Editor’s note:
On October 20, the 2023 European Society for Medical Oncology (ESMO) Congress officially opened in Madrid, Spain. As one of the most influential global oncology conferences, top experts from around the world gathered to discuss and share the latest international research findings and cancer treatment technologies. Professor Xiaohua Wu’s team from Fudan University Affiliated Cancer Hospital presented two significant studies at the ESMO 2023 Late-breaking Abstract (LBA) session, providing important references for clinical practice. “Oncology Frontier” had the privilege of inviting Professor Xiaohua Wu to share the research findings on-site.
01 Study Introduction
Effectiveness and Safety of Sennaparib Maintenance Therapy in Newly Diagnosed Advanced Ovarian Cancer Patients (FLAMES Study): A Randomized, Double-blind, Placebo-controlled Phase III Trial (Abstract No: LBA36)
Background: Ovarian cancer is one of the most lethal gynecological cancers. About 85% of newly diagnosed advanced ovarian cancer patients may experience recurrence after first-line platinum-based chemotherapy. PARP inhibitors are recommended as maintenance therapy to extend the efficacy of platinum drugs. Sennaparib (IMP4297) is a novel and efficient PARP inhibitor. The FLAMES Phase III study aimed to observe the efficacy and safety of Sennaparib as first-line maintenance therapy in newly diagnosed advanced ovarian cancer patients in China.
Methods: The study included patients with newly diagnosed FIGO III-IV stage, high-grade serous or endometrioid ovarian cancer who had completed first-line platinum-based chemotherapy and achieved complete response (CR) or partial response (PR). Patients were randomly assigned (2:1) to receive Sennaparib or placebo at a dose of 100 mg/day orally based on CR/PR and BRCA mutation status. The primary endpoint was progression-free survival (PFS), assessed by the blind independent review committee (BICR) according to RECIST v1.1.
Results: A total of 404 patients received randomized treatment. As of March 16, 2023, 270 patients received Sennaparib, and 133 received placebo, with median follow-up times of 22.4 months and 22.2 months, respectively. The main analysis results showed that compared to placebo, Sennaparib significantly improved PFS (HR 0.43, 95% CI: 0.32–0.58, P < 0.0001), and this improvement was independent of BRCA mutation status (HR 0.43, P < 0.01). Secondary endpoints supported the main analysis (Table 1). The incidence of grade ≥3 adverse events (AEs) in the Sennaparib and placebo groups was 66.3% vs. 20.3%, the rate of dose reduction due to AEs was 63.3% vs. 6.0%, and the rate of discontinuation due to AEs was 4.4% vs. 0%. No AEs led to death.
Table 1. Comparison of secondary endpoints between the two groups of patients
Conclusion: Compared to placebo, Sennaparib as first-line maintenance therapy can unprecedentedly reduce the risk of disease progression or death in ovarian cancer patients, regardless of biomarker status. Sennaparib is well-tolerated, and no new safety signals were identified.
Efficacy Comparison of Carirelizumab Combined with Famitinib vs. Carirelizumab Monotherapy vs. Investigator’s Choice Chemotherapy in Recurrent or Metastatic Cervical Cancer Patients (Abstract No: LBA44)
Background: Immunotherapy combined with anti-angiogenic drugs can enhance immune response by reversing the immunosuppressive tumor microenvironment. This study is a randomized, open-label Phase II trial designed to evaluate the efficacy of carirelizumab (CAM, anti-PD-1 antibody) combined with famitinib (FAM, a multi-target small molecule tyrosine kinase inhibitor targeting VEGFR2/3), carirelizumab monotherapy, and investigator’s choice chemotherapy (Chemo) in treating recurrent or metastatic cervical cancer (R/M CC).
Methods: The study included R/M CC patients who had previously failed platinum-based chemotherapy, excluding those who had received prior treatment with anti-PD-1/PD-L1/CTLA-4. Patients were randomly assigned to Group A: CAM (200 mg, IV, Q3W) + FAM (20 mg, PO, QD), Group B: CAM (200 mg, IV, Q3W), and Group C: investigator’s choice chemotherapy (every 3 weeks as one cycle). The primary endpoint was objective response rate (ORR) assessed by the blind independent review committee (BICR) according to RECIST v1.1.
Results: As of the data cutoff date on April 21, 2023, a total of 194 patients were randomized (Group A: n=105, Group B: n=54, Group C: n=35), with 46 patients (23.7%) still undergoing treatment. 77.8% of patients had squamous cell carcinoma, 63.9% were PD-L1 positive, and 31.4% had received prior targeted therapy. The median follow-up time was 9.9 months (IQR 7.3-15.1). Antitumor activity is shown in Table 2. The incidence of treatment-related adverse events (TRAE) was 100%, 94.3%, and 100% in Groups A, B, and C, respectively. Grade ≥3 TRAEs were reported by 84.8%, 15.1%, and 60.0% of patients, with the most common being neutrophil count decrease (23.8%, 1.9%, 30.0%), hypertension (22.9%, 0, 0), white blood cell count decrease (20.0%, 0, 33.3%), and anemia (20.0%, 1.9%, 13.3%). 19.0%, 5.7%, and 0 patients discontinued treatment due to AEs. In Group A, 2 patients (1.9%) reported treatment-related deaths (acute coronary syndrome, infection, and sepsis).
Table 2. Comparison of efficacy among the three groups of patients
Conclusion: In R/M CC patients, the antitumor activity of CAM+FAM was higher than CAM monotherapy or investigator’s choice chemotherapy, and the safety was tolerable.
02 Researcher’s Comments
“Oncology Frontier”: You presented two LBA studies at this year’s ESMO Congress and received wide recognition and discussion from scholars in the field. Could you please briefly introduce the main results and clinical significance of these two studies?
Professor Xiaohua Wu: The annual ESMO Congress is a highly influential global academic event. I am fortunate to have the opportunity to present two LBA studies, namely LBA36 and LBA44, at this year’s ESMO Congress. LBA36 is a priority oral presentation (Proffered Paper) that investigated the efficacy and safety of the PARP inhibitor Sennaparib as first-line maintenance therapy for advanced ovarian cancer. Firstly, the study yielded positive results, significantly improving PFS in patients (HR 0.43, 95% CI: 0.32–0.58, P < 0.0001), and this effect was effective for both BRCA-mutated and BRCA wild-type patients. Secondly, Sennaparib demonstrated a “highly effective, low toxicity” profile, with only 4.4% of patients discontinuing the drug due to toxicity, which is lower compared to other similar drugs (non-head-to-head comparison). Furthermore, the study indicated that the efficacy of Sennaparib remained unchanged after three dose reductions, which is crucial because, despite the numerous types of PARP inhibitors, few can achieve “highly effective, low toxicity,” especially when combined with chemotherapy or other drugs. This was corroborated by another study in the same session, LBA37 presented by Dr. Antonio Gonzalez Martin, which observed the efficacy of atezolizumab + chemotherapy + niraparib maintenance therapy in advanced recurrent ovarian cancer but unfortunately obtained negative results. This combination did not significantly improve PFS and ORR in such patients. Therefore, the FLAMES study from China opened up a new realm in this oral presentation.
The other LBA44 study is a mini-oral presentation, evaluating the efficacy of carirelizumab combined with famitinib in treating second-line R/M CC. As is well known, the recurrence and mortality rates of R/M CC in China are relatively high. Therefore, it is necessary for clinicians and drug development institutions to explore new drugs or treatment regimens to improve outcomes for these patients. While we already have options like chemotherapy and immune checkpoint inhibitors (such as PD-1/PD-L1), the effectiveness of these treatments is still limited. Can we enhance the efficacy of these treatment drugs through combination therapy? In that regard, I believe the LBA44 study is a good attempt. In fact, the efficacy of the combination of carirelizumab and famitinib has been confirmed in previous trials related to urological tumors. Therefore, we included this regimen in our Phase II study to further verify its efficacy in cervical cancer patients. The study included three groups: carirelizumab combined with famitinib, carirelizumab monotherapy, and investigator’s choice chemotherapy. The results showed that the efficacy of carirelizumab combined with famitinib was superior to the other two treatment regimens. Moreover, famitinib, as an oral, small-molecule TKI drug, combined with carirelizumab is also a new attempt. I am pleased to see this innovative option gaining recognition from the ESMO committee.
References :
[1] Xiaohua Wu, et al. Efficacy and safety of senaparib as maintenance treatment in patients with newly diagnosed advanced ovarian cancer (FLAMES study): A randomized, double-blind, placebo-controlled, phase III trial. ESMO 2023; abstract LBA36.
[2] Xiaohua Wu, et al. Camrelizumab plus famitinib versus camrelizumab alone and investigator’s choice of chemotherapy in women with recurrent or metastatic cervical cancer. ESMO 2023; abstract LBA44.
Professor Xiaohua Wu
Chief Physician, Doctoral Supervisor
Director of the Department of Gynecologic Oncology, Fudan University Affiliated Cancer Hospital
Chief Expert, Multidisciplinary Comprehensive Treatment Team for Gynecologic Oncology, Fudan University Affiliated Cancer Hospital
Chairman of the Ovarian Cancer Committee, China Anti-Cancer Association
Chairman of the Obstetrics and Gynecology Committee, China Primary Health Care Foundation
Former Chairman of the Gynecologic Oncology Committee, Shanghai Anti-Cancer Association
Executive Director, China Anti-Cancer Association
Executive Director, Shanghai Anti-Cancer Association
Director, Chinese Society of Clinical Oncology (CSCO)
Committee Member, International Gynecologic Cancer Society (IGCS), Nominee for Asia-Pacific Director
Committee Member, Society of Gynecologic Oncology (SGO) Education Committee, Executive Committee
Visiting Professor, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University
International Review Expert, National Comprehensive Cancer Network (NCCN); Editorial Board Member for journals including International Journal of Gynecological Cancer, Cancer Medicine, Journal of Gynecologic Cancer, Chinese Journal of Obstetrics and Gynecology, Chinese Journal of Clinical Anatomy
