Novartis announces that the European Commission (EC) has approved the inclusion of treatment-free remission (TFR) data in the nilotinib (Tasigna) Summary of Product Characteristics (SmPC). TFR is the ability to maintain molecular response (MR) after stopping tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) patients in chronic phase (CP). This is an important milestone for the Ph+ CML community because nilotinib is now the first and only TKI to include information on TFR in the European Union label. The approval by the EC was based on efficacy and safety findings from the 48-week analyses of 2 open-label trials, ENESTfreedom and ENESTop, which showed that more than 50% of Ph+ CML-CP patients who met the rigorous predefined response criteria of the trials were able to maintain TFR after stopping nilotinib in both in the first-line setting and after switching from imatinib. No new major safety findings were observed in these studies at the 48-week analyses in patients treated with nilotinib beyond those in the known safety profile of nilotinib. An important part of the ENESTfreedom and ENESTop trials was regular and frequent molecular monitoring of BCR-ABL levels with a well-validated assay able to measure BCR-ABL transcript levels down to MR4.5 (BCR-ABL1 International Scale [IS] ≤0.0032%). Frequent patient monitoring after discontinuation of nilotinib allows timely determination of loss of MR4.0 (BCR-ABL1 IS ≤0.01%) and major molecular response (BCR-ABL1 IS ≤0.1%), and need for treatment re-initiation.
Eli Lilly announces positive results of the MONARCH 2 study, which evaluated abemaciclib in combination with fulvestrant in women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) (ASCO, Abstract #1000). MONARCH 2 was a global, double-blind, phase III study of 669 women with HR+ and HER2– ABC whose disease progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), ≤12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease. Abemaciclib + fulvestrant significantly extended progression-free survival (primary endpoint) vs fulvestrant alone (median, 16.4 vs 9.3 months; hazard ratio, 0.553; 95% CI: 0.449–0.681; P <.001). In patients with measurable disease, abemaciclib + fulvestrant achieved an overall response rate of 48.1% (95% CI: 42.6%–53.6%) compared with 21.3% (95% CI: 15.1%–27.6%) in the control arm. The most common adverse events in the abemaciclib vs placebo arms were diarrhea (86.4% vs 24.7%), neutropenia (46.0% vs 4.0%), nausea (45.1% vs 22.9%), and fatigue (39.9% vs 26.9%).
Findings from ARCHER 1050, the first randomized phase III study to compare a second- (dacomitinib, Pfizer) and a first- (gefitinib, AstraZeneca) generation epidermal growth factor receptor (EGFR) inhibitor head-to-head for first-line treatment of patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) point to a potential new treatment option. The study that randomly assigned 452 patients with newly diagnosed stage IIIB or IV EGFR-positive (EGFR+) NSCLC shows that compared with gefitinib, dacomitinib delays cancer growth by a median of 5.5 months more. Progression-free survival (PFS) was 14.7 months with dacomitinib, compared with 9.2 months with gefitinib. Longer follow-up is needed to assess the median overall survival. The most common severe (grade 3) side effects of dacomitinib were acne (in 14% of patients) and diarrhea (in 8% of patients). The dose of dacomitinib was reduced in about 60% of patients due to side effects. Liver enzyme abnormalities were the most common severe (grade 3) side effect of gefitinib (in 8% of patients). Dacomitinib is a more potent second-generation EGFR inhibitor that shares the issue of increased side effects in the skin and gastrointestinal tract, like afatinib, which is already US Food and Drug Administration approved.
Roche announces (ASCO 2017. Abstract 9008) that the global, randomized phase III ALEX study shows alectinib (Alecensa) significantly reduced the risk of disease worsening or death (progression-free survival [PFS]) by more than half (53%) compared with crizotinib when given as initial (first-line) treatment of anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC; hazard ratio [HR] = 0.47, 95% CI: 0.34–0.65, P <.0001). Median PFS reported by the investigators, the primary endpoint of the study, was not yet reached in patients who received alectinib (95% CI: 17.7–not reached) vs 11.1 months (95% CI: 9.1–13.1 months) in those who received crizotinib. Median PFS assessed by an independent review committee, a secondary endpoint, was 25.7 months (95% CI: 19.9–not reached) for patients who received alectinib vs 10.4 months (95% CI: 7.7–14.6 months) for patients who received crizotinib (HR = 0.50, 95% CI: 0.36–0.70; P <.0001). The safety profile of alectinib was consistent with that observed in previous studies. The ALEX study also demonstrated that alectinib reduced the risk of disease progression in the central nervous system (CNS) by 84% (HR = 0.16, 95% CI: 0.10–0.28; P <.0001). The 12-month cumulative rate of CNS progression for patients with or without existing CNS metastases at baseline was 9.4% (95% CI: 5.4%–14.7%) for patients treated with alectinib and 41.4% (95% CI: 33.2%–49.4%) for those treated with crizotinib. Grade 3–5 adverse events (AEs) were less frequent in the alectinib arm (41%) compared with the crizotinib arm (50%). In the alectinib arm, the most common grade 3–5 AEs (≥5%) were increased alanine transferase and aspartate transferase (5%), and anemia (5%). AEs leading to discontinuation (11% vs 13%), dose reduction (16% vs 21%), and dose interruption (19% vs 25%) were all lower in the alectinib arm. Overall survival data are currently considered immature. ALEX is the second positive phase III head-to-head study to show alectinib superiority to crizotinib in patents with ALK+ lung cancer.
Mateon Therapeutics announces that the Food and Drug Administration (FDA) has granted Fast Track designation to the company’s product candidate OXi4503 for the treatment of acute myeloid leukemia (AML). The receipt of Fast Track designation from the FDA represents an important milestone for the OXi4503 program and follows promising results, including 3 complete remissions, from the initial cohorts of the ongoing OX1222 study in patients with relapsed/refractory AML.
AstraZeneca (AZ) presents data showing that osimertinib (Tagrisso) extends progression-free survival (PFS) for non-small cell lung cancer (NSCLC) patients who have central nervous system (CNS) metastases. According to findings from the AURA3 trial, patients with locally advanced or metastatic epidermal growth factor receptor T790M mutation-positive NSCLC given osimertinib lived without disease worsening or death for 11.7 months compared with 5.6 months for those receiving chemotherapy. Among patients evaluable for response, the CNS objective response rate was 70% with osimertinib and 31% with chemotherapy. The adverse event profiles for the drug and platinum-based doublet chemotherapy were consistent with previous trials.
Boehringer Ingelheim (BI) presents phase II results from LUME-Meso, a randomized, double-blind, placebo-controlled trial of nintedanib (Vargatef), an oral triple angiokinase inhibitor, demonstrating improved progression-free survival (PFS, primary endpoint) and overall survival (OS, secondary endpoint) when added to standard first-line chemotherapy (CHT) of pemetrexed/cisplatin in patients with malignant pleural mesothelioma (MPM) compared with CHT alone. The updated results from the LUME-Meso study show that nintedanib, when added to standard CHT, nearly halved the risk of disease progression. A 46% reduction was demonstrated (9.4 vs 5.7 months), with a significant improvement in median PFS of 3.7 months in the overall study population (patients with either an epithelioid or biphasic cell type) compared with placebo + standard CHT alone. In patients with an epithelioid cell type, nintedanib + CHT demonstrated a greater median PFS benefit of 4 months (9.7 vs 5.7 months). The primary OS analysis showed an encouraging 4.1-month improvement in the median OS for patients receiving nintedanib in addition to CHT (18.3 vs 14.2 months in placebo arm), demonstrating a positive trend in the overall population, without reaching significance. Similar to PFS, the effect was the greatest in patients with epithelioid histology, whose median OS was 20.6 months compared with 15.2 months with CHT alone. The safety profile of the experimental combination with nintedanib was as expected. A phase III trial to confirm the efficacy and safety profile of nintedanib as a potential first-line targeted therapy for MPM is ongoing.
Calithera Biosciences announces that the Food and Drug Administration (FDA) has granted Fast Track designation to CB-839 in combination with everolimus for the treatment of patients with metastatic renal cell carcinoma (mRCC) who have received 2 or more prior lines of therapy. CB-839 is a first-in-class, oral, selective, potent inhibitor of glutaminase being evaluated in phase I/II clinical trials for the treatment of solid tumors including RCC, triple-negative breast cancer, non-small cell lung cancer, and melanoma. A global randomized trial of CB-839 in combination with everolimus for the treatment of RCC is planned to start in the second half of 2017.
Results from APHINITY, a phase III clinical trial of 4,805 women with human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC), suggest the addition of a second HER2-targeted therapy, pertuzumab (Perjeta, Roche), to standard-of-care (SOC) trastuzumab (Herceptin, Roche) after surgery improves outcomes, although the benefit is modest. At an early follow-up of 3 years, 93.2% of women who received trastuzumab alone had not developed invasive disease, compared with 94.1% of those who received pertuzumab and trastuzumab—a difference of 1% (ASCO 2017. Abstract LBA500). The study was positive in the overall population, with greatest risk-reduction in patients with node-positive or hormone receptor-negative disease. The rates of serious side effects were low and similar in both groups—heart failure or heart-related death occurred in 0.7% of patients in the pertuzumab group and in 0.3% of patients in the placebo group. Severe diarrhea was more common with pertuzumab, occurring in 9.8% of patients, compared with 3.7% of those who received placebo. Data will be submitted to global health authorities.
Novartis announces the results of 2 phase II studies evaluating the combination of dabrafenib (Tafinlar) + trametinib (Mekinist) in malignant melanoma patients.
Results from the phase II study BRF113220 (ASCO, Abstract #9505) showed a durable survival benefit for some patients with BRAF V600 mutation-positive metastatic melanoma when treated with the combination of dabrafenib + trametinib. This represents the longest follow-up to date of a BRAF and MEK inhibitor combination therapy in this patient population. A total of 162 patients received either dabrafenib monotherapy or the dabrafenib + trametinib combination. After 5 years, 20 patients (37%) remain in the study, including 7 (13%) in the dabrafenib monotherapy arm and 13 (24%) in the combination therapy arm, demonstrating that overall survival (OS) with combination therapy is superior to monotherapy. The 4-year and 5-year OS rates with monotherapy were 23% and 21%, respectively. The 4-year and 5-year OS rates with combination therapy were 30% and 28%, respectively, reflecting a stabilization of OS in patients enrolled in the study. Progression-free survival (PFS) in the monotherapy arm was consistently 3% whereas PFS at both 4 and 5 years was 13%, also demonstrating stabilization. Forty-five of 54 patients (83%) in the dabrafenib monotherapy arm included in this updated analysis had crossed over to the dabrafenib + trametinib combination; the survival outcomes in these crossover patients continued to be followed under the dabrafenib arm. Adverse events were consistent with other dabrafenib + trametinib studies, and additional follow-up revealed no new safety signals.
Additionally, Novartis presents results from a phase II study showing findings from the 30-month trial, COMBI-MB, evaluating BRAF and MEK inhibitor combination therapy in 125 patients with BRAF V600-mutant melanoma brain metastases (MBM) treated with the combination of dabrafenib + trametinib (ASCO 2017, Abstract #9506). In Cohort A (patients who were BRAF V600E mutation-positive, had asymptomatic MBM and no local prior treatment), investigator-assessed intracranial response rate was 58% (95% CI: 46–69). Extracranial response rate was 55% (95% CI: 43–67) and overall response rate was 58% (95% CI: 46–69). Median PFS was 5.6 months (95% CI: 5.3–7.4). Six-month OS was 79%, with 31 patients (41%) still in follow-up. Preliminary median OS was 10.8 months (95% CI: 8.7–19.6). Adverse events (AEs) across cohorts (any, 98%; grade 3/4, 48%) were consistent with prior dabrafenib + trametinib studies; 10% of patients (8% in Cohort A) discontinued because of AEs.