Metastatic Gallbladder Cancer Research Articles

Observational Study of Best Supportive Care With or Without Oral Capecitabine in Patients With Metastatic Gallbladder Carcinoma at a Tertiary Center in India.

To compare overall survival (OS), toxicity, and quality of life (QOL) in patients with metastatic gallbladder cancer receiving oral capecitabine (X) with best supportive care (BSC) and BSC alone. Patients with metastatic gallbladder cancer and Karnofsky Performance Status (KPS) ≥70 were accrued and assigned to either arm A or B. Assignment to these two arms was based on physician/patient discretion. Arm A received oral capecitabine 825 mg/m2 twice a day d1-14, repeated every 3 weeks for six cycles with BSC, and arm B received BSC alone. The Kaplan-Meier method computed OS and comparison was using a log-rank test. QOL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 administered at baseline, 3 months, and 6 months. The linear mixed-effects model was used for the longitudinal analysis of QOL. Between December 2020 and April 2022, 64 patients diagnosed with metastatic gallbladder carcinoma and KPS ≥70 were accrued in the study, and 32 patients were assigned to each arm. In arm A versus B, the median age was 52 versus 55 (P = .21); the median KPS was 80 versus 70 (P = .008). The median OS in arm A versus B was 3.4 versus 2 months (P = .001). Grade 1-2 vomiting and diarrhea were seen in 50% versus 78% (P = .041) and 59% versus 9.3% (P = .01) patients in arm A versus B, respectively. Grade 1-2 hand-foot syndrome was seen in 12 (37.5%) patients in arm A. Dynamic changes showed an improvement in pain in the linear mixed model with a significant difference between the arms (P = .011); arm A experienced a significant improvement in pain over time (arm × time P = .020). Global QOL improved over time (P = .038) with parallel improvement between arms (arm × time P = .490). Compared with BSC alone, patients who receive X + BSC experience an OS improvement of 1.4 months and better pain control without grade 3 toxicities or negative impact on QOL.

Acute Anterior Wall Myocardial Infarction in a Gallbladder Cancer Patient: A Case of Sudden Coronary Thrombosis Post-normal Angiogram

Cancer patients face a heightened risk for thromboembolic events, including arterial thromboembolism such as myocardial infarction (MI). Thrombosis is a major cause of mortality in these patients due to the hypercoagulable state induced by malignancy and its treatments. Pro-inflammatory cytokines and pro-coagulants secreted by tumor cells lead to endothelial damage and an increased risk of thrombus formation. Despite extensive research on venous thromboembolism in cancer, arterial thromboembolism remains less studied. This case report highlights an acute anterior wall MI in a patient with metastatic gallbladder cancer, who developed a sudden thrombotic event despite having a normal coronary angiogram shortly before. A 52-year-old female with metastatic gallbladder cancer presented to the emergency department with acute chest pain. Her cancer, diagnosed 6 months earlier, had been managed with cholecystectomy and subsequent chemotherapy. Fifteen days before her current admission, she had undergone a coronary angiogram due to atypical chest pain, which showed no significant coronary artery disease. At presentation, the patient reported, sudden chest pain radiating to the left arm. She was hemodynamically stable with normal blood pressure and heart rate. The physical examination was unremarkable. Electrocardiogram segment elevation (ST)-segment elevation in anterior leads (V2-V6) and limb leads (II, II, and augmented vector foot [aVF]), indicative of an acute anterior wall MI. Elevated cardiac biomarkers confirmed myocardial injury. A two-dimensional echocardiogram showed mild hypokinesia of the distal interventricular septum and the apex. A repeat coronary angiogram identified a thrombus in the left anterior descending artery, which was not present in the previous angiogram. The rapid appearance of the thrombus pointed to an acute thrombotic event. This case illustrates the aggressive nature of thrombotic events in cancer patients. Despite a normal angiogram 2 weeks prior, the patient developed a sudden coronary thrombus, reflecting the hypercoagulable state associated with malignancy. The management involved thrombus aspiration and tirofiban, which effectively resolved the acute event. This aligns with existing literature, emphasizing the need for vigilant monitoring and proactive management in cancer patients to address the risk of rapid-onset thrombotic events. Cancer patients can experience sudden and severe thrombotic events, even with recent normal coronary evaluations. This case highlights the importance of ongoing cardiovascular assessment and tailored therapeutic strategies in managing cancer-associated thrombosis, underscoring the need for a collaborative approach between oncologists and cardiologists.

Heterogeneous ERBB gene pathways, their targeted treatment and possible molecular mechanisms of resistance in metastatic gallbladder cancer

BackgroundERBB amplifications and mutations are known in metastatic gallbladder cancer (GBC). We conducted a prospective study on targeted therapy based on comprehensive genomic profiling (CGP). We report molecular pathways of ERBB gene and outcomes and explored the molecular mechanism of resistance. MethodsCGP was done for all consecutive GBC patients aged >18 years. Foundation medicines CDx and TarGT Absolute were used for analysis. Patients were enrolled from Jan 2017 till Dec 2022. Patient recruitment was done after ethics committee approval. Trastuzumab and/ or lapatinib were used as targeted therapy. ResultsTwenty-six patients out of 60 had ERBB1-4 gene alteration (amplification and/or mutation) that resulted in activation of PI3K/AKT/MTOR and RAS/RAF/MEK pathways. ERBB amplification (16%) was the most common genetic aberration. Mutations in TP53, RB1, CDKs, and cyclins lead to dysregulation of cell cycle and evasion of apoptosis. A total of 50% of ERBB2-positive patients carry CDK12 amplifications. The intrinsic resistance to anti-ERBB2 therapy was primarily due to downstream activation in ERBB pathway (PIK3CA) and its crosstalk with cell cycle pathway (TP53 and CDK12), JAK/STAT, VEGF, CTNNB1, and ARID1A that are known to drive MAPK/ERK signaling. Mesenchymal epithelial transition amplification or activating mutations is mechanism of resistance to anti-ERBB2 therapy. Kinase/Juxta membrane domain mutations in ERBB family proteins are also one of the potential mechanisms of resistance. ConclusionGBC is enriched with ERBB gene aberrations. Targeted therapy of ERBB pathway has shown encouraging responses. CDK12 gene amplification is a possible mechanism of resistance identified.

Modification of gemcitabine with oxaliplatin in China for unresectable gallbladder cancer: a cost-effectiveness analysis.

The incidence of gall bladder cancer (GBC), one of the most prevalent bile duct malignancies, differs with ethnicity and geographic location. To treat unresected GBC in the Chinese setting, this study aimed to assess the financial effectiveness of a combination of modified gemcitabine and oxaliplatin. Data from a randomized controlled study in which individuals with metastatic GBC were treated with oxaliplatin and gemcitabine demonstrated improved survival. A Markov model is built to calculate the incremental cost-benefit ratio (ICER) from the viewpoint of Chinese society on the basis of clinical symptoms and disease development. One-way certainty and probability sensitivity analyses are used to describe the uncertainty in the model. Compared with those of fluorouracil (FU) and folinic acid, the utility value of modified oxaliplatin combined with gemcitabine increased by 0.22QALY throughout the course of the 10-year simulation (FA). In a Chinese healthcare setting, the cost-effectiveness ratio (ICER) is $52765.59/QALY, with a 0% chance of cost-benefit at the WTP (willing-to-pay) level of $37697.00/QALY. The ICERs predicted by sensitivity analysis were not significantly affected by cost variations related to the management of Grade 3-4 AEs, the diagnostics used, or hospitalization expenditures. In a Chinese healthcare context, modified gemcitabine coupled with oxaliplatin (mGEMOX) is not a cost-effective treatment option for unresectable GBC.

Uninvited Guest in the H ouse: A Rare Case of Metastatic Gallbladder Cancer

Gallbladder cancer is a rare malignancy. About 1–2% of surgical specimens demonstrated a gallbladder cancer as an incidental finding. Metastasis to ovaries by biliary origin, known as Krukenberg tumour, though known, is infrequent. It can mimic clinically and morphologically, as a primary ovarian tumour challenging the diagnosis. Diagnosis of secondary ovarian tumours though its challenging often misdiagnosed as primary ovarian cancer, specifically mucinous adenocarcinomas. The distinction from the latter is essential, as it requires different treatment. Immunohistochemistry plays an important role in distinguishing primary ovarian tumours from extra-ovarian metastases. Detailed diagnostic laparotomy with examination of upper abdomen , IHC and UGI scopy evaluation plays a major role in identifying the primary tumour and make the correct diagnosis. As treatment varies according to primary, detailed evaluation might help in deciding appropriate palliative chemotherapy. Keywords: Krukenberg tumour, Gall bladder cancer, Immunohistochemistry, UGI scopy, Metastatic gallbladder cancer, Ovarian metastasis, Ovarian mass

A nomogram predicting the outcome of gallbladder cancer patients with different target organ metastases.

Gallbladder cancer (GBC) is a highly aggressive malignancy that is associated with a high mortality rate globally. Unfortunately, distant metastases are often detected at the time of diagnosis. Therefore, we investigated the survival outcomes of gallbladder cancer patients with different metastases targeting organs, analyzed their prognosis, and explored their hidden clinical value. Through data screening, a total of 398 patients with GBC with different target organ metastases were analyzed retrospectively, including patients with solitary bone metastasis, solitary liver metastasis, solitary lung metastasis, and multiple organ metastases. The survival results of different variables were plotted as Kaplan-Meier survival curves. Univariate and multivariate Cox regression models were used to screen study variables and identify independent prognostic factors. Finally, a nomogram was established to systematically evaluate the prognosis of patients with multiple organ metastasis. In the patient cohort, thirteen (3.3%) had solitary bone metastasis, 290 (72.9%) had solitary liver metastasis, 22 (5.5%) had solitary lung metastasis, and 73 (18.3%) had multiple organ metastases (including liver, lung, bone and brain metastases). Multivariate Cox analysis showed that the overall survival (OS) of patients with solitary lung metastasis was significantly better than that of patients with other organ metastasis (p = 0.038), while the difference in tumor cancer-specific survival (CSS) of this factor was not statistically significant (p > 0.05). Surgery and chemotherapy were independent prognostic protective factors for OS and CSS. The OS-related models exhibited a C-index of 0.74 (95% CI: 0.71-0.77), while the CSS-related models showed a slightly lower C-index of 0.73 (0.70-0.76). Both the OS- and CSS-related clinical prediction models had good accuracy. This study shows that different target organ metastases may affect the OS of patients with distant metastatic GBC. Patients receiving palliative surgery, primary site resection, radical surgery, and chemotherapy have significant survival benefits in terms of OS and CSS.

Gemcitabine, Cisplatin, and Nab-Paclitaxel as a First-Line Therapy for Advanced Biliary Tract Cancers.

Locally advanced, inoperable, or metastatic gallbladder cancers (GBC) are treated with either gemcitabine-platinum combinations or gemcitabine alone based on physician discretion. However, the combination of gemcitabine, cisplatin, and nab-paclitaxel (GCNP) has shown increased response rates and prolonged survival in a phase II trial of biliary tract patients. Consecutive series of patients diagnosed with locally advanced (liver infiltration > 5cm, large nodes at porta, abutting duodenum), inoperable, and metastatic biliary tract patients between January 2018 and August 2022 were evaluated for first-line chemotherapy GCNP, in the multidisciplinary joint clinic (MDJC). The primary endpoint was ORR, and the major secondary endpoint was event-free survival (EFS). A total of 142 patients received GCNP during the specified time period. The median age of the cohort was 52years (range: 21-79), the majority were females (61.3%), and the majority were GB (81.7%). Response rates were available in 137 patients. Complete response, partial response, and stable disease were seen in 9 (6.3%), 87 (61.3%), and 24 (16.9%), respectively, for an ORR of 67.6% and a clinical benefit rate of 84.5%. The median EFS was 9.92 (95% CI, 7.69-12.14) months. Of the 52 patients in whom GCNP was given with NACT intent for locally advanced GBC, 17 patients underwent surgery (34%). Our study indicates that GCNP leads to improved response rates, increased chances of resectability, and possibly better survival in patients with GBC.

Efgartigimod for Pembrolizumab-induced Myasthenia Gravis Refractory to Standard Therapy (P1-8.006)

<h3>Objective:</h3> NA <h3>Background:</h3> Checkpoint inhibitor-induced myasthenia gravis is a life-threatening complication with mortality near 60%.¹ Two patients with pembrolizumab-induced myasthenia gravis responded favorably to efgartigimod. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 68-year-old female with metastatic gallbladder cancer developed ptosis, ophthalmoparesis, and weakness one month after receiving pembrolizumab. She has acetylcholine receptor (binding, blocking) and striated muscle antibodies without thymoma. Her ptosis improved with prednisone 20mg daily. She developed dysphagia, hoarseness, and gait instability which resolved with increased prednisone 60mg. Prednisone was tapered; proximal limb weakness and ptosis returned at 30mg. Efgartigimod improved symptoms after second infusion. Three weeks after cycle one while alternating prednisone 25mg–20mg, she developed exertional dyspnea, hoarseness, and worsening ptosis. Increased prednisone to 25mg. Her symptoms persisted; five weeks after cycle one, the second cycle of efgartigimod started and her symptoms nearly resolved, with intermittent ptosis. She is stable on prednisone 25mg with slow taper. A 78-year-old female with metastatic urothelial carcinoma status post two doses of pembrolizumab presented with dyspnea, leg weakness, and myalgias. She developed ptosis, ophthalmoparesis, and dysphagia. Acetylcholine receptor and MuSK antibodies were negative. Intravenous immunoglobulin was ineffective to prevent worsening. After the second dose, she developed respiratory failure requiring intubation. Prednisone 40mg BID and plasmapheresis (PLEX) were initiated. Her strength improved enough for extubation; subsequently aspirated and required reintubation. Rituximab was infused for long-term immunosuppression while another PLEX cycle was started. She developed thrombocytopenia and gastrointestinal bleeding; PLEX was discontinued after 3 doses. Efgartigimod initiation two days after the final PLEX infusion led to improved strength, ophthalmoparesis, and thrombocytopenia within one week. She died from urosepsis two days after the second dose. <h3>Conclusions:</h3> Current treatments for pembrolizumab-induced myasthenia gravis are corticosteroids, IVIG, and plasmapheresis. Rituximab is effective in refractory cases, although onset of action can take more than 6 weeks.² Efgartigimod rapidly improved myasthenia gravis symptoms in both patients. <b>Disclosure:</b> Miss Campbell has nothing to disclose. Dr. Rodriguez-Hernandez has nothing to disclose. Dr. Rizvi has nothing to disclose. Dr. Swerdloff has nothing to disclose. The institution of Dr. Zakin has received research support from American Board of Psychiatry and Neurology. Dr. Faktorovich has a non-compensated relationship as a Board of Directors with Brother’s Brother Foundation that is relevant to AAN interests or activities.

An observational study of best supportive care with or without oral capecitabine in patients with metastatic gallbladder cancer.

521 Background: Patients with metastatic (M+) gallbladder cancer (GBC) have a median survival between 3 - 6 months and therefore palliation of symptoms without compromising quality of life (QoL) is the principal goal of treatment. This study aimed to compare overall survival (OS), toxicity and QoL in patients receiving best supportive care (BSC) with or without oral capecitabine (X). Methods: Patients with M+ GBC and a KPS of ≥70 were prospectively assigned to BSC + X - arm A or BSC alone - arm B, based on physician discretion. Arm A received BSC + X @1650 mg/m2 d1-14, repeated every 21 days for a maximum of 6 cycles. BSC measures included pain palliation; ascitic fluid drainage; jaundice mitigation and other palliative measures. Overall survival (OS) was computed by the Kaplan-Meier method from the date of histologic confirmation and compared using log-rank test. Qol was measured using FACT-Hep v4 administered at baseline, 3 and 6 months. Mean differences in scores were compared using Mann Whitney / Independent t-test and the linear mixed effects model was used for longitudinal analysis to determine the impact of treatment and time on QoL. Results: Between December 2020 to April 2022, 64 patients were assigned, 32 to each arm; data analysed August 2022. For the arms A vs B, the mean age (years) ± SD was 53.3±10.3 vs 54.5±10.3, p=0.21; females, 72% vs 73%, p=0.21; KPS 70, 9% vs 44%, p=0.008; pre-treatment biliary drainage, 9% vs 31%, p=0.06. In arm A, 78% and 21% completed 3 and 6 cycles of X. Median survival was 3.6 vs 2.0 mo, p=0.001; 26 and 27 patients succumbed (~83%), and at 6 months the survival probability was 28% vs 0% respectively; vomiting grade 1-2, 50% vs 78%, p=0.02; diarrhoea grade 1-2, 59% vs 9%, p=0.00; hand-foot syndrome – only arm A, grade 1, 2 &amp; 3 were 32%, 6.5% &amp; 3.2% p=0.001. Baseline QoL mean scores (Table) were significantly worse for most domains in arm B. However, there was no difference in the longitudinal QoL scores between the two treatment arms – FACTG total score (arm*time p=0.759). Conclusions: Not withstanding better prognosis patients of M+ GBC receiving X with BSC compared to BSC alone, a 2 month difference in median survival in favour of arm A was associated with worse diarrhoea and hand-foot syndrome and no discernable impact on longitudinal QoL scores between the two treatment arms.[Table: see text]

Surgical resection in oligo-metastatic gallbladder cancer: Study protocol for a phase II randomized clinical trial.

Background: Gallbladder cancer incidence rates in India, ranging from 11.8 to 17.1/100,000 population are amongst some of the highest reported in the world. With India accounting for roughly 10% of the global gallbladder cancer burden, it is a disease of endemic proportions in the sub-continent. Metastatic gallbladder cancer has a very poor survival, with systemic chemotherapy being the only proven treatment option, that too, with limited benefit. There is however, emerging evidence for curative surgical resection in patients with limited metastases. This study aims to evaluate the benefit of surgical resection in addition to palliative chemotherapy in oligo-metastatic gallbladder cancer (OGBCa).

Update on Immunotherapy in the Management of Gallbladder Cancer

Gallbladder cancer (GBC) is a relatively infrequent but highly lethal cancer with a poor prognosis. Management remains challenging and controversial, and most patients are diagnosed at an advanced stage. However, with the progressive advances in the use of immunotherapies, new treatment modalities are being implemented. In September 2022, the USFDA approved durvalumab (a PD-L1 inhibitor) in combination with chemotherapy for adult patients with locally advanced or metastatic GBC. This groundbreaking news is the first FDA approval for the use of immunotherapy in biliary tract cancers. This article reviews the newest advances and trials regarding immunotherapy for GBC.

A clinicoepidemiological and management profile of metastatic carcinoma gallbladder in the northeast part of Indian patients in a tertiary care center.

Metastatic gallbladder cancer (GBC) is a highly fatal malignancy and it is difficult to treat the advanced stage of GBC. In India, northern and northeastern states are the worst affected by this disease. We, hereby, report the clinicoepidemiological and management profile of 242 patients of metastatic carcinoma of GB. In this study, a total of 242 cases of metastatic GBC (detected either on the first presentation or during follow-up) were managed at the Department of Medical Oncology tertiary care oncology center in the northeast part of India from May 2018 to September 2019. On presentation, all patients were subjected to detailed history and clinical examination, followed by requisite investigations and were treated as per the existent guidelines. One-hundred and forty-two patients were female, while 100 patients were male out of 242 patients. Female patients with metastatic GBC presented with the mean age of 54, while for males, 51.4 years. The most common presentation was pain abdomen (81.8%), while the second most common was anorexia (77.2%), followed by weight loss (62.8%) and mass per abdomen (60.7%). The most common site of metastasis recorded in our study was the liver (79.7%), followed by nonregional abdominal lymph node (69.4%) and ascites (64.4%). Out of the 242 patients, 24 patients had presented in poor Eastern Cooperative Oncology Group Performance Status (≥3) hence were deemed unfit for any oncological interventions. About 136 (56.1%) patients had presented with features of obstructive jaundice, however only 108 patients were subjected to biliary drainage procedure. After the biliary drainage procedures, only one-third (38 out of 136; 35.1%) of patients were finally able to receive chemotherapy. In India, unfortunately, many patients present very late during the course of their illness. There is a need for the development of effective chemotherapy or targeted therapy and also there is an unmet need for patients' education. There has been an increase in the incidence of this malignancy, especially in the Northeast part of India; hence, it is the need of the hour to study various epidemiological and causative factors of the disease. Furthermore, the development of therapies for the effective management of this malignancy is really required.

First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors

BackgroundOX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed...

A comparative study of gemcitabine and cisplatin versus oral capecitabine alone in metastatic gallbladder cancer.

There is no consensus for palliative chemotherapy regimen in metastatic gallbladder cancer. We did a retrospective study to compare the treatment outcome in patients of metastatic gallbladder cancer treated with either gemcitabine + cisplatin (regimen A) or oral capecitabine (regimen B) alone. A total of 67 patients between January 2015 and September 15 treated with either regimen A or regimen B were retrospectively evaluated. Statistical analysis was done in June 2019. Kaplan-Meir and Log rank test were used to compare survival between two arms. Out of 67 patients, 31/67 (46%) received regimen A, and 36/67 (54%) received regimen B. Male to female ratio was 1:3. About 42% patients in regimen A and 20% in regimen B required palliative stenting. Median number of chemotherapy cycles was 4 in both regimen A (range 1->6) and regimen B (range 1->6). Patients receiving 3 cycles and 6 cycles of chemotherapy in regimen A and regimen B was 68% and 31% versus 70% and 63%, respectively (P = 0.86). Response assessment as any response (complete response + partial response + disease was stable) after 3 cycles and 6 cycles was 71% and 57% (P = 0.20), 44% and 39% (P = 0.29), in regimen A and B, respectively. Median survival was 23 weeks (range 2-106 weeks) in regimen A and 15 weeks (range 4-83 weeks) in regimen B (P = 0.40). The present study shows gemcitabine and cisplatin has nonsignificant better survival compared to oral capecitabine. However, oral capecitabine is more convenient and easy to administer. Studies with larger sample size are needed to further establish the standard chemotherapy guidelines.

Abstract 5517: Addition of PD-1 antibody camrelizumab overcame resistance to trastuzumab plus chemotherapy in a HER2-positive, metastatic gallbladder cancer patient

Abstract HER2 amplification/overexpression is a common driver in a variety of cancers including gallbladder cancer (GBC). For patients with metastatic GBC, chemotherapy remains the standard of care with limited efficacy. The combination of HER2 antibody trastuzumab plus chemotherapy is the frontline treatment option for patients with HER2-positive breast/gastric cancer. Recently, this regime also showed antitumor activity in HER2-positive GBC. However, resistance to this regime represents a clinical challenge. Camrelizumab is a novel PD-1 antibody approved for Hodgkin lymphoma and hepatocellular carcinoma in China. Here we presented a HER2-positive metastatic GBC patient who was refractory to trastuzumab plus chemotherapy but experienced significant clinical benefit after the addition of camrelizumab. A 69-year-old male GBC patient was found disease progression in the lung six month after operation, staged IV (T3N0M1). Immunohistochemical (IHC) staining was positive for HER2 (3+) and negative for PD-L1 in both primary and pulmonary lesions. Chemotherapy including S-1 plus gemcitabine, as well as oxaliplatin plus paclitaxel consecutive failed, with a new lesion discovered in the liver. Genomic profiling with a multi-gene NGS panel testing (Onco Panscan࣪, Genetron Health) of the pulmonary lesion showed the presence of TP53 S241Y, ARID2 R273*, EGFR E872K mutations, HER2 amplification (fold change, 8.7), and high tumor mutational burden (TMB 10.33). He was treated with trastuzumab in combination with afatinib and capecitabine. Unfortunately, progressive disease in the lung and brain was observed after two cycles. Due to progression of disease and high TMB of the pulmonary biopsy, also based on the reported activity of PD-1 antibody plus trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer, a triplet regime of camrelizumab, trastuzumab, and oxaliplatin was administered. The lesions of the lung, liver, and brain completely regressed after five cycles. From cycle 8 of maintance regime, an anti-angiogenic agent apatinib was added to treat reactive cutaneous capillary endothelial proliferation (RCCEP), the most common immune-related adverse event (irAE) related to camrelizumab, with complete regression after four months. Currently, the patient remains in remission. Our case highlights the potential of immunotherapy in combination with HER2-targeted therapy in HER2-positive GBC. We also demonstrated that immune-related adverse events (irAEs) associated with camrelizumab can be managed with an anti-VEGF agent apatinib. This case not only highlights the importance of irAE management in patients treated with camrelizumab, but also demonstrates the potential of PD-1 antibody plus trastuzumab in HER2-positive GBCs who have developed resistance to chemotherapy and trastuzumab-based targeted therapy. Citation Format: Dong Yan, Xiaomo Li, Li Wang, Yurong Cheng, Si Liu. Addition of PD-1 antibody camrelizumab overcame resistance to trastuzumab plus chemotherapy in a HER2-positive, metastatic gallbladder cancer patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5517.

PD-9 Three-arm phase II/III randomized controlled trial in patients with unresectable/metastatic gall bladder cancer with poor performance status: Erlotinib or capecitabine v/s best supportive care

Currently there is no standard of care for Eastern Cooperative Oncology Group (ECOG) poor performance status (PS) patients (PS-III) with unresectable/metastatic Gall Bladder Cancer (GBC). Being unfit for chemotherapy, these patients receive only best supportive care (BSC) resulting in a very dismal outcome. A report published from M.D. Anderson Cancer Centre stated median overall survival (OS) of only one month in patients with poor PS with GBC. This single centre, prospective randomized controlled phase II/III, open label trial was done at a tertiary health care centre in India. Patients (above 18 years) with histologically confirmed unresectable/ metastatic GBC with adequate organ function and ECOG PS-III were included. Patients with prior adjuvant chemotherapy/erlotinib/capecitabine in last 6 months, active malignancy other than GBC, lactating and pregnant women, and HIV-positive status were excluded. Random allocation (1:1:1) was done to one of the three arms - Erlotinib (150 mg OD) + BSC, Capecitabine + BSC or BSC alone using computer-generated sequence. The primary end point was median OS, defined as time from randomisation to death, in the intention-to-treat population. A sample size of 105 was estimated, assuming median OS in BSC, Erlotinib+BSC and Capecitabine+BSC as 2, 4 and 5 months respectively (taking two-sided alpha error as 0.05 and power as 80%). Between Dec 27, 2017 and January 18, 2021, 201 patients were screened, of which 105 were randomized to Erlotinib +BSC (n = 36), Capecitabine +BSC (n = 36) or BSC alone arm (n = 33). After a median follow up of 10 months (IQR 3.9- 11.5), there were 82 deaths in the whole cohort. The median OS in Erlotinib arm was significantly higher at 3.84 months (2.33- 4.67) compared to 1.77 months (1.18- 2.73) in BSC only arm, with hazard ratio (HR) of 0.50 (95% CI - 0.26 -0.95), p = 0.02. However, there was no statistically significant difference observed in survival between Capecitabine +BSC over BSC alone - median OS 2.46 months (1.67-3.58), HR - 0.70 (95% CI - 0.38- 1.2), p = 0.30. Compared to only 15.1% (5/33) in BSC arm, the disease control rate (complete response + partial response + stable disease) at 6-8 weeks was 58.3% (21/36) in Erlotinib arm (p = 0.004) and 47.2% (17/36) in Capecitabine arm (p = 0.04). Grade III/IV toxicities were reported in 12 patients (33.3%) in Erlotinib arm (skin rash and diarrhea being most common at 8% each) and in 5 patients (13.8%) in Capecitabine arm (anemia and fatigue most common at 6 % each). No treatment related deaths were reported in either group. Addition of Erlotinib to BSC significantly improves OS in patients with unresectable/metastatic GBC, otherwise unfit to receive chemotherapy, with acceptable toxicity profile.

Capecitabine for advanced biliary tract cancers during COVID-19 pandemic.

e16116 Background: Despite chemotherapy, metastatic gall bladder cancers (mGBC) have the worst prognosis. Many patients are unfit for the standard of care Cisplatin-based injectable chemotherapy. The study evaluates single-agent Capecitabine as an effective therapy option for frontline advanced GBC patients in a COVID pandemic affected hospital access. Methods: This is a retrospective analysis of mGBC patients treated at the PGIMER Medical Oncology Clinic between December 2019 and August 2021. Patients with an Eastern Cooperative Oncology Group performance rating of 0-2 were given Capecitabine 1,000 mg/m2 twice daily for 14 days. The primary goal was to measure progression-free survival (PFS). The secondary objectives were overall survival (OS), safety, and the need for biliary diversion. Results: A total of 72 patients were analyzed. With a median follow up of 12 months, the median PFS was 5.4 months (4.0-9.1), and the interim overall survival OS was 11.9 months (5.2-16). During treatment, 12% of patients required biliary diversion. The safety profile was consistent with previous capecitabine use, and no new safety signals were detected. There were 9.7 percent (7/72) of grade 3/4 adverse events (AEs) reported. Due to poor tolerability, one-third of patients (30.5%) required dose reduction/interruption. Conclusions: In a COVID pandemic situation, Capecitabine is safe, effective, and comparable efficacy for patients with advanced mGBC. However, It needs to be evaluated in randomized clinical trials comparing the standard of care.[Table: see text]

An Investigator-Initiated Study of Gemcitabine and Capecitabine in Indian Patients with Unresectable or Metastatic Gallbladder Cancer

Abstract Background: Gallbladder cancer (GBC) has a high incidence rate in the Indo-Gangetic belt and is usually presented in the unresectable advanced or metastatic stage. In this study, we evaluated the response rate and toxicities of the gemcitabine plus capecitabine (GEM-CAP)-based combination chemotherapy in unresectable or metastatic GBC patients. Subjects and Methods: This was an investigator-initiated, single-arm, prospective study conducted on unresectable or metastatic GBC patients at Jaipur, India, for 1 year. All the patients received a GEM-CAP combination chemotherapy regimen which consisted of gemcitabine 1000 mg/m2 intravenously over 30 min on days 1 and 8 and capecitabine at 800 mg/m2 orally twice a day for 14 days, administered every 21 days. The response was evaluated in terms of overall response rate (ORR), tumor control rate (TCR), and progression-free survival (PFS). Both quantitative and qualitative toxicities were assessed. Results: A total of 35 patients were enrolled, of which 3 patients were excluded due to treatment interruption. The mean age of patients was 55 (32–80) years, with the majority being female (77.14%), having an ECOG score of 1 (71.43%), and with Stage IVB disease (77.14%). The ORR was 25%, TCR was 50%, and median PFS was 4 months. Major toxicities noted were Grade I and II hematological and nonhematological toxicities, which were managed adequately. Conclusion: The combination therapy of gemcitabine and capecitabine is reasonable, feasible, and well-tolerated approach for the treatment of unresectable advanced and metastatic GBC patients, a disease that had limited treatment options.

Evolving Paradigms in the Systemic Treatment of Advanced Gallbladder Cancer: Updates in Year 2022.

Simple SummaryGallbladder cancer is distinct type of biliart tract cancer that is rare, aggressive and with limited treatment options aside from surgical resection. As of now in year 2022, systemic chemotherapy remains as the mainstay treatment option for patients with advanced staged gallbladder cancer. Despite decades of scientific research, new treatment options have been struggling to succeed. Furthermore, almost all clinical studies on gallbladder cancer have included other tyes of biliary tract cancers, raising the need to specifically inspect the outcomes of these clinical trial regimens on gallbladder cancer. In this article, we summarized all seminal literature and the most recent advances in scientific discoveries and clinical trials on gallbladder cancer. We provide a succinct update on current understanding, treatment landscape and therapeutic challenges in gallbladder cancer, as well as future prospects in the management of this disease.Gallbladder cancer (GBC) is a biological, anatomical, and clinically distinct subset of biliary tract cancers (BTC), which also include extra- and intra-hepatic cholangiocarcinoma. The advent of next-generation sequencing (NGS) clearly shows that GBC is genetically different from cholangiocarcinoma. Although GBC is a relatively rare cancer, it is highly aggressive and carries a grave prognosis. To date, complete surgical resection remains the only path for cure but is limited to patients with early-stage disease. The majority of the patients are diagnosed at an advanced, inoperable stage when systemic treatment is administered as an attempt to enable surgery or for palliation. Gemcitabine and platinum-based chemotherapies have been the main treatment modality for unresectable, locally advanced, and metastatic gallbladder cancer. However, over the past decade, the treatment paradigm has evolved. These include the introduction of newer chemotherapeutic strategies after progression on frontline chemotherapy, incorporation of targeted therapeutics towards driver mutations of genes including HER2, FGFR, BRAF, as well as approaches to unleash host anti-tumor immunity using immune checkpoint inhibitors. Notably, due to the rarity of BTC in general, most clinical trials included both GBC and cholangiocarcinomas. Here, we provide a review on the pathogenesis of GBC, past and current systemic treatment options focusing specifically on GBC, clinical trials tailored towards its genetic mutations, and emerging treatment strategies based on promising recent clinical studies.

A phase Ib/II study (IMMCO-1) of atezolizumab plus tivozanib in castrate-resistant prostate cancer and certain other immunologically cold tumors.

TPS208 Background: Castrate resistant prostate cancer (CRPC) is an immunologically cold tumor, with a 5% response rate reported to the PD-L1 inhibitor pembrolizumab. VEGF secreted by tumors may play a key role in hindering the anti-tumor immune response, leading to the development of an abnormal vasculature that may limit immune surveillance. VEGF also inhibits dendritic cell differentiation, limiting the presentation of tumor antigens. The inhibition of VEGF may therefore potentiate the effect of PD-1/L1 directed therapy by enabling immune surveillance and antigen presentation. VEGF-TKI and checkpoint inhibitor combinations are currently approved in the treatment of advanced kidney, cervical, and endometrial cancers. This signal-seeking study aims to determine whether the combination of the VEGF-TKI tivozanib and the PD-L1 inhibitor atezolizumab may be effective in CRPC and certain other immunologically cold tumors. Methods: The trial is a single center phase Ib/II basket study in multiple immunologically cold tumors. Co-primary endpoints are safety and the overall response rate as measured via RECIST v1.1. The tivozanib dose will be determined via a 3+3 dose de-escalation phase Ib portion. Patients treated in the phase Ib portion will be included as study subjects for phase the II portion. The study is designed to test for a 25%+ response rate as compared to a null hypothesis of &lt;7% (one-sided alpha = 0.05; 80% power). A Simon’s two-stage design will be utilized and if ≥2 responses among the first 16 evaluable patients, a further 10 evaluable patients will be accrued for a total of 26. Up to 33 subjects will be enrolled to account for a 20% dropout rate. The null hypothesis will be rejected if at least 5 responses are observed. The University of Florida's Data Integrity and Safety Committee will review significant adverse events. Tivozanib will be given at a dose of 1.34 mg/day for 21 days of each 28-day cycle (potential dose reduction is to 0.89 mg/day). Atezolizumab is given at a dose of 1,680 mg every 28 days. Treatment is until disease progression or intolerance. Key inclusion criteria include a diagnosis of certain advanced and unresectable or metastatic immunologically cold tumors (CRPC previously treated with an androgen inhibitor or cytotoxic chemotherapy in the advanced or metastatic setting, bile duct or gallbladder cancer, certain HR-negative HER2-positive breast cancers, ovarian cancer, pancreatic adenocarcinoma, soft tissue sarcoma, or vulvar cancer), at least one prior systemic therapy in this setting, ECOG 0-1 (phase Ib) or ECOG 0-2 (phase II), age ≥ 18, adequate hematologic and end-organ function, life expectancy of at least 12 weeks, and measurable disease by RECIST v1.1. Key exclusion criteria include known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. Active enrollment continues. Clinical trial information: NCT05000294.