Bevacizumab, olaparib, and durvalumab in patients with relapsed ovarian cancer: a phase II clinical trial from the GINECO group.

Most patients with advanced ovarian cancer (AOC) ultimately relapse after platinum-based chemotherapy. Combining bevacizumab, olaparib, and durvalumab likely drives synergistic activity. This open-label phase 2 study (NCT04015739) aimed to assess activity and safety of this triple combination in female patients with relapsed high-grade AOC following prior platinum-based therapy. Patients were treated with olaparib (300 mg orally, twice daily), the bevacizumab biosimilar FKB238 (15 mg/kg intravenously, once-every-3-weeks), and durvalumab (1.12 g intravenously, once-every-3-weeks) in nine French centers. The primary endpoint was the non-progression rate at 3 months for platinum-resistant relapse or 6 months for platinum-sensitive relapse per RECIST 1.1 and irRECIST. Secondary endpoints were CA-125 decline with CA-125 ELIMination rate constant K (KELIM-B) per CA-125 longitudinal kinetics over 100 days, progression free survival and overall survival, tumor response, and safety. Non-progression rates were 69.8% (90%CI 55.9%-80.0%) at 3 months for platinum-resistant relapse patients (N = 41), meeting the prespecified endpoint, and 43.8% (90%CI 29.0%-57.4%) at 6 months for platinum-sensitive relapse (N = 33), not meeting the prespecified endpoint. Median progression-free survival was 4.1 months (95%CI 3.5-5.9) and 4.9 months (95%CI 2.9-7.0) respectively. Favorable KELIM-B was associated with better survival. No toxic deaths or major safety signals were observed. Here we show that further investigation of this triple combination may be considered in AOC patients with platinum-resistant relapse.

Impact of web application support versus standard management on adherence with adjuvant hormone therapy in patients treated for breast cancer: the WEBAPPAC study.

BACKGROUND: Non-metastatic breast cancer treatment is mainly based on surgery, with or without chemotherapy, radiotherapy and/or hormone therapy. To reduce the risk of hormone receptor positive (HR+) disease recurrence, hormone therapy is prescribed for at least 5 years. It may induce adverse drug reactions (ADRs) as joint pain, sexual dysfunction, weight increase, fatigue, mood disorders and vasomotor symptoms. Around 30-40% of patients withhold hormone therapy within 5 years after initiation. Based on encouraging results of mobile health in patient follow-up, we developed a web-application addressed for breast cancer patients initiating adjuvant hormonal therapy and aimed to assess its impact on hormone therapy adherence, ADRs management, and health-related quality of life. METHODS: The WEBAPPAC trial is a randomized, open-label, prospective, single-center phase 3 study aiming to assess the interest of a web-application support as compared to standard management among breast cancer patients initiating hormone therapy. The main endpoint is the proportion of patients with hormone therapy adherence failure within 18 months after treatment start, in each arm. Eligible patients will be 1:1 randomized between the WEBAPPAC web-application support (experimental arm,) or standard support (control arm), with stratification on type of hormone therapy (Aromatase inhibitor or Tamoxifen). We plan to enroll 438 patients overall. Failure to hormone therapy will be assessed using the Morisky 8-item self-questionnaire (MMSA8), patient adherence logbook, and medical consultations. Secondary outcomes include hormone therapy adherence at 6 months, pain (Visual Analogue Scale and Brief Pain Inventory), quality of life (EORTC QLQ-C30 and BR23 self-questionnaires), anxiety and depression (Hospital and Depression Scale), and return to work and/or daily activities. The user experience with the WEBAPPAC web-application will be assessed using the System Usability Scale (SUS) questionnaire. DISCUSSION: Hormone therapy discontinuation or adherence failure in breast cancer patients may be indirectly related to an increased risk of recurrence. A better control of medication adherence, through the detection of side effects and some proposed actions trying to reduce them, appears therefore essential to limit the risk of disease recurrence. The WEBAPPAC web-application thus aims better monitoring and allowing higher level of responsiveness in case of ADRs, thus improving treatment adherence. TRIAL REGISTRATION: NCT04554927, registered September 18, 2020. PROTOCOL VERSION: Version 2.1 dated from December 21, 2021.

HELENA: HER2-Low as a prEdictive factor of response to Neoadjuvant chemotherapy in eArly breast cancer.

BACKGROUND: HER2 expression has a prognostic and predictive impact in early-stage breast cancer (BC). HER2 positive BC (immunohistochemistry (IHC) score 3 + or 2 + with in situ hybridization (ISH) amplification) are treated with HER2 targeted therapies. The concept of HER2-low BC (IHC score 1 + or 2 + without ISH amplification) is drawing attention as anti-HER2 treatment has recently shown efficacy in this subgroup. We aimed to explore the response to neoadjuvant chemotherapy (NAC) in HER2-low early BC according to the HER2 score (1 + or 2 + without amplification). METHODS: We conducted a retrospective study in two French comprehensive cancer centers. All patients with HER2-low BC treated with NAC from January 2014 to December 2020 were included. The primary objective was to analyze the pathological complete response (pCR) rate to NAC using the Sataloff or RCB system, according to the HER2 score. Secondary objectives were to assess disease free survival (DFS), overall survival (OS) and to explore the immune environment through the Neutrophil-to-Lymphocyte Ratio (NLR), according to HER2 expression. Univariate and multivariate analyses were performed. RESULTS: We included 237 tumors for 229 patients. Of these, 160 (67.5%) tumors were HER2 1 + , 77 (32.5%) were HER2 2 + , and 152 (64.1%) were hormone receptor (HR) positive. The median age was 53.9 years. No differences in tumor characteristics were observed between HER2 1 + and HER2 2 + subgroups. pCR was achieved in 38 tumors (17%), without any difference between HER2 1 + and HER2 2 + subgroups (p = 0.77). DFS and OS were significantly different between HER2 1 + and HER2 2 + patients (HR = 0.41,CI95%[0.17;0.97] p = 0.037 and HR = 0.31,CI95%[0.09;1.02] p = 0.042, respectively). HER2 status was still associated with DFS and OS after adjustment for age, HR status and NLR, with better outcomes in favor of HER2 score 2 + (HR = 0.35 [0.15-0.84] and HR = 0.24 [0.07-0.81], respectively). NLR was not associated with worse DFS or OS. CONCLUSION: In HER2-low early BC, no differences in pCR were observed between HER2 1 + and HER2 2 + tumors, however patients with HER2 2 + tumors had a better DFS and OS than those with HER2 1 + . Further investigations are needed to describe the intrinsic differences in the spectrum of HER2-low BC.

Pretreatment neutrophil to lymphocyte ratio as prognostic factor in metastatic breast cancer treated with cyclin dependent kinase 4/6 inhibitors.

Background: Cyclin dependent kinase inhibitors (CdK4/6i) changed the course of hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (mBC). To date, no factors have been shown to predict response to CdK4/6i. Neutrophil-to-lymphocyte ratio (NLR), an indicator of the host systemic inflammatory response, is an independent prognostic factor for survival in cancers. We conducted this study to evaluate the impact of NLR on survival in mBC patients treated with first line CdK4/6i. Methods: All mBC patients treated with first line CdK4/6i between November 2015 and December 2019 were retrospectively included. The biomarker threshold was defined using ROC curves. We analyzed progression free survival (PFS), overall survival (OS), 12-month PFS and response rate according to NLR in univariable and multivariable analysis. Results: A total of 126 patients treated with palbociclib (n=101), ribociclib (n=18) or abemaciclib (n=7) were included, with a median follow-up of 33 months [range: 2.9-57]. Median age was 65 years [29-86], 40% patients had good performance status (ECOG-PS 0). Most patients (71%) were included at the metastatic relapse stage and 29% had only bone metastases. Median PFS and median OS were 27 and 51 months, respectively. High NLR (≥ 2.53) was significantly associated with worse PFS (Hazard Ratio (HR)=0.50, CI95% = [0.32-0.79]) and worse OS (HR=0.45, [CI95%: 0.23-0.87]). In multivariable analysis, NLR and ECOG PS were independently factors associated with PFS (p=0.016 and p=0.001, respectively). Conclusion: High NLR was associated with worse PFS and OS in HR+ HER2- mBC patients treated with first line CdK4/6i. NLR is a reliable and inexpensive prognostic marker, easily accessible in routine clinical practice, which could help optimize the therapeutic strategy. These results need to be confirmed in larger prospective studies.