Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but frequently cause immune-related adverse events (irAEs). Description of late-onset and duration of irAEs in the literature is often incomplete. METHODS: To investigate reporting and incidence of late-onset and long-lasting irAEs, we reviewed all registration trials leading to ICI's approval by the US FDA and/or EMA up to December 2019. We analysed real-world data from all lung cancer (LC) and melanoma (Mel) patients treated with approved ICIs at the University Hospital of Lausanne (CHUV) from 2011 to 2019. To account for the immortal time bias, we used a time-dependent analysis to assess the potential association between irAEs and overall survival (OS). RESULTS: Duration of irAEs and proportion of patients with ongoing toxicities at data cut-off were not specified in 56/62 (90%) publications of ICIs registration trials. In our real-world analysis, including 437 patients (217 LC, 220 Mel), 229 (52.4%) experienced at least one grade ≥2 toxicity, for a total of 318 reported irAEs, of which 112 (35.2%) were long-lasting (≥6 months) and about 40% were ongoing at a median follow-up of 369 days [194-695] or patient death. The cumulative probability of irAE onset from treatment initiation was 42.8%, 51.0% and 57.3% at 6, 12 and 24 months, respectively. The rate of ongoing toxicity from the time of first toxicity onset was 42.8%, 38.4% and 35.7% at 6, 12 and 24 months. Time-dependent analysis showed no significant association between the incidence of irAEs and OS in both cohorts (log Rank p = 0.67 and 0.19 for LC and Mel, respectively). CONCLUSIONS: Late-onset and long-lasting irAEs are underreported but common events during ICIs therapy. Time-dependent survival analysis is advocated to assess their impact on OS. Real-world evidence is warranted to fully capture and characterise late-onset and long-lasting irAEs in order to implement appropriate strategies for patient surveillance and follow-up.

Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: A retrospective analysis of clinical outcomes and systematic review of literature.

BACKGROUND: Hypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum in OC pts. with known BRCA status. PATIENTS AND METHODS: We retrospectively analyzed 432 pts. from 5 Italian Centers. In addition, we performed a systematic review and meta-analysis of published series. RESULTS: Four hundred nine pts. received at least one prior platinum-based treatment line: 314 were BRCA wild type (77%) and 95 were BRCA mutated (23%). There was no statistical difference in exposure to platinum. Incidence of any grade HSRs was higher among BRCA mutated pts. [9% vs 18%, p = 0.019] and the time-to-HSRs curves show that the risk increases with the duration of platinum exposure, in BRCA mutated pts. more than in BRCA wild type. A multivariable analysis showed that harboring a germline BRCA mutation was related to a higher incidence of HSRs (HR: 1.84, 95% CI 1.00-3.99, p = 0.05) while having received pegylated liposomal doxorubicin (PLD) was related to a lower incidence of HSRs (HR: 0.03 95% CI 0.004-0.22, p = 0.001). The systematic review confirmed the higher incidence of HSRs in BRCA mutated pts., though heterogeneity among series was significant. CONCLUSIONS: In OC pts. with BRCA mutations, there is a significantly higher incidence of HSRs to carboplatin, not justified by longer drug exposure. On the other hand, PLD exerted a protective role in our series.

Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer.

Despite improvements in surgery and medical treatments, epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy. Aim of this study is to investigate the preclinical immunotherapy activity of cytokine-induced killer lymphocytes (CIK) against epithelial ovarian cancers, focusing on platinum-resistant settings. We generated CIK ex vivo starting from human peripheral blood samples (PBMCs) collected from EOC patients. Their antitumor activity was tested in vitro and in vivo against platinum-resistant patient-derived ovarian cancer cells (pdOVCs) and a Patient Derived Xenograft (PDX), respectively. CIK were efficiently generated (48 fold median ex vivo expansion) from EOC patients; pdOVCs lines (n = 9) were successfully generated from metastatic ascites; the expression of CIK target molecules by pdOVC confirmed pre and post treatment in vitro with carboplatin. The results indicate that patient-derived CIK effectively killed autologous pdOVCs in vitro. Such intense activity was maintained against a subset of pdOVC that survived in vitro treatment with carboplatin. Moreover, CIK antitumor activity and tumor homing was confirmed in vivo within an EOC PDX model. Our preliminary data suggest that CIK are active in platinum resistant ovarian cancer models and should be therefore further investigated as a new therapeutic option in this extremely challenging setting.

Deficiencies in health-related quality-of-life assessment and reporting: a systematic review of oncology randomized phase III trials published between 2012 and 2016.

Quality of life (QoL) is a relevant end point and a topic of growing interest by both scientific community and regulatory authorities. Our aim was to review QoL prevalence as an end point in cancer phase III trials published in major journals and to evaluate QoL reporting deficiencies in terms of under-reporting and delay of publication. All issues published between 2012 and 2016 by 11 major journals were hand-searched for primary publications of phase III trials in adult patients with solid tumors. Information about end points was derived from paper and study protocol, when available. Secondary QoL publications were searched in PubMed. In total, 446 publications were eligible. In 210 (47.1%), QoL was not included among end points. QoL was not an end point in 40.1% of trials in the advanced/metastatic setting, 39.7% of profit trials and 53.6% of non-profit trials. Out of 231 primary publications of trials with QoL as secondary or exploratory end point, QoL results were available in 143 (61.9%). QoL results were absent in 37.6% of publications in the advanced/metastatic setting, in 37.1% of profit trials and 39.3% of non-profit trials. Proportion of trials not including QoL as end point or with missing QoL results was relevant in all tumor types and for all treatment types. Overall, 70 secondary QoL publications were found: for trials without QoL results in the primary publication, probability of secondary publication was 12.5%, 30.9% and 40.3% at 1, 2 and 3 years, respectively. Proportion of trials not reporting QoL results was similar in trials with positive results (36.5%) and with negative results (39.4%), but the probability of secondary publication was higher in positive trials. QoL is not included among end points in a relevant proportion of recently published phase III trials in solid tumors. In addition, QoL results are subject to significant under-reporting and delay in publication.

Oral etoposide in heavily pre-treated metastatic breast cancer: A retrospective series.

BACKGROUND: Patients with metastatic breast cancer (MBC) can derive clinical benefit from several subsequent lines of chemotherapy. However, in heavily pre-treated patients, agents with clinical activity, a favourable side effects profile and a convenient administration modality are preferred. PATIENTS AND METHODS: We retrospectively analyzed 110 patients with previously treated MBC, who received oral etoposide at the dose of 50 mg/day for 20 days in 28 days cycles, between 2003 and 2017. Because this was not a prospectively planned study, to describe the clinical performance of oral etoposide we adopted the approach suggested by Dzimitrowicz and colleagues (J Clin Oncol. 2016; 34:3511-17); Tumour Response (TR) was defined as the proportion of physician-reported clinical or imaging response; Prolonged Duration on Therapy (PDT) as the proportion of non-progressing patients whose treatment lasted more than 6 months. Furthermore, we evaluated median duration on therapy (TD) and median Overall Survival (OS) by the Kaplan Meier method. RESULTS: The median number of previous chemotherapy lines was 5 (range 2-8). TR, PDT, median TD and median OS were 6.4%, 18.2% 4 (range 3.5-4.5) and 10.6 (range 8.4-12.8) months respectively. Interestingly, etoposide activity was unrelated to the number of previous lines and type of metastatic involvement. Oral etoposide was well tolerated with only two patients discontinuing therapy due to toxicity. CONCLUSIONS: In this large, single Institution, real practice analysis oral etoposide is a valuable and safe option for pre-treated metastatic breast cancer patients and might be considered in patients failing other approaches, but still suitable for chemotherapy.