Purpose: This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG₁ monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab. Experimental Design: Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy. Results: Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with ≥600 mg necitumumab achieved target trough concentrations (≥40 μg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively. Conclusion: Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting. Clin Cancer Res; 16(6); 1915–23

Background: No standard treatment options are available for patients with advanced, recurrent or metastatic vulvar carcinoma not amenable for locoregional treatment. Patients and methods: In this phase II study, patients with advanced vulvar cancer received paclitaxel (Taxol) every 3 weeks for up to 10 cycles. Primary objective was response rate. Secondary objectives were response duration and toxicity. Response evaluation was assessed by World Health Organisation criteria, toxicity according to Common Toxicity Criteria. Results: Thirty-one women from 10 institutions were included, with a median age of 64 (range 47–84), of which 29 were assessable for response. On study patients received a median of four cycles (range 1–10). Safety: Grade 3 and 4 neutropenia was seen in eight patients (8/29 = 27.6%), which in one patient resulted in neutropenic fever and treatment-related death. Further treatment-related grade 3/4 toxicity includes fatigue in three patients (10.3%) and neuropathy in one patient (3.4%). Efficacy: Overall response was 13.8% (n = 4; two complete responses + two partial responses). With a median follow-up of 24 months, median PFS was 2.6 months (95%confidence interval 2.04–4.21). Conclusion: Paclitaxel shows moderate activity for local control in advanced vulvar cancer.

Adult granulosa cell tumors (AGCTs) harbor a somatic FOXL2 c.402C>G mutation in ~95% of cases and are mainly surgically removed due to limited systemic treatment effect. In this study, potentially targetable genomic alterations in AGCTs were investigated by whole genome sequencing on 46 tumor samples and matched normal DNA. Copy number variant (CNV) analysis confirmed gain of chromosome 12 and 14, and loss of 22. Pathogenic TP53 mutations were identified in three patients with highest tumor mutational burden and mitotic activity, defining a high-grade AGCT subgroup. Within-patient tumor comparisons showed 29–80% unique somatic mutations per sample, suggesting tumor heterogeneity. A higher mutational burden was found in recurrent tumors, as compared to primary AGCTs. FOXL2-wildtype AGCTs harbored DICER1, TERT(C228T) and TP53 mutations and similar CNV profiles as FOXL2-mutant tumors. Our study confirms that absence of the FOXL2 c.402C>G mutation does not exclude AGCT diagnosis. The lack of overlapping variants in targetable cancer genes indicates the need for personalized treatment for AGCT patients.

For adult granulosa cell tumors (aGCTs), the preferred treatment modality is surgery. Chemotherapy and anti-hormonal therapy are also frequently used in patients with recurrent aGCT. We aimed to review the existing literature on the response to chemotherapy and anti-hormonal therapy in patients with aGCT. Embase and MEDLINE were searched from inception to November 2021 for eligible studies. Objective response rate (ORR) was calculated as the total number of cases with a complete response (CR) or a partial response (PR). Disease control rate (DCR) was defined as the sum of cases with CR, PR or stable disease (SD). A total of 10 studies were included that reported on chemotherapy and 13 studies were included that reported on anti-hormonal therapy. The response rates of the 56 chemotherapy regimens that could be evaluated resulted in an ORR of 30% and DCR of 58%. For anti-hormonal therapy, the results of 73 regimens led to an ORR of 11% and a DCR of 66%. Evidence on systemic therapy in aGCT only is limited. For both chemotherapy and anti-hormonal therapy, the ORR is limited, but the response is considerably higher when patients achieving SD are included. New approaches are needed to provide more evidence and standardize treatment in aGCT.

Introduction: Gastric cancer during pregnancy is extremely rare and data on optimal treatment and possible chemotherapeutic regimens are scarce. The aim of this study is to describe the obstetric and maternal outcome of women with gastric cancer during pregnancy and review the literature on antenatal chemotherapy for gastric cancer.Material and methods: Treatment and outcome of patients registered in the International Network on Cancer, Infertility and Pregnancy database with gastric cancer diagnosed during pregnancy were analyzed.Results: In total, 13 women with gastric cancer during pregnancy were registered between 2002 and 2018. Median gestational age at diagnosis was 22 weeks (range 6‐30 weeks). Twelve women were diagnosed with advanced disease and died within 2 years after pregnancy, most within 6 months. In total, eight out of 10 live births ended in a preterm delivery because of preeclampsia, maternal deterioration, or therapy planning. Two out of six women who initiated chemotherapy during pregnancy delivered at term. Two neonates prenatally exposed to chemotherapy were growth restricted and one of them developed a systemic infection with brain abscess after preterm delivery for preeclampsia 2 weeks after chemotherapy. No malformations were reported.Conclusions: The prognosis of gastric cancer during pregnancy is poor, mainly due to advanced disease at diagnosis, emphasizing the need for early diagnosis. Antenatal chemotherapy can be considered to reach fetal maturity, taking possible complications such as growth restriction, preterm delivery, and hematopoietic suppression at birth into account.