blank">https://doi.org/1016/j.ejso.2023.107008</a></p><p dir="ltr">III. <b>Holmén A,</b> Lampi M, Rouvelas I, Sunde B, Agustsson T, Lindberg G, Klevebro F. Postoperative Treatment with Octreotide in Patients with Gastroesophageal Cancer: An Open-Label Phase 2 Study. [Submitted]</p><p dir="ltr">IV. Holmen A, Murad F, Nilsson K, Rouvelas I, Lindblad M, Szabo E, Halldestam I, Smedh U, Wallner B, Johansson J, Johnsen G, Aahlin E.K, Johannsessen H-O, Alexandersson von Döbeln G, Hjortland G.O, Wang N, Shang Y, Borg D, Quaas A, Bertella I, Bruns C, Schröder W, Nilsson M, Klevebro F, Sunde B. Health-related quality of life comparing standard and prolonged time-to-surgery after neoadjuvant chemoradiotherapy for esophageal cancer - results from the multicenter, randomized, controlled NeoRes II trial. [Manuscript]</p>

<p dir="ltr">Background: Gastroesophageal cancer (GEC) is notorious for causing extreme weight loss and symptoms contributing to weight loss are often the first sign of the disease. Malnutrition is not only associated with increased morbidity and mortality but does also impact on eligibility for multimodality treatment which might further deteriorate nutritional status and exacerbate weight loss. While nutrition is a key component in the standardized postoperative recovery protocol, nutritional route is not included due to lack of scientific evidence. At Karolinska University Hospital patients undergoing esophagectomy routinely receive a nutritional jejunostomy. Potential advantages of this approach were evaluated in study I. Quality of life measurements does not only assessing overall quality of life but also assess nutritional aspects. Study II assess effects of neoadjuvant treatment on Health-Related Quality of Life (HRQL) while study IV evaluates HRQL on time-to-surgery from neoadjuvant chemoradiotherapy (nCRT). Study III is a pilot-study for pharmacological treatment of nutritional issues in patients operated for GEC where HRQL serves as a secondary outcome.</p><p dir="ltr">Aim: The overall aim of this thesis was to investigate measures involved in the multimodal treatment of GEC to improve nutritional aspects and HRQL, enhancing understanding and treatment and ultimately contributing to reduce morbidity and mortality.</p><p dir="ltr">Method and results: Study I examined 1871 patients who underwent GEC surgery in Sweden between 2006 and 2017. Multivariable logistic regression showed that postoperative complications were more common in patients with a nutritional jejunostomy (39.0% vs. 44.4%, p=0.019). A sub-analysis demonstrated benefit of jejunostomy among patients with postoperative leakage (OR 0.19 for Clavien-Dindo score ≥ IIIb, range 0.04- 0.94). Study II evaluated the effects of neoadjuvant therapy vs. surgery alone in 361 patients undergoing curatively intended GEC surgery at Karolinska University Hospital between 2013 and 2020. Multivariable linear regression demonstrated less pain and fewer problems related to eating restrictions in patients assigned to neoadjuvant treatment (-11, p=0.004, - 12, p=0.005). Study III assessed safety and tolerability of Octreotide LAR depot, 10mg, administered intramuscularly at 7 days, 1 month and 2 months postoperatively. The study included 20 patients (10 gastrectomy, 10 esophagectomy) and was conducted from September 2021 to October 2023. Of the 20 participants, 19 (95%) completed the treatment. Mild to moderate adverse events were reported in 12 participants (60%). Two patients experienced serious adverse events, although none attributed to the exposure. Study IV was a secondary endpoint analysis within a multicenter randomized controlled trial, in which patients were randomized between standard time-to-surgery (4-6 weeks) and prolonged time-to-surgery (10-12 weeks). Among the 192 patients who completed at least one HRQL-questionnaire, 95 (49%) were assigned to the prolonged time-to-surgery. Preoperatively, after nCRT, patients in the prolonged time-to-surgery group reported better HRQL compared to those in the standard time-to-surgery group, but postoperatively no clinically significant differences were found.</p><p dir="ltr">Conclusions: The studies included in this thesis demonstrates beneficial use of selective jejunostomy and improved preoperative HRQL after neoadjuvant treatment compared to surgery alone. It demonstrates tolerability of Sandostatin LAR depot, which might potentially mitigate the undesired postoperative weight-loss in patients with GEC. Finally, the results demonstrates that postoperative HRQL is unaffected by time-to-surgery after esophagectomy for cancer.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Holmén A,</b> Hayami M, Szabo E, Rouvelas I, Agustsson T, Klevebro F. Nutritional jejunostomy in esophagectomy for cancer, a national register-based cohort study of associations with postoperative outcomes and survival. Langenbecks Arch Surg. 2021 Aug;406(5):1415-1423. <a href="https://doi.org/10.1007/s00423-020-02037-0" rel="noreferrer" target="_blank">https://doi.org/10.1007/s00423-020-02037-0</a></p><p dir="ltr">Il. Holmen A, Jebril W, Ida S, Agustsson T, Lampi M, Rouvelas I, Sunde B, Klevebro F. Effects of neoadjuvant therapy on health-related quality of life for patients with gastroesophageal cancer. Eur J Surg Oncol. 2023 Nov;49(11):107008. <a href="https://doi.org/1016/j.ejso.2023.107008" rel="noreferrer" target="_blank">https://doi.org/1016/j.ejso.2023.107008</a></p><p dir="ltr">III. <b>Holmén A,</b> Lampi M, Rouvelas I, Sunde B, Agustsson T, Lindberg G, Klevebro F. Postoperative Treatment with Octreotide in Patients with Gastroesophageal Cancer: An Open-Label Phase 2 Study. [Submitted]</p><p dir="ltr">IV. Holmen A, Murad F, Nilsson K, Rouvelas I, Lindblad M, Szabo E, Halldestam I, Smedh U, Wallner B, Johansson J, Johnsen G, Aahlin E.K, Johannsessen H-O, Alexandersson von Döbeln G, Hjortland G.O, Wang N, Shang Y, Borg D, Quaas A, Bertella I, Bruns C, Schröder W, Nilsson M, Klevebro F, Sunde B. Health-related quality of life comparing standard and prolonged time-to-surgery after neoadjuvant chemoradiotherapy for esophageal cancer - results from the multicenter, randomized, controlled NeoRes II trial. [Manuscript]</p>

398 Background: Phase III studies have shown a survival benefit for the addition of immune checkpoint inhibitors to conventional chemotherapy for patients with gastroesophageal cancer (GEC). Large scale studies of chemoimmunotherapy prior to and after surgery are under way. We sought to characterise the effects of the PDL1 inhibitor durvalumab (D) with standard neo-adjuvant chemo(radio)therapy regimens in an open label phase I/II study in patients (pts) with operable GEC (LUD2015-005, NCT02735239, EudraCT 2015-005298-19). Methods: In pts identified as suitable for potentially curative surgery we gave D (750mg q2w) alongside their standard treatment. Pts had D only at first then Oxaliplatin and Capecitabine (CapOx) q3w or fluorouracil, leucovorin, oxaliplatin and taxotere (FLOT) starting with the third cycle of D. Chemotherapy and further D were given for 6 (CapOx) or 8 (FLOT) weeks before pts had surgery and for up to 12 further infusions of D after operation. Patients on FLOT could also have more chemotherapy. Pts suitable for chemoradiotherapy (CXRT, CROSS regimen) were offered two cycles of D before starting their treatment, and were able to have up to 12 further cycles after recovering from surgery. Participants were followed for toxicity, response and survival from the time of study enrolment until death, for 3 years or until June 2022 when the study ended. Results: 11 pts received D-CapOx, 9 D-FLOT and 15 D-CXRT. All were evaluable for safety and efficacy. Treatment side effects were as expected for the agents used with diarrhoea, nausea and fatigue the most commonly reported and no new safety signals. 156 of 160 planned pre-op D doses were given. Only 2 out of 35 patients did not have surgery, both due to progressive disease on D-CXRT. 23 of the 33 patients having surgery had post-operative treatment. Amongst 33 evaluable pts 2 (5.7%) and 6 (17.1%) had complete or partial pre-op responses (RECIST) and 3 (8.6%) progression prior to surgery. Tumor regression at surgery (Mandard 1-3) occurred in 24/33 pts. Median recurrence free survival was 25.4 months (mo) (D-CapOx), 32.0 mo (D-FLOT) and not reached (D-CXRT). 2 year survival was 81.8%, 77.8% and 77.8% respectively in the 3 arms. Conclusions: Adding D to standard neo-adjuvant regimens for GEC is well tolerated. Survival times and response rates exceeded those expected for the regimens used (2 year survivals with FLOT 68% and CROSS 67%) in this non-randomised multi-centre trial. Clinical trial information: NCT02735239 .

Intratumoral heterogeneity in gastric cancer: a new challenge to face

Aspirin as an adjuvant treatment for cancer: feasibility results from the Add-Aspirin randomised trial

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study.

Patient-reported outcomes with paclitaxel and ramucirumab switch maintenance in advanced gastroesophageal cancer: A secondary endpoint of the ARMANI phase 3 trial.

Claudin 18.2—a FAST-moving target in gastric cancer?

Encouraging results for PD-1 inhibition in gastric cancer

How low can you go? PD-L1 expression as a biomarker in trials of cancer immunotherapy

PurposeOligometastatic gastroesophageal cancer is a clinical entity with no standard treatment recommendation. Treatment with curative intent has recently emerged as an option for selected patients in contrast to the traditional palliative treatment strategy. This prospective study aimed to assess the safety and efficacy of combined systemic and local treatment with curative intent for patients with oligometastatic gastroesophageal cancer.MethodsIn a multicenter study, consecutive patients with gastroesophageal cancer and metastases in the liver and/or extra-regional lymph nodes were screened for inclusion. Eligible patients were offered curatively intended perioperative chemotherapy followed by surgical resection or liver ablation. Primary endpoints were treatment safety and feasibility. Secondary outcomes included postoperative mortality, treatment response, progression-free survival, and overall survival. Subgroup analyses were stratified based on oligometastatic location.ResultsA total of 29 (82.9%) patients completed treatment with surgical resection (93.1%), liver ablation (3.4%), or definitive chemoradiotherapy (3.4%). Postoperative complications were found in 19 (73.1%) patients, whereas postoperative mortality was 0%. The most common complications included infection (34.6%) and respiratory complications (34.6%). Median overall survival was 20.9 months (interquartile range 11.2–42.6) from diagnosis and 17.0 months (interquartile range 6.4–35.9) from surgery in patients who were treated with neoadjuvant chemotherapy followed by surgery. Median progression-free survival was 5.8 months (interquartile range 3.1–11.3).ConclusionThis study found curative treatment to be a relatively safe option, with an overall survival of 20.8 months and no postoperative mortality.

TPS3647 Background: Nectin-4, a transmembrane cell adhesion protein, is highly expressed in urothelial carcinoma (UC), breast cancer (BC), non-small cell lung cancer (NSCLC), and gastroesophageal cancers (GEC); targeting Nectin-4 on these tumors may provide a novel treatment approach. Enfortumab vedotin (EV), an investigational human monoclonal antibody-drug conjugate, binds to Nectin-4 and upon internalization releases MMAE resulting in cell cycle arrest and cell death. Recently, EV received accelerated approval by the FDA for the treatment of adults with locally advanced/metastatic UC who previously received a PD-1 or PD-L1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Use of EV in this study is investigational. Methods: This open-label phase 2 study (NCT04225117) will assess the efficacy and safety/tolerability of EV in patients (pts) with previously treated locally advanced/metastatic malignant solid tumors. Adult pts (~240) with histologically or cytologically confirmed disease and an ECOG ≤1 will be enrolled into 1 of 6 tumor-specific cohorts (Table), with ~40 pts each. While Nectin-4 expression is not required for enrollment, it is being tested retrospectively. Patients with active CNS metastases, grade ≥2 preexisting sensory or motor neuropathy, grade ≥3 immunotherapy-related hypothyroidism or panhypopituitarism, ongoing grade >3 immunotherapy-related AEs requiring high-dose steroids, or a history of uncontrolled diabetes mellitus within 3 months of the study will be excluded. All pts will receive EV 1.25 mg/kg IV on Days 1, 8, and 15 of each 28-day cycle until treatment discontinuation criteria are met; dose reductions/interruptions will be permitted. For all cohorts, the primary endpoint is investigator-assessed confirmed objective response rate (RECIST v1.1); secondary endpoints include duration of response, disease control rate, progression-free and overall survival, and safety/tolerability of EV. This study is recruiting as of February 2020. Clinical trial information: NCT04225117 . [Table: see text]

Gastric and gastroesophageal junction (GEJ) cancers represent an aggressive group of malignancies with poor prognosis even when diagnosed in relatively early stage, with an increasing incidence both in Asia and in Western countries. These cancers are characterized by heterogeneity as a result of different pathogenetic mechanisms as shown in recent molecular analyses. Accordingly, the understanding of phenotypic and genotypic correlations/classifications has been improved. Current therapeutic strategies have also advanced and moved beyond surgical extirpation alone, with the incorporation of other treatment modalities, such as radiation and chemotherapy (including biologics). Chemoradiotherapy has been used as postoperative treatment after suboptimal gastrectomy to ensure local disease control but also improvement in survival. Preoperative chemoradiotherapy/chemotherapy has been employed to increase the chance of a successful R0 resection and pathologic complete response rate, which is associated with improved long-term outcomes. Several studies have defined various chemotherapy regimens to accompany radiation (before and after surgery). Recently, addition of immunotherapy after trimodality of gastroesophageal cancer has produced an advantage in disease-free interval. Targeted agents used in the metastatic setting are being investigated in the early setting with mixed results. The aim of this review is to summarize the existing data on trimodality approaches for gastric and GEJ cancers, highlight the remaining questions and present the current research effort addressing them.

4031 Background: Capecitabine plus oxaliplatin (CAPOX) is one of the standard first-line treatments for advanced or metastatic gastric cancer. Camrelizumab (SHR-1210, an anti–PD-1 antibody) shows promising anti-tumor activity in patients (pts) with advanced or metastatic gastric or gastroesophageal junction (G/GEJ) cancer. Camrelizumab combined with CAPOX for untreated G/GEJ cancer was assessed as a part of an ongoing multicenter, open-label phase 2 trial (cohort 1), and encouraging preliminary results were reported. Here, we present the updated safety and efficacy data. Methods: In this cohort, systemic treatment naïve pts with HER2– advanced or metastatic G/GEJ adenocarcinoma were given camrelizumab 200 mg on Day 1, capecitabine 1000 mg/m2 bid on Days 1–14 and oxaliplatin 130 mg/m2 on Day 1 of each 21-day-cycle for 4 to 6 cycles followed by camrelizumab 200 mg every 3 weeks plus apatinib 375 mg qd until disease progression or intolerable toxicity. The primary endpoint was objective response rate. Results: At data cutoff (Jan 20, 2019), 43 of the 48 enrolled pts were evaluable. Partial response was observed in 28 pts (65%), and 19 (44%) were confirmed. Stable disease in 14 pts and progressive disease in 10 pts were reported. Median estimates for duration of response and progression-free survival were not reached. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 9 pts (21%), included neutropenia, diarrhea, rash and elevated ALT, whereas none of the TRAEs was fatal. Ten pts without progression after 4–6 cycles of camrelizumab and CAPOX combination therapy all received camrelizumab plus apatinib as sequential therapy, and no new safety signals were observed. Conclusions: The updated results confirmed that camrelizumab plus CAPOX followed by camrelizumab plus apatinib was well tolerated with noteworthy responses as first-line therapy in advanced or metastatic G/GEJ cancer pts. Expansion of this cohort in a phase 3 study are under way. Clinical trial information: NCT03472365.

TPS709 Background: High Expression of Peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor-family transcription factor, drives the initiation and development of UC in luminal molecular subtype tumors. Genetic profiling of UC has identified recurrent oncogenic alterations in the PPARG transcriptional complex, including focal amplification, missense mutations, and fusions in the heterodimeric partner of PPARG, the retinoid X receptor alpha (RXRA). High levels of PPARG expression and recurrent oncogenic alterations are observed in other solid malignancies including colorectal, gastroesophageal, pancreatic and lung cancers. FX-909 is an oral, first-in-class, new molecular agent that specifically, potently, and covalently modifies PPARG to mediate basal and ligand-activated transcription. Treatment of genetically defined UC xenografts with FX-909 has shown an 84% tumor growth inhibition (TGI) at a dose expected to be equivalent to 50 mg dose in humans, which is the starting dose in this clinical study. Methods: FX-909-CLINPRO-1 (NCT05929235) is a first-in-human, multicenter, open-label Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FX-909 given orally in patients with advanced solid malignancies. Patients enrolled in the trial must have ECOG performance status ≤2 and must be ≥ 18 years of age. Initially, FX-909 will be given once daily to patients with any advanced solid malignancy in a dose-escalation phase (Part A) utilizing a 3+3 design. Five dose cohorts of 3 to 6 patients are planned. At the time of submission, three patients are enrolled in Part A- cohort one, 50mg. Additional patients will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or evidence of clinical activity. Once a RP2D has been determined, a monotherapy expansion phase (Part B) will proceed in a Simon 2-stage design in patients with locally advanced (unresectable) or metastatic UC with measurable disease and tumors harboring defined genetic alterations in PPARG, RXRA and FGFR3 (Motley et al, 2022). In stage 1, up to 19 evaluable patients will be enrolled. If ≥4 objective responses are observed, enrollment will continue into Stage 2 with an additional 14 evaluable patients. One treatment cycle is 28 days. Dose expansion will evaluate the safety, PK/PD profile, and antitumor activity of FX-909 at the RP2D. Exploratory objectives include the evaluation patient selection biomarkers from tissue and blood samples. FX-909 clinical activity will be assessed using RECIST v1.1 criteria. The study is currently enrolling patients in the US. Clinical trial information: NCT05929235 .