First-line Treatment For Patients Research Articles

Cabozantinib plus pembrolizumab as first-line therapy for cisplatin-ineligible advanced urothelial carcinoma (PemCab).

539 Background: Pembrolizumab (pem) was initially approved in the first line setting for cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients (pts) with high PD-L1 expression and platinum ineligible pts regardless of PD-L1 status; this later changed to only platinum ineligible pts. There is a high disease progression (PD) rate with pem monotherapy. Cabozantinib (cabo) is a multiple receptor tyrosine kinase inhibitor targeting MET and VEGFR2 approved in multiple other malignancies as monotherapy or in combination with PD-1 inhibition. We hypothesized that combination of pem and cabo therapy will be safe and efficacious in patients with treatment naïve mUC. Methods: This is a phase II, open label, multi-center, single arm trial evaluating the tolerability and activity of pem 200 mg every 3 weeks and cabo 40 mg daily as first-line treatment for patients with mUC. Key inclusion criteria were histologically proven locally advanced or mUC, ECOG-PS 0-2, cisplatin-ineligible (including patient refusal of cisplatin), treatment naïve, and no prior PD-1/L1 therapy. The primary endpoint was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS) and overall survival (OS). There was a lead-in safety cohort of 6 pts. We hypothesized that combination therapy would improve ORR to > 32%. With 35 evaluable subjects, the lower bound of the 95% confidence interval would extend no more than 26% from the observed proportion. With ≥17 objective responses, the confidence interval excludes 32%. Results: Between December 26, 2018, and April 19, 2023, 36 pts were enrolled of which 35 were evaluable for response with the median follow up of 14.4 months (95% CI 12.2 – 16.2). The median age was 72.5y [range, 47-82]; ECOG PS 0-1 in 89% pts. Responses were observed in 15 pts (ORR= 42.8%) including complete responses in 5 pts (14.3%). Stable disease was seen in 10 pts (28.6%). The disease control rate was 68.5% (25/35). Median PFS was 7.7 months (95% CI 4.2 – 11.2). Fifty-two percent of pts developed any grade treatment-related adverse events (TRAE) attributable to either cabozantinib or pembrolizumab. The most common grade 1/2 TRAE were diarrhea, anorexia, dysgeusia, weight loss, and nausea. Forty-four percent pts developed grade 3/4 TRAEs most common being hypertension, hypophosphatemia, alanine transaminase elevation, diarrhea, and fatigue. Conclusions: This novel phase II trial of pem + cabo demonstrated a manageable toxicity profile and promising efficacy as first-line therapy in mUC including patient’s ineligible for cisplatin. Further investigation with a focus on predictive biomarkers is ongoing. Clinical trial information: NCT03534804 .

Sustained Remission Without Corticosteroids Among Patients With Pemphigus Who Had Rituximab as First-Line Therapy

ImportanceThe Ritux 3 trial demonstrated the short-term efficacy and safety of first-line treatment with rituximab compared with a standard corticosteroid regimen in pemphigus. No data on the long-term follow-up of patients who received rituximab as first line are available.ObjectiveTo assess the long-term efficacy and safety of the Ritux 3 treatment regimen.Design, Setting, and ParticipantsThis 7-year follow-up study of the Ritux 3 trial included patients with pemphigus from 25 dermatology departments in France from January 1, 2010, to December 31, 2015.ExposurePatients were initially randomized in the rituximab plus prednisone group or prednisone-alone group.Main outcomes and measuresThe primary outcome was the 5- and 7-year disease-free survival (DFS) without corticosteroids, assessed by Kaplan-Meier curves. Secondary outcomes were occurrence of relapse, occurrence of severe adverse events (SAEs), and evolution of antidesmoglein (Dsg) antibody enzyme-linked immunosorbent assay values to predict long-term relapse.ResultsOf the 90 patients in the Ritux 3 trial, 83 were evaluated at the end of follow-up study visit (44 in the rituximab plus prednisone group; 39 in the prednisone-alone group) with a median (IQR) follow-up of 87.3 (79.1-97.5) months. Forty-three patients (93%) from the rituximab plus prednisone and 17 patients (39%) from the prednisone-alone group had achieved complete remission without corticosteroids at any time during the follow-up. Patients from the rituximab group had much longer 5- and 7-year DFS without corticosteroids than patients from the prednisone-alone group (76.7% and 72.1% vs 35.3% and 35.3%, respectively; P < .001), and had about half the relapses (42.2% vs 83.7%; P < .001). Patients who received rituximab as second-line treatment had shorter DFS than patients treated as first line (P = .007). Fewer SAEs were reported in the rituximab plus prednisone group compared with the prednisone-alone group, 31 vs 58 respectively, corresponding to 0.67 and 1.32 SAEs per patient, respectively (P = .003). The combination of anti-Dsg1 values of 20 or more IU/mL and/or anti-Dsg3 values of 48 or more IU/mL yielded 0.83 positive predictive value and 0.94 negative predictive value to predict long-term relapse.Conclusions and RelevanceIn this secondary analysis of the Ritux 3 trail, first-line treatment of patients with pemphigus with the Ritux 3 regimen was associated with long-term sustained complete remission without corticosteroid therapy without any additional maintenance infusion of rituximab.

P641 Faecal calprotectin determines non-response to corticosteroids in patients with immune checkpoint inhibitor colitis

Abstract Background Immune checkpoint inhibitor (ICI) therapy has improved survival outcomes in patients with advanced malignancy. ICI colitis (ICI-C) is one of the most common adverse events which often leads to cessation of an otherwise effective therapy.1,2 Corticosteroid therapy remains first-line treatment in patients with ICI-C. The aim of this study was to assess predictors of non-response to corticosteroid therapy to help guide early escalation to biologic therapy. Methods Multicentre retrospective analysis of adults hospitalized with ICI-C between July 2018 to March 2023. ICI-C was defined by patients who had current or prior immunotherapy who presented with diarrhoea with negative infective faeces PCR testing and admission diagnosis of ICI-C by their treating Physician. Baseline demographic, clinical, biochemical, and endoscopic data were collected. Grading of clinical severity on presentation and response to immunosuppression was defined by CTCAE diarrhoea grading with response defined as improvement to grade 1 or less. Results 82 patients were analysed. 31 (38%) female, median age was 65.5 years (IQR 59-72)], 27 (33%) failed corticosteroid therapy and required biologic therapy. 34 (42%) had a faecal calprotectin on admission. On univariable analysis faecal calprotectin emerged as the sole predictor of corticosteroid non-response. ROC analysis identified an optimal faecal calprotectin cut-off of 620 mcg/g to identify corticosteroid non-responders [Sensitivity 75% (57.6-92.7), Specificity 77.8% (52.4-93.6), Accuracy 76.5%, PLR 3.37 (1.36-8.38), NLR 0.32 (0.13-0.78), AUROC 0.76 (0.616-0.911), OR 10.5 (2.24-49.3), PPV 75 (47.6-92.7), NPV 77.8 ( 52.4-93.6)].12/16 (75%) of patients with a faecal calprotectin ≥ 620 required biologic therapy. Conclusion Faecal calprotectin is a predictor of non-response to corticosteroid therapy in patients with immune checkpoint inhibitor colitis. This study identified a faecal calprotectin threshold of 620mcg/g as the optimal cut-off to identify corticosteroid non-response and need for second-line immunosuppression. These findings may help to reduce the need for endoscopic assessment and guide early escalation to biologic therapy. REFERENCES: 1. Fujii T, Colen RR, Bilen MA, et al. Incidence of immune-related adverse events and its association with treatment outcomes: The MD Anderson Cancer Center experience. Invest New Drugs. 2018;36(4):638-646. doi:10.1007/s10637-017-0534-0 2. Wang Y, Abu-Sbeih H, Mao E, et al. Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis. Inflamm Bowel Dis. 2018;24(8):1695-1705. doi:10.1093/ibd/izy104.

Progress in the treatment of soft tissue sarcoma in the 2023 annual meeting of the American Society of Clinical Oncology

Soft tissue sarcoma (STS) is a group of rare malignant tumors originating from mesenchymal tissue, with a high degree of malignancy and a wide range of pathological subtypes. The prognosis varies among different subtypes, and treatment increasingly relies on selecting appropriate treatment methods for different subtypes. Surgical treatment is still the main treatment method at present, and the development of immune and targeted therapy also brings new hope for the treatment of soft tissue sarcoma. Immune checkpoint inhibitors, oncolytic viruses and T cell therapy have shown well safety and efficacy in clinical trials. Targeted drugs such as trabectedin and lenvatinib have changed the treatment pattern of soft tissue sarcoma. Currently, chemotherapy based on doxorubicin and ifosfamide is still the first line treatment for patients with advanced soft tissue sarcoma who have distant metastasis. However, the adverse reactions of doxorubicin limit its application in elderly patients, and trofosfamide has shown good efficacy and safety as an alternative in clinical trials. The efficacy of postoperative radiotherapy has been confirmed, which can reduce the local recurrence rate after surgical resection of soft tissue sarcoma. In summary, multimodal comprehensive treatment has become the main strategy for the treatment of soft tissue sarcoma. The combination of different treatment methods can generate synergistic effects and help patients obtain more clinical benefits, such as the combination of doxorubicin and immune checkpoint inhibitors, and the combination of antiangiogenic drugs and chemotherapy drugs. At the 2023 annual meeting of the American Society of Clinical Oncology (ASCO), oncologists from all over the world reported many researches related to the treatment of soft tissue sarcoma. This article aims to review the new progress in the treatment of soft tissue sarcoma in the 2023 annual meeting of ASCO.

Facile synthesis of nitrogen-doped carbon dots for ultrasensitive detection of anticancer drug gefitinib based on IFE

Gefitinib, a highly significant antitumor drug, is now commonly employed in clinical settings as a first-line treatment for patients with advanced or metastatic non-small cell lung cancer, colon cancer, and breast cancer. Herein, a convenient, rapid, and accurate fluorescence method based on nitrogen-doped carbon dots (NCDs) was designed for ultrasensitive detection of gefitinib. The NCDs were easily synthesized through one-pot hydrothermal process using p-phenylenediamine and D-glutamic acid as the precursors. The sensing strategy relied on the fluorescence of NCDs at 345 nm, which was selectively reduced by gefitinib based on the inner filter effect (IFE). With a broad linear range of 0.025–30 μg/mL and a low limit of detection of 5.5 ng/mL, the probe was successfully applied to the detection of gefitinib in human serum samples, demonstrating strong practicality, affordability, and high accuracy. The proposed sensor is simple in design, fast in detection and cost-effective, and exhibits promising application in drug real-time analysis.

Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study.

Lenvatinib is approved as a first-line treatment for patients with unresectable and/or recurrent hepatocellular carcinoma (HCC). Lenvatinib achieved promising clinical benefits in REFLECT but was associated with clinically significant treatment-emergent hypertension (CSTE-HTN, a grouped term), a common class effect of tyrosine kinase inhibitors. This post hoc analysis assessed the impact of CSTE-HTN on the efficacy and safety of lenvatinib in HCC. Patients from REFLECT who received lenvatinib (n=476) were stratified according to CSTE-HTN. Tumors were assessed by mRECIST. Overall survival (OS) and progression-free survival (PFS) were evaluated using landmark analyses at 4 and 8weeks. A total of 212 patients in the lenvatinib arm developed CSTE-HTN, and 264 did not. CSTE-HTN first occurred at 3.7weeks (median); the worst grade CSTE-HTN occurred at 4.1weeks (median). No patients had life-threatening CSTE-HTN and/or died due to CSTE-HTN. Median OS was numerically longer in patients with versus without CSTE-HTN (at 4weeks: 16.3 vs. 11.6months; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.621-1.004; at 8weeks: 13.5 vs. 11.6months; HR, 0.87; 95% CI, 0.696-1.089). Median PFS was similar between patients with and without CSTE-HTN (at 4weeks: 6.6 vs. 6.4months; HR, 0.887; 95% CI, 0.680-1.157; at 8weeks: 5.7 vs. 6.4months; HR, 1.09; 95% CI, 0.84-1.41). Objective response rate was numerically higher in patients with (48.6%) versus without CSTE-HTN (34.5%). In this retrospective analysis, CSTE-HTN was associated with improved OS but not PFS. CSTE-HTN did not impair the outcomes of patients with HCC treated with lenvatinib when detected early and managed appropriately.

Promising first-line immuno-combination therapies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis.

469 Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death all over the world, bringing a heavy social economic burden especially in China. Several immuno-combination therapies have shown promising efficacy in the first-line treatment of unresectable HCC and are widely used in clinical practice. However, which combination is the most affordable is unknown. The current study assessed the cost-effectiveness of the immuno-combinations as first-line treatment for patients with unresectable HCC from the Chinese payers' perspective. Methods: A Markov model was built based on five global, multicenter, open-label, phase III randomized trials (Himalaya, IMbrave150, ORIENT-32, CARES-310, LEAP-002) to investigate the cost-effectiveness of tremelimumab plus durvalumab (STRIDE), atezolizumab plus bevacizumab (A+B), sintilimab plus bevacizumab biosimilar (IBI305) (S+B), camrelizumab plus rivoceranib (C+R) and pembrolizumab plus lenvatinib (P+L). Three disease states were included: progression free survival (PFS), progressive disease (PD), and death. Medical costs were searched from the Red Book, published literatures, and West China Hospital. Cost-effectiveness ratios (CERs) and incremental cost-effectiveness ratios (ICERs) were evaluated to compare costs among different combinations. Sensitivity analyses were performed to assess the robust of the model. Results: The total cost and quality-adjusted life years (QALYs) of C+R, S+B, P+L, A+B and STRIDE were $12,109.27 and 0.91, $26,961.60 and 1.12, $55,382.53 and 0.83, $70,985.06 and 0.90, $84,589.01 and 0.73 respectively, resulting in the most cost-effective strategy of C+R with CER of $13,306.89 per QALY followed by S+B with CER of $24,072.86 per QALY. The S+B strategy would become the most cost-effective when the willing-to-pay threshold exceeded $73,500/QALY. In the subgroup analysis, with the application of Asia results in Leap-002 trial, the model results were the same as global data. In the sensitivity analysis, with the variation of parameters, the results were robust. Conclusions: As one of the promising immuno-combination therapies in the first-line systemic treatment for unresectable HCC, camrelizumab plus rivoceranib demonstrated the potential to be the most cost-effective strategy, which warranted further studies to best inform the real-world clinical practices.

Camrelizumab plus apatinib and SOX as first-line treatment in patients with alpha-fetoprotein–producing gastric or gastroesophageal junction adenocarcinoma: A single-arm, multi-center, phase 2 trial.

351 Background: Patients (pts) with AFP-producing G/GEJ adenocarcinoma generally respond poorly to first-line standard chemotherapy. We aimed to assess the efficacy and safety of first-line camrelizumab plus apatinib given concurrently with chemotherapy, followed by camrelizumab plus apatinib in AFP-producing G/GEJ adenocarcinoma pts. Methods: In this open-label, single-arm, multi-center, phase 2 trial (NCT04609176), pts with aged ≥18 years, clinical stage III-IV, unresectable/recurrent or metastatic G/GEJ adenocarcinoma with no prior systemic therapy, serum AFP &gt; 2×ULN or AFP positive by the IHC staining method were enrolled. Pts received 4 cycles of standard S-1 plus oxaliplatin (SOX) and camrelizumab (200mg, iv, d1, q3w) plus apatinib (250mg, po, qd). Pts without disease progression then continued to receive camrelizumab plus apatinib for up to 24 months, or until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1; secondary endpoints included the duration of response (DoR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Results: A total of 36 pts were enrolled and received treatment between Dec 4, 2020 and Aug 4, 2023. 35 pts were evaluable for tumor response. Median age was 63 years (range: 28, 78), with 30 pts (83.3%) were male. 13 pts (36.1%) presented with GEJ. 34 pts (94.5%) were diagnosed with stage IV. 20 pts (55.6%) had distant lymph node involvement, 18 (50.0%) had liver metastasis, 8 (22.2%) had peritoneal metastasis, and 2 (5.6%) had lung metastasis. Median serum AFP level was 739.8 ng/ml (range: 77.7, 321847.0). At data cut-off (Sep 1, 2023), the median follow-up duration was 6.4 months (range: 0.7, 27.0). Efficacy was assessed in the FAS population (n = 36). 2 pts showed complete response (CR, all confirmed), 22 had partial response (PR, 18 confirmed) and 7 had stable disease (SD). In consequent, the unconfirmed ORR was 66.7% (24/36) and DCR was 86.1% (31/36), with a confirmed ORR of 55.6% (20/36). The median PFS and OS were still immature. However, the estimated 12-month PFS rate was 42.1%. Any grade treatment-related adverse events (TRAEs) occurred in 33 pts (91.7%) and grade ≥ 3 in 13 (36.1%) pts. The most common grade ≥ 3 TRAEs were decreased neutrophil count (13.9%), hypertension (8.3%) and diarrhea (5.6%). 16 pts (44.4%) experienced immune-related adverse events (irAEs) of any grade. No new safety signals were reported. Conclusions: In AFP-producing G/GEJ adenocarcinoma pts who had not previously received systemic therapy, camrelizumab plus apatinib with SOX followed by camrelizumab plus apatinib showed promising antitumor activity and acceptable safety profile. Clinical trial information: NCT04609176 .

Patient-reported outcomes (PROs) &lt;65 or ≥ 65 years old (yo) from CARES-310 camrelizumab + rivoceranib vs sorafenib as first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC).

456 Background: CARES-310 (NCT03764293) evaluated the combination of the anti-PD-1 inhibitor, camrelizumab (cam), and the VEGFR-2 tyrosine kinase inhibitor, rivoceranib (rivo), compared to sorafenib (sor) for the treatment of uHCC. Cam + rivo significantly improved OS and PFS compared to sor (OS, 22.1 months [mo] [95% CI 19.1-27.2] vs 15.2 mo [13.0-18.5] HR 0.62 [95% CI 0.49-0.80]; one-sided p&lt;0.0001); PFS, 5.6 mo [95% CI 5.5-6.3] vs 3.7 mo [2.8-3.7]; HR 0.52 [95% CI 0.41-0.65]; one-sided p&lt;0.0001). The most common (≥20%) grade ≥3 treatment-related adverse events for cam + rivo were hypertension (37.5%) and increased AST (16.5%) vs palmar-plantar erythrodysesthesia syndrome (15.2%) for sor. This analysis evaluated PROs stratified by age: &lt;65 yo (baseline, overall cam + rivo n=191, sor n=210) or ≥65 yo (baseline, overall cam + rivo n=81, sor n=61). Methods: Patients completed EORTC QLQ-C30 and EORTC QLQ-HCC18 at baseline, each visit, and post-last-dose follow-up periods. Endpoints included time to deterioration (TTD) with a ≥10-point decrease from baseline of patient reported QoL, physical functioning, role functioning, and patient-reported symptoms. Results: Mean completion rates across questionnaires were 98.56% and 96.78% for cam + rivo and 98.91% and 98.75% for sor in the &lt;65 and ≥65 yo groups, respectively, from baseline through ≥121 weeks of treatment. In the &lt;65 yo group, cam + rivo vs sor had improved TTD in fatigue measured by EROTC-QLQ-C30. In the ≥65 yo group, cam + rivo had significantly longer median TTD of pain measured by EROTC-QLQ-HCC18 and QLQ-C30, respectively. The median TTD of appetite loss in the ≥65 yo group favored cam + rivo. Median TTD for jaundice was significant for sor in both &lt;65 yo and ≥65 yo group. Median GHS/HRQoL in the ≥65 yo group favored cam + rivo. Conclusions: Cam + rivo was associated with improvement in varied QoL aspects in both patient groups. These PRO results support the clinical benefit and use of cam + rivo in patients with uHCC who have not received prior systemic therapy. Clinical trial information: NCT03764293 . [Table: see text]

Colorectal cancer metastatic dMMR immuno-therapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC)—NRG-GI004/SWOG-S1610.

TPS231 Background: Approximately 45% of dMMR/MSI-H mCRC in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC pts may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Upon AtezoTRIBE subgroup analysis of the 8 pts with dMMR mCRC treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first patient having progression ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+/-atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow up have been reduced; as has measurable disease per RECIST. The primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). The sample size has been modified with the accrual goal of 120 patients randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228 .

First-line FOLFOX therapy for advanced esophageal squamous cell carcinoma: Multicenter prospective study in Japan.

280 Background: Cisplatin (CDDP) plus fluoropyrimidine was the standard first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). FOLFOX is promising option especially in patients with ESCC intolerant to CDDP but there were limited data on efficacy and safety of FOLFOX. We conducted a multicenter prospective observational study of FOLFOX for Japanese patients with ESCC intolerant to CDDP. Methods: Eligible participants had clinical stage IVB ESCC, with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, intolerant to CDDP, but tolerant to FOLFOX. FOLFOX (oxaliplatin 85 mg/m², leucovorin 200 mg/m², bolus fluorouracil 400 mg/m², and infusional fluorouracil 2400 mg/m²) was administered every 14 days. The primary endpoint was the response rate (RR) by RECIST v1.1 and the null hypothesis of RR was 10%. Based on the assumption of performing a one-sided test with an α of 0.10, 29 patients were needed to ensure the statistical power of 90% assuming RR of 30%. Results: In this study, 31 patients were enrolled from 14 hospitals between Apr. 2021, and Jul. 2022 and 30 patients received FOLFOX. The patient characteristics were: median age, 77 (range 66–89); male/female, 30/1; ECOG PS 0/1/2, 16/12/3; median creatinine clearance, 49.9 ml/min (33.4–80.2); median G8 score, 12 (range 7–17); and median CARG score, 8 (range 6–13). As the data cutoff of Jul 2023, all 30 patients discontinued FOLFOX. The reason for treatment discontinuation was disease progression, 86.7%; adverse events, 13.3%. Median follow-up time (interquartile range: IQR) was 20.2 (IQR 13.7–23.1) months. Median number of cycles administered were 5 (range 1–24). The RR was 22.6% (80%CI 0.13–0.35; p = 0.031) and disease control rate was 42.0%. Median progression-free survival was 3.9 months (95% CI 2.3–6.1). Median overall survival was 13.3 months (95% CI 9.5–not reached). The incidence of grade 3 or higher adverse events was 40% (neutropenia 26.7%, anemia 3.3%, nausea 6.7%, anorexia 6.7%, infection 6.7%, peripheral sensory neuropathy 3.3%). There was no treatment related death. Twenty-three patients (76.7%) received subsequent therapies, such as nivolumab (70%). Conclusions: First-line FOLFOX showed an acceptable safety profile and the prespecified statistical efficacy target was achieved. FOLFOX might be a treatment option for advanced ESCC patients who are intolerant to CDDP. Clinical trial information: UMIN000044485 .

Clinical pharmacology profile of the claudin 18.2 antibody zolbetuximab.

316 Background: Zolbetuximab is an investigational first-in-class chimeric (mouse/human) monoclonal antibody directed against the tight junction protein claudin 18.2 (CLDN18.2). Zolbetuximab is currently being developed as first-line treatment of patients with locally advanced unresectable or metastatic HER2– gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, in combination with fluoropyrimidine- and platinum-containing chemotherapy. Methods: The clinical pharmacology of zolbetuximab (pharmacokinetics [PK] and impact of covariates, potential for drug-drug interactions and QTc prolongation, exposure-response [E-R] for efficacy and safety, immunogenicity [antidrug antibodies; ADAs]) was characterized from 9 studies in adults with advanced CLDN18.2-positive adenocarcinoma of the stomach, esophagus, or GEJ. Results: Zolbetuximab exhibited dose-proportional PK at doses of 33 to 1000 mg/m2. Based on population PK modeling using data from 714 participants, zolbetuximab exposure (Table) was not meaningfully affected by sex, race/ethnicity, age, mild/moderate renal impairment, or mild hepatic impairment. Gastrectomy was predicted to increase Cave by 36%. Coadministration of zolbetuximab with chemotherapy did not show clinically meaningful changes in drug exposures of zolbetuximab or chemotherapy. At therapeutic doses, zolbetuximab had no clinically meaningful effect on QTc prolongation. In phase 3 studies, zolbetuximab (800 mg/m2 loading dose/600 mg/m2 Q3W) had a manageable safety profile and was associated with significant prolongation of progression-free survival (PFS) and overall survival (OS). E-R analyses suggested that higher zolbetuximab exposure may further prolong PFS and OS but with increased probability of gastrointestinal events and infusion-related reactions. E-R model simulations suggested comparable zolbetuximab efficacy and safety between the 800/600 mg/m2 Q3W regimen and an alternative 800/400 mg/m2 Q2W regimen for use in combination with chemotherapy. ADAs were detected in 4.4% of patients in phase 3 studies with no apparent impact on zolbetuximab PK, efficacy, or safety. Conclusions: The clinical pharmacology of zolbetuximab was well characterized using data from 9 clinical trials. The integrated data support the proposed 800/600 mg/m2 Q3W regimen as well as an 800/400 mg/m2 Q2W regimen in combination with chemotherapy. Clinical trial information: NCT00909025 , NCT01671774 , NCT03528629 , NCT04086758 , NCT01197885 , NCT01630083 , NCT03505320 , NCT03504397 , NCT03653507 . [Table: see text]

Application of laser interstitial thermal therapy in the treatment of patients with euthyroid nodular goiter: aingle-center prospective study

Background. Laser interstitial thermal therapy (LITT) is one of the most effective and economically justified methods, which is recommended as the first-line treatment for patients with compression syndrome, a significant cosmetic defect, and those who categorically refuse surgery or have contraindications to it. The purpose of the study was to analyze the short-term outcomes of LITT in patients with euthyroid nodular goiter. Materials and methods. The results of LITT were analyzed in 20 patients with euthyroid nodular goiter, Bethesda category II, and solid echostructure for 2021–2023. The average volume of nodules was 0.67 (0.16; 1.39) cm3. Medical GaAlAs diode laser VELAS II-30F was used. The response of the nodules was classified as positive effect if volume reduction rate (VRR) was above 70 %, absent with VRR 69–0 %, negative effect with VRR &lt; 0 %. The total follow-up ranged from 1 to 24 months. Results. A linear regression analysis revealed that shrinkage of the final nodule volume after the first session (0.37 (0.06; 0.9) cm3) statistically significantly depended on the initial volume (0.67 (0.16; 1.39) cm3), R2 = 0.955, p &lt; 0.001. A positive effect was observed only in nodules up to 1.0 cm3 (average of 0.16 (0.085; 0.31) cm3). Statistically significant correlation was not found after the first session between the effect and the initial nodule volume (r = –0.163, p = 0.49). A linear regression analysis showed the absence of statistically significant correlation between the final nodule volume, final VRR, and laser characteristics (p &gt; 0.05). The final nodule volume after the second session decreased statistically significantly vs. initial one (p = 0.007) and vs. the final volume after the first session (p = 0.028). There was no statistically significant difference between the frequency of effect in patients after single LITT and in those with two sessions (χ2 = 2.14, p = 0.34). A linear regression analysis did not show statistically significant causal relationship between these indicators (R2 = 0.27, p = 0.12). Conclusions. Laser interstitial thermal therapy is a safe method of organ-preserving treatment in patients with the euthyroid nodular goiter, which can be performed on an outpatient basis and does not lead to thyroid dysfunction. LITT is the most effective with a volume nodule of up to 1.0 cm3. The use of LITT in nodules larger than 1.0 cm3 does not meet the criteria of technical “success” but this does not necessarily indicate the overall ineffectiveness since the sample volume was insufficient. For greater validity, a study should be conducted on a larger sample of patients, which will allow reliably assessing the effectiveness of the method and determining clear criteria of selecting patients for this intervention. The study is still in progress.

QL1604 plus paclitaxel-cisplatin/carboplatin in patients with recurrent or metastatic cervical cancer: an open-label, single-arm, phase II trial.

QL1604 is a highly selective, humanized monoclonal antibody against programmed death protein 1. We assessed the efficacy and safety of QL1604 plus chemotherapy as first-line treatment in patients with advanced cervical cancer. This was a multicenter, open-label, single-arm, phase II study. Patients with advanced cervical cancer and not previously treated with systemic chemotherapy were enrolled to receive QL1604 plus paclitaxel and cisplatin/carboplatin on day 1 of each 21-day cycle for up to 6 cycles, followed by QL1604 maintenance treatment. Forty-six patients were enrolled and the median follow-up duration was 16.5 months. An 84.8% of patients had recurrent disease and 13.0% had stage IVB disease. The objective response rate (ORR) per Response Evaluation Criteria in Advanced Solid Tumors (RECIST) v1.1 was 58.7% (27/46). The immune ORR per immune RECIST was 60.9% (28/46). The median duration of response was 9.6 months (95% confidence interval [CI]=5.5-not estimable). The median progression-free survival was 8.1 months (95% CI=5.7-14.0). Forty-five (97.8%) patients experienced treatment-related adverse events (TRAEs). The most common grade≥3 TRAEs (>30%) were neutrophil count decrease (50.0%), anemia (32.6%), and white blood cell count decrease (30.4%). QL1604 plus paclitaxel-cisplatin/carboplatin showed promising antitumor activity and manageable safety profile as first-line treatment in patients with advanced cervical cancer. Programmed cell death protein 1 inhibitor plus chemotherapy may be a potential treatment option for the patient population who have contraindications or can't tolerate bevacizumab, which needs to be further verified in phase III confirmatory study. Trial RegistrationClinicalTrials.gov Identifier: NCT04864782.

Real-world analysis of afatinib as a first-line treatment for patients with advanced stage non-small-cell lung cancer with uncommon EGFR mutations: a multicenter study in Vietnam.

Afatinib is indicated for advanced-stage non-small-cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) and uncommon mutations. However, real-world studies on this topic are limited. This study aimed to evaluate afatinib as first-line therapy for locally advanced and metastatic NSCLC with uncommon EGFR mutations. A retrospective study included 92 patients with advanced NSCLC with uncommon and compound EGFR mutations, treated with afatinib as first-line therapy. Patients were followed up and evaluated every 3 months or when symptoms of progressive disease arose. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and adverse events. The G719X EGFR mutation had the highest occurrence rate (53.3% for both monotherapy and the compound). By contrast, the compound mutation G719X-S768I was observed at a rate of 22.8%. The ORR was 75%, with 15.2% of patients achieving complete response. The overall median TTF was 13.8 months. Patients with the G719X EGFR mutation (single and compound) had a median TTF of 19.3 months, longer than that of patients with other mutations, who had a median TTF of 11.2 months. Patients with compound EGFR mutations (G719X and S768I) demonstrated a median TTF of 23.2 months compared to that of 12.3 months for other mutations. Tolerated doses of 20 or 30 mg achieved a longer median TTF of 17.1 months compared to 11.2 months with 40 mg. Median TTF differed between patients with and without brain metastasis, at 11.2 and 16.9 months, respectively. Rash (55.4%) and diarrhea (53.3%) were the most common adverse events, primarily grades 1 and 2. Other side effects occurred at a low rate. Afatinib is effective for locally advanced metastatic NSCLC with uncommon EGFR mutations. Patients with G719X, compound G719X-S768I mutations, and tolerated doses of 20 or 30 mg had a longer median TTF than those with other mutations.

Efficacy and Safety of Transarterial Chemoembolization Plus Donafenib with or without Immune Checkpoint Inhibitors as the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

To compare the efficacy and safety of transarterial chemoembolization (TACE) plus donafenib with immune checkpoint inhibitors (ICIs) (T+D+I) versus TACE plus donafenib (T+D) as the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). This retrospective study included patients with unresectable HCC who received T+D+I or T+D between June 2021 and February 2023. The tumor response was analyzed according to the modified Response Evaluation Criteria in Solid Tumors. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) in the two groups were compared before and after propensity score matching (PSM). Cox's proportional-hazards regression model was used to analyze factors affecting PFS and OS. This study included 69 patients: 41 patients in the T+D group and 28 patients in the T+D+I group. After PSM, 26 patients in each group were analyzed. Patients in the T+D+I group had a higher DCR (96.2% vs 73.1%, P = 0.021), longer median PFS (13.1 vs 7.2 months, P = 0.017), and longer median OS (23.1 vs 14.7 months, P = 0.021) than those in the T+D group. The ORR in the two groups was similar (53.8% vs 50.0%, P = 0.781). Multivariate analyses revealed that T+D+I treatment and total bilirubin levels of <20 μmol/L were independent prognostic factors for long PFS. T+D+I treatment, Child-Pugh class A, and single-lobe tumor distribution were independent prognostic factors for long OS. The incidence of TRAEs in the two groups was similar (P > 0.05). In comparison with TACE plus donafenib, TACE plus donafenib with ICIs could significantly improve DCR, PFS, and OS as a potential first-line treatment for unresectable HCC with an acceptable safety profile.

Camrelizumab combined with apatinib and nanoparticle albumin-bound paclitaxel in lung adenocarcinoma (CAPAP-lung): a single-arm phase II study

Platinum-doublet chemotherapy plus immunotherapy has been the standard of care for the first-line treatment of advanced non-small cell lung cancer lacking actional driver mutations. However, optimization of drug combinations is still needed to find a better balance between therapeutic efficacy and safety in the immunotherapy era. We aimed to investigate the efficacy and safety of platinum-free albumin bound paclitaxel (nab-paclitaxel) combined with camrelizumab and apatinib as first-line treatment for patients with advanced lung adenocarcinoma. In this multicenter open-label, single-arm phase II trial, patients with systemic treatment-naïve advanced lung adenocarcinoma without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations received a rational-based combination of camrelizumab (200mg intravenously, day one), apatinib (250mg, q.d., five continuous days per week), and nab-paclitaxel (135mg/m2 intravenously, days one and eight) every three weeks for four to six cycles in China. Patients with controlled disease were maintained with camrelizumab and apatinib. The primary end point was progression-free survival (PFS). This trial is registered with ClinicalTrials.gov (No. NCT04459078). Between August 26, 2020 and May 20, 2022, 64 patients were enrolled. The median PFS was 14.3 (95% CI: 9.9, not reached) months. The confirmed objective response rate was 64.1% (95% CI: 51.1, 75.7). The grade 3-4 hematologic treatment-related adverse events (TRAEs) were decreased neutrophil count (14.1%), decreased white blood cell count (7.8%), and anemia (3.1%). The most common non-hematologic TRAEs of grade 3-4 were increased alanine transaminase (18.8%) and aspartate transaminase (15.6%). No treatment-related death occurred. The quality of life was on average not clinically meaningful worse through treatment cycle14. Nab-paclitaxel plus camrelizumab and apatinib showed clinically meaningful anti-tumor activity and manageable safety, with few hematologic toxicities, and might be a potential treatment option in patients with advanced lung adenocarcinoma lacking EGFR/ALK mutations. Heath Research Foundation of Chinese Society of Clinical Oncology, Hunan Provincial Natural Science Foundation of China, Hunan Cancer Hospital Climb Plan, Sister Institution Network Fund of The University of Texas MD Anderson Cancer Center, The Science and Technology Innovation Program of Hunan Province, and Suzhou Sheng Diya Biomedical Co., Ltd, a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Shanghai, China).

Efficacy of Platinum-based Chemotherapy in Patients With Metastatic Urothelial Carcinoma With Variant Histology.

Variant urothelial carcinoma (VUC, defined herein as urothelial carcinoma with any histological variant) is frequently observed at an advanced stage. However, the efficacy of systemic chemotherapy against VUC in metastatic disease has rarely been reported. This study assessed the therapeutic response and survival outcomes of platinum-based chemotherapy as first-line treatment in patients with metastatic VUC. We retrospectively analyzed consecutive patients with metastatic bladder and upper urinary tract cancer who received gemcitabine plus cisplatin (or carboplatin) at the University of Occupational and Environmental Health Hospital between November 2008 and November 2022. Progression-free survival and overall survival were evaluated using the Kaplan-Meier method and Cox proportional hazard models. Out of 131 patients recorded, 86 (65.6%) had pure urothelial carcinoma (PUC) and 45 (34.4%) had VUC. The most common variant element was squamous differentiation (44.4%). Compared to those with PUC, patients with VUC showed a comparable objective response rate (33.3% vs. 41.9%, p=0.451) and disease control rate (64.5% vs. 75.6%, p=0.221). They also had poorer progression-free survival (median=4.9 months vs. 7.9 months, p=0.014) and overall survival (median=10.9 months vs. 18.2 months, p=0.037) than those with PUC. On multivariate analysis, VUC was an independent predictor of progression (hazard ratio=1.79; 95% confidence interval=1.19-2.69; p=0.005) and mortality (hazard ratio=1.64; 95% confidence interval=1.08-2.48; p=0.020). Although the response of metastatic VUC to platinum-based chemotherapy was not inferior to that of PUC, VUC had progressed faster than PUC. VUC was significantly associated with a poor prognosis after platinum-based chemotherapy as first-line treatment.

The Reallife Comparison of FOLFIRINOX vs Gemcitabine Platinum Combination as a First-Line Treatment in Patients with Pancreatic Carcinoma

The Reallife Comparison of FOLFIRINOX vs Gemcitabine Platinum Combination as a First-Line Treatment in Patients with Pancreatic Carcinoma

PD-L1 expression guidance on sintilimab versus pembrolizumab with or without platinum-doublet chemotherapy in untreated patients with advanced non-small cell lung cancer (CTONG1901): A phase 2, randomized, controlled trial

No direct comparison has been performed between different programmed cell death-1 (PD-1) inhibitors for first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). The feasibility of using PD-L1-expression-guided immunotherapy remains unknown. In this open-label, phase 2 study (NCT04252365), patients with advanced NSCLC without EGFR or ALK alterations were randomized (1:1) to receive sintilimab or pembrolizumab monotherapy (PD-L1 expression ≥ 50%), or sintilimab or pembrolizumab plus platinum-based chemotherapy (PD-L1 expression < 50%). The sample size was calculated by optimal two-stage design. The primary endpoint was the objective response rate (ORR). The study included 71 patients (sintilimab arms, n = 35; pembrolizumab arms, n = 36) and met its primary endpoint, with a confirmed ORR of 51.4% (18/35) in the sintilimab arms. The confirmed ORR (95% confidence interval) was 46.2% (19.2%, 74.9%) and 42.9% (17.7%, 71.1%) for patients treated with sintilimab and pembrolizumab monotherapy; and 54.5% (32.2%, 75.6%) and 45.4% (24.4%, 67.8%) for those treated with sintilimab- and pembrolizumab-based combination therapies. The median progression-free survival was 6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies. The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies. Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies. However, the incidence of rash was higher with sintilimab than pembrolizumab monotherapy. This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab.