Induction chemotherapy leads to remission in many patients with acute myeloid leukemia (AML) aged ≥60 years; however, the disease relapses in most patients, resulting in poor overall survival (OS). For patients with AML who are not candidates for hematopoietic stem-cell transplant, there is a need for effective maintenance treatments that can reduce the risk for relapse and improve OS, without causing unacceptable adverse events or compromising quality of life.
In September 2020, the FDA approved azacitidine (Onureg) tablets for adults with AML who are not candidates for transplant. This approval was based on data from a recent study (Wei AH, et al. N Engl J Med. 2020;383:2526-2537).
QUAZAR AML-001 was an international, randomized, double-blind, placebo-controlled, phase 3 study that evaluated the efficacy and safety of azacitidine as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Eligible patients were aged ≥55 years, were in complete remission (regardless of complete blood count recovery), and were not candidates for transplant.
A total of 472 adults were randomized in a 1:1 ratio to azacitidine 300 mg (N = 238) or to placebo (N = 234) once daily, on days 1 to 14 of each 28-day treatment cycle. Patients had intermediate-risk (86%) or poor-risk (14%) cytogenetics and an Eastern Cooperative Oncology Group performance status score of ≤3.
The primary end point was OS. The secondary end points included relapse-free survival (RFS) and health-related quality of life.
At a median follow-up of 42.1 months, treatment with azacitidine led to a significant improvement in OS compared with placebo (24.7 months vs 14.8 months, respectively; P <.001). In a subgroup analysis, OS benefit was seen in the azacitidine group regardless of baseline cytogenetic risk, initial response to induction chemotherapy, receipt of consolidation therapy, or measurable residual disease status at trial entry. The median RFS was also significantly longer in the azacitidine group than in the placebo group (10.2 months vs 4.8 months, respectively; P <.001).
In addition, azacitidine demonstrated a manageable safety profile consistent with that of injectable azacitidine. The grade 1 or 2 gastrointestinal adverse events that were common in both groups included nausea, vomiting, and diarrhea, which were controllable with antiemetic and antidiarrheal agents. The most common grade 3 or 4 hematologic adverse events were neutropenia (41% with azacitidine vs 24% with placebo), thrombocytopenia (22% vs 21%, respectively), and anemia (14% vs 13%, respectively). Overall, quality of life was maintained throughout the treatment with azacitidine.
In this trial, azacitidine “maintenance therapy prolonged overall and relapse-free survival among patients with AML who were in remission after intensive chemotherapy,” concluded the researchers, noting that the benefits of azacitidine for patients with AML in other clinical contexts requires further investigation.
Patients with advanced urothelial carcinoma and disease progression after treatment with platinum-based chemotherapy and PD-1 or PD-L1 inhibitors have limited treatment options. Enfortumab vedotin (Padcev), a Nectin-4–directed antibody and microtubule inhibitor conjugate, demonstrated an objective response rate (ORR) in more than 40% of patients with advanced urothelial carcinoma who had experienced progression after previous treatment.
In a new study, researchers reported the results from the confirmatory phase 3 EV-301 study for the benefit of enfortumab vedotin versus chemotherapy in this setting (Powles T, et al. N Engl J Med. 2021 Feb 12. Epub ahead of print).
EV-301 was a global, open-label, phase 3 study that included 608 patients with histologically or cytologically confirmed urothelial cancer, including patients with squamous differentiation or mixed cell types. Eligible patients had radiographic progression or had relapsed during or after immune checkpoint inhibitor for the treatment of advanced urothelial cancer and had received previous platinum-containing chemotherapy. They also had an Eastern Cooperative Oncology Group performance status score of 0 or 1.
The patients were randomized in a 1:1 ratio to enfortumab vedotin 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle or to investigator-chosen chemotherapy on day 1 of every 21-day cycle. The primary end point was overall survival (OS). The secondary end points included progression-free survival (PFS), ORR, and safety.
As of the data cutoff, a total of 301 deaths occurred (134 deaths in the enfortumab vedotin cohort and 167 deaths in the chemotherapy cohort). At a median follow-up of 11.1 months, the median treatment exposure was 5 months in the enfortumab vedotin arm and 3.5 months in the chemotherapy arm.
Enfortumab vedotin demonstrated a 30% lower risk for death, indicating a significantly longer OS. The median OS with enfortumab vedotin was 12.88 months versus 8.97 months with chemotherapy (hazard ratio [HR], 0.7; 95% confidence interval [CI], 0.56-0.89; P = .001).
Treatment with enfortumab vedotin also resulted in a significantly longer PFS compared with chemotherapy and a 38% lower risk for disease progression or death (HR, 0.62; 95% CI, 0.51-0.75; P <.001).
The median PFS was 5.5 months in the enfortumab vedotin group and 3.7 months in the chemotherapy group. The confirmed ORR was also higher in the enfortumab vedotin arm than in the chemotherapy arm (40.6% vs 17.9%, respectively), with a complete response observed in 4.9% and 2.7% of patients, respectively.
The researchers noted that the incidence of treatment-related adverse events was high overall but was similar in the 2 arms (93.9% in the enfortumab vedotin group and 91.8% in the chemotherapy group). Treatment-related adverse events of special interest in the enfortumab vedotin arm included rash (43.9%), peripheral neuropathy (46.3%), and hyperglycemia (6.4%); these events were mild to moderate in severity.
“The efficacy data from this trial suggest that enfortumab vedotin may play a role in the treatment of advanced urothelial carcinoma. In light of recent data that support maintenance treatment with the PD-L1 inhibitor avelumab [Bavencio] after platinum-containing chemotherapy for advanced urothelial carcinoma, enfortumab vedotin may be considered at the time of the first relapse after maintenance immunotherapy,” noted the researchers.
Patients with triple-negative breast cancer (TNBC) experience high relapse rates and poor outcomes after standard treatment. According to the results of a recent study, capecitabine (Xeloda), a chemotherapeutic agent used widely in the treatment of metastatic breast cancer, has the potential to be an effective maintenance therapy for the prevention of TNBC recurrence.
In this study, researchers evaluated low-dose capecitabine maintenance after standard adjuvant chemotherapy in patients with early-stage TNBC (Wang X, et al. JAMA. 2021;325:50-58).
SYSUCC-001 was an open-label, multicenter, randomized, phase 3 study in China that included 443 patients with early-stage TNBC who had completed standard adjuvant chemotherapy. The patients were randomized in a 1:1 ratio to low-dose (650 mg/m2 twice daily) capecitabine continuously for 1 year or to the observational group.
The primary end point was 5-year disease-free survival (DFS). Secondary end points included distant DFS, overall survival (OS), locoregional recurrence-free survival, and adverse events.
Of the 443 patients who were randomized, 434 completed the trial. At a median follow-up of 61 months, 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine arm and 56 events (56 recurrences and 40 deaths) in the observation arm. The estimated 5-year DFS was significantly improved in the capecitabine group compared with the observation group (82.8% vs 73%, respectively; hazard ratio [HR] for risk of recurrence or death, 0.64; 95% confidence interval [CI], 0.42-0.95; P = .03). The estimated 5-year distant DFS rates were 85.8% and 75.8%, respectively (HR, 0.6; 95% CI, 0.38-0.92; P = .02).
Treatment effects on DFS were consistent across all patient subgroups. However, capecitabine was not associated with significant improvement in the estimated 5-year OS or the estimated 5-year locoregional recurrence-free survival compared with the observation group (85.5% vs 85% and 81.3% vs 80.8%, respectively).
Low-dose capecitabine was generally well-tolerated. The most common capecitabine-related adverse event was hand-foot syndrome occurring in 100 patients (45.2%), of which 7.7% were grade 3. Other common grade 1 or 2 adverse events observed in the capecitabine group included leukopenia (23.5%), elevated bilirubin (12.7%), abdominal pain or diarrhea (6.8%), and elevated alanine aminotransferase or aspartate transaminase levels (5%).
“The current trial demonstrated that a year of capecitabine was tolerable for most women without significant treatment discontinuation due to toxicity,” stated the researchers. “More than 80% of participants completed a year of treatment and less than a quarter required any treatment interruption.”
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