The abscopal effect has been mentioned since 1953. The increase in knowledge about the immune system and the development of immunotherapies support its potential therapeutic interest. While it is accepted that radiotherapy induces an immune response, demonstrating its systemic impact is not easy. The preclinical basis is solid but its clinical validation pending. Radiotherapy rarely induces tumor reduction at a distance from the beams, probably due to its immunosuppressive effect. This is why a synergy between radiotherapy and systemic treatments targeting these immunosuppressive mechanisms was observed. Several parameters can modulate the induction of the abscopal effect. Among these, the fractionation of the dose seems to be determining with currently a pre-eminence of hypofractionated stereotaxis. On the other hand, even if the choice of more immunogenic targets (liver, lung) should be favoured, the optimal number of lesions to be irradiated remains to be defined as well as the minimum volume allowing sufficient release of tumor antigens. The impact of radiation-induced lymphopenia on radiotherapy/immunotherapy efficacy needs to be assessed more precisely, as does the effect of radiotherapy techniques on them. Finally, the choice of immunotherapy(ies) and the combination regimen with radiotherapy remain under discussion. A sequential scheme appears to provide less toxicities but the concomitant would lead to a better response. The study of these different parameters should allow us to deliver optimized radiotherapy/immunotherapy(ies) combinations to our metastatic patients in order to benefit as many people as possible from this abscopal effect.

Numerous clinical studies aim to integrate immunotherapy in radiotherapy oncology, either for generating abscopal responses in metastatic patients in combination with radiotherapy, or in the treatment of a locally advanced tumor. The search for biomarkers of response to treatment is a major axis in the development of these therapeutic combinations, to allow the early identification of patients who will benefit from the treatment, in the context of an increasingly personalized approach. We review some of the strategies that can be applied for personalization to combined radiotherapy and immunotherapy treatments.

BACKGROUND: COVID-19 pandemics required changes in medical practices. In thoracic oncology, pembrolizumab was doubled to 400mg every 6weeks, nivolumab to 480mg every 4weeks. The objective of our study was to assess the impact on quality of life, and on psychological state, as well as the tolerance, of this new schedule.
METHODS: Thoracic oncologic patients who underwent these therapeutic changes in our center during the first COVID-19 epidemic wave were included. Their quality of life was assessed using the Quality of Life Questionnaire-30, their psychological state by the Hospital Anxiety Depression (HAD) scale. We also reported the preferred administration schedule, as well as adverse events.
RESULTS: Thirty patients were included. The overall quality of life was preserved. Rates on HAD scale were low. Tolerance was acceptable. In majority, patients preferred the new procedure. They had a significantly better quality of life compared to those who preferred the old one.
CONCLUSIONS: This new immunotherapy schedule in thoracic oncology is well tolerated and allows a preservation of quality of life. This therapeutic option may be favored in the context of COVID-19 pandemics.

OBJECTIVE: Stereotactic radiotherapy (SRT) is the standard treatment for brain metastases of non-small-cell lung cancer (NSCLC) and melanoma, mostly in combination with immunotherapy. The objective was to retrospectively evaluate the influence of the time-lapse between immunotherapy and stereotactic radiotherapy on toxicity.
METHODS: From 2016 to 2019, 59 patients treated with SRT for 103 brain metastases of NSCLC (60%) and melanoma (40%) in combination with concomitant immunotherapy (≤30 days) were included. The prescribed dose was 20Gy/1f or 33Gy/3f at the isocentre and 14Gy or 23.1Gy (70%) respectively at the PTV envelope (PTV=GTV+2mm). The mean tumour diameter was 14mm (4-52mm). The immunotherapies used were anti-PD1 and anti-PDL1. The 103 metastases were classified into 3 groups according to the time-lapse between instatement of immunotherapy and instatement of SRT for the patient concerned: 7 (7%) in group A (≤7 days), 38 (37%) in group B (7 to 14 days) and 58 (56%) in group C (14 to 30 days).
RESULTS: The mean follow-up was 10.1 months. The median overall survival was 11.5 months for NSCLC and 12.5 months for melanoma. The percentage of local control (LC) at one year was 65.1% (93.6% for NSCLC and 26.5% for melanoma). The time-lapse between immunotherapy and SRT was not a significant predictor of LC (P=0.86), while the histology was (P<0.001). The proportion of grade≥3 toxicities was 5.1%, and that of radionecrosis was 9.7% (among these patients, 80% were non-symptomatic): 0%, 13.1% and 8.6% for groups A, B and C respectively. The time-lapse between immunotherapy and SRT was not a significant predictor of toxicity. Only tumour volume was a significant predictive factor (P=0.03).
CONCLUSIONS: The time lapse between immunotherapy and SRT does not influence brain toxicity. The tumour volume remains the main factor.

BACKGROUND: Cancer therapy has greatly progressed in the past few years, due to development of immune checkpoint proteins. These immunotherapies, when applied to eligible patients, have significantly reduced mortality but are prone to induce immune side-effects, including pituitary disorder and low adreno-corticotropic hormone (ACTH) and cortisol levels. We aimed to assess the prevalence and etiology of corticotropic insufficiency through a systematic screening of cortisol and ACTH levels in patients with lung cancer treated with nivolumab perfusion.
METHODS: All patients from our Center with indications for nivolumab treatment for pulmonary squamous cell carcinoma or adenocarcinoma resistant to chemotherapy were successively included and underwent cortisol and ACTH assay before each nivolumab perfusion. When cortisol was below normal without ACTH elevation, we screened for pituitary metastasis, hypophysitis or corticosteroid treatment that could explain the corticotropic insufficiency.
RESULTS: Data from 75 patients (80.0% men, 20.0% women) showed 10.7% asymptomatic corticotropic insufficiency, with a mean cortisol level of 2.76±1.27μg/dl. Diagnosis was made during the first 2 months of nivolumab treatment in 88% of cases. Corticosteroid treatment explained the low cortisol level in 25.0% of cases. No pituitary metastases were found. Hypophysitis was suspected in 75.0% of cases.
CONCLUSIONS: In a 75-patient cohort with non-small cell lung cancer treated with the PD1 antibody nivolumab and systematically screened for cortisol abnormalities, 10.7% of patients showed asymptomatic corticotropic insufficiency. Excluding corticotropic insufficiency secondary to corticosteroid treatment, 8.0% of patients presented cortisol level<5μg/dl attributed to hypophysitis. Cortisol screening enables hydrocortisone replacement treatment to be prescribed if necessary, preventing risk of adrenal crisis.

Adrenocortical carcinoma is a rare malignant tumor of poor prognosis, frequently requiring additional treatments after initial surgery. Due to its adrenolytic action, mitotane has become the first-line medical treatment in patients with aggressive adrenocortical carcinoma. Over the last 2years, apart from the classical chemotherapy based on etoposide and platinum salts, several studies reported the use of drugs such as temozolomide, tyrosine kinase inhibitors or immunotherapy, with more or less convincing results. The aim of this review is to give further insights in the use of these drugs, and to describe potential therapeutic perspectives based on recent pangenomic studies, for the future management of these still difficult to treat tumors.

BACKGROUND: We previously studied anti-PD-1 safety in elderly (≥80 years) patients and reported a retrospective two-centre cohort with a similar safety profile in elderly and in younger patients. Quality-of-life evaluation data is still lacking in this specific population.
METHODS: A prospective, single-centre study in patients aged over 75 years presenting metastatic melanoma treated with anti-PD-1. The endpoint was monitoring of quality of life (by a specific survey) and onco-geriatric assessment at the beginning of therapy, then at 3 and 6 months (nutritional status, comorbidities, autonomy, thymic and cognitive disorders).
RESULTS: Fourteen patients were included of median age 86.5 years [range: 78-94] from March to September 2018. General status was good, with a median Charlson score of 0 [extremes 0-4]. Nine patients were evaluated at 3 months and six patients at 6 months. There was no significant difference in quality-of-life scores obtained at baseline, 3 months and 6 months.
CONCLUSIONS: This study shows that neither quality of life nor autonomy appears to be affected by anti-PD-1 treatment in patients aged over 75 years. However, these results should be interpreted with caution due to the small number of patients included, the short follow-up period and the single-centre data. Nevertheless, the prospective analysis and the complete onco-geriatric evaluation and monitoring yielded unique and original data.

Immunotherapy by immune check-points inhibitors (ICIs) recently improved many solid tumors survival data. ICIs target and inhibit down-regulation signals between T cells and tumor cells involved in carcinogenesis, in order to enhance anti-tumor immunity. With few years\' hindsight of ICIs utilization in daily practice, we learned about their safety profile. By releasing the brakes of the host immune-system, ICIs exposure leads to on-target off-tumor immune related adverse events (IRAEs). Compared to standard chemotherapiy regimens, IRAEs remain rare, but sometimes serious and compromising treatment continuation, mostly despite objective tumor response. Several immunotherapy molecules are currently developed, with various mechanisms of action but always targeting the immune anti-tumor response. New drugs imply new safety profiles, especially since a lot of ongoing clinical trials are assessing combination of multiples drugs. Consequently, a good knowledge and management of these new toxicities will be essential to choose the new therapeutic schedules in many tumor types. Indeed, despite the actual poor prognosis of concerned tumor types, the progressive outcomes improvement implies long-term exposure to treatments. Safety and quality of life under treatment will become key endpoints for therapeutic decision.

Pharmacological immune checkpoint inhibitors (ICI) restore the anti-tumor properties of T-lymphocytes, but unfortunately can engender auto-immune-like disorders. Those, frequent and of variable severity, sometimes target the liver parenchyma. Liver toxicity of ICI firstly leads to alteration of liver function tests (ALFT) with a risk of clinical decompensation. The appearance of ALFT should lead the clinician to exclude a non-immunological injury or a tumoral invasion of the liver parenchyma. In case of high grade ALFT, liver biopsy is necessary for diagnosis purpose. In ICI-induced hepatoxicity, histology examination shows most frequently a lobular acute hepatitis associated with lymphocytic infiltrates, but with different features than those encountered in primary auto-immune hepatitis. The management of ICI-related ALFT depends of their severity. Discontinuation of ICI is recommended for ALFT≥grade 2, and corticosteroid therapy for ALFT≥grade 3, or grade 2 without any improvement after ICI discontinuation. Addition of mycophenolate may be indicated whether corticosteroid inefficiency. Reintroduction of ICI is inadvisable for the most severe toxicities. The management of ALFT occurring on underlying chronic hepatopathy has not got consensual guidelines so far, but they should take account of the basal grade of ALFT and their worsening level under ICI therapy. The situation becomes more complex with associations between ICI and anti-angiogenic agents or cytotoxic chemotherapies where each of the drugs can be hepatotoxic. Thus, liver biopsy is primordial to figure out the mechanism of liver toxicity.

BACKGROUND: The nivolumab-ipilimumab combination provides an overall response rate of 42% in first-line metastatic treatment of clear cell renal carcinoma (mccRCC). To date, there is no robust predictive biomarker of response to immune checkpoint inhibitor (ICI). In addition, severe autoimmune disorders occur more frequently with ICI combination than with ICI alone. The objective of this study is to compare the efficacy of ICI alone or in combination in patients according to tumor molecular characteristics.
METHODS: Using a 35-gene expression mRNA signature, patients were divided into 4 molecular groups (1 to 4). Patients in groups 1 and 4 were randomized to receive nivolumab alone (arms 1A and 4A) or nivolumab plus ipilimumab for 4 injections followed by nivolumab alone (arms 1B and 4B). Patients in groups 2 and 3 were randomized to receive nivolumab plus ipilimumab followed by nivolumab alone (arms 2B and 3B) or a tyrosine kinase inhibitor (sunitinib or pazopanib at the investigator\'s choice (arms 2C and 3C)). The main objective is the overall response rate by treatment and molecular group.
CONCLUSIONS: BIONIKK is the first trial in mccRCC to study the personalization of treatment with ICI or TKI according to tumor molecular characteristics in mccRCC. This trial is the most appropriate to prospectively identify biomarkers of response to nivolumab used alone or in combination or TKI monotherapy in patients with mccRCC. NCT02960906.