Drug Development in Tissue-Agnostic Indications

A better understanding of cancer biology has led to the development of targeted therapies specifically designed to modulate an altered molecular pathway in the cancer cells or their microenvironment. Despite the identification of molecular targets across cancer types, most of targeted therapies were developed per cancer type. In this ancestral paradigm, randomization was the gold-standard approach for market access. Randomization of large patient populations was feasible for drugs developed in common cancer types but more challenging in rare cancer types. The traditional paradigm of drug development in oncology was further challenged by the ever-expanding molecular segmentation of cancer with ever-smaller subgroups of patients who might benefit from specific targeted therapies or immunotherapies and the identification of molecular alterations against which drugs may be effective across cancer types. In this novel drug development paradigm, novel ways of evaluating the efficacy of drugs are highly needed in these small patient populations. One approach is to use each patient as his/her own control by comparing the efficacy of a drug to the efficacy of prior treatments received. This approach allows to overcome patient heterogeneity, especially in a tissue-agnostic drug development paradigm

Totally implantable venous access ports: a prospective long-term study of early and late complications in adult patients with cancer

International audiencePURPOSE: Totally implantable venous access ports (TIVAP) have been widely used for many years in the management of patients suffering from cancer. The implantation and long-term use of TIVAPs are associated with mechanical, thrombotic, and infectious complications. This is the first exhaustive prospective study of all complications occurring in a whole population on long-term follow-up and therefore allows an objective assessment to be made of the safety of TIVAPs.METHODS: We carried out a prospective single-center observational study. All adult patients with cancer who had a TIVAP implanted between January 1 and December 31, 2006 were registered. Early and late complications were recorded until the removal of the device, the patient's death, or until December 31, 2013. Exhaustive data concerning patients and TIVAP was recorded at time of implantation.RESULTS: Four hundred and ninety-three TIVAPs were implanted in 483 adult cancer patients and were followed during a period from 1 to 94 months (median = 18 months) representing a global quantity of 367,359 catheter-days. Eighty-seven complications were recorded (0.237/1000 catheter-days), including 37 infections (0.101/1000 catheter-days), 17 thrombotic events (0.046/1000 catheter-days), and 9 extravasations. Out of the 87 events, 62 (71.3%) occurred during the first year after implantation. Events were therefore extremely rare after 1 year. Thromboembolic and infectious complications were rare and no risk factors for these were found.CONCLUSIONS: This study demonstrates excellent tolerability, with only occasional complications. Most of these occurred during the year following implantation. A TIVAP may also be left in place for an extremely long time

Accelerated subsequent lung cancer after post-operative radiotherapy for breast cancer

International audienceBackground: Post-operative whole breast radiotherapy for breast cancer (BC) may increase the risk of subsequent lung cancer (LC). The impact of radiotherapy intensification (boost) has not been specifically explored in this context. We investigated the role of radiation modalities on the development of subsequent LC among our patients treated by radiotherapy for localized BC. Methods: All patients with a diagnosis of LC between 2000 and 2020 with a history of prior localized BC treated by surgery and post-operative radiotherapy were retrospectively reviewed. Primary endpoint was time to first diagnosis of LC after BC treatment with radiotherapy (RT). Results: From 98 patients who developed subsequent LC after primary BC treated with post-operative RT, 38% of patients (n = 37) received an additional RT boost, and 46% (n = 45) received hormonal treatment post radiation. A total of 61% (n = 60) were smokers. With regards to LC characteristics, adenocarcinoma was the most frequent histology (68%, n = 66); 36% (n = 35) harbored at least 1 molecular alteration, 57% (n = 20) of them being amenable to targeted therapy. Median time to first diagnosis of LC was 6 years [1.7–28.4 yrs] in the whole cohort. In the subgroup of patients treated with boost this time was reduced to 4 years [1.8–20.8 years] compared to 8 years for patients without boost [1.7–28.4 yrs] (p = 0.007). Boost, smoking usage, endocrine therapy, and age <50 yrs old at BC radiation remained independent factors associated with shorter time to first diagnosis of LC after BC treatment. Discussion: We report for the first time the potential impact of boost -part of BC radiation treatment- for BC on the risk of subsequent LC. The impact of low dose radiation on lung parenchyma could explain this phenomenon, but the underlying physiopathology is still under investigation. This work highlights the need for clinicians to identify patients at risk of developing faster subsequent thoracic malignancy after BC radiation, for implementing personalized surveillance

Fine‐needle aspiration as an alternative to core needle biopsy for tumour molecular profiling in precision oncology: prospective comparative study of next‐generation sequencing in cancer patients included in the SHIVA02 trial

High‐throughput molecular profiling of solid tumours using core needle biopsies (CNB) allows the identification of actionable molecular alterations, with around 70% success rate. Although several studies have demonstrated the utility of small biopsy specimens for molecular testing, there remains debate as to the sensitivity of the less invasive fine‐needle aspiration (FNA) compared to CNB to detect molecular alterations. We aimed to prospectively evaluate the potential of FNA to detect such alterations in various tumour types as compared to CNB in cancer patients included in the SHIVA02 trial. An in‐house amplicon‐based targeted sequencing panel (Illumina TSCA 99.3 kb panel covering 87 genes) was used to identify pathogenic variants and gene copy number variations (CNV) in concomitant CNB and FNA samples obtained from 61 patients enrolled in the SHIVA02 trial (NCT03084757). The main tumour types analysed were breast (38%), colon (15%), pancreas (11%), followed by cervix and stomach (7% each). We report 123 molecular alterations (85 variants, 23 amplifications and 15 homozygous deletions) among which 98 (80%) were concordant between CNB and FNA. The remaining discordances were mainly related to deletions status, yet undetected alterations were not exclusively specific to FNA. Comparative analysis of molecular alterations in CNB and FNA showed high concordance in terms of variants as well as CNVs identified. We conclude FNA could therefore be used in routine diagnostics workflow and clinical trials for tumour molecular profiling with the advantages of being minimally invasive and preserve tissue material needed for diagnostic, prognostic or theranostic purposes

Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study

International audienceBACKGROUND:Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy.METHODS:We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively.FINDINGS:Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1.INTERPRETATION:Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS