Possibly the biggest news at ESMO this year was the new practice changing data presented for two different CDK4/6 inhibitors in women with advanced breast cancer. While CDK4/6 inhibitors have changed the way oncologists treat HR+, HER2- advanced breast cancer over the past few years, we are just beginning to understand which of these therapies can help significantly extend overall survival in patients with advanced breast cancer. Verzenio (abemaciclib) and Kisqali (ribociclib) are both inhibitors of cyclin-dependent kinases CDK 4 and 6, which are activated by binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4 & 6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. Overall survival (OS) results presented at ESMO from the MONARCH 2 and MONALEESA-3 trials confirmed OS benefits for the CDK4/6 inhibitors abemaciclib and ribociclib in hormone receptor–positive, human epidermal receptor–negative (HR+/HER2-) metastatic breast cancer.
MONARCH-2 study in women with HR+/HER2- advanced breast cancer
MONARCH 2 is a Phase 3, randomized, double-blind, placebo-controlled trial that enrolled 669 patients with HR+, HER2- advanced or metastatic breast cancer who progressed on endocrine therapy. Patients were randomized 2:1 to abemaciclib + fulvestrant or placebo plus fulvestrant. Abemaciclib was dosed on a continuous dosing schedule until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were objective response rate (ORR), overall survival (OS), and duration of response (DoR). Patients enrolled in the study had experienced disease progression on or within 12 months of receiving endocrine treatment in the neoadjuvant or adjuvant setting or while receiving first-line endocrine therapy for advanced disease. Patients could not have received chemotherapy or more than one line of endocrine therapy for advanced breast cancer.
In the primary analysis of MONARCH 2, the most frequent adverse events (AEs) of any grade in the abemaciclib + fulvestrant arm were diarrhea, neutropenia, nausea, and fatigue. Of these, the reported Grade 3 AEs (abemaciclib vs. placebo arm) were diarrhea (13.4% vs. 0.4%), neutropenia (23.6% vs. 1.3%), nausea (2.7% vs. 0.9%), and fatigue (2.7% vs. 0.4%). No patients in either arm experienced Grade 4 diarrhea, nausea or fatigue, and Grade 4 neutropenia was observed in 2.9 percent versus 0.4 percent of patients in the abemaciclib versus placebo arms, respectively.
Interestingly, in addition to improving OS, an exploratory analysis showed that abemaciclib in combination with fulvestrant delayed the time to chemotherapy, with a median time to chemotherapy of 50.2 months versus 22.1 months in the placebo arm (HR: 0.625; 95% CI: 0.501, 0.779). This finding may be an important treatment consideration as oncologists may be able to postpone the use of chemotherapy for many women and preventing exposure to additional toxicity.
MONALEESA-3 study in postmenopausal women with HR+/HER2- advanced breast cancer
MONALEESA-3 is the second phase 3 trial to evaluate a CDK4/6 inhibitor plus fulvestrant as initial therapy in postmenopausal women (N=726) during ESMO. The trial included women with no prior endocrine therapy, including those diagnosed de novo, women who relapsed within 12 months of adjuvant therapy and women who progressed on endocrine therapy for advanced disease. The most common grade 3/4 adverse events of special interest observed in this analysis in patients who received ribociclib + fulvestrant compared to fulvestrant alone were neutropenia (57.1% vs 0.8%), hepatobiliary toxicity (13.7% vs 5.8%), QTc prolongation (3.1% vs 1.2%), respiratory disorders (2.3% vs 3.3%) and interstitial lung disease (0.2% vs 0%).
Ribociclib in combination with fulvestrant met its secondary endpoint of overall survival, demonstrating a statistically significant improvement in survival with a 28% reduction in risk of death (median OS not reached vs. 40.0 months; HR=0.724; 95% CI: 0.568-0.924; p=0.00455). The significant extension in survival met the early efficacy stopping criteria at a pre-specified interim analysis. At 42 months, estimated rates of survival were 58% for ribociclib combination treatment and 46% for fulvestrant alone.
Median PFS in the 1L was also reached at this analysis and demonstrated that ribociclib + fulvestrant had a median PFS of 33.6 months compared to 19.2 months in the placebo arm (HR=0.546; 95% CI: 0.415-0.718). Additionally, the need for chemotherapy was delayed in all patients who were prescribed ribociclib + fulvestrant (HR=0.696; 95% CI: 0.551-0.879).
BROCADE3 data in HER2- advanced breast cancer with BRCA1/BRCA2 mutations
An underwhelming performance in breast cancer has added to a flat ESMO congress for Abbvie’s PARP inhibitor veliparib. Veliparib is a PARP1/2 inhibitor with antitumor activity as a single-agent or combined with carboplatin + paclitaxel (C/P) in pts with BRCA mutated breast cancer. BRCA mutated tumors are susceptible to both platinum and PARP inhibitors due to deficiency in homologous recombination repair.
The BROCADE3 trial tested veliparib + C/P with chemo in 2L, HER2-, BRCA+ patients with advanced disease, generating less than two months’ survival advantage versus C/P alone. The result was statistically significant, but Abbvie might struggle to argue its clinical relevance, particularly as the overall response rate was largely the same in both arms. No impact on overall survival was seen – although no PARP inhibitor has demonstrated efficacy in this tumor type. PARP inhibitors are only approved 3L in this tumor type, but it is unclear whether the company will file on these data, or on ovarian results (featured below) neither of which would afford velaparib a position of strength in an extremely competitive market.
In the trial, patients were randomly assigned 2:1 to receive oral veliparib 120 mg twice daily or placebo on days 2 to 5, administered with carboplatin area under the curve 6 on day 1 and weekly paclitaxel 80 mg/m2 on days 1, 8, and 15 in 21-day cycles. Patients were treated until disease progression or unacceptable toxicity. All patients had germline BRCA1/2 mutations and had previously received two or fewer lines of cytotoxic therapy for metastatic breast cancer; 8% of patients had received prior platinum therapy and 19% had received chemotherapy for metastatic disease. The median patient age was 47 years old; 48% of patients had estrogen receptor–negative/progesterone receptor–negative disease, and 4% had a history of central nervous system metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival, clinical benefit rate (CBR), objective response rate (ORR), and time to second progression.
Median PFS per investigator assessment in 337 patients treated with veliparib + C/P was 14.5 months (95% confidence interval [CI] =12.5–17.7) vs 12.6 months (95% CI = 10.6–14.4) in 172 patients receiving placebo/chemotherapy (hazard ratio [HR] = 0.71; 95% CI = 0.57–0.88; P = .002). Median PFS per independent review committee was longer at 19.3 (95% CI = 16.5–23.3) months vs 13.5 (95% CI = 12.5–16.3) months, respectively (HR = 0.70; 95% CI, 0.54-0.90). PFS at 3 years was doubled with veliparib; the respective cohorts demonstrated 3-year PFS rates of 26% vs 11%. At the interim analysis, median OS was 33.5 (95% CI = 27.6–37.9) months with veliparib + C/P compared to 28.2 (95% CI = 24.7–35.2) months with placebo + C/P (HR = 0.95; 95% CI = 0.73–1.2, P = .67).
CBR and ORR were high and were similar between the two arms. At 24 weeks, the CBR was 90.7% in the veliparib/chemotherapy arm and 93.2% in the placebo/chemotherapy arm, while ORR was 75.8% vs 74.1%. However, prolonged time to second progression was seen in the veliparib + C/P arm, 21.3 months (95% CI = 19.8–25.1) vs 17.4 months (95% CI = 16.0–20.0) in the placebo + C/P arm (HR = 0.76; 95% CI = 0.60–0.96). The median duration of response was 14.7 months (95% CI = 12.1–18.7) vs 11.0 months (95% CI = 10.2–12.3), respectively.
While the BROCADE3 trial did show a statistically significant OS benefit of less than two months versus C/P alone, Abbvie might struggle to demonstrate that the results are clinically meaningful, especially since the ORR was essentially the same in both patient cohorts. PARP inhibitors are only approved 3L in this setting and it is unclear whether Abbvie will file on the BROCADE3 data, or on ovarian results (featured below) neither of which would afford velaparib a position of strength in an extremely competitive market.
BEACON trial in BRAF-mutant metastatic colorectal cancer
Follow-up data from the pivotal Phase 3 BEACON study presented at ESMO suggest that the three-drug combination, encorafenib, binimetinib and cetuximab, could replace chemotherapy for the approximately 15% of patients with BRAF+ metastatic colorectal cancer. The BRAF mutation has a large unmet need and has long been a poor prognostic factor for patients with metastatic colorectal cancer.
In the BEACON study, 665 patients with BRAF V600E-mutant colorectal cancer who had progressed after one or two prior regimens in the metastatic setting were randomized to receive triplet therapy, doublet therapy (encorafenib and cetuximab) or the investigator’s choice of FOLFIRI + cetuximab. Median OS was 9 months (95% confidence interval [CI]: 8, 11,4) for the triplet targeted therapy compared to 5.4 months (95% CI: 4.8, 6.6) for standard therapy (hazard ratio [HR] 0.52; 95% CI: 0.39, 0.7, p<0.0001). Confirmed ORR by blinded central review for the triplet targeted therapy was 26% (95% CI: 18, 35) compared to 2% (95% CI: 0,7, p<0.0001) for standard therapy. Once approved by the FDA, this triplet combination is likely to become standard of care for patients with BRAF+ metastatic colorectal cancer.
Impressive findings were presented for three PARP inhibitors in front-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer. Experts predict that these findings will reshape the treatment landscape of front-line advanced ovarian cancer. In women with newly diagnosed stage III/IV ovarian cancer, PRIMA/GOG-3012, PAOLA-1, and VELIA/GOG-3005 evaluated three inhibitors of poly (ADP-ribose) polymerase (PARP): niraparib (as maintenance), olaparib plus bevacizumab (as maintenance), and veliparib (with chemotherapy, then maintenance). Currently, olaparib, rucaparib, and niraparib are indicated for high-grade epithelial ovarian cancer, but only olaparib is approved as maintenance therapy for patients with BRCA mutations after response to 1L chemotherapy.
Key takeaways are featured below:
VELIA/GOG-3005 trial in newly diagnosed ovarian cancer
This study tested veliparib earlier in the ovarian cancer disease continuum—as maintenance therapy after its concurrent use with 1L chemotherapy (carboplatin/paclitaxel) in 1,140 patients. Patients who received veliparib throughout treatment had a significantly improved PFS, and the effect was most pronounced in HRD-positive patients. In VELIA/GOG-3005, the study included homologous recombination deficient (HRD) patients who carried a germline BRCA mutation or with a deleterious BRCA mutation in the tumor, as well as those without a BRCA mutation who had HRD as assessed by a tissue-based assay. For the overall population, the median PFS was 23.5 months with veliparib and 17.3 months with placebo (HR = 0.68; P < .001), but the benefit rose to 34.7 months vs 22.0 months, respectively (HR = 0.44; P < .001), for the cohort with a BRCA mutation and to 31.9 months and 20.5 months, respectively (HR = 0.57; P < .001), for HRD-positive patients. One of the arms evaluated veliparib given during chemotherapy but not continued as maintenance, and outcomes in this arm were not significantly better than those in the control arm.
PRIMA/GOG-3012 trial of maintenance niraparib after initial therapy for ovarian cancer
The PRIMA/GOG-3012 study evaluated niraparib vs placebo in 733 patients who responded to platinum-based chemotherapy. In PRIMA patients with stage III disease were required to have visible residual disease after debulking. Patients receiving maintenance niraparib had a median PFS of 13.8 months vs 8.2 months (hazard ratio [HR] = 0.62; P < .001). In the 51% of patients whose tumors had homologous recombination deficiency (HRD), the median PFS was 21.9 months vs 10.4 months (HR = 0.43; P < .001). At 24 months, OS rates were 84% and 77%, respectively (HR = 0.70; 95% confidence interval [CI] = 0.44–1.11). Benefit was shown regardless of the presence or absence of HRD, although the greatest benefit was seen in HRD-positive patients. Niraparib is the first PARP inhibitor to demonstrate benefit in patients across biomarker subgroups after 1L platinum-based chemotherapy, consistent with prior clinical studies of niraparib in recurrent ovarian cancer.
PAOLA-1 trial of maintenance olaparib after initial therapy for ovarian cancer
The PAOLA-1 study evaluated olaparib + bevacizumab maintenance in 806 patients who responded to platinum-based chemotherapy + bevacizumab as a standard of care for most patients in 1L treatment.
Compared with bevacizumab and placebo, maintenance therapy with the combination improved median PFS from 16.6 months to 22.1 months (hazard ratio = 0.59; P < .0001) in the overall population, regardless of BRCA mutation status or surgical outcome. Then, patients received their 1L therapy for a median time of 7 months before randomization, so they benefited with a median time of 29.1 months without relapse since the beginning of systemic treatment in the combination maintenance arm. Although all patient subsets benefited from olaparib, the magnitude was greatest for those whose tumors tested positive for BRCA1/2 mutations, 37.2 vs 21.7 months (HR = 0.31; 95% CI = 0.20–0.47) and was consistent with previously reported data for olaparib in SOLO-1, despite an active treatment in the control arm.
An additional key finding from the study was the substantial benefit reported in the HRD-positive subgroup (including BRCA-mutated), where the median PFS was also impressive among HRD-positive patients, a group that included both those with BRCA-mutation and BRCA wild-type disease: 37.2 months vs 17.7 months (HR = 0.33; 95% CI = 0.25–0.45). In HRD-positive patients lacking a BRCA mutation, the benefit remains substantial, with a median progression-free survival of 28.1 months with olaparib compared with 16.6 months with placebo (HR = 0.43; 95% CI = 0.28–0.92).
Be sure to check out Part 1 of our Insights from ESMO 2019 series where we reviewed key immunotherapy studies.