Bevacizumab in real-life patients with recurrent glioblastoma: benefit or futility?

PURPOSE: Angiogenesis plays a key role in glioblastoma, but most anti-angiogenic therapy trials have failed to change the poor outcome of this disease. Despite this, and because bevacizumab is known to alleviate symptoms, it is used in daily practice. We aimed to assess the real-life benefit in terms of overall survival, time to treatment failure, objective response, and clinical benefit in patients with recurrent glioblastoma treated with bevacizumab. METHODS: This was a monocentric, retrospective study including patients treated between 2006 and 2016 in our institution. RESULTS: 202 patients were included. The median duration of bevacizumab treatment was 6 months. Median time to treatment failure was 6.8 months (95%CI 5.3-8.2) and median overall survival was 23.7 months (95%CI 20.6-26.8). Fifty percent of patients had a radiological response at first MRI evaluation, and 56% experienced symptom amelioration. Grade 1/2 hypertension (n = 34, 17%) and grade one proteinuria (n = 20, 10%) were the most common side effects. CONCLUSIONS: This study reports a clinical benefit and an acceptable toxicity profile in patients with recurrent glioblastoma treated with bevacizumab. As the panel of therapies is still very limited for these tumors, this work supports the use of bevacizumab as a therapeutic option.

Efficacy of trastuzumab emtansine (T-DM1) and lapatinib after dual HER2 inhibition with trastuzumab and pertuzumab in patient with metastatic breast cancer: Retrospective data from a French multicenter real-life cohort.

PURPOSE: Trastuzumab-emtansine (T-DM1), as well as lapatinib plus capecitabine were proven effective in two Phase III studies, following first-line trastuzumab plus a taxane. The introduction of dual HER2 blockade by trastuzumab and pertuzumab as first-line has positioned T-DM1 into second-line, and lapatinib plus capecitabine beyond, without formal evaluation of these strategies. METHODS: ESME Data Platform (NCT03275311) included individual data from all patients aged ≥18 years, in whom first-line treatment for metastatic breast cancer (MBC) was initiated between January 1, 2008 and December 31, 2016 in one of the 18 French Comprehensive Cancer Centers. The efficacy of T-DM1 and lapatinib plus capecitabine combination, following double blockade associating trastuzumab and pertuzumab were evaluated in this national real-life database. Eligibility criteria were: female, MBC, HER2+ tumor, first-line taxane-based chemotherapy and dual HER2-blockage by trastuzumab plus pertuzumab. Cohort A received second-line T-DM1, and Cohort B second-line T-DM1 and third or fourth-line lapatinib plus capecitabine. RESULTS: Cohort A comprised 233 patients, and Cohort B 47 patients. Median progression-free survival (PFS) was 7.1 months in Cohort A and 4.6 months in Cohort B. Median overall survival were 36.7 months and 12.9 months, respectively. PFS was significantly dependent on the preceding treatment line's duration. In cohort A, HER2 expression status was a significant predictive factor of PFS. CONCLUSION: First-line trastuzumab plus pertuzumab do not markedly diminish T-DM1's efficacy in second-line. Similarly, sequential treatment with trastuzumab plus pertuzumab then T-DM1 does not noticeably modify the efficacy of lapatinib plus capecitabine.

Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer.

BACKGROUND: At diagnosis, tumor-infiltrating lymphocytes (TILs) are prognostic in epithelial ovarian cancer (EOC). We recently demonstrated that neoadjuvant chemotherapy (NACT) significantly increased stromal TILs. Here, we investigated the impact of NACT on immune subpopulations with a particular focus on the balance of immune-reactive to tolerant subpopulations. MATERIALS AND METHODS: Tissue microarrays of EOC (145 pre-NACT, 139 post-NACT) were analyzed for CD3+, CD8+, FOXP3+, CD68+, and CD163+ by immunohistochemistry and CD4+ cells from deduction. Stromal TILs scored as percentage of stromal area, while intra-epithelial TILs scored as number of TILs in contact with tumor cells/HPF. Differences were evaluated by Wilcoxon or Chi square tests, Wilcoxon signed-rank for paired analyses, and cox model for PFS and OS. RESULTS: NACT significantly increased stromal CD3+ (p = 0.003) and CD8+ (p = 0.001) and intra-epithelial CD8+ (p = 0.022) and CD68+ (p = 0.0003) infiltration in unmatched samples and among paired samples for stromal CD3+ and CD8+. Neither CD3+, CD8+, CD4+, and CD68+ nor CD163+ expression correlated with outcome at diagnosis or post NACT. Using median value as a cut-off, high stromal CD8+/FOXP3+ ratio (HR = 0.59; p = 0.017) and high stromal CD3+/FOXP3+ ratio post NACT were associated with prolonged PFS (p = 0.0226). The more the balance shifted in favor of effector versus regulatory TILs, the better the survival. Similarly, high CD68+/CD163+ ratio post NACT improved PFS (p = 0.0445). CONCLUSION: NACT has a significant impact on the balance of immune-reactive to immune-tolerant subpopulations and a high ratio of CD8+/FOXP3+, CD3+/FOXP3+, and CD68+/CD163+ post NACT was significantly associated with improved outcomes. Whether this could select patients for immunotherapy in the post-operative setting should be investigated.

Oral etoposide in heavily pre-treated metastatic breast cancer: results from the ESME cohort and comparison with other chemotherapy regimens.

INTRODUCTION: HER2-negative metastatic breast cancer (MBC) is a common setting in which chemotherapy could be effective even in later lines of treatment. Oral etoposide has demonstrated clinical activity in this setting in small-scale studies, but its efficacy has not been compared to that of other chemotherapy regimens. METHODS: We used the ESME database (Epidemiological Strategy and Medical Economics), a real-life national French multicentre cohort of MBC patients initiating therapy between 1 January 2008 to 31 December 2014. HER2-negative MBC patients who received oral etoposide as > 3rd chemotherapy line and for more than 14 days were included. Primary objective was progression-free survival (PFS); secondary objectives were overall survival (OS), and propensity-score matched Cox models including comparison with other therapies in the same setting. RESULTS: Three hundred forty-five out of 16,702 patients received oral etoposide and 222 were eligible. Median PFS was 3.2 months [95% CI 2.8-4] and median OS 7.3 months [95% CI 5.7-10.3]. Median PFS did not significantly differ according to the therapeutic line. The only prognostic factor for both PFS and OS was the MBC phenotype (hormone receptor-positive versus triple-negative, HR = 0.71 [95% CI 0.52-0.97], p = 0.028 for PFS and HR = 0.65 [0.46-0.92], p = 0.014 for OS). After matching for the propensity score, no differential effect on PFS or OS was observed between oral etoposide and other chemotherapy regimens administered in the same setting (HR = 0.94 [95% CI 0.77-1.15], p = 0.55 for PFS and HR = 1.10 [95% CI 0.88-1.37], p = 0.40 for OS). CONCLUSION: Oral etoposide retains some efficacy in selected heavily pre-treated patients with HER2-negative MBC, with the advantages of oral administration.

The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges.

The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.