NEWS OF THE ESMO 2019 CONGRESS: ONCOGYNECOLOGY AND BREAST CANCER TREATMENT

By Alexey Rumyantsev, MD, Department of Chemotherapy and Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology

In September 2019, the annual congress of the European Society for Medical Oncology (ESMO) was held in Barcelona. This is the largest European conference in oncology, where the results of the studies, which could make an impact on clinical practice of cancer treatment in the very near future, were presented.

During the first presidential symposium, the results of three large randomized trials on maintenance therapy with PARP inhibitors after the first-line treatment of ovarian cancer were presented.

PAOLA-1: Olaparib plus bevacizumab in the first-line treatment of ovarian cancer [1]

Objective: to evaluate the efficacy of maintenance therapy with olaparib and bevacizumab after the first-line treatment for ovarian cancer.
Study Design Description: Phase III randomized trial. Patients with stage III-IV ovarian cancer were included. All patients underwent surgical treatment (primary or interval cytoreduction) and standard chemotherapy (taxanes + platinum), all patients received bevacizumab. Patients were randomized 2: 1 to the olaparib group or placebo. The primary endpoint was investigator-assessed progression-free survival (PFS). The study enrolled patients regardless of BRCA status. Stratification factors: mutational status of BRCA1/2 genes, response to the first line of therapy.
Main results: 806 patients were included; the groups were well balanced by the demographic characteristics. The median PFS was 22.1 months in the olaparib group compared with 16.6 months in the placebo group (hazard ratio [HR] 0.59; 95% confidence interval (CI) 0.49-0.72; p<0.0001), which corresponds to a decrease in the relative risk of disease progression or death by 41%. Data on overall survival (OS) of patients are currently not presented. Among patients with mutations in the BRCA1/2 genes, the median PFS was 37.2 months in the olaparib group, compared to 21.7 months in the placebo group (HR 0.31; 95% CI 0.20-0.47); among patients with the “wild” type of these genes – 18.9 months and 16.0 months, respectively (HR 0.71; 95% CI 0.58-0.88). An additional analysis showed that patients with wild type BRCA1/2, but with a homologous recombination deficiency (HRD), derived a significant benefit from olaparib (HR 0.43; 95% CI 0.28-0.66). Among severe adverse events (grade 3 or higher), an increased risk of anemia (17% compared with 1% in the placebo group), neutropenia (6% and 3%), lymphocytopenia (7% and 1%), asthenia (5% and 1%) was noted.

Why it is important: in a previous SOLO-1 study, it was shown that the use of olaparib after the first-line chemotherapy can reduce the risk of disease progression or death by 70% in patients with BRCA-associated ovarian cancer [2]. The results of the PAOLA study showed that the use of olaparib in combination with bevacizumab is an effective approach in the treatment of patients with the “wild” type of these genes, subject to the presence of HRD. Of great interest are the results of a subgroup analysis of the results of the study – it is known that bevacizumab is most effective in stage IV ovarian cancer. We hope that these data will be published in the near future.

Veliparib in the maintenance therapy of ovarian cancer: results of the VELIA / GOG-3005 study [3]

 Objective: to study the efficacy of maintenance therapy with veliparib after the first-line therapy for ovarian cancer.
Study Design Description: Phase III randomized trial. Patients with stages III-IV ovarian cancer were eligible. All patients underwent surgical treatment (primary or interval cytoreduction) and standard chemotherapy (taxanes + platinum). Patients were randomized at a 1:1 ratio to the veliparib group throughout the treatment (150 mg BID during chemotherapy + 400 mg BID after chemotherapy) or placebo. The primary endpoint was progression-free survival (PFS). The study enrolled patients regardless of BRCA status. Stratification factors included mutational status of BRCA1/2 genes, response to the first-line therapy, chemotherapy regimen, type of cytoreduction.
Main results: 757 patients were included. The groups were balanced according to the main characteristics. According to the results of the study, the median PFS was 23.5 months in the veliparib group compared with 17.3 months in the placebo group (HR 0.68; 95% CI 0.56-0.83; p<0.001), which corresponds to a decrease in the relative risk of disease progression by 32%. Among patients with mutations in the BRCA1/2 genes, the median PFS was 34.7 months and 22.0 months, respectively (HR 0.44; 95% CI 0.28-0.68, p <0.001); in HRD+ subgroup – 31.9 months and 20.5 months (HR 0.59; 95% CI 0.43-0.76; p <0.001). In the subgroup of patients with the “wild” type of BRCA1/2 genes and the absence of HRD, there were no significant differences in the treatment efficacy (HR 0.81; 95% CI 0.60-1.09). Among severe adverse events, there was an increased risk of neutropenia (58% and 49%), anemia (38% and 26%) and thrombocytopenia (28% and 8%).

Why this is important: this is the first positive study to show that veliparib really works.

Niraparib in maintenance treatment of ovarian cancer: results of a phase III study ENGOT-OV26/GOG-3012 [4]

 Objective: to assess the efficacy of maintenance therapy with niraparib after the first-line therapy for ovarian cancer.
Study Design Description: Phase III randomized trial. Patients with stages III-IV of ovarian cancer were enrolled. All patients underwent surgical treatment (primary or interval debulking) and standard chemotherapy (taxanes + platinum). Patients were randomized at a 2:1 ratio to the niraparib or placebo group. The primary endpoint was progression-free survival (PFS) among HRD+ patients. The study enrolled patients regardless of BRCA status. Stratification factors included response to the first-line treatment, chemotherapy regimen, type of cytoreduction, HRD status.
Main results: 733 patients were included. The groups were balanced according to the main characteristics. The median PFS was 13.8 months in the niraparib group compared with 8.2 months in the placebo group (HR 0.62; 95% CI 0.50-0.76; p<0.001). Among patients with BRCA1/2 mutations, the median PFS was 19.6 months and 8.2 months, respectively (HR 0.50; 95% CI 0.31-0.83). It is noteworthy that among patients with no HRD there was also a significant improvement in treatment outcomes: in this subgroup, the median PFS was 8.1 months. and 5.4 months, respectively (HR 0.50; 95% CI 0.31-0.83). Among severe adverse events, there was an increased risk of anemia (31.0% in the niraparib group compared with 1.6% in the placebo group), thrombocytopenia (28.7% and 0.4%) and neutropenia (12.8% and 1,2%).

Why this is important: Another study that demonstrated the of maintenance therapy with PARP inhibitors after completing the first line of ovarian cancer treatment.

Pembrolizumab in neoadjuvant treatment for triple-negative breast cancer: phase III KEYNOTE-522 study [5]

 Objective: to evaluate the efficacy of adding the immunotherapeutic agent pembrolizumab to standard neoadjuvant therapy for triple-negative breast cancer.
Study Design: Phase III randomized trial. Randomization was in a 2:1 ratio to the pembrolizumab or placebo group. All patients received chemotherapy with paclitaxel + carboplatin regimen (4 courses), followed by switching to anthracyclines in combination with cyclophosphamide (4 courses). Pembrolizumab / placebo was used throughout the course of chemotherapy, and after chemotherapy was completed, pembrolizumab or placebo therapy was continued (another 9 courses). The primary endpoint was the rate of pathological complete response (pCR). Stratification factors included carboplatin administration regimen (weekly or once every 3 weeks), the presence of lymph node involvement, stage of the primary tumor.
Main results: 1174 patients were included; the groups were well-balanced by the demographic characteristics. The rate of pCR was 64.8% in the pembrolizumab group compared to 51.2% in the placebo group (p <0,00055). Moreover, among PD-L1 + patients (positive expression of PD-L1 in tumor tissue), the pCR rate was 68.9% and 54.9%, respectively, and among PD-L1 negative patients – 45.3% and 30.3%, respectively. Pembrolizumab therapy was well tolerated, the incidence of severe adverse events was 76.8% in the pembrolizumab group compared to 72.2% in the placebo group.

Why it is important: the efficacy of pembrolizumab in neoadjuvant therapy of triple-negative breast cancer has been proven – achieving complete pathomorphological tumor regression is one of the most important prognostic factors in this disease. In addition, carboplatin has been shown to be effective in the same context.

 

References

  1. Ray-Coquard I, Pautier P, Pignata S, et al. Phase III PAOLA-1/ENGOT-ov25: maintenance olaparib with bevacizumab in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy and bevacizumab as standard of care. ESMO 2019 Annual Meeting.
  2. Moore K, Colombo N, Scambia G, et al. SOLO1: Phase III trial of maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients with advanced ovarian cancer and a BRCA1/2 mutation. ESMO 2018 Annual Meeting.
  3. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. New England Journal of Medicine. September 2019. doi:10.1056/NEJMoa1909707
  4. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. New England Journal of Medicine. September 2019. doi:10.1056/NEJMoa1910962
  5. Schmid P, Cortes J, Dent R, et al. KEYNOTE-522: Phase 3 Study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy as neoadjuvant treatment for early triple-negative breast cancer. ESMO 2019 Annual Meeting.