The generation of antibodies following exposure to therapeutic drugs has been widely studied, however in oncology, data in relation to their clinical relevance are limited. Anti-drug antibodies (ADAs) can cause a decrease in the amount of drug available, resulting in some cases in decreased anti-tumour activity and a consequent impact on clinical outcomes. Several immunological factors can influence the development of ADAs, and in addition, the sensitivity of the different testing methods used in different studies can vary, representing an additional potential confounding factor. The reported frequency of ADA-positive patients following treatment with immune checkpoint inhibitors varies from as low as 1.5% for pembrolizumab to 54% for atezolizumab. This latter drug is the only immune checkpoint inhibitor to have undergone an expanded analysis of the clinical implications of ADAs, but with discordant results. Given that immune checkpoint inhibitors can modify the immune response and potentially impact ADA formation, data from published as well as prospective trials need to be evaluated for a better understanding of the clinical implications of ADAs in this setting.

(1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients’ monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy.

Purpose: Arm D of the AcSé-ESMART proof-of-concept phase I/II platform trial aimed to define the recommended phase II dose (RP2D), pharmacokinetics, activity, and biomarkers of the PARP inhibitor olaparib with irinotecan in pediatric patients with recurrent/refractory malignancies. Patients and Methods: Olaparib was administered orally twice daily on days 1 to 10 and irinotecan intravenously on days 4 to 8 of a 21-day cycle. Dose escalation followed the continuous reassessment method; activity was assessed in diverse tumor types (cohort 1) and Ewing sarcoma (cohort 2) according to a minimax Simon 2-stage design. Cohorts were enriched for alterations in homologous recombination repair (HRR) pathways. Results: Seventy patients (median age, 14.9 years; range, 5.0–23.8) were included, 34 with diverse tumor types (25 with HRR gene alterations) and 36 with Ewing sarcoma. Sixty-six patients received 348 treatment cycles (median, 2; range, 1–51) over four dose levels. Main toxicities were gastrointestinal and myelosuppression; the RP2D was olaparib 90 mg/m2 twice daily and irinotecan 20 mg/m2/day. Olaparib exposure in children was equivalent to that in adults. The overall response rate was 9.1% (cohort 1, 11.8%; cohort 2, 6.3%). Four patients with osteosarcoma, pineoblastoma, choroid plexus carcinoma, and neuroblastoma experienced a partial response and were treated for nine to 51 cycles. Two patients with Ewing sarcoma experienced a complete and a partial response for 10 and 42 cycles, respectively. Genetic analyses suggest a high aneuploidy score possibly associated with objective response and prolonged stable disease. Conclusions: Olaparib combined with irinotecan demonstrated activity in pediatric tumors, which was enriched among tumors that exhibited aneuploidy.

Oncoplot of Germline Cancer Risk Variants Across Patient Cohorts.

Duration of Treatment Overall and per Dose Level: 66 Patients Receiving a Total of 348 Cycles

Purpose:Arm D of the AcSé-ESMART proof-of-concept phase I/II platform trial aimed to define the recommended phase II dose (RP2D), pharmacokinetics, activity, and biomarkers of the PARP inhibitor olaparib with irinotecan in pediatric patients with recurrent/refractory malignancies.Patients and Methods:Olaparib was administered orally twice daily on days 1 to 10 and irinotecan intravenously on days 4 to 8 of a 21-day cycle. Dose escalation followed the continuous reassessment method; activity was assessed in diverse tumor types (cohort 1) and Ewing sarcoma (cohort 2) according to a minimax Simon 2-stage design. Cohorts were enriched for alterations in homologous recombination repair (HRR) pathways.Results:Seventy patients (median age, 14.9 years; range, 5.0–23.8) were included, 34 with diverse tumor types (25 with HRR gene alterations) and 36 with Ewing sarcoma. Sixty-six patients received 348 treatment cycles (median, 2; range, 1–51) over four dose levels. Main toxicities were gastrointestinal and myelosuppression; the RP2D was olaparib 90 mg/m2 twice daily and irinotecan 20 mg/m2/day. Olaparib exposure in children was equivalent to that in adults. The overall response rate was 9.1% (cohort 1, 11.8%; cohort 2, 6.3%). Four patients with osteosarcoma, pineoblastoma, choroid plexus carcinoma, and neuroblastoma experienced a partial response and were treated for nine to 51 cycles. Two patients with Ewing sarcoma experienced a complete and a partial response for 10 and 42 cycles, respectively. Genetic analyses suggest a high aneuploidy score possibly associated with objective response and prolonged stable disease.Conclusions:Olaparib combined with irinotecan demonstrated activity in pediatric tumors, which was enriched among tumors that exhibited aneuploidy.