Obesity, cancer, and response to immune checkpoint inhibitors: Could the gut microbiota be the mechanistic link?

International audienceImmune checkpoint inhibitors (ICI) have deeply changed the therapeutic management of a broad spectrum of solid tumors. Recent observations showed that obese patients receiving ICIs might have better outcomes than those with normal weight, while obesity was historically associated with a worse prognosis in cancer patients. Of note, obesity is associated with alterations in the gut microbiome profile, which interacts with immune and inflammatory pathways, both at the systemic and intratumoral levels. As the influence of the gut microbiota on the response to ICI has been repeatedly reported, a specific gut microbiome profile in obese cancer patients may be involved in their better response to ICI. This review summarizes recent data on the interactions between obesity, gut microbiota, and ICIs. In addition, we highlight possible pathophysiological mechanisms supporting the hypothesis that gut microbiota could be one of the links between obesity and poor response to ICIs

Association of TP53 mutations with response and longer survival under immune checkpoint inhibitors in advanced non-small-cell lung cancer

International audienceIntroduction: Tumor mutational burden (TMB) correlates with response to immune checkpoint inhibitors (ICI) in advanced non-small-cell lung cancer (aNSCLC). We hypothesized that TP53 mutations could reflect TMB and be associated with ICI benefit.Methods: TP53 mutations were assessed by next-generation sequencing in aNSCLC patients treated with programmed death-1 (PD-1) blockers. Clinical data, tumor programmed death ligand-1 (PD-L1) expression, and KRAS mutational status were collected. The primary endpoint was overall survival (OS).Results: In total, 72 patients (median [interquartile range] age: 61 [33-83] years) were included; 52 (72%) were male; 39 (54%) had performance status 0-1; 53 (74%) had adenocarcinoma; 20 (28%) received first-line ICI, 52 (72%) second line or more. In 65 patients with available data, 36 (55%) expressed PD-L1 in ≥50% of tumor cells, 20 (31%) in 1-49% of cells, and nine (14%) were PD-L1-negative. Non-synonymous TP53 mutations were observed in 41 (57%) and 25 (35%) harbored KRAS-mutated tumors. After a median follow-up of 15.2 months (95% confidence interval [CI] 10.3-17.4 m), the median OS in the TP53-mutated group was 18.1 months (95% CI 6.6-not reached), vs. 8.1 months (95% CI 2.2-14.5, hazard ratio [HR] = 0.48; 95% CI 0.25-0.95, p = 0.04) in the TP53-wild-type group. Median progression-free survival was significantly longer in TP53-mutated patients (4.5 months, 95% CI 2.8-18.1 versus 1.4, 95% CI 1.1-3.5; p = 0.03), although TP53 mutation status failed to significantly influence PFS in the multivariate analysis (p = 0.32). Objective response rate (ORR) was higher in patients with TP53 mutation (51.2% vs. 20.7%; p = 0.01). In multivariate analysis, TP53 mutations independently associated with longer OS (HR = 0.35, 95% CI 0.16-0.77, p = 0.009).Conclusions: TP53-mutated status correlated with immunotherapy OS benefit in aNSCLC

Long-term effectiveness and treatment sequences in patients with extensive stage small cell lung cancer receiving atezolizumab plus chemotherapy: Results of the IFCT-1905 CLINATEZO real-world study

International audienceBackground: Small cell lung cancer (SCLC) has a tendency towards recurrence and limited survival. Standard-of-care in 1st-line is platinum-etoposide chemotherapy plus atezolizumab or durvalumab, based on landmark clinical trials. Methods: IFCT-1905 CLINATEZO is a nationwide, non-interventional, retrospective study of patients with extensive-SCLC receiving atezolizumab plus chemotherapy as part of French Early Access Program. Objectives were to analyse effectiveness, safety and subsequent treatments. Results: The population analyzed included 518 patients who received atezolizumab in 65 participating centers. There were 66.2% male, mean age was 65.7 years; 89.1% had a performance status (PS) 0/1 and 26.6% brain metastases. Almost all (95.9%) were smokers. Fifty-five (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7.0 (range [1.0–48.0]) for a median duration of 4.9 months (95% CI 4.5–5.1). Atezolizumab was continued beyond progression in 122 patients (23.6%) for a median duration of 1.9 months (95% CI: [1.4–2.3]). Best objective response was complete and partial in 19 (3.9%) and 378 (77.1%) patients. Stable disease was observed in 50 patients (10.2%). Median follow-up was 30.8 months (95% CI: [29.9–31.5]). Median overall survival (OS), 12-, 24-month OS rates were 11.3 months (95% CI: [10.1–12.4]), 46.7% (95% CI [42.3–50.9]) and 21.2% (95% CI [17.7–24.8]). Median real-world progression-free survival, 6-, 12-month rates were 5.2 months (95% CI [5.0–5.4]), 37.5% (95% CI [33.3–41.7]) and 15.2% (95% CI [12.2–18.6]). For patients with PS 0/1, median OS was 12.2 months (95% CI [11.0–13.5]). For patients with previous treatment, median OS was 14.9 months (95% CI [10.1–21.5]). Three-hundred-and-twenty-six patients (66.4%) received subsequent treatment and 27 (5.2%) were still under atezolizumab at date of last news. Conclusions: IFCT-1905 CLINATEZO shows reproductibility, in real-life, of IMpower-133 survival outcomes, possibly attributed to selection of patients fit for this regimen, adoption of pragmatic approaches, including concurrent radiotherapy and treatment beyond progression

Dietary practices in methylmalonic acidaemia: a European survey.

Background The dietary management of methylmalonic acidaemia (MMA) is a low-protein diet providing sufficient energy to avoid catabolism and to limit production of methylmalonic acid. The goal is to achieve normal growth, good nutritional status and the maintenance of metabolic stability. Aim To describe the dietary management of patients with MMA across Europe. Methods A cross-sectional questionnaire was sent to European colleagues managing inherited metabolic disorders (IMDs) (n=53) with 27 questions about the nutritional management of organic acidaemias. Data were analysed by different age ranges (0-6 months; 7-12 months; 1-10 years; 11-16 years; >16 years). Results Questionnaires were returned from 53 centres. Twenty-five centres cared for 80 patients with MMA vitamin B12 responsive (MMAB12r) and 43 centres managed 215 patients with MMA vitamin B12 non-responsive (MMAB12nr). For MMAB12r patients, 44% of centres (n=11/25) prescribed natural protein below the World Health Organization/Food and Agriculture Organization/United Nations University (WHO/FAO/UNU) 2007 safe levels of protein intake in at least one age range. Precursor-free amino acids (PFAA) were prescribed by 40% of centres (10/25) caring for 36% (29/80) of all the patients. For MMAB12nr patients, 72% of centres (n=31/43) prescribed natural protein below the safe levels of protein intake (WHO/FAO/UNU 2007) in at least one age range. PFAA were prescribed by 77% of centres (n=33/43) managing 81% (n=174/215) of patients. In MMAB12nr patients, 90 (42%) required tube feeding: 25 via a nasogastric tube and 65 via a gastrostomy. Conclusions A high percentage of centres used PFAA in MMA patients together with a protein prescription that provided less than the safe levels of natural protein intake. However, there was inconsistent practices across Europe. Long-term efficacy studies are needed to study patient outcome when using PFAA with different severities of natural protein restrictions in patients with MMA to guide future practice