Failure Of First-line Treatment Research Articles

Efficacy of rechallenge after first-line immunotherapy for advanced gastric cancer: A retrospective real-world study

ABSTRACT We aimed to explore the efficacy of rechallenge after first-line immunotherapy in advanced gastric cancer (AGC) and to analyze the factors affecting prognosis based on clinical characteristics. Eighty-five AGC patients who underwent rechallenged after the failure of first-line treatment with immune checkpoint inhibitors (ICIs) were retrospectively collected from July 2019 to December 2022 in Jiangsu Cancer Hospital. Potential factors affecting prognosis were analyzed by univariate and multivariate Cox analysis. Survival analysis was performed by Kaplan–Meier method and Log rank test. Stratified factors included human epidermal growth factor receptor 2 (HER-2) and programmed cell death-ligand 1 combined positive score (PD-L1 CPS). The objective response rate (ORR) was 15.3%, and the disease control rate (DCR) was 74.1%. The median progression-free survival (PFS) was 4.8 months. Results showed that patients in the I + C group had the best response. The ORR was 20.0% VS 8.7% in the I + C group and I + C + AAD group. The DCR was 78.0% VS 65.2%, and the median PFS was 6.7 VS 4.7 months [hazard ratio (HR): 0.55, 95% confidence interval (CI): 0.30–1.00, p = .022]. The ORR was 20.0% VS 8.3% in the I + C group and I + C + ADC group. The DCR was 78.0% VS 75.0%, and the median PFS was 6.7 VS 4.4 months (HR: 0.59, 95%CI: 0.26–1.30, p = .112). The median PFS was 4.7 VS 4.4 months in the I + C + AAD group and I + C + ADC group (HR: 1.21, 95%CI: 0.60–2.47, p = .580). Adverse events (AEs) were found in 34 patients, mainly including leukopenia 9 (10.6%), and neutropenia 8 (9.4%). The incidence of grade 3–4 AEs was 8.2%. There were no drug-related deaths and all AEs were manageable. Rechallenge after first-line immunotherapy showed good survival benefit and acceptable safety in the therapy of AGC. Especially for patients with HER-2-positive and PD-L1 CPS ≥ 1%, rechallenge may be an effective treatment modality.

Surufatinib plus toripalimab in advanced soft tissue sarcoma (STS): Results from a multicenter, single-arm, basket study.

42 Background: Soft tissue sarcomas (STS) are highly malignant despite their low incidence and prone to recurrence, with limited therapeutic options after failure of first-line treatment. Several antiangiogenic monotherapies have shown some efficacy but limited benefit. The open-label, multi-cohort, single-arm, basket study was performed to evaluate the efficacy and safety of the combination of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) with toripalimab (an anti-programmed death 1 [PD-1] antibody) for Chinese patients (pts) with advanced solid tumors. Here, we reported the results from the STS cohort. Methods: Pts with STS who had progressed on ≤ 2 lines of systemic chemotherapy, or were intolerant to standard treatment, or for whom there was currently no effective therapy were eligible. They received 21-day cycles of surufatinib 250 mg orally, once daily, plus toripalimab 240 mg intravenously, once every 3 weeks, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of data cutoff (Feb 28, 2023), a total of 20 pts (incl. 4 treatment-naïve pts) were enrolled and received the combination treatment (mean duration: 5.81 months [m]). Median (range) age was 50 (23-74) years, 10 pts were male, 17 pts were TNM stage IV. The pathological types include leiomyosarcoma (n=4, incl. 1 naïve patient), synovial sarcoma (n=4), alveolar soft part sarcoma (n=3, incl. 2 naïve pts), undifferentiated pleomorphic sarcoma (n=3), liposarcoma (n=2, incl. 1 naïve patient) and fibrosarcoma (n=1), malignant fibrous histiocytoma (n=1) and others (n=2). Seven (35%) pts had PD-L1 combined positive score of ≥1. The median follow-up duration was 27.14 m. Confirmed ORR and disease control rate (DCR) for 19 efficacy-evaluable pts was 10.5% and 68.4%, respectively; median duration of response was 7.05m. The median progression-free survival (mPFS) and median overall survival (mOS) was 2.69 m and 16.23 m for all dosed pts. For 16 previously treated pts, ORR and DCR was 6.3% and 62.5% respectively; median duration of response (DoR) was 7.13 m; mPFS was 2.65 m; mOS was 14.32 m. 18 (90%) pts experienced at least one treatment-related adverse event (TRAE), and 7 (35%) of them reported grade ≥3 TRAEs. The incidence of immune-related adverse events (irAEs) was 70%, only 2 pts had grade ≥3 irAEs, which were immune-related pancreatitis and immune-related diabetes. 2 pts were permanently discontinued due to TRAEs, which were grade 2 renal impairment and grade 3 hyperglycemia. No new safety signals were observed. Conclusions: Surufatinib plus toripalimab had a promising antitumor activity and a manageable safety profile in pts with advanced STS. Clinical trial information: NCT04169672 .

Challenges of liquid panel in genomic profiling of esophageal squamous cell carcinoma (ESCC): Insights from an analysis of over 1000 cases.

86 Background: Genomic analysis of ctDNA from cancer patients can allow identification of actionable alterations of tumor without an invasive biopsy. ctDNA analysis has been reported to be superior for global summary of tumor heterogeneity and a short turnaround time compared to tissue analysis,however, there are potential issues including the detection sensitivity, threshold to determine TMB-H, and clonal hematopoiesis of indeterminate potential (CHIP). In order to elucidate the impact of ctDNA analysis on personalized cancer treatment, we decided to examine the genetic landscape and clinical outcomes of ESCC cohort registered in the C-CAT database. Methods: We retrospectively analyzed data from 1059 cases of ESCC registered in the C-CAT from June 2019 to February 2024. Clinical characteristics, TMB status, pathological gene variants, and time to treatment failure (TTF) of first-line treatment were examined. Results: The panels applied to eligible patients consisted of 925 tumor tissue panels (87.3%) and 134 liquid panels (12.7%). Pathological gene mutations were detected in 924 cases (99.8%) in tissue panels and 133 cases (99.2%) in liquid panels. The top 10 detected genes were TP53 (93.4%), CDKN2A (57.8%), CDKN2B (45.5%), CCND1 (43.9%), FGF19 (41.0%), PIK3CA (29.0%), NFE2L2 (28.3%), BCL6 (16.5%), NOTCH1 (13.5%), and KMT2D (12.2%). The detection rate for these genes excluding NOTCH1 and KMT2D were significantly higher in tissue panels than in liquid panels (P≤0.01). The median TMB was 5.00 Muts/Mb for both. In first-line treatment, the TTF for immune checkpoint inhibitors (ICIs) and chemotherapy was significantly longer in TMB-H (≧10 Muts/Mb) compared to TMB-L (3.1M vs. 1.9M, P<0.01) in patients evaluated by tissue panels, but it was not proven in patients evaluated by liquid panels (P=0.38). Furthermore, the results suggest that patients with CDKN2A, CCND1, and FGF19 variants benefit more by adding ICIs to chemotherapy than patients without these variants and while the opposite was true for BCL6 and NOTCH1 and KMT2D. Conclusions: In this ESCC cohort, detection rates in the liquid panels were generally lower than in the tissue panels, suggesting that sufficient ctDNA could not be obtained in many cases. The appropriate patient selection for the liquid panels and the timing of blood collection should be discussed. Furthermore, the ideal threshold for determining TMB-H in the liquid panels needs to be further investigated.

Nordic inflammatory bowel disease treatment strategy trial: protocol for the NORDTREAT randomised controlled biomarker-strategy trial

IntroductionThe absence of reliable prognostic markers poses a challenge to the management of inflammatory bowel disease (IBD). Patients with aggressive disease may not receive sufficient treatment with conventional ‘step-up’ therapy,...

Successful medical management of a pituitary macroadenoma with features of resistant acromegaly and hyperprolactinemia using pasireotide.

The somatostatin analog, pasireotide, is used for the treatment of acromegaly after the failure of surgery and/or first-line medical treatment. A 48-year-old male reported that during a workup for obesity in his home country, hyperprolactinemia was diagnosed and a 3.5 × 3.5 cm pituitary macroadenoma was identified on pituitary MRI. He received cabergoline for 6 months; then he was lost to follow-up. He presented at our Endocrine clinic 2 years later for treatment of obesity (BMI 49.5 kg/m2). Biochemical workup revealed that in addition to hyperprolactinemia (7,237 [normal: 85-323 mIU/L), he had acromegaly, evident by elevated insulin-like growth factor 1 (IGF-1) level (450 [normal: 88-210 µg/L]), and a positive growth hormone suppression test, secondary hypothyroidism, and secondary hypogonadism. Pituitary MRI showed that the adenoma encased parts of the left and right internal carotid arteries and encroached on the optic chiasm. Surgical excision was therefore not feasible. He was treated with cabergoline and later, long-acting release (LAR) octreotide. Prolactin levels were reduced with cabergoline, but IGF-1 levels did not respond to octreotide, and it was discontinued. The patient abandoned radiotherapy after two sessions. He was started on LAR pasireotide 40 mg every 4 weeks and continued on cabergoline 0.5 mg per week. His biochemical response was dramatic, with a near normalization of IGF-1 levels in 3 months. After 6 months from starting pasireotide, we increased cabergoline dose from 0.5 mg/week to 3 mg/week. Three months later, IGF-1 level was normalized. The patient developed type 2 diabetes as a side effect of pasireotide; however, this was well-controlled with medications. The case suggests that pasireotide can provide marked biochemical improvement in acromegaly after the failure of both cabergoline monotherapy and cabergoline plus octreotide. This further confirms a potentially efficacious treatment regimen in treatment-resistant acromegaly with hyperprolactinemia.

Cost-effectiveness of treating advanced melanoma with tumor-infiltrating lymphocytes based on an international randomized phase 3 clinical trial

IntroductionIn a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved...

Management of cytomegalovirus reactivation in patient with immunotherapy-induced gastritis.

We present the case of a 52-year-old woman diagnosed with stage IV clear cell renal cell carcinoma who received combination of surgery and systemic therapy with nivolumab (anti-PD1) and ipilimumab (anti-CTLA-4). During treatment, patient presented oral intolerance, vomiting and abdominal pain. Computed tomography (CT) and gastroscopy (EGD) were performed, identifying findings suggestive of severe gastro-duodenitis with friability and diffuse oedema of the mucosa and deep ulcers. A gastrointestinal immunotherapy-induced toxicity was suspected so patient was managed with proton pump inhibitors (PPIs) and intravenous corticosteroids 1mg/Kg. Three weeks later, corticosteroid treatment failed. EGD was repeated and gastric biopsies were taken for histological and microbiological tests. Gastric biopsies revealed the presence of cytomegalovirus (CMV) inclusion bodies by immunohistochemistry (IHC). CMV viral load by quantitative PCR in plasma was 2,000 IU/mL so intravenous ganciclovir was prescribed. Then, the patient presented poor clinical course with persistent vomiting due to a failure of first-line corticosteroid and antiviral treatment. Another EGD was performed. Last IHC reveals a low CMV viral load. Second-line treatment with Anti-TNF was performed using a single-dose regimen of intravenous infliximab 5 mg/Kg. Finally, the patient presented a clinical and endoscopic response and a negative CMV DNA test in the blood after completing the antiviral treatment.

Evaluation of the m7-FLIPI in Patients with Follicular Lymphoma: FOXO1 Mutational Status May be a Predictive Marker of Early Progression and Long-Term Outcome

DISCUSSION In pts with follicular lymphoma (FL) who received chemoimmunotherapy (CIT) as first-line treatment, progression of disease within 24 months of diagnosis (POD24) was associated with increased risk of death (Casulo, 2015). A clinicogenetic risk model that includes the mutation status of 7 genes ( EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), FLIPI and ECOG, known as the m7-FLIPI, was shown to improve risk stratification in frontline pts with advanced stage FL treated with CIT (Pastore, 2015), as well as predict POD24 after first-line CIT (Jurinovic, 2016). With the hypothesis that there are distinguishing features in the mutational landscape between pts with FL who experience POD24 vs those who don't, we evaluated the prognostic utility of the m7-FLIPI and its components in a retrospective series. MSK-IMPACT Heme (Ptashkin, 2019) is a 468 targeted gene panel that includes the 7 genes required to calculate the m7-FLIPI. We identified all pts with FL, grade 1-3A, who had IMPACT testing, excluding pts with FL grade IIIB, mixed histology, or de novo transformation at diagnosis (n = 295). Three pts were excluded for inadequate clinical data (n = 292). The m7-FLIPI was calculated as previously described. Progression-free survival (PFS) was calculated from date of diagnosis till date of progression after first-line treatment, death, or censored at date of last follow-up. Overall survival (OS) was calculated from date of diagnosis till death or censored at date of last follow-up. Cox proportional hazard models were used to compare differences in survival and the Fisher's exact test for categorical variables in SAS 9.4. A cohort of 292 pts was analyzed. Genomic alterations were identified in the 7 genes . Median age of diagnosis was 57 years (range 26-92) with a slight male predominance (53%). The median follow-up was 5.2 years (95% CI, 4.6-5.7). Initial treatment included monoclonal antibody + chemotherapy (57%), single-agent rituximab (17%), chemotherapy (2%), radiotherapy alone (8%), and other treatments (5%). Thirty-four pts (12%) were never treated. Out of 292 pts, 86 (29%) were high-risk by FLIPI and 42 (14%) were high-risk m7-FLIPI. Forty-four out of 86 pts with high-risk FLIPI (51%) were reclassified as low-risk by the m7-FLIPI. High-risk FLIPI was associated with shorter PFS (HR 1.54, 95% CI 1.12 - 2.11, p = 0.0085) and OS (HR 3.73, 95% CI 1.74 - 7.98, p = 0.0007). High-risk m7-FLIPI was associated with shorter PFS (HR 1.55, 95% CI 1.05 - 2.28, p = 0.027) but not OS (HR 2.09, 95% CI 0.92 - 4.76, p = 0.08). C-statistics showed that m7-FLIPI did not outperform FLIPI alone as a prognostic tool for PFS (FLIPI c-statistic = 0.55, 95% CI 0.51 - 0.59; m7-FLIPI c-statistic = 0.53, 95% CI 0.50 - 0.56) or OS (FLIPI c-statistic = 0.68, 95% CI 0.58 - 0.78; m7-FLIPI c-statistic = 0.55, 95% CI 0.47 - 0.63). Mutations in ARID1A as a single factor were associated with shorter PFS (HR 1.52, 95% CI 1.01-2.29, p=0.047), but this association did not remain significant after adjusting for FLIPI and ECOG (HR 1.49, 95% CI 0.97-2.28, p=0.07). Mutations in FOXO1 were associated with shorter PFS (HR 1.48, 95% CI 1.00-2.19, p=0.049) and OS (HR 2.65, 95% CI 1.21-5.79, p=0.015) as a single factor. This association remained significant after adjusting for FLIPI and ECOG: PFS (HR 1.60, 95% CI 1.08-2.37, p=0.020) and OS (HR 2.65, 95% CI 1.21-5.83, p=0.015; Table 1). High-risk m7-FLIPI and FLIPI pts were not more significantly likely to experience POD24, OR 1.44, 95% CI 0.73-2.83, p=0.37 for m7-FLIPI and 1.48, 95% CI 0.87-2.51, p=0.17 for FLIPI. Pts with mutated FOXO1 were more likely to experience POD24, OR 2.47, 95% CI 1.29-4.71, p=0.008. The m7-FLIPI neither improved risk stratification compared to FLIPI nor did it predict POD24 in this series. Mutations in FOXO1 were associated with shorter PFS and OS independent of FLIPI and ECOG. Pts with mutated FOXO1 were enriched among those with POD24, suggesting that FOXO1 mutation may be a predictive marker for early failure of first-line treatment and death, including pts not fulfilling the POD24 criteria. Similar negative impact of FOXO1 was reported in a comprehensive genomic analysis of FL (Mozas, 2023). Both series are limited by patient numbers. Additional efforts to confirm this observation may be useful for understanding the mechanisms behind the prognostic effect of POD24 on survival and improving long-term outcome in this high-risk FL group.

Pet-2 Positive during Frontline Therapy: An Early Unfavorable Predictor for Subsequent Salvage High-Dose Chemotherapy (HD-CT) and Autologous Stem Cell Transplant in Relapsed or Refractory Classical Hodgkin Lymphoma

Background: Interim PET (PET-2), performed after two cycles of chemotherapy (CT), is widely adopted to select patients (pt) with classical Hodgkin lymphoma (cHL), who might benefit from omitting radiotherapy (RT) or reducing the number of CT cycles in early stages, as well as intensifying or de-escalating first-line therapy in advanced stages. Furthermore, PET-2 has prognostic value in the front-line and in the salvage treatment. In a retrospective multicenter Italian study on patients experiencing failure of first-line treatment, we recently observed that PET-2 seems to be an early unfavorable predictor for subsequent salvage high-dose (HD) CT and autologous stem cell transplant (ASCT). Aims of Study and Methods: To evaluate the impact of the prognostic factor PET-2, we performed a retrospective observational multicenter study on individual data of 184 pt with relapsed or refractory (R/R) cHL after first-line CT given according to a PET-adapted strategy. R/R pt were treated at 11 Italian centers with one or more lines of salvage CT followed by HD-CT and ASCT from 2009 to 2021. We compared characteristics and outcomes of 125 PET-2 negative with those of 59 PET-2 positive (PET-2+) R/R pt. Study endpoints included Progression-free survival (PFS) (defined as the time from the date of ASCT to progression or death after ASCT, whichever occurred first), Overall Survival (OS) (defined as the time from the date of ASCT to death from any cause or the last date for which information was available), and factors associated with ASCT outcome evaluated by univariate and multivariate analysis. Results Main pt characteristics at relapse or progression among 125 PET-2 negative and 59 PET-2+ pt were as follows: median age 34 vs 32 years, M/F 64/61 vs 28/31, refractory disease 38% vs 76%, early relapse (within 12 months from end of first-line CT) 27% vs 19%, late relapse 35% vs 5%, stage III or IV 43% vs 44%, B symptoms 24% vs 27%, extranodal involvement 26% vs 24% bulky disease 12% each, anemia 9% vs 22%, ECOG PS >1 11% vs 8%. First salvage treatment regimen was BeGEV in 34% vs 14%, IGEV in 34% each, Brentuximab Vedotin +/- Bendamustine in 6% vs 24%, DHAP or DHAOX in 17% vs 24% and other regimens in 10% vs 5% of pt, respectively. Before ASCT, 95 (76%) in the PET-2 negative and 32 (54%) in the PET-2+ group achieved a complete metabolic remission (mCR). After a median follow-up of 36 months, the 3-year PFS and OS were 73.8% (95% CI: 66.2-80.0%) and 89.3% (95% CI: 83.0-93.3%), respectively. Figure 1 shows PFS by PET-2 status. A total of 99 patients underwent ASCT after one line of salvage therapy. At 3 years PFS and OS in patients who underwent ASCT after one line of salvage therapy were 80.6% (95% CI: 68.9-88.3) and 92.2% (95% CI: 82.2-96.7) in the PET-2 negative group, and 56.2% (95% CI: 33.6-73.7) and 90.9% (95% CI: 68.1-97.6) in the PET-2+ group. Thirty-six patients required two and 14 more than two lines of salvage therapy in the PET-2 negative group; the same figures in the PET-2+ group were 21 and 14. There was no significant difference in PFS or OS by type of salvage therapy received in the two groups. In univariate analysis PET-2+ during frontline treatment (HR 2.68, P=0.001), anemia (HR 2.18, P=0.038), >2 lines of salvage therapy to enter a response (HR 3.68, P<0.001), achieving less than mCR prior to ASCT (HR 3.19, P<0.001) and RT performed before ASCT (HR 3.11, P=0.017) were associated with inferior PFS. Achieving less than mCR prior to ASCT (HR 2.86, P= 0.026), >2 lines of salvage therapy needed to enter a response prior to ASCT (HR 4.93, P=0.002), anemia (HR 2.96, P=0.040) and checkpoint inhibitors before ASCT (HR=5.10, P=0.032) were adverse prognostic factors for OS, whereas transplant performed after 2012 was associated with improved OS (HR 0.20, P<0.001). Cox regression multivariable analysis led to the identification of more than two lines of salvage therapy needed before ASCT (HR 3.14, P=0.008) as an independent adverse prognostic factor for PFS. PET-2+ at front-line treatment (HR 1.94, P=0.052), anemia at relapse or progression (HR 2.07, P=0.080) and RT before ASCT (HR=2.52, P=0.086) were associated with increased risk of failing ASCT, although they did not reach statistical significance Conclusions: PET-2+ during frontline CT may represent an early marker of chemo-refractoriness. Nevertheless, PET-2+ patients experiencing failure of a PET-guided treatment intensification can benefit from a prolonged OS after HDCT and ASCT.

Prevalence, management, and new treatment modalities of EBV-DNA-emia and EBV-PTLD after allo-HCT: survey of Infectious Diseases Working Party EBMT.

The aim of this study was to determine the current approach of EBV-driven post-transplant complications in context of monitoring, diagnosis, prevalence and treatment in EBMT transplant centers. Routine serology testing in patient and donor before HCT is performed in 95.5% centers. Pretransplant EBV-DNA is routinely tested in all patients in 32.7% centers. Monitoring for EBV infection is feasible in 98.2% centers: including 66.7% centers using standardized PCR. Post-HCT regular monitoring is performed in all patients in 80.5% centers. Anti-EBV prophylaxis with rituximab is used in 12.4% centers. Frequency of csEBV-DNA-emia was 7.4% (adults: 6.2%, children: 12.6%). The PCR threshold used to start preemptive treatment was differentiated among centers. Frequency of EBV-PTLD was 1.6% (adults: 1.3%; children: 3.5%). First-line therapy of EBV-driven complications was rituximab and reduction of immunosuppressive therapy. The rate of failure of first-line preemptive treatment was 12.0%. EBV-specific viral-specific T-lymphocytes were available in 46.0% centers. A number of new experimental therapies were given in 28 patients with resistant/refractory PTLD. In conclusion, the prevalence of EBV-DNA-emia and EBV-PTLD over the period 2020-2021 decreased in comparison to historical data. New trends (routine pretransplant screening for EBV-DNA, wider access to VST, new experimental therapies) are being observed in management of EBV infection after allo-HCT.

Real world evidence reveals improved survival outcomes in biliary tract cancer through molecular matched targeted treatment

Biliary tract cancers are rare cancers with poor prognosis due to a lack of therapeutic options, especially after the failure of first-line systemic treatment. Targeted treatments for this clinical situation are promising and have entered clinical practice. We aimed to describe the overall survival of matched targeted treatment after first-line treatment in patients with biliary tract cancers in an Austrian real-world multicenter cohort. We performed a multicenter retrospective chart review of patients with biliary tract cancer between September 2015 and January 2022. Data, including comprehensive molecular characteristics—next generation sequencing (NGS) and immunohistochemistry (IHC), clinical history, surgical procedures, ablative treatments, patient history, and systemic chemotherapy, were extracted from the records of the participating institutions. Targeted treatment was matched according to the ESMO scale for the clinical actionability of molecular targets (ESCAT). We identified 159 patients with the available molecular characteristics. A total of 79 patients underwent second-line treatment. Of these, 36 patients received matched targeted treatment beyond the first-line and were compared with 43 patients treated with cytotoxic chemotherapy in terms of efficacy outcomes. For Tier I/II alterations, we observed a progression free survival ratio (PFStargeted/PFSpre-chemotherapy) of 1.86, p = 0.059. The overall survival for patients receiving at least two lines of systemic treatment significantly favored the targeted approach, with an overall survival of 22.3 months (95% CI 14.7–29.3) vs. 17.5 months (95% CI 1.7–19.8; p = 0.048). Our results underscore the value of targeted treatment approaches based on extended molecular characterization of biliary tract cancer to improve clinical outcomes.

Systemic treatment of patients with locally advanced or metastatic cholangiocarcinoma - an Austrian expert consensus statement.

Locally advanced or metastatic cholangiocarcinoma is an aggressive carcinoma with a dismal prognosis. For the first-line treatment of locally advanced or metastatic cholangiocarcinoma, cisplatin/gemcitabine has been the standard of care for more than 10 years. Its combination with the immune checkpoint inhibitor durvalumab resulted in an efficiency improvement in the phase III setting. Regarding the use of chemotherapy in the second line, positive phase III data could only be generated for FOLFOX. The evidence base for nanoliposomal irinotecan (Nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) is contradictory. After the failure of first-line treatment, targeted therapies can be offered if the molecular targets microsatellite instability-high (MSI-H), IDH1, FGFR2, BRAF V600E, and NTRK are detected. These targeted agents are generally preferable to second-line chemotherapy. Broad molecular testing should be performed, preferably from tumor tissue, at the initiation of first-line therapy to timely identify potential molecular targets.

403. END-STAGE ACHALASIA: FEASIBILITY OF CARDIOMYOTOMY WITH ANTERIOR 90-DEGREE FUNDOPLICATION AS TREATMENT

Abstract Achalasia is a primary motor disorder of the oesophagus. End-stage achalasia is characterised by a grossly dilated sigmoid-shaped oesophagus with food stasis leading to chronic inflammation. Despite treatment, approximately 5% of patients progress to this late stage, needing oesophagectomy. Current guidelines recommend oesophagectomy as the last resort after failure of first-line endoscopic treatment or cardiomyotomy. We review a case of a 70 years old female with end-stage achalasia who successfully underwent cardiomyotomy but required a looser wrap for oesophageal emptying. Patient first presented in her 50s with dysphagia and Oesophago-Gastro-Duodenoscopy (OGD) showed a dilated oesophagus with food stasis and no contractions. Barium swallow confirmed the diagnosis of achalasia. She underwent pneumatic dilatations with minimal symptom improvement and eventually defaulted follow-up. Several years later she presented with haematemesis due to severe oesophagitis and Eckardt score of 7. Both OGD and CT scans showed a grossly dilated megaoesophagus. High-resolution manometry confirmed Type I achalasia with IRP (integrated relaxation pressure) 25.8 and complete absence of peristalsis. She was initiated on nasogastric feeding and was also diagnosed with pulmonary embolism (PE). In view of PE and patient’s comorbidities, she was not fit for oesophagectomy. Peroral endoscopic myotomy (POEM) was also deemed challenging in the presence of severe, chronic oesophagitis and patient’s need for anticoagulation with potential difficulty in endoscopic haemostasis. She underwent laparoscopic cardiomyotomy with anterior 180-degree fundoplication. However, post-operation contrast swallow showed hold up of contrast despite intraoperative OGD showing smooth passage of scope through LES. Decision was made for revision of fundoplication to anterior 90-degree to further promote oesophageal emptying. Post-operation contrast swallow showed satisfactory drainage into stomach and patient tolerated post-fundoplication diet regime. This case illustrates the role of cardiomyotomy as first-line in patients with end-stage achalasia who are not fit for oesophagectomy. However, an anterior 180-degree fundoplication may not allow adequate drainage from a megaoesophagus and a less tight wrap should be considered in such cases. Post-operation, reported Eckardt score of our patient was 1 with no reflux symptoms, indicating marked alleviation of symptoms. Thus, cardiomyotomy with a lesser 90-degree fundoplication is feasible as first-line treatment in end-stage achalasia.

Focal Onset Seizures: New Treatment Options in The Clinical Practice

This symposium took place during the 2023 Congress of the European Academy of Neurology (EAN). Mar Carreño, Director, Epilepsy Unit, Hospital Clínic and Instituto Clavel, Barcelona, Spain, presented the definition of drug-resistant epilepsy (DRE), and stressed that uncontrolled epilepsy does not necessarily indicate DRE. Before a diagnosis of DRE is made in a patient not responding to medication, questions should be asked regarding the initial epilepsy diagnosis. Carreño discussed paroxysmal events that may mimic epilepsy, and presented three cases of misdiagnosed DRE that were subsequently correctly identified as cardiac syncope, a psychogenic event, and use of inappropriate medication in a patient with generalised epilepsy. The second part of Carreño’s presentation focused on patients with confirmed DRE. They outlined the complications of DRE, including sudden unexpected death in epilepsy (SUDEP), which should be discussed with the patient. Carreño finished their lecture with a discussion of comorbid conditions, including neuropsychiatric comorbidities, which affect one in three patients with epilepsy. Bernhard J. Steinhoff, Medical Director, Kork Epilepsy Center, Kehl, Germany, then discussed the clinical approach to patients with DRE, including treatment options, the range of anti-seizure medications (ASM), and the reasons for failure of first-line treatment, noting that the probability of achieving seizure freedom decreases with each failed ASM. Steinhoff explored the options of substitution monotherapy or combination therapy after failure of the first ASM, before describing cenobamate (CNB) add-on therapy. A randomised, placebo-controlled, dose-response trial showed that adjunctive CNB reduced focal (partial)-onset seizure frequency in a dose-related fashion. Several papers have been published providing real-world evidence to show that adjunctive CNB therapy is associated with improved seizure outcomes, and that the number of concomitant ASMs could be reduced. The symposium concluded with a question and answer session.

Circulating tumor DNA in decision-making of patients with metastatic colorectal cancer after failure of first-line treatment containing cetuximab: A single-center, phase II trial.

e15584 Background: Genetic status is constantly changing after receiving cetuximab. To analyze the molecular characteristics in mCRC after first-line treatment containing cetuximab and adjust second-line targeted therapy strategies, we conducted this prospective study. Methods: Patients with measurable mCRC were enrolled. Main eligibility criteria included initial RAS and BRAF wild-type genetic status on tumor tissue; prior first-line regimens including cetuximab, and then showed progression disease. The ctDNA status was detected: bevacizumab would be applied if there was RAS mutation; the combination of vemurafenib, cetuximab and irinotecan would be used if there was BRAF mutation; trastuzumab would be used if there was HER2 amplification; cetuximab or bevacizumab would be applied according to investigators discretion if no related secondary variation. The primary endpoint was ORR; secondary endpoints were DCR, PFS, OS, safety and tolerability. Results: Twenty-two patients were enrolled from Apr 8, 2021 to Nov 18, 2022. Fifty percent (11/22) were males and the median age was 56.5 years. 59.1% (13/22) patients received bevacizumab, 36.4% (8/22) patients received cetuximab, and 4.5% (1/22) patients received trastuzumab and pyrotinib. 52 variations were detected in 22 patients before second-line therapy, with a positive rate of 95.5%. TP53 (90.9%, 20/22) was the most mutated gene, followed by APC (86.4%, 19/22). The percentage of secondary KRAS mutation was 9.1% (2/22), BRAF mutation was 0, ERBB2 amplification was 4.5% (1/22), and ERBB2 mutation was 9.1% (2/22). For 8 patients with serial ctDNA detection, the number of gene variation was decreased during disease remission (10 vs. 23) and increased again during progression (23 vs. 10). The ORR was 40.9% (9/22) for all patients. And it was 38.5% (5/13) and 37.5 % (3/8) separately for patients received bevacizumab or cetuximab (p = n.s.). The DCR was 86.4% (19/22) for all patients. And it was 92.3% (12/13), and 75% (6/8) for patients received bevacizumab or cetuximab separately (p = 0.013). The median PFS was 8.6 months in all patients. And it was 11.6 months and 4.6 months separately in patients received bevacizumab or cetuximab (p = 0.013). The median OS was 12.4 months in all patients. And it was 14.5 months and 11 months separately in patients received bevacizumab or cetuximab (P = 0.27). In addition, no difference in treatment related serious adverse advents grade 3-5 was observed. Conclusions: Circulating Tumor DNA is a promising biomarker for assessing treatment efficiency and guiding second-line treatment decisions in patients with mCRC. The bevacizumab-based second line treatment increases DCR and PFS than continuously cetuximab-based treatment, and had a better tendency in OS. Clinical trial information: NCT04831528 .

A multicenter, single-arm, phase 2 study of surufatinib plus toripalimab for patients with advanced endometrial cancer.

5609 Background: Several immunotherapy monotherapies, or combined with antiangiogenic inhibitors, have shown antitumor efficacy in endometrial cancer (EMC) and been approved by FDA. However, therapeutic options for EMC after failure of first-line treatment remain scarce in China. The open-label, multi-cohort, single-arm phase 2 study was performed to evaluate the efficacy and safety of the combination of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) with toripalimab (an anti-PD-1 antibody) for Chinese patients (pts) with EMC after failure of one or more prior lines of systemic treatment. Methods: Pts with EMC who progressed or were intolerable after at least one prior line of systemic antitumor therapy were eligible and enrolled. They received 21-day cycles of surufatinib 250 mg orally, QD, plus toripalimab 240 mg IV, Q3W, until disease progression or reaching the maximum treatment duration with toripalimab of 24 months, or other protocol-specified criteria. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From August 2020 to March 2022, 28 pts were enrolled and received the combination treatment (median duration: 4.6 months). Median age was 58 years (range: 50-71), and 22 (78.6%) pts were endometrioid adenocarcinoma at diagnosis. 9 (32.1%) pts had received ≥2 prior lines of therapy. As of 28 Dec 2022, the median follow-up duration was 16.8 months. Microsatellite status was available in 25 pts. 20 with mismatch repair-proficient (pMMR) and 5 with mismatch repair-deficient (dMMR) were determined. All 28 pts were evaluable with at least one post-baseline tumor assessment. Efficacy results were: confirmed ORR, 28.6% (8 partial response [PRs]); DCR, 82.1%; mDoR, 5.7 months; mPFS (95%CI), 5.4 months (2.7, 8.3); 12-month OS rate, 71.0%. Among pts with pMMR, the confirmed ORR was 25.0%; DCR was 85.0%; mDoR was 4.2 months; mPFS (95%CI) was 4.0 months (2.7, 8.3); 12-month OS rate was 75.4%. All pts experienced at least one treatment-emergent adverse event (TEAE), and 19 (67.9%) of them reported grade ≥3 TEAEs. The most common (≥5% pts) grade ≥3 TEAEs were hypertension (28.6%), aspartate aminotransferase increased (14.3%), alanine aminotransferase increased (10.7%), proteinuria (7.1%), Gamma-glutamyltransferase increased (7.1%) and malignant neoplasm progression (7.1%). No new safety signals were observed. Conclusions: Surufatinib plus toripalimab had a promising antitumor activity and a manageable safety profile in pts with EMC after failure of one or more prior lines of systemic therapy. Clinical trial information: NCT04169672 .

Photobiomodulation et troubles vulvovaginaux après traitements anticancéreux

Anticancer treatments induce vulvovaginal complications that alter the quality of life and sexuality of patients. New technologies, such as photobiomodulation, could address this problem, for which few effective therapeutic solutions exist. The objective of this study was to describe the characteristics of patients seeking treatment and to observe the effects of photobiomodulation. This is a prospective cohort of patients treated for cancer, in failure of first-line medical treatment, managed at the University Hospital of Nîmes. The history, symptoms and impact of the disorders on their quality of life were collected. At follow-up, improvement was assessed using the PGI-I and FSFI questionnaires. Twenty-eight patients were treated. They were all menopausal, half of them after anticancer treatments [chemotherapy (78%), radiotherapy (36%), hormone therapy (36%)]. The main symptom reported was vaginal dryness (72%). Seventy-one percent of patients (n=20) felt that their daily life was affected≥8/10. All patients had sexual dysfunction. Twenty-two patients received at least 6 sessions of photobiomodulation. Seventy-two percent (n=18) of patients felt better or much better after treatment (PGI-I≤2). The median improvement estimated by the patients was 65% (Q1=50%; Q3=72.5%). There was also a significant clinical improvement. No serious adverse events were reported. Due to the small number of patients in a heterogeneous population with no control group, we cannot extrapolate our results. However, the objective was to assess the status of these pathologies and the contribution of photobiomodulation in patients who have failed first-line treatment; and these results are encouraging.

Favorable outcomes of navigated percutaneous ablation and cementoplasty of bone metastasis in the extremities and pelvis-a case series of 13 cases.

Palliative treatment options for bone metastasis are limited, especially in cases where standard protocols have already failed. The purpose of this study was to evaluate the efficacy and safety of percutaneous ablation, either by cryoablation or radiofrequency, combined with percutaneous cementoplasty using cone-beam guided navigation. The objective was to relieve symptoms and improve functionality in patients suffering from pain secondary to bone metastases, as well as evaluate local disease progression post ablation. We conducted a retrospective study of 13 patients (average age 63.6 ± 9.8, nine females) with symptomatic skeletal metastases treated using 3D imaging with navigation and followed for at least 12months. The treatment protocol was implemented either after failure of first line treatment, or as first line when mechanical instability was present. Percutaneous lesion ablation was performed along with percutaneous cementation. In this study, we observed a statistically significant decrease in pain. The mean Visual Analog Scale pain score decreased from 7.1 ± 0.4 prior to CRA/RFA to 2.2 ± 0.3 after the procedure (p < 0.001). At the 12-months follow-up, all patients were able to ambulate with no assistance (Eastern Cooperative Oncology Group <2). One minor adverse event (paresthesia) and one major adverse event (drop foot) were resolved at 1year of follow-up. Treatment of bone metastasis with RFA and CRA in conjunction with cementoplasty using Cone-beam computed tomography navigation provides patients with significant palliative outcomes and in most cases, local tumor control.

Prediction of Clinical Outcomes with Explainable Artificial Intelligence in Patients with Chronic Lymphocytic Leukemia.

The International Prognostic Index (IPI) is applied to predict the outcome of chronic lymphocytic leukemia (CLL) with five prognostic factors, including genetic analysis. We investigated whether multiparameter flow cytometry (MPFC) data of CLL samples could predict the outcome by methods of explainable artificial intelligence (XAI). Further, XAI should explain the results based on distinctive cell populations in MPFC dot plots. We analyzed MPFC data from the peripheral blood of 157 patients with CLL. The ALPODS XAI algorithm was used to identify cell populations that were predictive of inferior outcomes (death, failure of first-line treatment). The diagnostic ability of each XAI population was evaluated with receiver operating characteristic (ROC) curves. ALPODS defined 17 populations with higher ability than the CLL-IPI to classify clinical outcomes (ROC: area under curve (AUC) 0.95 vs. 0.78). The best single classifier was an XAI population consisting of CD4+ T cells (AUC 0.78; 95% CI 0.70-0.86; p < 0.0001). Patients with low CD4+ T cells had an inferior outcome. The addition of the CD4+ T-cell population enhanced the predictive ability of the CLL-IPI (AUC 0.83; 95% CI 0.77-0.90; p < 0.0001). The ALPODS XAI algorithm detected highly predictive cell populations in CLL that may be able to refine conventional prognostic scores such as IPI.

Management of the patient with extensive stage microcytoma. The importance of collaboration between oncology and radiotherapy.

Small cell lung cancer (SCLC) represents one of the most complex challenges in the oncological field, with a very slow advancement in research, contrary to the rapid evolutionary of the disease. For nearly two years, the mainstay of treatment for extensive-stage disease (ES-SCLC) has been the combination of platinum-based chemotherapy and immunotherapy, following the approval of atezolizumab and subsequently durvalumab, based on a modest, but significant improvement in overall survival compared to chemotherapy alone. The poor prognosis after the failure of first-line treatment explains the need to maximize the duration and efficacy of up-front systemic therapies, in particular, the emerging role of radiotherapy, also in ES-SCLC. On 10 November 2022, a meeting concerning the integrated treatment of patients with ES-SCLC was held in Rome and was attended by 12 specialists in oncology and radiotherapy from various centers in Lazio, under the direction of Federico Cappuzzo, Emilio Bria and Sara Ramella. The aim of the meeting was to share their clinical experience and to provide a series of practical indications in order to support physicians in the correct integration between first-line chemo-immunotherapy and radiotherapy treatments in ES-SCLC.