Abstract Introduction Lenvatinib is approved for the treatment of patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, clinical outcomes of lenvatinib therapy in patients with post‐liver transplantation (LT) HCC recurrence remain unclear. We investigated the efficacy and safety of lenvatinib in patients with post‐LT HCC recurrence. Methods This multinational, multicenter, retrospective study included 45 patients with recurrent HCC after LT who received lenvatinib at six institutions in three countries (Korea, Italy, and Hong Kong) from June 2017 to October 2021. Results At the time of lenvatinib initiation, 95.6% ( n = 43) of patients had Child–Pugh A status, and 35 (77.8%) and 10 (22.2%) participants were classified as having albumin–bilirubin (ALBI) grades 1 and 2, respectively. The objective response rate was 20.0%. With a median follow‐up duration of 12.9 months (95% confidence interval [CI]: 11.2–14.7), the median progression‐free survival and overall survival (OS) were 7.6 (95% CI: 5.3–9.8) months, and 14.5 (95% CI: 0.8–28.2) months, respectively. Patients with ALBI grade 1 showed significantly better OS (52.3 months, [95% CI: not assessable]) than patients with ALBI grade 2 (11.1 months [95% CI: 0.0–30.4 months], p = 0.003). The most common adverse events were hypertension ( n = 25, 55.6%), fatigue ( n = 17, 37.8%), and anorexia ( n = 14, 31.1%). Conclusion Lenvatinib showed consistent efficacy and toxicity profiles in patients with post‐LT HCC recurrence that were comparable to those reported from previous studies among non‐LT HCC patients. The baseline ALBI grade correlated with better OS in post‐LT lenvatinib‐treated patients.
TPS4137 Background: In stage I (by AJCC 6thedition) gastric cancer (GC), recurrence rate is generally low, and long-term outcomes are considered very good after curative resection. For this reason, only limited number of stage I GC patients (pts) were included in most previous studies of adjuvant treatment, and no stage I GC pts were included in ACTS-GC and CLASSIC trials which compared adjuvant chemotherapy vs observation after D2 dissection. However, a large scale retrospective study (Park et al, Gastric Cancer. 2015 Jan 23 [Epub ahead]) demonstrated that pts with stage IB GC with other risk factors showed high recurrence rate more than 20%. Considering more than 30% risk reduction of recurrence by adjuvant chemotherapy in stage II GC, stage I GC pts at high risk of recurrence may also get benefit from adjuvant chemotherapy. Moreover, in Korea, more than 50% of GC pts have stage I disease, which is increasing due to nationwide screening program. Based on this background, a phase III randomized study has been initiated and here we present the progress. Methods: Since November 2013, pts with curatively resected gastric or gastroesophageal junction adenocarcinoma at stage IB have been recruited from 12 sites in Korean Cancer Study Group (KCSG). Other key eligibility criteria include ECOG performance status 0-2, age of 18-74 years, at least one more other risk factors for recurrence-free survival (RFS) (i.e., age ≥ 65 years, male gender, lymphovascular invasion, and/or perineural invasion). Three to 6 weeks after curative surgery (D1 beta or D2 dissection), pts are randomized 1:1 in open label to adjuvant capecitabine arm vs observation arm. In adjuvant chemotherapy arm, pts receive capecitabine 1,250 mg/m2 p.o. twice daily on days1-14 every 3 weeks for 8 cycles. Primary endpoint is 5-year RFS rate. Secondary endpoints include overall survival, safety, compliance, and pharmacokinetic study of capecitabine. With power of 80% and two-sided α level of 5%, 174 events are required to detect 7% difference in 5-year RFS rate, i.e., 85% in adjuvant capecitabine arm vs. 78% in observation arm (HR = 0.654). Considering 10% of drop-out rate, target enrollment is 870 subjects. NCT01917552 Clinical trial information: NCT01917552.
Abstract SAR439459, a ‘second‐generation’ human anti‐transforming growth factor‐beta (TGFβ) monoclonal antibody, inhibits all TGFβ isoforms and improves the antitumor activity of anti‐programmed cell death protein‐1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first‐in‐human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose‐escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose‐expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFβ, downregulation of TGFβ‐pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from ‘immune‐excluded’ to ‘immune‐infiltrated’ phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFβ1 was more consistently elevated followed by TGFβ2, whereas TGFβ3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFβ alteration. However, further studies are needed to identify biomarkers of response.
Clinical characteristics and risk factors of hand-foot syndrome were investigated in patients who received capecitabine-containing chemotherapy. Toxicity data were analyzed from 179 patients in 4 prospective clinical trials testing docetaxel/capecitabine/cisplatin in stomach cancer, capecitabine/cisplatin in biliary or stomach cancer, and vinorelbine/capecitabine in breast cancer. Hand-foot syndrome was reported in 116/179 (64.8%) of patients, with grade 3 hand-foot syndrome in 8/179 (4.5%). Hand-foot syndrome first developed within the first 3 chemotherapy cycles in 100/116 (86.2%) patients, with the median onset for all 3 treatment regimens occurring during cycle 2. Because severe reactions were rare, hand-foot syndrome was not a major factor influencing treatment schedule. Risk factor analyses showed that combined use of docetaxel and preceding chemotherapy-related stomatitis were significant risk factors for the development of hand-foot syndrome. Our results suggest that a combined treatment agent and a patient's susceptibility to chemotherapy-related toxicity may increase the risk of capecitabine-induced hand-foot syndrome.
Vorinostat, a histone deacetylase (HDAC) inhibitor, was investigated in combination with capecitabine plus cisplatin (XP) as a first-line chemotherapy for patients with unresectable or metastatic gastric cancer (GC).Eligible patients received 400 mg vorinostat once daily on days 1-14, 1000 mg m(-2) capecitabine twice daily on days 1-14, and 60 mg m(-2) cisplatin on day 1 every 3 weeks. Plasma levels of acetyl-H3, HDAC2, and p21 were measured for correlative analysis. The primary end point was the 6-month progression-free survival (PFS) rate. Secondary end points included the response rate, PFS, overall survival (OS), and safety profile.A total of 45 patients with HER2-negative GC were included in this study. The objective response rate was 42%. The median PFS was 5.9 months, and the 6-month PFS rate was 44.4%. The median OS was 12.7 months. Most common grade 3-4 toxicities were neutropenia (41%), fatigue (34%), anorexia (32%), thromboembolism (27%), stomatitis (14%), and thrombocytopenia (11%). High plasma acetyl-H3 and p21 levels were significantly associated with a poor OS (P=0.02 and P=0.03, respectively).Vorinostat-XP is a feasible first-line chemotherapy for patients with advanced GC. However, this trial did not meet its primary end point, and more adverse events were observed in comparison with the historical data of flouropyrimidine-platinium doublet regimens.
444 Background: Although adjuvant chemotherapy has been known to have a detrimental effect on MMR-D patients (pts) with resectable GC, it is unclear whether palliative chemotherapy for advanced GC would also adversely affect the survival outcome of MMR-D pts. Immune-checkpoint inhibitor (ICI) monotherapy was approved as a standard treatment for ≥ 3rd line of advanced GC and also showed a remarkable efficacy in MMR-D pts regardless of line of therapy. ICI is now being investigated in combination with 1st-line cytotoxic chemotherapy. Hence, we aim to evaluate the prognostic impact of MMR on cytotoxic chemotherapy in advanced GC. Methods: We reviewed our prospective database to identify pts with initally metastatic, recurrent and locally advanced unresectable GC who received F-P doublet from 2015 to 2018. MMR was assessed by immunohistochemistry with previously-collected tumor tissue and correlated with clinical characteristics and survival outcomes. Results: Out of 892 pts identified from the database, 543 underwent MMR test [382 initally metastatic (70.3%); 127 recurrent (23.3%); 32 locally advanced unresectable (6.3%)]. Median age was 58 years (range, 24–86) with male comprising 64.0%. MMR-D was found in 4.4% (n = 24) and associated with age ≥ 65 (50% vs 29.9%; P = 0.037), antrum-origin (62.5% vs 34.1%, P = 0.004) and well/moderately-differentiated histology (41.7% vs 25.8%, P = 0.110). According to our prognostic model (Koo DH et al, 2011), MMR-D pts were less likely to be classified into poor-risk group (4.2% vs 16.8%, P = 0.102). In good-risk group, MMR-D pts had significantly shorter PFS (6.0 vs 9.0 months, P = 0.045) and OS (10.1 vs 20.9 months, P = 0.047), while pts in moderate and poor risk group showed no difference in survival depending on MMR status. Conclusions: MMR-D GC showed significantly shorter PFS and OS on F-P doublet in good-risk pts and further investigation is needed to determine underlying molecular mechanisms. With the negative impact of MMR-D on the effect of cytotoxic chemotherapy, exclusion of MMR-D pts should be considered in future trials of ICI and cytotoxic chemothrapy combination.
4045 Background: At the protocol-specified interim analysis of the KEYNOTE-859 study (NCT03675737), first-line pembro + chemo significantly improved OS (HR, 0.78; 95% CI, 0.70-0.87; P<0.0001), PFS (HR, 0.76; 95% CI, 0.67-0.85; P<0.0001), and ORR (51.3% vs 42.0%; P=0.00009) vs placebo (pbo) + chemo in patients (pts) with HER2-negative G/GEJ cancer. We report results after an additional 11 months of follow-up. Methods: Pts with previously untreated locally advanced or metastatic HER2-negative G/GEJ cancer, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and known PD-L1 combined positive score (CPS) were eligible. Pts were randomly assigned 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles + investigator’s choice of chemo (5-FU + cisplatin [FP] vs capecitabine + oxaliplatin [CAPOX]). The primary end point was OS. Secondary end points included PFS, ORR, and DOR, all per RECIST v1.1 by BICR, and safety. The data cutoff was August 22, 2023. Results: The intention-to-treat (ITT) population comprised 1579 pts (pembro + chemo, n=790; pbo + chemo, n=789). Median follow-up from randomization to data cutoff was 41.6 mo (range, 33.6-48.9). In the ITT population, median OS was 12.9 mo (95% CI, 11.9-14.0) for pembro + chemo vs 11.5 mo (95% CI, 10.6-12.1) for pbo + chemo (HR, 0.79; 95% CI, 0.71-0.88), median PFS was 6.9 mo (95% CI, 6.3-7.2) vs 5.6 mo (95% CI, 5.5-5.7; HR, 0.76 [95% CI, 0.68-0.85]), ORR was 51.0% vs 42.0%, and median DOR was 8.0 mo (range, 1.2+ to 52.6+) vs 5.7 mo (range, 1.3+ to 44.3+). In pts with PD-L1 CPS ≥1 (pembro + chemo, n=618; pbo + chemo, n=617), median OS was 13.0 mo (95% CI, 11.6-14.2) vs 11.4 mo (95% CI, 10.5-12.0; HR, 0.75 [95% CI, 0.66-0.85]), median PFS was 6.9 mo (95% CI, 6.0-7.2) vs 5.6 mo (95% CI, 5.4-5.7; HR, 0.73 [95% CI, 0.64-0.83]), ORR was 51.8% vs 42.6%, and median DOR was 8.3 mo (range, 1.2+ to 52.6+) vs 5.6 mo (range, 1.3+ to 44.3+). In pts with PD-L1 CPS ≥10 (pembro + chemo, n=280; pbo + chemo, n=273), median OS was 15.8 mo (95% CI, 14.0-19.3) vs 11.8 mo (95% CI, 10.3-12.7; HR, 0.64 [95% CI, 0.53-0.78]), median PFS was 7.8 mo (95% CI, 6.8-8.5) vs 5.6 mo (95% CI, 5.4-6.7; HR, 0.63 [95% CI, 0.51-0.77]), ORR was 60.0% vs 43.2%, and median DOR was 10.0 mo (range, 1.2+ to 52.6+) vs 5.7 mo (range, 1.4+ to 41.0+). Among all treated pts, treatment-related AEs were reported in 751 (95.7%; grade 3-5, 466 [59.4%]) for pembro + chemo and 736 (93.5%; grade 3-5, 404 [51.3%]) for pbo + chemo. Conclusions: With a median follow-up of 41.6 months, use of pembro + chemo continued to show improved OS, PFS, and ORR vs pbo + chemo, regardless of PD-L1 expression. These results continue to support pembro + chemo as a first-line treatment option for pts with locally advanced or metastatic HER2-negative G/GEJ adenocarcinoma. Clinical trial information: NCT03675737 .
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