Trastuzumab Plus Gemcitabine-Cisplatin for Treatment-Naïve Human Epidermal Growth Factor Receptor 2-Positive Biliary Tract Adenocarcinoma: A Multicenter, Open-Label, Phase II Study (TAB).

PURPOSE: Human epidermal growth factor receptor 2 (HER2) overexpression is seen in 4%-16% of biliary tract cancers (BTCs). We aimed to evaluate the clinical activity of gemcitabine-cisplatin (GC) plus anti-HER2 antibody trastuzumab as initial treatment in HER2-positive BTCs. METHODS: This study was an investigator-initiated, open-label, single-arm, multi-institutional, phase II trial in adult patients with HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+ and fluorescent in situ hybridization-positive), treatment-naïve BTCs. The primary end point of the study was 6-month progression-free survival (PFS). Next-generation sequencing was performed on tissue samples to evaluate mutational status. RESULTS: From March 2020 to August 2022, of the 876 screened patients, 118 (13.4%) were found to have HER2-positive status, of whom 90 were enrolled in the study. Most patients had GBC (n = 96; 96%) with two or more sites of metastatic disease (n = 70; 78%). With a median follow-up of 17.3 (95% CI, 15.22 to 19.32) months, 72 patients had disease progression with a median PFS of 7 (95% CI, 6.2 to 7.8) months. The diagnosis to event 6-month PFS rate was 75.6% (95% CI, 66.6 to 84.6). A complete or partial response was seen in 50 (55.5%) patients and 22 (24.4%) patients had stable disease as the best response to treatment, for an overall disease control rate of 80%. The presence of isolated TP53 mutations was associated with inferior PFS compared with other mutations (TERT promoter, HER2, PIK3CA, etc) or no detected mutations (6.51 v 12.02 v 10.58 months; P < .001). CONCLUSION: The combination of GC and trastuzumab achieved its primary end point of improving PFS compared with historical data in the treatment-naïve HER2-positive BTC. Evaluating additional mutations such as TP53 and PIK3CA along with HER2 testing may help to preferentially select patients for anti-HER2 therapy in the future (Clinical Trial Registry India number: CTRI/2019/11/021955).

Bevacizumab Erlotinib Switch Maintenance in Chemo-Responsive Advanced Gallbladder and Cholangiocarcinoma (BEER BTC): A Multicenter, Open-Label, Randomized, Phase II Trial.

PURPOSE: Patients with chemotherapy-responsive advanced biliary tract cancers (BTCs) are usually observed after 6 months of gemcitabine-based therapy. There is limited prospective evidence for maintenance strategies after chemotherapy. METHODS: This investigator-initiated, open-label, randomized, integrated phase II-III study enrolled adult patients with advanced BTC from two cancer centers in India. Patients with histologically confirmed advanced biliary tract adenocarcinoma who had at least disease stabilization after 6 months of gemcitabine-based chemotherapy were randomly assigned (1:1) to either active surveillance or switch maintenance, which was a combination of bevacizumab 5 mg/kg intravenous once every 21 days plus erlotinib 100 mg once daily. Both arms were continued until disease progression, unacceptable toxicity, or patient decision to withdraw. The primary end point of the phase II component of the trial was investigator-evaluated progression-free survival. This trial is registered with Clinical Trials Registry of India (CTRI/2019/05/019323I). RESULTS: From May 2021 to November 2022, 98 patients were randomly assigned to active surveillance (n = 49) or bevacizumab-erlotinib (n = 49). A majority of patients had gallbladder cancer (80%). The median follow-up was 13.4 months. The median progression-free survival was 3.1 months (95% CI, 2.47 to 3.64) in the active surveillance group versus 5.3 months (95% CI, 3.53 to 7.04) in the bevacizumab-erlotinib group (hazard ratio, 0.51 [95% CI, 0.33 to 0·74]; P = .0013). The most common grade 3 class-specific adverse events associated with bevacizumab-erlotinib were acneiform rash 1 (2%) and oral stomatitis 1 (2%) with erlotinib and bleeding 1 (2%) with bevacizumab. CONCLUSION: The combination of bevacizumab and erlotinib as switch maintenance improves progression-free survival with an acceptable safety profile compared with active surveillance in patients with advanced BTCs in this phase II study. The trial moves on to the phase III component to evaluate improvement in overall survival.

Adjuvant Gemcitabine Plus Cisplatin and Chemoradiation in Patients With Gallbladder Cancer: A Randomized Clinical Trial.

Importance: There is limited evidence with regard to the benefit of adjuvant chemotherapy chemoradiotherapy in resected gallbladder cancers (GBCs). Objective: To establish a baseline survival rate for operated GBCs in patients receiving either gemcitabine plus cisplatin (GC) or capecitabine and capecitabine concurrent with chemoradiation (CCRT). Design, Setting, and Participants: The GECCOR-GB study was a multicenter, open-label, randomized phase 2 noncomparator "pick the winner" design trial of adjuvant GC and CCRT in patients with resected histologically confirmed adenocarcinoma or adenosquamous carcinoma of the gallbladder, (stage II/III) with no local residual tumor (R0) or microscopic residual tumor (R1). The study was carried out in 3 tertiary cancer institutions in India. Patients 18 years or older with adequate end-organ functions, and Eastern Cooperative Oncology Group Performance Status of 1 or lower between May 2019 and February 2022 were enrolled. The cutoff date for data analysis was February 28, 2023. Interventions: Patients were randomized 1:1 to receive either GC every 3 weeks (maximum of 6 cycles) or CCRT comprising capecitabine with concurrent chemoradiation (capecitabine concurrent with radiotherapy) sandwiched between capecitabine chemotherapy. Main Outcomes and Measures: The primary outcome was disease-free survival (DFS) at 1 year in randomized patients. This study was conducted as 2 parallel, single-stage phase 2 clinical trials. Within each treatment arm, a 1-year DFS rate of less than 59% was considered as insufficient activity, whereas a 1-year DFS rate of 77% or higher would be considered as sufficient activity. Results: With a median follow-up of 23 months, 90 patients were randomized, 45 in each arm. Overall, there were 31 women (69%) and 14 men (31%) in the GC arm with a mean (range) age of 56 (33-72) years and 34 women (76%) and 11 men (24%) in the CCRT group with a mean (range) age of 55 (26-69) years. In the GC and CCRT arms, 1-year DFS and estimated 2-year DFS was 88.9% (95% CI, 79.5-98.3) and 74.8% (95% CI, 60.4-89.2), and 77.8% (95% CI, 65.4-90.2) and 74.8% (95% CI, 59.9-86.3), respectively. Completion rates for planned treatment was 82% in the GC arm and 62% in the CCRT arm. Conclusions and Relevance: In this randomized clinical trial, GC and CCRT crossed the prespecified trial end points of 1-year DFS in patients with resected stage II/III GBCs. The results set a baseline for a larger phase 3 trial evaluating both regimens in operated GBCs. Trial Registration: ClinicalTrials.gov Identifier: CTRI/2019/05/019323I.

Olanzapine as Antiemetic Prophylaxis in Moderately Emetogenic Chemotherapy: A Phase 3 Randomized Clinical Trial.

Importance: The role of olanzapine has not been adequately evaluated in moderately emetogenic chemotherapy (MEC) regimens with or without neurokinin-1 receptor antagonists. Objective: To evaluate whether addition of olanzapine to an MEC regimen reduces nausea, vomiting, and use of nausea rescue medications among patients with solid malignant tumors. Design, Setting, and Participants: This multicenter, open-label phase 3 randomized clinical trial included patients aged 18 years or older with solid malignant tumors who were receiving oxaliplatin-, carboplatin-, or irinotecan-based chemotherapy. The trial was conducted at 3 institutes in India from March 26, 2019, to August 26, 2023; the final cutoff date for analysis was September 10, 2023. Exposure: Patients were randomized 1:1 to dexamethasone, aprepitant, and palonosetron with olanzapine (experimental group) or without olanzapine (observation group). The experimental group received 10 mg of olanzapine orally once at night on days 1 through 3 of the chemotherapy regimen. Main Outcomes and Measures: The primary end point was complete response (CR), defined as the proportion of patients with no vomiting, no significant nausea (scored as <5 on a visual analog scale of 1 to 100), and no use of rescue medications for nausea. Secondary end points included the proportion of patients experiencing nausea and chemotherapy-induced nausea and vomiting (CINV), receiving rescue medications, and experiencing adverse events. Results: A total of 560 patients (259 [64%] male; median age, 51 years [range, 19-80 years]) were randomized. The analysis included 544 patients with evaluable data (274 assigned to olanzapine and 270 to observation). Baseline characteristics were evenly matched between the 2 groups. The proportion of patients with CR was significantly greater in the group with (248 [91%]) than without (222 [82%]) olanzapine in the overall 120-hour treatment period (P = .005). Likewise, there were significant differences between the olanzapine and observation groups for nausea control (264 [96%] vs 234 [87%]; P < .001) and CINV (262 [96%] vs 245 [91%]; P = .02) during the overall assessment period, and the proportion of patients receiving rescue medications significantly increased in the observation group (30 [11%]) compared with the olanzapine group (11 [4%]) (P = .001). Grade 1 somnolence was reported by 27 patients (10%) following administration of chemotherapy and olanzapine and by no patients in the observation group. Conclusions and Relevance: In this randomized clinical trial, the addition of olanzapine significantly improved CR rates as well as nausea and vomiting prevention rates in chemotherapy-naive patients who were receiving MEC regimens containing oxaliplatin, carboplatin, or irinotecan. These findings suggest that use of olanzapine should be considered as one of the standards of care in these chemotherapy regimens. Trial Registration: Clinical Trials Registry-India (CTRI) Identifier: CTRI/2018/12/016643.

Docetaxel-oxaliplatin-capecitabine/5-fluorouracil (DOX/F) followed by docetaxel versus oxaliplatin-capecitabine/5-fluorouracil (CAPOX/FOLFOX) in HER2-negative advanced gastric cancers.

BACKGROUND: We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ). METHODS: This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue. RESULTS: Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations. CONCLUSION: FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944).

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

INTRODUCTION: 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. MATERIALS AND METHODS: Consecutive series of patients diagnosed with locally advanced (liver infiltration > 5 cm, 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). RESULTS: A total of 142 patients received GCNP during the specified time period. The median age of the cohort was 52 years (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%). CONCLUSION: Our study indicates that GCNP leads to improved response rates, increased chances of resectability, and possibly better survival in patients with GBC.

Perioperative Modified FLOT Versus EOX in Locally Advanced Resectable Gastric and Gastro-Oesophageal Junction Adenocarcinoma: Results of a Matched-Pair Analysis.

BACKGROUND AND OBJECTIVES: There is limited real-world data on the efficacy of 2-weekly cycles of docetaxel, oxaliplatin, leucovorin, and fluorouracil (FLOT) compared to epirubicin, oxaliplatin, and capecitabine (EOX) as perioperative therapy in esophagogastric adenocarcinomas (EGAC). METHODS: The data of 611 patients with EGAC treated with perioperative chemotherapy and planned for curative resection between January 2013 and December 2019 were retrieved. Patients receiving EOX and a dose-modified version of FLOT (mFLOT) were evaluated. A 1:1 matching, using age, tumour location, signet ring histology, and Eastern Cooperative Oncology Group performance status, without replacement was performed by using nearest neighbour matching method. The primary endpoint of the study was 3-year event-free survival (EFS). RESULTS: A total of 593 patients (261 with EOX and 332 with mFLOT) were matched. One hundred and nighty-eight patients (76%) and 285 patients (86%) in the EOX and mFLOT cohorts underwent curative resection, respectively (p = 0.002). With a median follow-up of 35 and 53 months, respectively, the primary outcome of 3-year EFS was statistically superior in patients receiving mFLOT as compared to the EOX regimen (60% vs. 39%; p < 0.001). There was a greater incidence of grade 3 and grade 4 neutropenia (neoadjuvant: 18% vs. 2%; p < 0.001, adjuvant: 18% vs. 1%; p = 0.001) and febrile neutropenia (neoadjuvant: 8% vs. 1.1%; p < 0.001, adjuvant: 6% vs. 0; p = 0.001) with mFLOT. INTERPRETATION AND CONCLUSION: mFLOT is associated with improved resection rates and survival in comparison to EOX as perioperative therapy in gastric adenocarcinomas in this large real-world cohort, with manageable increase in clinically relevant toxicities such as grade 3 and grade 4 febrile neutropenia and neutropenia.

A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer: results of a prospective open label phase II single-arm study (RESCU III study).

It has been reported that chemotherapy toxicity is primarily not due to the drugs themselves, but is caused by cell-free chromatin particles (cfChPs) that are released from chemotherapy-induced dying cells. cfChPs from dying cells are readily internalized by healthy cells, wherein they inflict dsDNA breaks and activate inflammatory cytokines. cfChPs can be deactivated by oxygen radicals that are generated upon admixing the nutraceuticals resveratrol (R) and copper (Cu). Pre-clinical studies have shown that administration of R-Cu can reduce chemotherapy toxicity via the generation of oxygen radicals which deactivate cfChPs released from chemotherapy-induced dying cells. We investigated if R-Cu would reduce toxicity of docetaxel-based multi-agent chemotherapy in advanced gastric cancer. This single-arm phase II study was designed to assess the efficacy of orally administered R-Cu in ameliorating toxic side effects, as per National Cancer Institute Common Terminology Criteria for Adverse Events v4.03, in patients with advanced gastric cancer receiving docetaxel-based multi-agent chemotherapy. The primary objective was to reduce the proportion of patients experiencing grade ≥ 3 toxicity from 90 to 70%. Between October 2019 and April 2021, 30 patients, with a median age of 54 years, were enrolled of whom 73% were male. R-Cu treatment did not reduce the overall cumulative incidence of grade ≥ 3 toxicity (77%), or of ≥ 3 haematological toxicity (73%). However, the incidence of non-haematological toxicities comprising hand-foot syndrome (N = 4), diarrhoea (N = 3) and vomiting (N = 1) were markedly reduced (13%). Median progression-free survival (PFS) was 8 months (95% CI: 5.9-10.1), and overall survival (OS) was 16 months (95% confidence interval: 6.3-28.3). A marked reduction in non-haematological toxicities was seen in patients receiving R-Cu compared to historical data without adversely affecting PFS or OS. (292).Clinical trial information CTRI/2019/07/020289.