2nd Line Chemotherapy Research Articles

Systemic therapy in NF-1 associated malignant peripheral nerve sheath tumors (MPNST).

11583 Background: MPNST are rare sarcomas that have a poor prognosis and are challenging to treat. Around 50% of MPNSTs are associated with NF1, 40% are sporadic, and 10% are radiation-associated. Doxorubicin (D) based chemotherapy (CT) regimens are commonly used in the front-line, and combinations have better response rates than single agents. Response to second-line regimens is not well documented. The objective of this study is to document efficacy of systemic regimens in MPNST as a benchmark for future novel therapeutics in this space. Methods: 72 patients (pts) with NF1-associated MPNSTs in an MD Anderson database were reviewed retrospectively from EMR. Variables collected included demographics, primary MPNST location, localized vs metastatic, and treatments received (+/- radiation, +/-surgery, +/- lines of CT). Responses (progressive disease (PD), stable disease (SD), partial response (PR)) as interpreted by treating physician and radiology reports and time on treatment for 1st and 2nd line chemotherapy regimens were assessed. Cox proportional-hazard regression was used to investigate associations of variables with overall survival (OS: from time of diagnosis to death or last follow-up). Results: Demographic and CT details are provided (Table). The median age at diagnosis was 34.5 yrs (range: 9-71). The most common MPNST location was the trunk (56.94%). D based regimens were the most frequent 1st-line CT (65.7%), and gemcitabine- docetaxel was the most frequent 2nd-line CT (33.3%). In pts with metastases, 74.4% got 1st line, 44.7% 2nd line, 25.5% 3rd line, and 12.7% got 4th line therapy. Median follow-up was 2.46 yrs (IQR 1.24-9.52). The median time on treatment for 1st and 2nd line CT was 110 (IQR 48-153) and 57 (IQR 41-133) days, respectively. In the multivariate COX model for the entire cohort, male sex (HR: 0.35, 95%CI: 0.18-0.68), lower extremity primary (HR: 0.09, 95%CI: 0.02-0.40), and absence of metastases at last follow up (HR: 0.05, 95%CI: 0.02-0.17) were associated with decreased risk of death. Additional analysis on efficacy and survival of the systemic therapy regimens will be presented at the meeting. Conclusions: In this study < 50% pts with advanced NF1 related MPNST made it to 2nd line CT and outcomes were inferior to the predominantly D based 1st line regimens. This highlights an area of high unmet need. [Table: see text]

Early onset pancreatic cancer-exploring contemporary treatment and outcomes using real-world data.

Pancreatic cancer incidence is increasing in younger populations. Differences between early onset pancreatic cancer (EOPC) and later onset pancreatic cancer (LOPC), and how these should inform management warrant exploration in the contemporary setting. A prospectively collected multi-site dataset on consecutive pancreatic adenocarcinoma patients was interrogated. Patient, tumour, treatment, and outcome data were extracted for EOPC (≤50 years old) vs LOPC (>50 years old). Of 1683 patients diagnosed between 2016 and 2022, 112 (6.7%) were EOPC. EOPC more frequently had the tail of pancreas tumours, earlier stage disease, surgical resection, and trended towards increased receipt of chemotherapy in the curative setting compared to LOPC. EOPC more frequently received 1st line chemotherapy, 2nd line chemotherapy, and chemoradiotherapy than LOPC in the palliative setting. Recurrence-free survival was improved for the tail of pancreas EOPC vs LOPC in the resected setting; overall survival was superior for EOPC compared to LOPC across the resected, locally advanced unresectable and metastatic settings. EOPC remains a small proportion of pancreatic cancer diagnoses. The more favourable outcomes in EOPC suggest these younger patients are overall deriving benefits from increased treatment in the curative setting and increased therapy in the palliative setting.

Progression-free survival after first recurrence in patients with glioblastoma.

Relevance. Despite all the treatment glioblastoma recurs as an aggressive and therapy-resistant tumor, and patients quickly die from these neoplasms. The study of glioblastoma recurrence processes and search for prognostic factors of the disease should lead to the improvement of survival rates of patients with this pathology. Purpose of the study. To study the influence of clinical and molecular-genetic factors on the median second recurrence-free period. Materials and methods. Progression-free survival after first recurrence in 34 patients aged 28 to 81 years with recurrent glioblastoma was analyzed. The diagnosis was established according to the WHO 2021 classification of CNS tumors. In each observation we studied such clinical parameters as patient’s age, functional status according to the Karnovsky scale pre- and postoperatively, peculiarities of neuroimaging picture (prevalence of tumor process, localization of recurrence, tumor volume), conducted treatment and molecular-genetic characteristics of the tumor (determination of mRNA expression level of genes: MGMT, VEGF, PDGFRA, β-tubulin III, ERCC-1, TOP2A). Results. Among the clinical and demographic characteristics, the median of the survival was influenced by the patients’ age and functional status after surgery. The median of the survival was more than 2 times higher in the group of patients under 50 years old, compared to patients over 50 years old (18.5 vs 8 weeks). The dependence of the median of the survival on the post- operative functional status (according to the Karnovsky scale) was determined (p = 0.001). The median of the survival in case of a single brain lobe lesion was more than 5 times higher than in case of widespread tumor process, though without statistical reliability (p = 0.09, 21.5 vs 4 weeks). Survival rates were higher when recurrence was localized within 2 cm of the area of removal of the primary neoplasm. After disease progression, the MGMT gene lost its predictive value. Patients with low expression of the TOR2A gene had a higher survival rate than those with medium and high expression (47.5 vs 3 weeks, p = 0.001; 47.5 vs 22.5 weeks, p = 0.06). The median of survival was higher than at high levels at low and medium PDGFRA gene expression levels (29 vs 0 weeks, p = 0.04; 21 vs 0 weeks; p = 0.05, respectively). Maximum survival rates were recorded in the group of patients after total and subtotal removal of tumor recurrence (22 and 18.5 weeks, p = 0.05). Administration of second-line chemotherapy with temozolomide statistically significantly increased the median of the second BRS (p = 0.01). Conclusion. Recurrent glioblastomas are characterized by an extremely aggressive course. Therefore, such prognostic factors as patient age, degree of tumor resection, tumor process prevalence, degree of tumor resection and 2nd line chemotherapy come to the forefront. It should be noted that the MGMT gene loses its predictive value during disease progression, while the TOR2A gene and PDGFRA gene become prognostic markers.

PATH-04. TRANSFORMATION OF GRADE 2 OLIGODENDROGLIOMA TO GLIOSARCOMA WITH RAPID AND EXTENSIVE PROGRESSION: CASE REPORT.

Abstract Transition of WHO grade 2 oligodendroglioma to gliosarcoma is rare. We report a case of a 40 year-old gentleman with WHO grade 2 oligodendroglioma, isocitrate dehydrogenase enzyme (IDH)-mutant, 1p/19q co-deletion positive, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated, tumor mutational burden of 5 mutations/megabase, with microsatellite stability. He underwent rapid and extensive transformation to WHO grade 4 glioblastoma with gliosarcomatous features, mesenchymal subclass on DNA methylation, IDH-wild type, 1p/19q co-deletion negative, MGMT promoter methylated. He was diagnosed with bi-hemispheric multifocal partially enhancing, T2-FLAIR hyperintense lesions. Pathology revealed WHO grade 2 oligodendroglioma. He enrolled on a clinical trial to receive proton radiation (45 Gray in 25 fractions) to the involved tumor sites. Three weeks after initiation of radiation, he developed headache, imbalance, and confusion. MRI brain 3 weeks after completion of radiation revealed worsening enhancement, edema, and a new region of non-enhancing T2-FLAIR hyperintensity. Bevacizumab was added for presumed pseudo-progression; followed by chemotherapy with procarbazine and lomustine (PC). Four cycles of PC were completed with observations of gradual clinical and radiographic worsening after each cycle. Re-resection of multifocal tumor for tissue diagnosis and tumor debulking revealed progression to WHO grade 3 oligodendroglioma with high mitotic activity and regions of palisading necrosis. Two weeks postoperatively, malignant cerebral edema developed, requiring left sided decompressive craniectomy. Despite early introduction of 2nd-line chemotherapy with temozolomide, his disease continued to progress and he succumbed 1.5 years after initial diagnosis. Autopsy revealed extensive bi-hemispheric involvement of WHO grade 4 glioblastoma. Our patient demonstrated unusually rapid clinical and radiographic progression within one month after completion of radiation. Other reported cases in the literature have documented progression at 1 to 5 years after initial treatment. Both IDH mutation and 1p19q co-deletion were lost in the gliosarcomatous transformation. This tumor did not respond to alkylating agents despite the MGMT promoter-methylated status.

Updated Results of a Prospective Study: Rituximab and Lenalidomide Plus Chidamide (RLC) for Patients with Relapsed/Refractory Angioimmunoblastic T-Cell Lymphoma

Introduction Angioimmunoblastic T-cell lymphoma (AITL) is the second most common subtype of peripheral T-cell lymphoma (PTCL). The therapeutic effect of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), the most common first-line chemotherapy regimen, is not satisfactory, and most patients experience relapse or disease progression. The 5-year progression-free survival (PFS) of AITL is 13%-23%, and 5-year overall survival (OS) is 33%-36%. The benzamide histone deacetylase inhibitor (HDACi) Chidamide and lenalidomide (a second-generation immunomodulatory compound) are both approved for the treatment of relapsed or refractory PTCL in China. About 70%-100% of the AITL patients have EBV infection, which may cause abnormal immune functions in hosts. EBV infects immunocytes such as B cells, T cells, and natural killer cells, and it impairs immune functions that can clear neoplastic cells from the body. Rituximab may eradicate EBV-B cells and activated B cells and may prevent the progression to AITL. When combined with rituximab, lenalidomide augmented antibody-dependent cell-mediated cytotoxicity by enhancing NK cells, which overcomes rituximab resistance in lymphoma patients. In this prospective phase II study, the efficacy and safety of a new regimen consisting of rituximab, lenalidomide and chidamide has been evaluated in relapsed/refractory AITL patients. We have reported the preliminary results (2022 ASH, poster 1600), and now we update the data of this study. Methods Patients with relapsed/refractory AITL after at least first-line chemotherapy were treated with up to 6 cycles of a rituximab and lenalidomide plus chidamide (RLC) regimen every 3 weeks. The initial dose of each drug has been reported. The primary endpoint of the study was PFS. The secondary endpoints included overall response rate (ORR), OS, and adverse events (AEs). Results Between Aug 2019 and May 2023, 24 patients with relapsed/refractory AITL were enrolled. The characteristics of these patients are listed in table 1. On enrollment, 16 (66.7%) patients had received 1st-line chemotherapy, 7 (29.1%) patients had received 2nd-line chemotherapy, and 1 (4.2%) patient had received 3rd-line chemotherapy. The median age was 63 years (range 43-78) and 9 (37.5%) patients were female. Fifteen (62.5%) patients had B symptoms, including weight loss in 3 (12.5%) cases, night sweat in 1 (4.2%) case and fever in 11 (45.8%) cases. Sixteen (66.7%) patients had elevated serum lactate dehydrogenase (LDH), and 21 (87.5%) patients had IPI score≥2. All patients had completed RLC treatment for at least 1 cycle and underwent imaging assessment. The ORR was 75% (18/24) with a complete remission (CR) rate of 20.8% (5/24), and 13 (54.2%) patients achieved partial remission (PR). While 1 (4.2%) patient achieved stable disease (SD) and 5 (20.8%) patients achieved progressive disease (PD). Two patients received autologous hematopoietic stem cell transplantation as consolidation treatment after achieving CR from RLC chemotherapy. With a median follow-up of 9.7 months, 9 patients had died. The median PFS was 10.8 months (95% confidence interval <CI>, 9.0 to 12.6 months), but the median OS was not reached. No patient presented with Grade 5 AE. The most frequent all-grade hematological toxicity included leucopenia (35.7%, 5/14), followed by anemia (21.4%, 3/14) and thrombocytopenia (41.7%, 10/24). Other common toxicities included infusion reaction (16.7%, 4/24), skin rash (20.8%, 5/24), pulmonary pneumonia (41.7%, 10/24), and nausea (12.5%, 3/24). Dose reduction was performed in 8 patients. The exploratory analysis of possible prognostic factors by mass spectrum flow are undergoing. Conclusions The updated results of this prospective study confirmed the good response rate and manageable toxicity of rituximab and lenalidomide plus chidamide (RLC) regimen. This combination may be a promising regimen in patients with relapsed/refractory AITL.

Clinicopathological characteristics, evolution, treatment pattern and outcomes of hormone-receptor-positive/HER2-low metastatic breast cancer.

Despite the promising efficacy of the novel antibody-drug conjugate trastuzumab deruxtecan in treating Hormone Receptor (HoR)-positive/Human Epidermal Growth Factor Receptor 2 (HER2)-low metastatic breast cancer (MBC), its categorization as a distinct entity remains disputed, as does the divergence in its endocrine and chemotherapy outcomes. This study aimed to elucidate the clinical characteristics, primary/metastatic lesion HER2 expression, and treatment outcomes of HoR-positive/HER2-low patients. We included HoR-positive/HER2-negative MBC patients who underwent 1st and 2nd line endocrine treatment from July 2010 to October 2022 at the Fudan University Shanghai Cancer Center, comparing the clinical pathological characteristics, HER2 expression in primary/metastatic lesions, treatment, and therapeutic effects of the HER2-low and HER2-zero groups. Among the 458 HoR-positive/HER2-negative MBC patients, 54.37% (249/458) were HER2-low. The HER2-low group and the HER2-zero group had similar clinical pathological characteristics and similar progression-free survival (PFS) of 1st and 2nd line endocrine treatment (median PFS: 8.05 months vs 10.12 months, p=0.114, HR 1.257, 95% CI 0.771 to 1.028). The PFS of the HER2-low and HER2-zero groups was also similar, treated with different endocrine drugs (including aromatase inhibitors, tamoxifen/toremifene, fulvestrant, palbociclib, and everolimus). However, the HER2-low group had significantly shorter PFS during 1st and 2nd line chemotherapy compared to the HER2-zero group (median PFS: 8.64 vs 9.03 months, p=0.027, HR 0.841, 95% CI 0.721-0.980). Additionally, 41.18% (63/153) of patients exhibited a change in HER2 expression between primary and metastatic lesions. Notably, patients whose HER2 status changed from zero to low expression had significantly prolonged PFS during chemotherapy compared to those who maintained low HER2 expression (median PFS: 14.29 vs 11.27 months, p=0.048, HR 0.597, 95% CI 0.358-0.996). In HoR-positive MBC, patients with low and zero HER2 expression have similar clinical characteristics and respond similarly to endocrine treatment, but the chemotherapy effect is worse in the HER2-low patients. Moreover, the transformation of HER2 status from primary to metastatic lesions may have potential influence on chemotherapy outcomes. Therefore, the expression and heterogeneity of HER2 should be considered in clinical decisions.

594P The efficacy of anti-EGFR therapy for RAS mutant metastatic colorectal cancer (mCRC) patients with RAS mutation negative in circulating-tumor DNA (ctDNA) after 1st- or 2nd-line chemotherapy

594P The efficacy of anti-EGFR therapy for RAS mutant metastatic colorectal cancer (mCRC) patients with RAS mutation negative in circulating-tumor DNA (ctDNA) after 1st- or 2nd-line chemotherapy

Comparing effectiveness and safety of paclitaxel plus raltitrexed vs. paclitaxel alone in second-line palliative chemotherapy for metastatic gastric adenocarcinoma: A randomized phase II clinical trial.

Paclitaxel (P) is a standard second-line chemotherapy in the treatment of advanced gastric cancer. This study compared the clinical outcome of a paclitaxel plus raltitrexed (RP) regimen as second-line treatment in metastatic gastric cancer (MGC) patients. An open, randomized, multi-center phase II clinical trial was conducted involving 148 patients who were randomly assigned and treated with RP [raltitrexed (3 mg/m2 on day 1) and paclitaxel (135 mg/m2 on day 1 every 3 weeks)] or P [paclitaxel (135 mg/m2 on day 1 every 3 weeks)] as 2nd-line chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), and safety. PFS had a tendency to be prolonged with RP compared to P (2.7 months vs. 1.7 months; P = 0.148). OS was also prolonged with RP compared to P (10.2 months vs. 6.1 months; P = 0.140). The ORR was equal in the RP and P groups (6.8% and 4.0%; P = 0.72). The disease control rate (DCR) in the RP and P groups was 56.2% and 36.0%, respectively. Grade 3-4 treatment-related adverse events occurred in 36.2% (RP) and 28.2% (P) of patients. Frequent grade 3-4 toxicities for RP and P were neutropenia (11.0% and 4.0%), anemia (1.4% and 4.0%), and thrombocytopenia (1.4% and 5.3%), and all grades of peripheral neurotoxicity (12.3% vs. 17.3%). All grades of hepatic toxicity were demonstrated for the RP and P groups based on elevated aminotransferase levels (27.4% and 14.1%). Subgroup analysis shows if MGC was combined with ascites or peritoneal involvement, the OS of the RP regimen was longer (P = 0.05). Second-line palliative chemotherapy with RP was shown to prolong the PFS and OS, especially among patients with ascites or peritoneal involvement, which warrants confirmation using larger sample studies.

Real world study on the effect of PARPi as maintenance therapy after first-line and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer.

e17574 Background: This study investigated the effect of PARPi as maintenance therapy after 1st-line and 2nd-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). Methods: 172 patients with rHGSOC at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital from Jan 2017 to Dec 2021were retrospectively analyzed. Patients who received PARPi as maintenance therapy after first-line chemotherapy were enrolled to the 1st-PARPi group (n=23), and subjects who did not receive PARPi maintenance therapy were enrolled to the 1st control group (n=105). Similarly, 2nd- PARPi group (had not use PARPi in first-line treatment n=30), 2nd-control group (n=89) were divided. To evaluate progression-free survival (PFS), the first progression to second progression (TTSP), the second progression to third progressio (TTTP), PFS between the second progression and the end of the second-line chemotherapy (PFSs), PFS between the third progression and the end of the third-line chemotherapy (PFSt) and to compare whether PARPi as maintenance therapy affects the platinum sensitivity of these patients. Results: PFSs in 1st-PARPi vs.1st-control group (median 5 vs. 11 m; p=0.0037). PFSt in 2nd-PARPi vs. 2nd-control group(median 4.5 vs. 9.0 m; p=0.0009). TTSP in 1st-PARPi vs. 1st-control group (median 11 vs. 16 m; p=0.0045). TTTP in 2nd-PARPi vs. 2nd-control group (median 10 vs. 15 m; p=0.0007). Among the 23 patients in 1st-PARPi group and 105 patients in 1st-control group, 9 and 99 patients were platinum sensitive while 14 and 6 patients were platinum resistant respectively (HR 14.46, 95% CI =4.07-51.53, P < 0.0001). Among the 30 patients in 2nd-PARPi group and 89 patients in 2nd-control group, 10 and 71 patients were platinum sensitive while and 20 and 18 patients were platinum resistant respectively (HR 4.37 95% CI=1.98-9.64, P < 0.0001). Age, stage, residual tumor after initial surgery treatment and the courses of platinum-based chemotherapy before PARPi,BRCA gene mutation were not the related factors affecting the platinum sensitivity of next line chemotherapy. There was no statistical difference in the effect of duration of PARPi on the platinum sensitivity of next line chemotherapy (duration of PARPi≥ 18 months vs. <18 months in 1st-PARPi group, HR 0.60, 95% CI=0.18-2.04, P=0.41; duration of PARPi≥ 12 months vs. <12 months in 2nd-PARPi group, HR 0.62, 95% CI=0.26-1.48, P=0.24, respectively). Conclusions: Patients with rHGSOC using PARPi affected the platinum sensitivity and were more likely to lead to platinum resistance no matter how long the during of PARPi were.This conclusion was consistent with the cross resistance between PARPi and platinum. Care should be taken when using PARPi after 1st-line and 2nd-line chemotherapy as maintenance therapy.

Efficacy and safety of Kras inhibitors in pancreatic cancer: A systematic review of clinical trials.

e16297 Background: Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive tumor and is one of the leading causes of cancer related deaths worldwide. Kirsten Rat Sarcoma (KRAS)mutation resulting in tumor cell proliferation and cancer progression is a frequently mutated oncogene in various cancers and is approximately seen in 90% of pancreatic ductal adenocarcinoma. Efforts are being done to target Kras mutation in the last 3–4 decades. Here in, we report the results of the systemic review of clinical trials done on chemotherapeutic agents targeting Kras mutated pancreatic cancer. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Clinicaltrials.gov, and Embase with mesh terms, “pancreatic neoplasm’’ and “kras” from the inception of data till 01/05/2023. We screened 4191 articles and included 3 clinical trials with published study results and 3 ongoing clinical trials. Results: In this systematic review, data on 2 chemotherapeutic agents Sotorasib (AMG510) and Adagrasib (MRTX849) which are Kras G12C inhibitors, are obtained from Code Break-100 and preliminary results of KRYSTAL-1 clinical trials, respectively. In these 2 clinical trials (N-48), all the patients had advanced pancreatic cancer with Kras G12C mutation and were previously treated with chemotherapy. 10 patients in Krystal-1 trial, who received adagrasib showed progression-free survival (PFS) of 6.6 months, disease control rate (DCR) of 100 % and partial response (PR) of 50%. 38 patients in the Code Break-100 trial, who received Sotorasib showed PFS of 4 months, DCR of 84.2% and PR of 21.1%. However, 50% of patients in the KRYSTAL-1 trial are still receiving treatment. Grade 3 /4 adverse events were seen in 21% and 16% of patients in the KRYSTAL-1 and Code Break-100 trial, respectively. Other Kras G12C inhibitors like D-1553, Sotorasib in combination with 2nd line chemotherapy are under investigation. Results of a clinical trial on anti KrasG12D siRNA done on locally advanced pancreatic cancer patients showed a median overall survival of 15.12 months with no dose limiting adverse events. A multinational randomized phase 2b clinical trial is ongoing for the evaluation of efficacy of siRNA based drug in combination with chemotherapy. Conclusions: Both Adagrasib and Sotorasib showed promising results in the pretreated Kras G12C pancreatic cancer patients with acceptable safety profile. Further exploration of these drugs and their combination with other chemotherapeutic agents is necessary. [Table: see text]

Analysis of real-world data to investigate evolving treatment sequencing patterns in advanced non-small cell lung cancers and their impact on survival.

Although optimal sequencing of systemic therapy in cancer care is critical to achieving maximal clinical benefit, there is a lack of analysis of treatment sequencing in advanced non-small cell lung cancer (aNSCLC) in real-world settings. A retrospective cohort study of 13,340 lung cancer patients within the Mount Sinai Health System (MSHS) was performed. Systemic therapy data of aNSCLC in 2,106 patients was the starting point in our analysis to investigate how treatment sequencing has evolved, the impact of sequencing patterns on clinical outcomes, and the effectiveness of 2nd line chemotherapy after patients progressed on immune checkpoint inhibitor (ICI)-based therapy as the 1st line of therapy (LOT). There is a significant shift to more ICI-based therapy and multiple lines of targeted therapy after 2015. We compared clinical outcomes of two patient populations with different treatment sequencing patterns, with the 1st group receiving chemotherapy as the 1st LOT followed by ICI-based treatment, and the 2nd group treated in the opposite order receiving a 1st line ICI-containing regimen followed by a 2nd line chemotherapy. No statistically significant difference in overall survival (OS) was observed between the two groups [group 2 vs. group 1, adjusted hazard ratio (aHR) =1.36, P=0.39]. We assessed the efficacy of the 2nd line chemotherapy in three patient populations given either 1st line ICI single agent, 1st line ICI-chemotherapy combination, or 1st line chemotherapy alone, there was no statistically significant difference in time-to-next treatment (TTNT) and in OS among the three patient groups. Analysis of real-world data has shown two treatment sequencing patterns in aNSCLC, ICI followed by chemotherapy or chemotherapy followed by ICI, achieved similar clinical benefit. The chemotherapies routinely used following platinum doublet 1st LOT, is effective as the 2nd line option after ICI-chemotherapy combination in the 1st line setting.

First-line chemotherapy regimens associated with survival in advanced pancreatic cancer: A Mexican single-center, real-world study.

683 Background: Effectiveness of FOLFIRINOX and Gemcitabine – Nabpaclitaxel as first-line chemotherapy regimens in advanced pancreatic cancer has been demonstrated in phase III clinical trials. However, prospective studies directly comparing both interventions are lacking. Gemcitabine has proved effective when combined with other drugs such as Oxaliplatin. Despite GEMOX has not proved overall survival benefit over Gemcitabine and it is unclear if its effectiveness could be similar to FOLFIRINOX or Gemcitabine-Nabpaclitaxel, it is broadly used as first line chemotherapy in our center due to safety concerns and higher costs associated to FOLFIRINOX and Nabpaclitaxel. Methods: We retrospectively analyzed data of patients with stage IV Pancreatic Adenocarcinoma treated at Instituto Nacional de Cancerología from 2014 to 2021. Our aim was to compare Overall Survival (OS) in patients treated with GEMOX, FOLFIRINOX, Gemcitabine-Nabpaclitaxel, or Gemcitabine in the front-line setting. Progression Free Survival (PFS), Overall Response Rate (ORR) and Adverse Effects (AEs) were also assessed. Results: A total of 141 patients were analyzed, 72 (51.0%) were treated with GEMOX, 13 (9.2%) with FOLFIRINOX, 9 (6.4%) with Gemcitabine-Nabpaclitaxel and 47 (33.3%) with Gemcitabine. Median Overall Survival for each regimen was: 11.0, 10.7, 6.7 and 4.7 months; (p = 0.078), and median PFS was 9.2, 6.5, 5.7 and 4.0 months, respectively (p = 0.026).ORR was 21.6%, 20.0%, 11.1%, 4.8% with GEMOX, FOLFIRINOX, Gemcitabine-Nabpaclitaxel and Gemcitabine, respectively. The percentage of patients who received a second line chemotherapy after progression was 43.1%, 61.5%, 55.6% and 23.4%, (p = 0.031). Regarding AEs, G3/4 most common effects ( > 5%) were Neutropenia (9.8%, 30.0%, 55.6%, 4.8%; p = 0.001), Diarrhea (2.0%, 10.0%, 11.1%, 0.0%; p = 0.247), and Increased Liver Enzymes (7.8%, 20.0%, 0.0%, 4.8%; p = 0.371). Grade 1/2 Neuropathy was found in 43.1%, 60.0%, 44.4% and 9.5%, p = 0.018. The percentage of patients who required GCSF was 9.8%, 60.0%, 22.2% and 9.5%, P = 0.001. Conclusions: In patients with advanced pancreatic cancer treated with different chemotherapy regimens, median OS was similar in this real-world analysis. Though PFS was higher in the group of patients treated with GEMOX, a higher percentage of patients initially treated with FOLFIRINOX or Gemcitabine – Nabpaclitaxel reached 2nd line chemotherapy after progression. Percentage G3/4 Neutropenia, G1/2 Neuropathy and use of GCSF were significantly higher in patients treated with FOLFIRINOX.

Hemoglobin and Neutrophil Count as Prognostic Factors in Cholangiocarcinoma Patients in 2nd Line Treatment Setting: Results from a Small Monocentric Retrospective Study.

Unresectable cholangiocarcinoma prognosis can be extremely variable due to different symptoms and sites of disease involvement at diagnosis and unpredictable chemotherapy response rates. Most patients will usually receive 1st line palliative chemotherapy with platinum compounds and Gemcitabine or Gemcitabine alone. Only a few patients maintain adequate performance status after first-line treatment failure: second-line treatment with FOLFOX or FOLFIRI chemotherapy has been used in this setting with modest overall survival improvement. There is a lack of data concerning whether laboratory findings might help clinicians in identifying those patients with the highest likelihood of benefiting from 2nd line treatment. The aim of this analysis is to assess the prognostic role of a series of easily available laboratory tests in patients with bile duct cancer who received 2nd line chemotherapy. Patients with unresectable bile duct cancer treated in 2nd-line setting with platinum-based chemotherapy doublet or FOLFIRI were enrolled. The primary objective of the analysis was to assess overall survival (OS) differences among patients based on the results of lab tests. Serum hemoglobin, neutrophil, lymphocyte, monocyte, platelet absolute count, creatinine, total bilirubin, albumin, LDH, circulating CEA and CA19.9 values were collected at the start of 2nd line treatment. Cut-off values for all lab tests were set by ROC curve analysis. Survival was calculated by the Kaplan-Meier method and differences in survival among stratification factors were assessed by Log-rank test. Cox-proportional-hazard regression was used for multivariate analysis. Level of statistical significance p was set at 0.05 for all tests. Correction for false discovery error rate was performed by Holm's stepdown procedure. A total of 46 patients were eligible. Median overall survival of the entire cohort was 8.98 months (95%CI: 6.68-13.93) while mean OS was 17.10 months (standard error: 3.16). Using 6.2 months OS landmark as classification variable for ROC curve analysis, only serum hemoglobin (cut-off: >10 g/dL), albumin (cut-off: >3.5 mg/dL), CA19.9 (cut-off: ≤668 UI/mL), monocyte (cut-off: ≤510/mmc) and neutrophil count (cut-off: ≤5140/mmc) were significantly associated with the chosen end-point. Multivariate analysis confirmed an independent statistically significant impact on overall survival only for hemoglobin (Exp(b): 0.12, p = 0.0023) and neutrophil count (Exp(b): 0.30, p = 0.0039). Based on these results, using both hemoglobin and neutrophil count, three prognostic groups were defined: patients with both favorable factors had 12.63 months median OS vs. 6.75 months of patients with only one favorable factor vs. 1.31 months of those with neither. The difference between these three groups of patients was statistically significant (p < 0.0001). Second-line palliative chemotherapy can be a potentially useful option for a few patients with unresectable/metastatic bile duct cancer. Even though assessment of patients' prognosis might be difficult due to the complex behavior of this disease, a series of easily available laboratory tests might be used for these means: serum hemoglobin and neutrophil count we0re able to define subsets of patients with entirely different prognoses. It is hoped that this score will be prospectively validated in a larger group of patients in order to improve treatment decisions in patients with unresectable bile duct cancer candidate to receive palliative 2nd line chemotherapy.

A Prospective Study of Short-Term Chemotherapy Bridging Allogeneic-SCT in High Risk Peripheral T-Cell Lymphoma

Background: Results of conventional therapy in patients with peripheral T-cell lymphoma (PTCL) are dismal. Current guidelines recommend consolidation with autoSCT after 6 course of induction for most PTCL patients, but one third of new diagnosed patients progressed before autoSCT. Allogeneic hematopoietic stem cell transplantation (alloSCT) can cure relapsed/refractory patients, even those failured to HDT/ASCT. We hypothesized that AlloSCT as first-line consolidation post short course of induction could improve outcome in high-risk PTCL patients. Patients and Methods: A prospective study was conducted in high-risk PTCL patients (except ALK+ ALCL, and stage 1 with aaIPI 0) who were scheduled to undergo upfront allo-SCT after 3 x CHOEP(or -like) induction chemotherapy (registered in Clinical Trials, NCT03672084). Matched sibling donor(MSD) was the first choice, an unrelated donor or haploidentical family donor(Haplo-donor) search was performed in patients without MSD. From Jan.2018 to June 2022, 23 newly diagnosed patients enrolled, 8 PTCL-NOS, 1 ALK-negative ALCL, 6 AITL and 9 HSTL. After 1st line induction, 12 proceeded upfront alloSCT(10 in CR,1 in PR and 1 in SD), 9 of 11 with progressive disease received transplant after 2nd line chemotherapy (salvage alloSCT), the other 2 (diagnosed with PTCL-NOS) did not undergo transplantation because of PD. All patients received myeloablative conditioning and antithymocyte globulin was administered for Haplo-SCT (with 2.5mg/kg daily on days -5 to -2). All patients received cyclosporineA, MMF and short-term MTX as GVHD prophylaxis (Patients characters were in Table 1). Results: Untill July 30,2022，we had an interim results with the median follow up of 367(38-1237)d. For all transplanted patients, the median age was 38(4-63) years old, five had a MSD and the other 16 had a haplo-donor. Before alloSCT, 11 patients (52.4%) were in CR and 6 (28.6%) in PR, 1 (4.7%) in SD, and 3(14.3%) in PD. All but one patients had CR post alloSCT, 1 in PR received donor lymphocyte infusion(DLI) on D30 then had got CR on D60. One patient received a second alloSCT from another haplo-donor because of secondary graft failure. Acute GVHD of grade II-IV occurred in 9 of 21 patients (42.9%) (6 of grade III-IV). Thirteen of 20 (65%) evaluable patients developed chronic GVHD, which was extensive in 4 cases(20%). Four patients, all diagnosed with HSTL, experienced with post-SCT relapse on day 60,75, 180 and 455 respectively. Two had response to salvage chemotherapy with DLI, and stay in CR at last follow-up. Three patients died, 2 of lymphoma and 1 of pneumonia on day 280. The estimated 1- and 2-year event-free survival (EFS) in all transplanted cases were 78% and 67%, and those of overall survival(OS) were all 83%. The D100 and 1-y toxicity-related mortality(TRM) were 0% and 6.4%, respectively. There were no differences in PFS and OS between upfront and salvage alloSCT. The patients who diagnosed with HSTL had a significant poor PFS compared to other types of PTCL, with the 1y PFS of 56% vs 92% (p=.017), and had a comparable 1-y OS ,78% vs 92% (p=.337). This result may due to the higher relapsed rate of HSTL (44% vs 0%, p=0.003). So we involved a prophylaxis DLI in HSTL patients recently. Conclusions: Upfront AlloSCT in high-risk PTCLs was feasible with low TRM, and it could provide long-term disease control. And the strategy of haplo-donor SCT can bring more patients to AlloSCT. However, half of patients had progressed disease after 1st line induction, due to the strong anti-lymphoma effect of allograft, salvage alloSCT had been shown increased response rate in this group of refractory patients. The treatment strategy of short-term induction followed by alloSCT may improve the outcome for high-risk PTCL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Gemcitabine-Paclitaxel Chemotherapy for Patients with Advanced Urothelial Cancer Refractory to Cisplatin-Based Chemotherapy: Predictive Role of PGK1 for Treatment Response to Cytotoxic Chemotherapy.

An investigation of alternatives to immune checkpoint inhibitors for advanced urothelial cancer (aUC), with biologic information, is urgently needed. Clinical data for 53 patients who received gemcitabine–paclitaxel therapy (GP) as 2nd-line chemotherapy for aUC refractory to platinum-based chemotherapy were retrospectively reviewed. The efficacy and tolerability of GP were evaluated, and the predictive value of phosphoglycerate kinase 1 (PGK1) immunostained in surgical specimens was investigated for treatment outcomes in 1st- and 2nd-line chemotherapy. GP was associated with an objective response rate of 35.8% and a median overall survival duration of 12.3 months. Multivariate analysis showed that PS2 and 1st- and 2nd-line non-response are independent predictors of worse progression-free survival and that PS2 and 1st-line non-response are independent predictors of worse overall survival. Adverse events were manageable, and no therapy-related deaths occurred. Non-response rates to 1st-line chemotherapy were significantly higher in patients with a high expression of PGK1 in the nucleus than in those with low expression (p = 0.006). Our study demonstrates the efficacy and tolerability of 2nd-line GP for patients with aUC who are refractory to platinum-based chemotherapy. Moreover, PGK1 in the nucleus was predictive values for resistance to platinum-based chemotherapy in aUC.

494. GIANT GASTROINTESTINAL STROMAL TUMOR OF THE ESOPHAGUS: REPORT OF TWO CASES

Abstract Gastrointestinal stromal tumor (GIST) accounts for 1-3% of all gastrointestinal tumors. Most of GIST occurs in the stomach and small intestine, but GIST from the esophagus is relatively rare at about 2-5%. Surgical resection is the treatment of choice, but no routine procedure has been established. We report two cases of esophageal GIST that underwent surgical resection. [Case 1] A 75-year-old woman. She was diagnosed with an 11 cm-sized submucosal tumor was found in the esophagus by upper gastrointestinal endoscopy. Histopathological examination showed that the tumor was GIST. The patient's postoperative course was uneventful and the patient was discharged home in good condition on the 22nd postoperative day. [Case 2] A 58-year-old man. He was diagnosed a 9 cm-sized elevated lesion in the by CECT. The tumor suspected esophageal cancer sarcoma, we underwent esophagectomy. Finally, histopathological examination revealed that the tumor was GIST. His postoperative course was uneventful and he was discharged on the 19th postoperative day. [Case 1 result] Postoperative adjuvant chemotherapy with imatinib was failed, but the follow-up period continued without recurrence. [Case2 result] Postoperative adjuvant chemotherapy with imatinib was introduced. Contrast-enhanced CT 6 months after surgery revealed multiple liver metastases. 2nd line chemotherapy with sunitinib is still ongoing. [Discussion] Surgical treatment is the first choice for esophageal GIST, but no standard surgical procedure has been established. In the past, esophagectomy similar to esophageal cancer was often performed, but thoracoscopic local resection may be selected in recent years. Even in the case of giant esophageal GIST as like this two cases, if the general condition is stable and preoperative treatment is possible, it is possible to choose to perform preoperative neoadjuvant chemotherapy.

3P Beyond first-line therapy in metastatic adrenal cortical cancer (ACC): Is it time to move on from chemotherapy?

Metastatic ACC is a rare and aggressive tumor with limited treatment options beyond first-line chemotherapy. Unfortunately, survival outcomes are poor with 2nd line chemotherapy, which is frequently adopted for treatment. Data on outcomes with non-chemotherapeutic approaches including immunotherapy is scarce. A retrospective review (2002-2020) of metastatic ACC patients treated at Princess Margaret Cancer Center was performed. Patients who received any 2nd line therapy and beyond were identified. Descriptive statistics were used to summarize clinical and demographic data. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Survival outcomes were compared using log-rank test. Out of 84 patients with metastatic ACC, 30 (20.7%) had de novo and 54 (37.2%) recurrent disease after local definitive therapy; 51 (60.7%) and 30 (58.8%) received 1st and 2nd line systemic therapy respectively. Median age was 49 years (36-58); 18 (60%) were female,14 (47%) had functional tumors, 4 (13.3%), 25 (83.3%), and 1 (3.3%) were ECOG 0, 1 and 2 respectively. One patient had MMR deficiency out of 16 patients in which it was evaluated. Seventeen patients (56.6%) received chemotherapy (14-gemcitabine capecitabine, 1-gemcitabine, 2-etoposide doxorubicin and cisplatin rechallenge) and 13 patients (43.4%) received non chemotherapy treatment (8- clinical trial, 4-sunitinib, 1-pembrolizumab ). Mitotane was continued in 16 of 22 (72.7%) patients for which data was available. Baseline characteristics and disease control rate were similar between the two groups (18% for chemotherapy vs 31% for non -chemotherapy, p=0.46). Median PFS was similar (2.6 months (2-4) and 3 months (1.7-4.5), p=0.48), however OS was numerically better with non- chemotherapy (6.6 months (4.9-13.1) vs 10.2 months (5.9-22.7) p=0.08. This study shows favorable outcomes with non-chemotherapy approaches compared to chemotherapy. Although this needs to be confirmed in larger studies, given the lack of randomized data for superiority of chemotherapy, non-chemotherapy approaches including immunotherapy and clinical trials should be considered where appropriate.

349P Analysis of plasma angiogenesis factors on the efficacy of 2nd-line (2L) chemotherapy (chemo) combined with angiogenesis inhibitors (AIs) in metastatic colorectal cancer (mCRC): Results from GI-SCREEN CRC Ukit study

Angiogenesis factors have been reported as prognostic and predictive biomarkers of AIs for mCRC, but its significance as a predictor of efficacy in 2L chemo combined with AIs has not been established. In 295 enrolled patients (pts) with mCRC receiving chemo plus AI in 2L treatment from Sep 2017 to Dec 2020, serial plasma samples were prospectively collected at the time points of pre- and post-treatment. 17 plasma angiogenesis factors were analyzed by the multiplex assay with Luminex technology. Interactions of their pre-treatment measurements with treatment groups on PFS were assessed via Cox proportional hazards model. The strength of interactions was examined using estimated generalized propensity score as weight, and the continuous plasma angiogenesis variables were dichotomized according to the median. The significance level for the interaction was defined as two-sided p ≤0.1. 283 pts were included in adjusted 2L cohort (chemo plus bevacizumab [BEV [reference]: n=100], FOLFIRI plus ramucirumab [RAM: n=98], FOLFIRI plus aflibercept [AFL: n=85]). Baseline characteristics in this cohort were as follows; median age 67 years; male 57.2%; left-sided tumor 70.3%; RAS mutant 50.2%; prior BEV 72.8%. Propensity-score weighted Cox model for PFS compared RAM with BEV showed significant interactions in HGF (median 174 pg/mL, High: HR 1.278, Low: HR 0.737, interaction p = 0.0485), sVEGFR-1 (median 985 pg/mL, High: HR 0.692, Low: HR 1.419, interaction p = 0.0106), and sVEGFR-3 (median 17200 pg/mL, High: HR 0.658, Low: HR 1.396, interaction p = 0.0065). On the other hand, there were no significant interactions for PFS compared AFL with BEV.Table: 349PBelow medianAbove medianInteraction p-value∗BEVRAMBEVRAMBelow vs above medianHGF6.9 m6.7 m4.0 m2.1 m0.0485sVEGFR-16.2 m3.9 m5.9 m5.8 m0.0106sVEGFR-36.4 m3.7 m5.7 m6.7 m0.0065Median PFS, ∗defined as p ≤0.1 Open table in a new tab Pre-treatment plasma HGF, sVEGFR-1 and sVEGFR-3 could be biomarkers that contribute to the optimal regimen selection of FOLFIRI plus RAM or chemo+BEV in 2L treatment of mCRC.

O18-3 Impact of plasma VEGF-A, VEGF-D and PlGF on the efficacy of 2nd-line chemotherapy combined with biologics in mCRC

Plasma angiogenesis factors are known to be a prognostic factor for metastatic colorectal cancer (mCRC), but its significance as a predictor of efficacy in 2nd-line (2L) chemotherapy (chemo) combined with angiogenesis inhibitors has not been established.

The PRODIGE 59-DURIGAST trial: A randomized phase II study evaluating FOLFIRI plus durvalumab and FOLFIRI plus durvalumab plus tremelimumab in second-line treatment of patients with advanced gastric or gastro-esophageal junction adenocarcinoma.

4036 Background: Efficacy of 2nd line chemotherapy in advanced gastric/gastro-oesphageal junction (GEJ) adenocarcinoma remains limited. No study up until now has evaluated the efficacy of immune checkpoint inhibitors combined with chemotherapy as 2ndline treatment of advanced gastric/GEJ adenocarcinoma. Methods: DURIGAST PRODIGE 59 is a randomized, multicenter, phase II study designed to assess the efficacy and safety of the combination of FOLFIRI plus durvalumab (anti-PD-L1 until progression) (FD) versus FOLFIRI plus durvalumab and tremelimumab (anti-CTLA-4 for 4 cycles) (FDT). Key eligibility criteria included advanced gastric/GEJ adenocarcinoma, platinum-based first-line chemotherapy and ECOG performance status (PS) 0 or 1. Patients were randomized in a 1:1 ratio to FD versus FDT. The primary endpoint is progression-free survival (PFS) at 4 months, which was expected to be 70% (H0:50%). With an α risk of 5%, a power of 85% and 5% of non-evaluable patients, 47 evaluable patients are needed by arm. Secondary endpoints included safety, overall survival (OS) and quality of life. Results: Between August 2020 and June 2021, 96 patients were randomized, 48 in each arm. The median age was 59.7 years, 30.4% were women and 66.3% ECOG PS 1. All in all, 22.8% had HER2+ tumors and 4.3% dMMR/MSI tumors. The 4-month PFS were 44.7% [90%CI: 32.3–57.7] and 57.8% [90%CI: 44.5–70.3] in the FD and FDT arms, respectively. Primary endpoint was not met. Median PFS were 3.8 and 5.9 months, disease control rates 68.9% and 73.8% and median OS not reached and 10.1 months in FD and FDT arms, respectively. Eight patients in FDT arm had tremelimumab re-introduction at progression. Twenty-one patients, 8 in FD arm and 13 in FDT arm, are still being treated with a median duration of treatment of 7.8 and 10.9 months. All in all, 50.0% and 47.8% of patients experienced at least one grade 3-4 adverse events related to the treatment (neutropenia: 13.0 vs 21.7%, anemia: 10.9 vs 6.5%, diarrhea: 2.2 vs 8.7% and vomiting: 6.5 vs 10.9%), in FD and FDT arms, respectively. In both arms there was no clinically significant deterioration of quality of life superior to 10 points according to EORTC QLQ-C30 global health status. Conclusions: The DURIGAST PRODIGE 59 trial demonstrates an acceptable safety profile of immune checkpoint inhibitors plus FOLFIRI in 2nd line treatment for advanced gastric/GEJ adenocarcinoma. FDT combination demonstrates a clinically relevant efficacy never before achieved with a median PFS of 6 months and should be evaluated in a phase III trial. Updated results including PFS according to centralized review and PD-L1 status will be presented during ASCO meeting. Clinical trial information: NCT03959293.