Gemcitabine, carboplatin, and Epstein Barr virus-specific autologous cytotoxic T lymphocytes for recurrent or metastatic nasopharyngeal carcinoma: VANCE, an international randomized Phase 3 trial.

BACKGROUND: Epstein-Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) is an autologous adoptive T cell immunotherapy generated from the blood of individuals and manufactured without genetic modification. In a previous Phase 2 trial of locally recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients, first-line gemcitabine and carboplatin (GC) and EBV-CTL combination demonstrated objective anti-tumor EBV-CTL activity and a favorable safety profile. The present study explored whether this combined first-line chemo-immunotherapy strategy would produce superior clinical efficacy and better quality of life compared to conventional chemotherapy treatment. PATIENTS AND METHODS: This multicenter, randomized, Phase 3 trial evaluated the efficacy and safety of GC followed by EBV-CTL vs. GC alone as first-line treatment for R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the United States (US) were included. Subjects were randomized to first-line GC (4 cycles) and EBV-CTL (6 cycles) or GC (6 cycles) in a 1:1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety. CLINICALTRIALS: gov identifier: NCT02578641. RESULTS: 330 subjects with NPC were enrolled. Most subjects in both treatment arms received ≥4 cycles of chemotherapy and most subjects in the GC+EBV-CTL group received ≥2 infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC+EBV-CTL subjects. The median OS was 25.0 months in the GC+EBV-CTL group and 24.9 months in the GC group (hazard ratio = 1.19; 95% CI: 0.91, 1.56; P = 0.194). Only 1 subject experienced a Grade 2 serious adverse event related to EBV-CTL. CONCLUSION: GC+EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS vs. chemotherapy. This is the largest adoptive T cell therapy trial reported in solid tumors to date.

Molecular alterations and clinical prognostic factors in resectable non-small cell lung cancer.

BACKGROUND: EGFR inhibitor and immunotherapy have been approved for adjuvant treatment in resectable non-small cell lung cancer (NSCLC). Limited reports of molecular and clinical characteristics as prognostic factors in NSCLC have been published. METHODS: Medical records of patients with resectable NSCLC stage I-III diagnosed during 2015-2020 were reviewed. Real time-PCR (RT-PCR) was performed for EGFR mutations (EGFRm). Immunohistochemistry staining was conducted for ALK and PD-L1 expression. Categorical variables were compared using chi-square test and Fisher's exact test. Survival analysis was done by cox-regression method. RESULTS: Total 441 patients were included. The prevalence of EGFRm, ALK fusion, and PD-L1 expression were 57.8%, 1.9%, and 20.5% (SP263), respectively. The most common EGFRm were Del19 (43%) and L858R (41%). There was no significant difference of recurrence free survival (RFS) by EGFRm status whereas patients with PD-L1 expression (PD-L1 positive patients) had lower RFS compared to without PD-L1 expression (PD-L1 negative patients) (HR = 1.75, P = 0.036). Patients with both EGFRm and PD-L1 expression had worse RFS compared with EGFRm and PD-L1 negative patients (HR = 3.38, P = 0.001). Multivariable analysis showed higher CEA at cut-off 3.8 ng/ml, pT4, pN2, pStage II, and margin were significant poor prognostic factors for RFS in the overall population, which was similar to EGFRm population (exception of pT and pStage). Only pStage was a significant poor prognostic factor for PD-L1 positive patients. The predictive score for predicting of recurrence were 6 for all population (63% sensitivity and 86% specificity) and 5 for EGFRm population (62% sensitivity and 93% specificity). CONCLUSION: The prevalence and types of EGFRm were similar between early stage and advanced stage NSCLC. While lower prevalence of PD-L1 expression was found in early stage disease. Patients with both EGFRm and PD-L1 expression had poorer outcome. Thus PD-L1 expression would be one of the prognostic factor in EGFRm patients. Validation of the predictive score should be performed in a larger cohort.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Molecular alterations and clinical prognostic factors for cholangiocarcinoma in Thai population.

This study explores genomic alterations in cholangiocarcinoma (CCC) tissues in Thai patients. We identified and reviewed the records of patients who had been diagnosed with CCC and for whom sufficient tumor samples for DNA and RNA extraction were available in our database. The specimens were explored for EGFR, KRAS, BRAF, and PIK3CA mutations and ROS1 translocation in 81 samples. Immunohistochemistry staining for HER2, ALK, and Ki-67 expression was tested in 74 samples. Prevalence of EGFR, KRAS, and PIK3CA mutations in this study was 21%, 12%, and 16%, respectively. No BRAF V600 mutation or ROS1 translocation was found. Patients with T790M mutation had a significantly longer overall survival (18.84 months) than those with the other types of EGFR mutations (4.08 months; hazard ratio [HR]: 0.26, P=0.038) and also had a significantly lower median Ki-67 (22.5% vs 80%, P=0.025). Furthermore, patients with PIK3CA mutations had a significantly longer median progression-free survival (15.87 vs 7.01 months; HR: 0.46, P=0.043). Strongly positive HER2 expression was found in only 1 patient, whereas ALK expression was not found. The presence of EGFR and/or PIK3CA mutations implies that targeted drugs may provide a feasible CCC treatment in the future.

Effects of paclitaxel and carboplatin on quality of life and survival in patients with advanced non-small-cell lung cancer.

The purpose of this phase II study was to determine the effects of paclitaxel plus carboplatin administered by short duration on response rate, toxicity, and quality of life (QOL) in patients with non-small cell lung cancer (NSCLC). Twenty-seven patients were enrolled in this study. The objective response rate was 48.2 per cent, grade 3 or 4 granulocytopenia and thrombocytopenia were observed in 22 per cent and 1.6 per cent, respectively. QOL was assessed in nineteen patients who completed six cycles of chemotherapy. Quality of Life Index (QLI) after six cycles of treatment showed no significant change from the baseline QOL. Compliance with the QOL protocol in this study diminished with the course of chemotherapy which is comparable to the literature figure. Thus, withholding current effective chemotherapy in patients with NSCLC with good performance status is no longer justified.

Clinical activity and benefit of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma pre-treated with fluorouracil-based chemotherapy.

The purpose of this prospective study was to assess the efficacy, clinical benefit and safety of irinotecan (CPT-11) in patients with 5-fluorouracil-resistant metastatic colorectal cancer (CRC). Sixteen patients with World Health Organization (WHO) performance status < or = 2 were treated with CPT-11 350 mg/m2 every 3 weeks. The observed partial response (PR) rate was 6.3 per cent with a high rate of stable disease (SD) (43.7%) which was of long duration (21.1 weeks for the best response; 1PR, 7SD). The median survival time for the 16 patients entered into this study was 69.6 weeks. There was no toxic death. The most frequent adverse events were neutropenia (31% grade 3/4) and delayed diarrhea (9.7%). CPT-11 has definite activity in the treatment of progressive metastatic CRC truly resistant to 5-FU which translated into clinical survival benefit. Median survival from first administration of CPT-11 was 78.6 weeks for patients with best response (PR + SD) compared with 28.1 weeks for patients with progressive disease (PD) (P = 0.01). With the appearance of new active drugs in this highly chemotherapy-resistant disease, the definition of response should be reassessed in CRC.

Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer (NSCLC): a preliminary study.

This study was aimed to determine the activity and toxicity of combination paclitaxel and carboplatin in stage III B and IV NSCLC. Eligibililty required performance status. Paclitaxel was administered at a dose of 200 mg/m2, 3-hour infusion, followed by carboplatin at a tartgeted area under the concentration-time curve (AUC) of 6. Treatment was repeated at 3-week intervals for 6 courses. G-CSF 5 micrograms/kg was subcutaneously injected during subsequent courses if there was grade 3-4 leukopenia or granulocytopenia in the previous course. From August 1996 through June 1997, 15 patients were enrolled. The median age was 47 years (range 20-68 years), 60 per cent were female. 73.3 per cent had adenocarcinoma, and 66.7 per cent had stage III B disease. Eighty three courses were administered; 13 patients (86.7%) completed all six cycles. The objective response rate was 53.3 per cent, with 1 (6.7%) complete response and 7 (46.7%) partial responses. Pleural effusion, lung lesion and lymph node were the three most common sites that responded to chemotherapy. The major toxicity was myelosuppression. Grade 3 or 4 granulocytopenia, anemia and thrombocytopenia were observed in 18 per cent, 7.2 per cent and 1.2 per cent, respectively, of 83 courses administered. Four episodes of febrile neutropenia (4.8%) occurred in 3 patients. There was one episode of anaphylaxis during Paclitaxel infusion. Other common toxicities were mild myalgia, paresthesias, alopecia and fatigue. Most of the toxicities showed cumulative effect. Paclitaxel plus carboplatin is a moderately active regimen in advanced NSCLC. Toxicities of this regimen are well tolerated.

Phase II study of concurrent chemoradiotherapy for inoperable (bulky) stage III (A/B) non-small cell lung cancer (NSCLC): a preliminary report.

We designed a phase II study to determine the feasibility and toxicity of concomitant radiotherapy and Paclitaxel/Carboplatin followed by adjuvant chemotherapy of the same regimen in patients with newly diagnosed inoperable stage III A/B non-small cell lung cancer. Patients were irradiated with a total dose of 66 Gy. Weekly courses of Paclitaxel 45 mg/m2 and Carboplatin AUC 2 were administered intravenously during the irradiation period. After completion of concurrent chemoradiotherapy, adjuvant chemotherapy with Paclitaxel 175 mg/m2 and Carboplatin AUC 6 intravenously every 3 weeks for 4 cycles were given. Since March 1998, 15 patients have been enrolled. All patients were assessable for efficacy and toxicity after concurrent chemoradiotherapy. Eleven patients were assessable for efficacy and toxicity after adjuvant chemotherapy. After concomitant chemoradiotherapy, complete response (CR) was documented in 2 of 15 (13%). Partial response (PR) was documented in 9 of 15 (60%). After completion of adjuvant chemotherapy in 11 patients, the overall response rate was 91 per cent. (18% CR, 73% PR). There were 8 per cent gr. 3-4 neutropenia which occurred during adjuvant chemotherapy. Concomitant Paclitaxel/Carboplatin and radiotherapy are promising modalities in the treatment of inoperable stage III A/B non-small cell lung cancer.