Novel patterns of response under immunotherapy.

Novel patterns of response and progression to immunotherapy have been reported that are not observed with conventional cytotoxic or targeted anticancer treatments. A major breakthrough with immunotherapy is its potential to achieve durable responses in a subset of patients with advanced cancer that can be maintained several years even after stopping the treatment. No standardized definition of durable response exists in the literature, and the optimal duration of treatment in case of durable response is not clearly established. However, the majority of patients do not respond to immunotherapy. Initially reported in advanced melanoma patients, pseudoprogression occurs when tumor index lesions regress after initial progression, supporting the concept of treating some patients beyond progression. Overall, reported rates of pseudoprogression never exceeded 10%, meaning that the large majority of patients who have a disease progression will not eventually respond to treatment. The decision to pursue treatment beyond progression must therefore only be taken in carefully selected patients with clinical benefit, who did not experience severe toxicities with immunotherapy. Conversely, rapid progressions, called hyperprogressions, were reported by several teams with rates ranging from 4% to 29%. These observations need to be confirmed from randomized trials. It is essential to interrupt the treatment in patients with hyperprogression, in order to switch to another potentially active treatment. Finally, some patients experience dissociated responses, with some lesions shrinking and others growing. Local treatment with surgery or radiotherapy for growing lesions may be considered. Several immune-specific-related response criteria were developed to better capture benefits of immunotherapy. These criteria only address the pseudoprogression pattern of response, and do not capture the other patterns of response such as hyperprogression and dissociated response. The classic RECIST remains a reasonable and meaningful method to assess response to immunotherapy in the clinic.

Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials.

BACKGROUND: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. PATIENTS AND METHODS: Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. RESULTS: A total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95-5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001). CONCLUSIONS: In our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.

Benefit from cytoreductive nephrectomy and the prognostic role of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma.

BACKGROUND: The role of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of targeted therapies is currently undefined. In recent years, neutrophil-to-lymphocyte ratio (NLR) has emerged as a prognostic marker in several cancers, including mRCC. In this multicentre retrospective study, we aim to assess the impact of CN in mRCC and the value of NLR in risk stratification and patient selection. METHODS: Retrospective data from patients with de novo mRCC from four large Australian hospitals were collected. Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards method. RESULTS: Our study identified 91 de novo mRCC patients. Patients who underwent CN (n = 46, 51%) were more likely to be younger (59.0 years vs 64.6 years, P = 0.019) and to have received systemic therapy (91% vs 76%, P = 0.043). Median overall survival (mOS) was significantly improved in patients who underwent CN (23.0 months vs 10.9 months, hazard ratios (HR) 0.33, 95% confidence interval (CI) 0.20-0.55, P < 0.0001). Patients with NLR ≥ 5 also had inferior mOS (6.2 months vs 16.7 months, HR 1.94, 95% CI 1.14-3.29, P = 0.014). CN was associated with substantially improved survival in patients with both NLR < 5 (mOS 31.1 months vs 7.0 months, HR 0.41, 95% CI, 0.18-0.64, P = 0.0009) and NLR ≥ 5 (mOS 10.9 months vs 2.3 months, HR 0.33, 95% CI, 0.11-0.69, P = 0.009). Significant survival benefits associated with CN were maintained in multivariate analyses (HR 0.39, 95% CI 0.22-0.70, P = 0.0014). CONCLUSIONS: CN is associated with significantly improved overall survival in de novo mRCC. The incremental survival benefit associated with CN was seen irrespective of NLR.

Denosumab-induced hypocalcaemia in high bone turnover states of malignancy and secondary hyperparathyroidism from renal failure.

Denosumab, an anti-resorptive treatment for osteoporosis and skeletal metastases from solid tumours, can cause hypocalcaemia. The incidence may be higher than previously reported due to varying serum calcium cut-off and timing of measurement. The following cases illustrate patients at risk of hypocalcaemia despite supplementation. These populations, with underlying high bone turnover from metastatic bone disease or secondary hyperparathyroidism due to renal failure, may require closer monitoring of calcium levels post-denosumab administration.