Sylvie Chabaud’s research while affiliated with Centre Léon Bérard and other places

Background - Early triple negative breast cancer (TNBC) with moderate to extensive residual disease after neoadjuvant chemotherapy and surgery is associated with high risk of recurrence. Before the era of (neo)adjuvant anti-PD-1 antibody treatment, capecitabine was a treatment option in the adjuvant setting. BreastImmune-03 trial was designed to evaluate the efficacy of post-operative nivolumab + ipilimumab (NIVO+IPI) compared to capecitabine for patients (pts) with class II or III Residual Cancer Burden (RCB) after standard neoadjuvant chemotherapy. Methods - BreastImmune-03 was a multicenter, randomised, open-label phase II trial comparing a dual immunotherapy regimen (NIVO+IPI: nivolumab (360 mg intravenously [IV], every 3 weeks for 8 doses) and ipilimumab (1 mg/kg IV, every 6 weeks for 4 doses)) versus capecitabine (1000 mg/m2 BID, 14 days on / 7 days off for 8 cycles) as adjuvant treatment in TNBC with RCB II-III after neoadjuvant chemotherapy and surgery. Randomization (1:1) was stratified by center, ECOG performance status (PS), and RCB class. A total of 114 pts (46 events) were needed to detect an improvement from 60 to 80% of the 2-year disease free survival (DFS) rate (Hazard ratio [HR]: 0.44; 80% power, alpha 5%). Secondary endpoints include overall survival (OS), local-regional recurrence rate (LRR), distant metastasis-free survival (DMFS), safety according to CTCAE 5.0, and quality of life scales. Results - From July 2019 to October 2021, 95 pts were randomized: 50 in the capecitabine arm and 45 in the NIVO+IPI arm (median age: 47 years [29-82], ECOG PS 0: 80%, RCB III: 40%) across 17 French centers. Due to an unexpectedly high rate of biological myocarditis in the NIVO+IPI arm (11% versus 2% in capecitabin arm), enrollment was prematurely closed based on independent data monitoring committee recommendation. With a median follow-up of 34.3 months (interquartile range: 33-36), 39 events (relapse or death) were reported: 17 (38%) in the NIVO+IPI arm versus 22 (44%) in the capecitabine arm (HR: 0.84; 95% CI: 0.45-1.59; log-rank test p-value: 0.59). There was no difference in terms of OS (HR: 0.98; 95% CI: 0.44-2.20; log-rank test p-value: 0.97), nor in LRR and DMFS. Notably, 38% of pts discontinued treatment prematurely due to treatment-related adverse events (AE) in the NIVO+IPI arm, compared to 14% in the capecitabine arm. The most common AE (>10%) in the NIVO+IPI arm were myocarditis (grade 3 only), hyperthyroidism (28.9%), hypothyroidism (22.2%), diarrhea (11.1%) and fatigue (31.1%). Conclusion – Although BreastImmune-03 trial was prematurely ended, a 6-month postoperative NIVO+IPI combination does not seem to improve clinical outcomes in TNBC pts with RCB II-III compared to capecitabine. In addition, immune-mediated AE limit the use of the NIVO+IPI combination in this setting. A centralized collection of tumor and blood tissue has been performed and translational correlative studies are ongoing. Clinical trial information: NCT03818685 Citation Format: Olivier Trédan, Delphine Loirat, Sylvie Chabaud, Thierry Petit, Frédéric Viret, Christelle Levy, Philippe Toussaint, Aurélien Robert, Julien Grenier, Laura Mansi, Jean-Philippe Spano, Anne Patsouris, Olfa Derbel, Christelle Jouannaud, Jean Marc Ferrero, Jean Sébastien Frenel, Yann Molin, Louis Doublet, Pierre-Etienne Heudel, Mathilde Bernardin, Delphine Tatu, Gwenaële Garin, David Pérol, Jean-Yves Pierga, Thomas Bachelot. Nivolumab + Ipilimumab (NIVO+IPI) compared to capecitabine for triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy – Final results of BreastImmune-03, a multicenter randomized open-label phase II trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr RF3-03.

TPS8657 Background: LCNECs of the lung are rare lung tumors (2%) with difficult histopathological diagnosis (70-80% confirmation rate after centralized review). Platinum–based regimen is currently the recommended first-line treatment for advanced LCNECs. However it results in poor median progression-free survival (PFS) and overall survival (OS) of 5 months and 7.7 months, respectively. Retrospective studies have suggested efficacy of immune checkpoint inhibitors against LCNECs with significantly prolonged OS. In addition, the CASPIAN trial demonstrated the superiority of durvalumab plus platinum-etoposide over chemotherapy alone in patients with extensive-stage neuroendocrine small cell lung cancer, with an acceptable toxicity profile. Methods: This ongoing single-arm phase II trial is designed to evaluate the efficacy and safety of durvalumab in combination with platinum-etoposide as first line treatment in pts with locally diagnosed advanced LCNEC. Key selection criteria are age ≥ 18 years, ECOG PS 0-1, measurable disease (RECIST 1.1) and locally advanced (Stage III) ineligible for loco-regional therapy or metastatic (Stage IV). Central confirmation of the histopathological diagnosis will be performed for all pts at the start of treatment. All pts will receive 4 cycles of induction with durvalumab 1500mg, platinum (either carboplatin AUC5 or cisplatin 80mg/m² at D1) and etoposide 100mg/m² (D1-D3), repeated every 3 weeks. Durvalumab 1500mg will be continued alone every 4 weeks for a maximum of 24 additional cycles or until disease progression or unacceptable toxicity. The primary endpoint is to determine, in pts with confirmed diagnosis, 12-month progression-free rate (12M-PFR) as per central radiological review. Secondary endpoints include PFS, OS and safety. Radiological criteria will be described using the RECIST 1.1 both as per investigator’s assessment and as per central radiological review. Biomarkers will be studied as predictive and prognostic factors of efficacy. Efficacy will be assessed sequentially every ten pts using a Bayesian approach. Analogous to a frequentist approach from an A’Hern-Fleming single-stage design, 51 evaluable pts will be enrolled. A futility stopping rule will stop the trial if there is a high probability (>80%) that the 12M-PFR is less than or equal to P0 (15%). Finally, a trial emulation will be performed as an exploratory analysis to assess PFS and OS compared to an external control arm by using real-world data from the ESME database. Since the start of recruitment (June 2024), 13 patients with a confirmed diagnosis have been included. Clinical trial information: NCT06393816 .

TPS5626 Background: The patients with an advanced epithelial ovarian cancer (EOC) treated with a neo-adjuvant platinum-based chemotherapy who are not amenable to a complete interval debulking surgery (IDS) due to a poorly chemosensitive disease (CA-125 KELIM score <1.0) have a particular poor prognosis (~20% overall survival at 5 years). Several studies suggested that these patients may have a benefit from a chemotherapy densification with the weekly dose-dense carboplatin-paclitaxel regimen. Methods: SALVOVAR trial (NCT06476184) is an academic pragmatic open-label multicentre international randomized phase III trial, including stage III-IV high-grade EOC patients who present 2 poor prognostic features after 3-4 cycles of standard neo-adjuvant chemotherapy with carboplatin-paclitaxel administered every 3 weeks: 1) an unfavorable standardized KELIM score <1.0; and 2) a disease considered to be not amenable to a complete IDS. The enrolled patients are randomly allocated (ratio 1:1) to an experimental arm (weekly dose-dense regimen: carboplatin AUC5 and paclitaxel 80 mg/m ² on day1, day8, and day15, with 3 week cycles) or a control arm (continuation of the standard regimen given every 3 weeks) for 3 cycles. Bevacizumab will be added at investigator discretion. The stratification factors are: Planned administration of bevacizumab (yes, vs no); BRCA mutation (yes, vs no/unknown); and KELIM score strate (moderately unfavorable ≥0.7, vs very unfavorable <0.7). The objective is to show the superiority of the experimental arm with 2 co-primary endpoints: 1) percentage of patients achieving late complete cytoreductive surgery after chemotherapy densification (15% increase), and of overall survival (Hazard-ratio, 0.61). 250 patients will be randomized. The secondary endpoints include overall response rate, progression-free survival, percentage of patients receiving PARP inhibitor and safety. Social human sciences are planned with assessment of the patient/physician perceptions in the shared-decision-making; quality-of-life/patient-reported-outcomes; medico-economic investigation, along with surgical definition of standardized criteria for non-resectability, and inventory of BRCA/homologous-recombination assays used in real-life. The trial is activated in France and Japan. It will be open in United Kingdom, The Netherlands, Italy, Czech Republic, Slovenia, Hungary, Slovakia, and Israel. The recruitment started in July 2024. On January 15 2024, 62 patients had been pre-screened and 18 patients had been randomized. SALVOVAR trial is funded by a European Union HORIZON-MISS-CANCER-2022-01 research program, sponsored by ARCAGY-GINECO (France), and coordinated by Lyon University Hospital (HCL, France). Clinical trial information: NCT06476184 .

Background Implant-based reconstruction has advanced with the introduction of acellular dermal matrices (ADMs). However, ADMs are associated with higher complication rates. Synthetic meshes have emerged as cost- effective alternatives. This retrospective, single-center study evaluates the clinical outcomes of immediate implant-based breast reconstruction with TIGR® Mesh (Novus Scientific, Uppsala, Sweden) on 76 patients (100 breasts) performed between February 2020 and June 2022. Methods Eligible patients were ≥18 years old with no major comorbidities and underwent direct-to-implant (DTI) mastectomy. Complications were assessed using the Clavien-Dindo classification (grade III or higher). Cosmetic outcomes were refined with lipofilling when required. Results The mean patient age was 45.5 years, with a mean follow-up of 17.3 months. Twelve mesh-related grade III complications were observed (10 infections and two seromas) over a total of 21 events. Implant loss occurred in 10 cases, which were later reconstructed in a subsequent procedure. No variable was identified as a significant predictor of complications. A significant inverse correlation (p=0.03) was found between mastectomy weight and complication rate, with lower weights associated with higher risk. Additionally, 57 reconstructions required at least one lipofilling session, with heavier mastectomy specimens needing fewer sessions. Conclusions TIGR® Mesh demonstrated an acceptable safety profile, with infection and seroma rates falling within the lower range reported for synthetic meshes and lower than most ADM series. Its cost-effectiveness and favorable outcomes support its use in selected patients. Further prospective studies are warranted to confirm these findings.

Background Regorafenib, an antiangiogenic multikinase inhibitor (MKI), showed antitumour activity in the second line of treatment for sarcomas in the phase II, randomised versus placebo, multicentre clinical trials REGOSARC (NCT01900743) and REGOBONE (NCT02389244). MKIs are drugs with a narrow therapeutic index subject to drug–drug interactions. The co-medications were not included in the trials’ analyses. Materials and methods We conducted an ancillary exploratory analysis of the two trials to evaluate the interactions between regorafenib and patients’ co-medications administered at baseline in terms of efficacy [progression-free survival (PFS)] and toxicity. The efficacy analysis was stratified according to histology groups. Results Overall, 289 patients were included in the efficacy analysis and 339 in the toxicity analysis. Of the entire population, 71.7% of patients had at least one co-medication (median = 2, range 0-14). Overall, we found an improvement in PFS with regorafenib versus placebo (hazard ratio 0.40, 95% confidence interval 0.30-0.53, P < 0.0001). In the multivariate model adjusted on sex, histological grade, and performance status, we did not find any significant interaction between treatment effect (regorafenib versus placebo) and the co-medications on PFS. In the safety analysis, we observed no significant interaction analysis between treatment effect (regorafenib versus placebo) and the co-medications, for all the adverse events, even when considering co-medications with treatments known to be at risk of similar toxicities, or with co-medications at risk of pharmacological overdose (like cytochrome P-450 3A4 inhibitors, organic anion-transporting polypeptide inhibitors, UDP-glucuronosyltransferase inhibitors, treatments competing on protein binding). We did not find any significant interaction between regorafenib and anti-acid drugs either in the efficacy analysis (P = 0.35) or in the toxicity analysis (P = 0.53). Conclusion We did not find any significant unfavourable interaction between regorafenib and patients’ co-medications, from any pharmacological class (e.g. anti-acid), either in terms of efficacy or regarding the occurrence of adverse events. These results are reassuring for the safety of regorafenib administered in association with co-medications.

Background The randomized, double-blind UNIRAD trial evaluating the addition of 2 years of everolimus to endocrine therapy in patients with high-risk, early luminal breast cancer failed to demonstrate a benefit. We report the subgroup analyses. Patients and methods We randomly assigned 1278 patients in a 1 : 1 ratio to receive 2 years of placebo or everolimus, added to endocrine therapy for up to 4 years after initiation. Randomization was stratified by endocrine therapy agent, prior adjuvant versus neoadjuvant therapy, progesterone receptor expression, and lymph node involvement. Subgroup analyses by each stratification factor were pre-specified. Post hoc analyses were carried out according to menopausal status and age. Treatment adherence was also analyzed. Results We observed a limited trend toward more favorable prognostic features in tamoxifen-treated patients, with more frequent estrogen receptor-positive/progesterone receptor-positive tumors (88.5% versus 84.1%, P = 0.026) and less frequent pN2-positive status (39.8% versus 46.0%, P = 0.032). In premenopausal women, we observed a numerical benefit of everolimus: 3-year disease-free survival was 86% in the placebo group and 90% in the everolimus group (hazard ratio 0.76, 95% confidence interval 0.43-1.34). In premenopausal patients treated with tamoxifen (n = 153; 12.3%), we observed an even stronger trend in favor of everolimus as 3-year DFS was 84% in the placebo group and 91% in the everolimus group (hazard ratio 0.54, 95% confidence interval 0.28-1.02). Early discontinuation of either everolimus or placebo was less frequent in the tamoxifen group than in the aromatase inhibitor group: 48.0% versus 56.9% (P = 0.028). Conclusions The present post hoc analyses generate hypotheses regarding the interaction between menopausal status, tamoxifen, and everolimus in patients with high-risk, ER-positive, human epidermal growth factor receptor type 2-negative early breast cancer. They suggest that tamoxifen alone is an underpowered endocrine treatment in high-risk premenopausal patients.

Large genomic programs have contributed to improving drug development in cancer. To assess the potential benefit of using larger gene panels to guide molecular-based treatments, we conducted a multicenter randomized trial in patients with advanced and/or metastatic solid cancer. Molecular alterations were determined using either a panel of 324 cancer-related genes (Foundation OneCDX (F1CDX)) or a limited panel of 87 single-nucleotide/indel genes and genome-wide copy number variations (CTL) and reviewed by a molecular tumor board to identify molecular-based recommended therapies (MBRTs). Using paired data from both panels for each patient, the primary endpoint was the proportion of patients with an MBRT identified. Main secondary endpoints included the number of patients with at least one actionable alteration leading to MBRT identification, the number of patients with and without MBRTs initiated, progression-free survival, best overall response, duration of response and safety. Among the 741 patients screened, 45.7% had quality-checked tumor samples. MBRTs were identified with F1CDX in 175 (51.6%) patients and with CTL in 125 (36.9%) patients, translating to a significant increase of 14.8 percentage points (P < 0.001) with the more comprehensive gene panel versus the more limited panel, meeting the primary endpoint. However, no differences in clinical outcomes were observed in these patients with advanced and/or metastatic cancer in need of treatment beyond standard genomic alterations. These findings illustrate the potential for larger gene panels to increase the number of molecularly matched therapies. Larger studies are needed to assess the clinical benefit of expanded MBRTs. ClinicalTrials.gov registration: NCT03163732.