Phase I/II study of DHA–paclitaxel in combination with carboplatin in patients with advanced malignant solid tumours

DHA–paclitaxel is a conjugate of paclitaxel and the fatty acid, docosahexaenoic acid. Preclinical studies have demonstrated increased activity, relative to paclitaxel, with the potential for an improved therapeutic ratio. We conducted a phase I study to determine the maximum tolerated doses of DHA–paclitaxel and carboplatin when administered in combination. Two cohorts of patients were treated: carboplatin AUC 5 with DHA–paclitaxel 660 mg m-2 and carboplatin AUC 5 with DHA–paclitaxel 880 mg m-2. Both drugs were given on day 1 every 21 days. A total of 15 patients were enrolled with a median age of 59 years (range 33–71). All patients had advanced cancer refractory to standard treatment, performance status 0–2 and were without major organ dysfunction. A total of 54 cycles of treatment were delivered. No dose-limiting toxicity (DLT) was seen in the first cohort of three patients. In an expanded second cohort, neutropenia was the main DLT, occurring in the first cycle of treatment in five of 12 patients: three of these patients and one additional patient also experienced dose-limiting grade 3 transient rises in liver transaminases. No alopecia was seen and one patient developed clinically significant neuropathy. One partial response was seen in a patient with advanced adenocarcinoma of the oesophago-gastric junction and 12 patients had stable disease with a median time to progression of 184 days (range 60–506 days). The recommended phase II dose in pretreated patients is Carboplatin AUC 5 and DHA–paclitaxel 660 mg m-2 given every 21 days. Further studies with Carboplatin AUC 5 and DHA-paclitaxel 880 mg m-2, given every 28 days, are warranted in chemo-naive patients

The role of the residual stresses of the epoxy-aluminum interphase on the interfacial fracture toughness

When an epoxy-diamine system (DGEBA-IPDA) is applied onto aluminum alloy (5754) and cured, an interphase having chemical, physical, and mechanical properties quite different from those of the bulk polymer is created between the substrate and the part of the polymer having bulk properties. To get a better understanding of the role of the interphase on the interfacial fracture toughness either a tri-layer (bulk coating=interphase=substrate) or a bi-layer model (bulk coating=substrate) were used for quantitative determination of the critical strain energy release rate (noted Gc). Indeed, as the interphase formation results from both dissolution and diffusion phenomena, we were able to control the interphase formation within coated systems by controlling the liquid-solid contact time and then to make tri- or bi-layered systems. The particularity of models used is to consider residual stress profiles developed within the entire system leading to an intrinsic parameter representing the work of adhesion between the polymer and the metallic substrate. The aim of this publication is to clearly establish the role of the interphase mechanical properties, such as Young's modulus and residual stress on the interfacial fracture toughness. Results are presented and discussed for three different aluminum surface treatments (chemical etching, degreasing and anodizing)

Immune checkpoint inhibitor therapy for advanced cutaneous squamous cell carcinoma in Australia: A retrospective real world cohort study

Objectives: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials. Study design: Retrospective observational study; review of patient records in fifteen Australian institutions. Setting, participants: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 – 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme. Main outcome measures: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival. Results: A total of 286 people with advanced CSCC received ICI therapy during May 2017 – May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3–97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5–20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72–83%); progression-free survival was 65% (95% CI, 58–70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0–4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8–3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1–3.0; progression-free: aHR, 1.8; 95% CI, 1.2–2.7). Fifty-five people (19%) reported immune-related adverse events of grade 2 or higher; there were no treatment-related deaths. Conclusion: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials

Reply to 'Comment on 'Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy''.

Background: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. Methods: We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. Results: Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. Conclusions: Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma

Background: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-Iymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS.Patients and methods: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry.Results: There was strong interobserver reproducibility in assessment of pathological response (kappa = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had >= 70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P = 70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.Analysis and support of clinical decision makin

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma

BACKGROUNDNo systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma.METHODSWe report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review.RESULTSIn the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event.CONCLUSIONSAmong patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors

Effects of Sonidegib Following Dose Reduction and Treatment Interruption in Patients with Advanced Basal Cell Carcinoma During 42-Month BOLT Trial

Introduction Sonidegib is a Hedgehog pathway inhibitor approved to treat locally advanced basal cell carcinoma and, depending on regulatory approval, metastatic basal cell carcinoma. Results from the BOLT study demonstrated robust efficacy and continued tolerability through 42 months. This analysis evaluated the impact of sonidegib dose reductions and interruptions in patients with advanced basal cell carcinoma through 42 months. Methods BOLT was a randomized, double-blind, multicenter, phase 2 study. Adults with no previous Hedgehog pathway inhibitor therapy were randomized 1:2 to sonidegib 200 or 800 mg once daily. Primary endpoint was objective response rate. Dose modifications were permitted in patients unable to tolerate the dosing schedule or if a treatment-related adverse event was suspected. Results The incidence of dose interruptions was similar between the 200- and 800-mg groups (68.4% vs 65.3%, respectively). Dose reductions occurred more frequently in patients receiving sonidegib 800 mg (36.7%) than 200 mg (16.5%). Overall response rate for all patients receiving sonidegib 200 mg daily was 48.1% and was similar to those of patients without dose reduction or interruption (48.5%) and patients with at least one dose reduction or interruption (46.2%). Conclusion Dose reductions and interruptions were practical and did not impact the efficacy of sonidegib. In patients with advanced basal cell carcinoma who necessitate long-term treatment, dose interruptions may be beneficial for continued treatment and disease control