Liquid Biopsy in Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer deaths worldwide. To date, the gold standard for the molecular analysis of a patient affected by NSCLC is the tissue biopsy. The discovery of activating mutations and rearrangements in specific genes has revolutionized the therapeutic approaches of lung cancer over the last years. For this reason, a strict \u201cmolecular follow-up\u201d is mandatory to evaluate patient\u2019s disease evolution. Indeed, liquid biopsy has raised as the \u201cnew ambrosia of researchers\u201d as it could help clinicians to identify both prognostic and predictive biomarkers in a more accessible way. Liquid biopsy analysis can be used in different moments starting from diagnosis to relapse, earning multiple clinical meanings, offering thus a noninvasive but valid method to detect actionable mutations. Although the implementation of both exosomes and CTCs in clinical practice is several steps back, new advances and discoveries make them, together with the ctDNA, a very promising tool. In the following chapter we will discuss the recent advances of liquid biopsy in NSCLC highlighting the possible clinical utility of CTCs, ctDNA and exosomes

Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data

Pauline du Rusquec, Ombline de Calbiac, Marie Robert, Mario Campone, Jean Sebastien FrenelMedical Oncology Department, Institut de Cancérologie de l’Ouest, Saint-Herblain 44800, FranceAbstract: Pembrolizumab is a full-length human immunoglobulin G4 (IgG4) monoclonal antibody directed against the immune checkpoint PD-1 to remove its binding with PD-L1 and thus to restore an anti-tumor immune response of T cells. Pembrolizumab is one of the most advanced immune checkpoint inhibitors for cancer care. Apart from rare and serious adverse effects, its favorable tolerance profile enables to treat fragile patients who have often no other choice than best supportive care. The effective retained dose of pembrolizumab is a venous administration of 200 mg every 3 weeks until disease progression, intolerance or up to 24 months. Pembrolizumab has already proven its efficacy and thus obtained marketing authorization in so-called hot or hypermutated tumors or tumors expressing PD-L1 such as melanomas, non-small cell lung cancers, urothelial carcinomas, cervical cancer, etc. Pembrolizumab is also authorized in the United States in the treatment of mismatch repair-deficient tumors or with microsatellite instability. The current challenge is to expand its use in tumor types that are supposed to be less immunogenic, for example, by attempting to warm up the tumor microenvironment, or by combining pembrolizumab with other molecules. An acceptable toxicity profile of such combinations remains to explore. We review here the current indications of this drug, the main prognostic and predictive factors of its efficacy as well as the potential forthcoming indications.Keywords: pembrolizumab, immune checkpoint inhibitor, anti PD-1 antibod

Radiation therapy and concurrent plus adjuvant temsirolimus (CCI-779) versus chemoirradiation with temozolomide in newly diagnosed glioblastoma without methylation of the MGMT gene promoter.

Background: Preclinical data indicate activity of mammalian target of rapamycin inhibitors and synergistic activity together with radiotherapy in glioblastoma. The aim of this trial is to assess the therapeutic activity of temsirolimus (CCI-779), an intravenous mTOR inhibitor, in patients with newly diagnosed glioblastoma with unmethylated O6 methlyguanine-DNA-methlytransferase (MGMT)promoter. Methods: Patients (n=257) with newly diagnosed glioblastoma after open surgical biopsy or resection fulfilling basic eligibility criteria underwent a central MGMT promoter analysis using quantitative methylation specific PCR. Patients with glioblastoma harboring an unmethylated MGMT promoter (n=111) were randomized 1:1 between radiotherapy (60 Gy; 5 times 2 Gy per week) plus concomitant and six cycles of maintenance temozolomide or radiotherapy plus weekly temsirolimus at 25 mg flat dose to be continued until progression or undue toxicity. Primary endpoint was overall survival at 12 months (OS12). Sample size of the investigational treatment arm required 54 patients to assess adequacy of temsirolimus activity set at 80%. More than 38 patients alive at 12 months in the per protocol population was considered a positive signal. A control arm of 54 patients treated with the standard of care was implemented to evaluate the assumptions on OS12. Results: Between December 2009 and October 2012, 111 pts in 14 centers were randomized and treated. Median age was 55 and 58 years in the temsirolimus and standard arm, respectively. Most patients (95.5%) had a WHO performance status of 0 or 1. Both therapies were properly administered with a median of 13 cycles of maintenance temsirolimus. In the per protocolpopulation, exactly 38 patients treated with temsirolimus (out of 54 eligible) reached OS12. In the intention to treat population OS12 was 72.2% [95% CI (58.2, 82.2)] in the temozolomide arm and 69.6% [95% CI (55.8, 79.9) in the temsirolimus arm [HR=1.16 95% CI (0.77, 1.76), p=0.47]. Conclusions: The therapeutic activity of temsirolimus in patients with newly diagnosed glioblastoma with an unmethylated MGMT promoter is too low

Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial

BACKGROUND: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. PATIENTS AND METHODS: We conducted post-hoc hypothesis-generating analysis of SOLO-2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to next progression/death. RESULTS: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than olaparib arm: 12.1 vs. 6.9 months (hazard ratio [HR] 2.17; 95% CI 1.47-3.19). Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13; 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (N = 96), TTSP was significantly longer in the placebo arm: 14.3 vs. 7.0 months (HR 2.89; 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (N = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 vs. 6.0 months (HR 1.58; 95% CI 0.86-2.90). CONCLUSION: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2 mutated patients with PSROC compared to patients not previously receiving PARPi. The optimal strategy for patients who relapse after PARP inhibitors is an area of ongoing research

Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer

International audiencePalbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC