Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma

The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma

Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial

Background The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. Methods In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatmentnaive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intentionto-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. Findings Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2–34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3–not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55–0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7–18·9] vs 11·1 months [9·1–12·5]; 0·71 [0·60–0·84], p<0·0001). The most frequent (≥10% patients in either group) treatmentrelated grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. Interpretation With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma

Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.450

Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): Updated analysis of KEYNOTE-426

The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) demonstrated that pembrolizumab (pembro) + axitinib (axi) significantly improved OS, PFS, and ORR vs sunitinib as first-line therapy for advanced RCC (aRCC) at the first pre-planned interim analysis (minimum study follow-up of 7 mo). Updated analyses are presented here

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

Analyse observationnelle des facteurs pronostiques et prédictifs de tolérence d'une chimiothérapie d'induction par docétaxel, platine et 5-fluoro-uracile (TPF) dans les carcinomes épidermoïdes de la tête et du cou (CETEC)

NICE-BU Médecine Odontologie (060882102) / SudocSudocFranceF

Comparative Efficacy of First-Line Immune-Based Combination Therapies in Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-Analysis

Three drug combinations, ipilimumab-nivolumab (Ipi-Nivo), pembrolizumab-axitinib (Pembro-Axi), and avelumab-axitinib (Ave-Axi), have received regulatory approval in the USA and Europe for the treatment of metastatic renal cell carcinoma with clear cell component (mRCC). However, no head-to-head comparison data are available to identify the best option. Therefore, we aimed to compare these new treatments in a first-line setting. We conducted a systematic search in PubMed, the Cochrane Library, and clinicaltrials.gov for any randomized controlled trials of treatment-na&iuml;ve patients with mRCC, from January 2015 to October 2019. The process was performed according to PRISMA guidelines. We performed a Bayesian network meta-analysis with two different approaches, a contrast-based model comparing HRs and ORs between studies and arm-based using parametric modeling. The outcomes for the analysis were overall survival, progression-free survival (PFS), and objective response rate. Our search identified 3 published phase 3 randomized clinical trials (2835 patients). In the contrast-based model, Ave-Axi (SUCRA = 83%) and Pembro-Axi (SUCRA = 80%) exhibited the best ranking probabilities for PFS. For overall survival (OS), Pembro-Axi (SUCRA = 96%) was the most preferable option against Ave-Axi and Ipi-Nivo. Objective response rate analysis showed Ave-Axi as the best (SUCRA: 94%) and Pembro-Axi as the second best option. In the parametric models, the risk of progression was comparable for Ave-Axi and Ipi-Nivo, whereas Pembro-Axi exhibited a lower risk during the first 6 months of treatment and a higher risk afterwards. Furthermore, Pembro-Axi exhibited a net advantage in terms of OS over the two other regimens, while Ave-Axi was the least preferable option. Overall evidence suggests that pembrolizumab plus axitinib seems to have a slight advantage over the other two combinations

To exploit the 5 ‘R’ of radiobiology and unleash the 3 ‘E’ of immunoediting: ‘RE’-inventing the radiotherapy-immunotherapy combination

International audienceHow radiotherapy counters immune evasion In conventional radiotherapy (RT), the relative biologic effectiveness of radiation is influenced by radiobiological determinants, the so-called ‘5Rs’: Repair, Repopulation, Redistribution, Reoxygenation, and Radiosensitivity.1 A linear-quadratic model prevails to describe the radiation response of the tumor, in which the α/β ratio is used to characterize the sensitivity of a particular tissue type to fractionation. Fractionation serves to decrease acute, and especially late, toxicity to surrounding normal tissue exposed to RT. Commonly, curative RT is delivered in daily doses of 1.8–2.2 Gy for 5–8 weeks, whereas hypofractionation is defined as a delivery of greater than 2.2 Gy per fraction. With sophisticated advances in RT technologies, delivering higher doses of RT per fraction [i.e. increased biologically effective dose (BED)] in a shorter timeframe appears a safe option. Indeed, increased BED could be achieved with larger fraction sizes relative to conventionally fractionated RT. While early radiobiological studies had found that the major mechanisms of action of radiation were related to DNA damage and subsequent cell death of dividing cells, novel insights on radiation effects have uncovered the immunomodulatory properties of ionizing radiation.

Hyperprogression under Immune Checkpoint Inhibitor: a potential role for germinal immunogenetics

International audienceHyperprogressive disease (HPD), an unexpected acceleration of tumor growth kinetics, is described in cancer patients treated with anti-PD-1/anti-PD-L1 agents. Here, our aim was to take into consideration the host and explore whether single nucleotide polymorphisms (SNPs) in key genes involved in immune response might predispose to HPD. DNA was extracted from blood-samples from 98 patients treated under CPI monotherapy. Four candidate genes (PD-1, PD-L1, IDO1 and VEGFR2) and 15 potential SNPs were selected. The TGKR (ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR≥2. TGKR calculation was feasible for 80 patients (82%). HPD was observed for 11 patients (14%) and was associated with shorter overall survival (P = 0.003). In univariate analysis, HPD was significantly associated with age ≥70 y (P = 0.025), immune-related toxicity (P = 0.016), VEGFR2 rs1870377 A/T or A/A (P = 0.005), PD-L1 rs2282055 G/T or G/G (P = 0.024) and PD-L1 rs2227981 G/A or A/A (P = 0.024). Multivariate analysis confirmed the correlation between HPD and age ≥70 y (P = 0.006), VEGFR2 rs1870377 A/T or A/A (P = 0.007) and PD-L1 rs2282055 G/T or G/G (P = 0.018). Immunogenetics could become integral predictive factors for CPI-based immunotherapy

The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma.

Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed.ccRCC of 45 patients were analyzed. HIF-1α, HIF-2α, HAF, GLUT1, MCT1, MCT4, CAIX and CAXII expression was assessed by immunohistochemistry in a semi-quantitative and qualitative manner. The GLUT1, MCT1, MCT4, CAIX and CAXII mRNA levels were analyzed in an independent cohort of 43 patients.A significant correlation was observed between increased GLUT1, MCT1, CAXII protein expression and a high Fuhrman grade in ccRCC patients. Moreover, while HIF-1α, HIF-2α and HAF expression was heterogenous within tumors, we observed and confirmed that HIF-2α co-localized with HAF. We confirmed, in an independent cohort, that GLUT1, MCT1 and CAXII mRNA levels correlated with the Fuhrman grade. Moreover, we demonstrated that the high mRNA level of both MCT1 and GLUT1 correlated with poor prognosis.This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming. It also confirms the role of HIF-2α and HAF in tumor invasiveness. Finally, these results demonstrate that MCT1 and GLUT1 are strong prognostic markers and promising therapeutic targets