A Phase 3 Trial Comparing Axitinib and Sorafenib in Advanced Renal-Cell Cancer
Background: More than 170,000 people are diagnosed annually with renal carcinoma, resulting in 72,000 deaths and a 30% relapse rate. Many patients are resistant to existing chemotherapy and cytokine treatments. However, the treatment of advanced renal-cell cancers has been changing through the use of drugs that inhibit angiogenesis by targeting the vascular endothelial growth factor receptors. This is the first phase 3 clinical trial to compare the effectiveness of 2 second-generation antiangiogenic agents—axitinib and sorafenib—in the treatment of metastatic renal-cell cancer.
Design: This multicenter, randomized, unmasked, phase 3 clinical trial included 723 patients aged ≥18 years from 175 sites, hospitals, and outpatient clinics in 22 countries who had been diagnosed with renal-cell carcinoma that had progressed despite first-line therapy with sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. From September 2008 to July 2010, patients were randomized to axitinib 5 mg initially, increased to 7 mg and then to 10 mg, twice daily (N = 361) or to sorafenib 400 mg twice daily (N = 362). Patients were randomized according to previous treatment type and Eastern Cooperative Oncology Group (ECOG) performance score. The primary end point was progression-free survival (PFS), assessed by a masked, independent radiology review of the intention-to-treat (ITT) population. Secondary end points were overall survival (OS), objective response rate, response duration, and time to deterioration.
Summary: The median PFS was significantly (42%) longer with axitinib than with sorafenib (6.7 months vs 4.7 months, respectively; hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.54-0.81; 1-sided P <.001). In patients who previously received cytokines, the median PFS was 12.1 months with axitinib and 6.5 months with sorafenib (HR, 0.46; 95% CI, 0.32-0.68; P <.001), and among those who had received sunitinib, the median PFS was 4.8 months and 3.4 months (HR, 0.74; 95% CI, 0.57-0.96; P = .011). The objective response rate was 19% with axitinib and 9% with sorafenib (P = .001), and the median duration of response was 11 months and 10.6 months, respectively. Treatment discontinuation from toxic effects was observed in 14 (4%) of the 359 patients who received axitinib and 29 (8%) of the 355 patients who received sorafenib. The most common adverse events reported were diarrhea, hypertension, and fatigue in the axitinib group and diarrhea, palmar-plantar erythrodysesthesia, and alopecia in the sorafenib group.
Takeaway: This new agent, axitinib, appears to be a very good second-line agent in the treatment of advanced renal-cell cancer. It appears to be as safe as sorafenib, with a better objective response rate and a longer PFS.
The maker of axitinib received a unanimous vote by the US Food and Drug Administration (FDA) advisory committee favoring the use of this drug for patients with advanced renal-cell cancer who have failed first-line systemic therapy. The FDA will be reviewing the product in this setting early in 2012.
Letrozole More Effective than Tamoxifen for Long- Term Mortality Reduction in Postmenopausal Women with Breast Cancer
Background: Postmenopausal women with hormone receptor–positive early invasive breast cancer are often managed with an aromatase inhibitor, such as letrozole. The aim of the Breast International Group (BIG) 1-98 study was to compare tamoxifen and letrozole as monotherapies and as sequential treatments. Because of the long-term risk of recurrence and death in this patient population, an extended, 8.1-year median follow-up was conducted to assess patient outcomes after the treatment regimens ended in 2008.
Design: Currently in its twelfth year, BIG 1-98 is an international, randomized, phase 3, double-blind clinical trial with 8010 postmenopausal women (median age, 61 years) from 148 hospitals in 27 countries who tested positive for estrogen-receptor or progesterone-receptor cancer. Women who had evidence of metastatic disease and previous or concurrent cancer other than adequately treated noninvasive breast cancer, cervical cancer, or carcinoma of the skin were excluded. Patients were randomized to monotherapy with either letrozole 2.5 mg orally once daily or tamoxifen 20 mg orally once daily for 5 years. They then were randomized to 1 of 4 groups: monotherapy with tamoxifen or letrozole for 5 years, sequential therapy with letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. After a significant disease- free survival benefit with letrozole reported in 2005, the study protocol was amended to allow a crossover from tamoxifen to letrozole. The final treatment phase ended in 2008. Efficacy comparisons were based on ITT analyses and on inverse probability of censoring weighted Cox models, which addressed the potential bias introduced from the selective crossover from tamoxifen to letrozole. The primary study end point was disease-free survival. Secondary end points included OS, distant recurrencefree interval (DRFI), and invasive breast cancer–free interval (BCFI).
Summary: After a median follow-up period of 8.1 years, 2074 patients showed disease-free survival compared with 1569 patients showing disease-free survival by the protocol-specified update in 2009. The additional 505 events (a 32% increase) occurred between 2003 and 2011, in the latter phases of the study. In addition, 5936 (74%) of the patients were reported to be alive and without a disease-free survival event at their most recent follow- up. At a median follow-up of 8.7 years, letrozole monotherapy was associated with significantly better disease- free survival compared with tamoxifen therapy (HR, 0.82; 95% CI, 0.74-0.92; P = .002), OS (HR, 0.79; 95% CI, 0.69-0.90; P = .006), DRFI (HR, 0.79; 95% CI, 0.68-0.92; P = .003), and BCFI (HR, 0.80; 95% CI, 0.70- 0.92; P = .002).
Takeaway: In early-stage hormone-responsive breast cancer, 5 years of letrozole monotherapy reduced both recurrence (HR, 0.79) and mortality (HR, 0.82) when compared with 5 years of tamoxifen monotherapy. Sequential treatment with letrozole for 2 years, followed by 3 years of tamoxifen therapy or vice versa, was not different from letrozole monotherapy in patients with BCFI or DRFI. With more than 8 years of follow-up, this study confirms that letrozole is more effective than tamoxifen in the management of early-stage postmenopausal breast cancer.
Bortezomib plus Rituximab Superior to Rituximab Alone in Relapsed Follicular Lymphoma
Background: Bortezomib and rituximab have demonstrated additive activity in preclinical models of lymphoma. Both are active and usually well tolerated in patients with follicular lymphoma (FL) and marginal zone lymphoma. A phase 3 study compared the efficacy and safety of rituximab alone and in combination with bortezomib in patients who were rituximab-naive or rituximab-sensitive and aged 18 years or older with relapsed grade 1 or 2 disease.
Design: This unmasked, open-label, phase 3 trial included 676 rituximab-naïve and rituximab-sensitive patients with relapsed grade 1 or 2 FL from 164 centers in 29 countries across Europe, the Americas, and Asia from April 2006 to August 2008. All patients had an ECOG performance score of 0 to 2, no active central nervous system lymphoma, and adequate hematologic, renal, and hepatic functions. Patients were excluded if they had grade 2 or higher peripheral neuropathy or neuropathic pain; clinical evidence of transformation to aggressive lymphoma; or treatment with antineoplastics, investigational therapy, or radiation therapy within 3 weeks of enrollment, nitrosoureas within 6 weeks, radioimmunoconjugates or toxin immunoconjugates within 10 weeks, stem-cell transplantation within 6 months, or bortezomib at any time before randomization. Eligible patients were randomized to receive five 35-day cycles of intravenous (IV) infusions of rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 2 through 5, either alone (N = 340) or in combination with bortezomib 1.6 mg/m2 (N = 336), which was administered by IV injection on days 1, 8, 15, and 22 in all treatment cycles. Randomization was stratified by FL international prognostic index (FLIPI) score, previous use of rituximab, time since last therapy, and region. The primary end point was PFS, analyzed in the ITT population. Secondary end points included time to progression, time to next treatment, and OS.
Summary: After a median follow-up of 34 months, the median PFS was 11.0 months (95% CI, 9.1-12.0) in the rituximab group and 12.8 months (95% CI, 11.5- 15.0) in the bortezomib plus rituximab group (HR, 0.82; 95% CI, 0.68-0.99; P = .039). The estimated 2- year PFS rates were 23.5% and 31.2%, respectively. In a subgroup analysis, bortezomib plus rituximab was associated with a longer PFS in patients with high-risk features, including high FLIPI score (P = .013) and high tumor burden (P = .019). PFS was also significantly longer in patients aged ?65 years (P = .005) but not in older patients (P = .353). The combination therapy was also associated with a longer PFS than rituximab alone in patients who received previous lines of therapy, but the differences were not significant. Among patients who had received any previous rituximab therapy, the median PFS was 9.2 months in the rituximab group versus 11.4 months in the bortezomib plus rituximab group (HR, 0.93; 95% CI, 0.70-1.24; P = .609). In a post-hoc multivariate analysis for independent prognostic factors for PFS, treatment with bortezomib plus rituximab, time since last antilymphoma treatment >1 year, female sex, absence of tumor burden, and stage I or II disease were associated with a longer PFS. Most patients in both groups who did not receive the 5-cycle median (range, 1-5) of treatment discontinued early in response to disease progression. The rate of adverse events was higher with bortezomib plus rituximab (95%) than with rituximab alone (78%). The most common grade 3 or higher adverse events were neutropenia, infection, diarrhea, herpes zoster, nausea or vomiting, and thrombocytopenia. Drug-related adverse events leading to death occurred in 3 (1%) patients who received bor - tezomib plus rituximab but in none of those who received rituximab alone.
Takeaway: This study shows that bortezomib combined with rituximab improved PFS in relapsed or refractory FL. The greatest benefit for the combination was observed in patients aged <65 years and in those with poor prognostic factors. Significant improvements were also noted in response rates, durability of response, and time to next treatment for the combination. Bortezomib plus rituximab produced a higher rate of adverse events, including grade 3 toxicities such as diarrhea, neutropenia, and infections. This is the first phase 3 study to show the benefits of rituximab alone or in combination in relapsed or refractory FL.
Second-Generation TKIs Produce Faster Response than Imatinib in Newly Diagnosed CML
Background: The second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib have a proven efficacy in the treatment of chronic myeloid leukemia (CML) in patients resistant to or intolerant of imatinib. However, it is unknown whether the European LeukemiaNet (ELN) response definitions (ie, “optimal,” “suboptimal,” and “failure”) that were based on imatinib treatment as front-line therapy are relevant to the second-generation TKIs, because most patients who receive these more potent drugs achieve early complete cytogenetic response (CCyR).
Design: In 2 simultaneous phase 2 trials, 167 patients with newly diagnosed CML in the chronic phase were randomized to nilotinib 400 mg twice daily (N = 81) or to dasatinib 100 mg once daily (N = 86). At 3, 6, 12, and 18 months of therapy, the incidence of optimal, suboptimal, and failure responses (determined according to ELN guidelines) was assessed in patients who were still receiving therapy and had demonstrated a hematologic, cytogenetic, and/or molecular response. Also evaluated at these time points was event-free survival, defined by the period from the start of treatment to the loss of complete hematologic response, the loss of CCyR or major cytogenetic response, the discontinuation of therapy because of toxicity or lack of efficacy, the progression of CML to accelerated or blastic phases, or death. Survival probabilities were estimated by the Kaplan-Meier method and compared by the log-rank test.
Summary: Overall, 155 patients (93%) achieved a CCyR after a median follow-up period of 33 months, including 146 (87%) who achieved a major molecular response (MMR) and 46 (28%) who achieved complete molecular response (CMR). At 3 months, all 160 evaluable patients demonstrated optimal response (ie, complete hematologic response). By 18 months, 99 (84%) of 118 evaluable patients achieved an optimal response. At months 6, 12, and 18, the rates of suboptimal response (ie, less than MMR) were 2%, 1%, and 12%, respectively. The failure response was not demonstrated until month 18, when it occurred in 5 (4%) patients. At each time point, disease-free survival did not differ significantly between patients who achieved CCyR without an MMR or CMR and those who achieved CCyR with an MMR or CMR.
These results confirm that second-generation TKIs used in the frontline setting are highly efficacious, with the majority of responses occurring within the first 3 months of therapy. In contrast, imatinib therapy produces CCyR rates that peak around 12 to 18 months. Since the majority of patients (99%) achieved an optimal response within 3 months, the ELN definitions of response are not applicable in patients being treated with second-generation TKIs.
Takeaway: This study shows that the second-generation TKIs produce CCyRs after 3 months of treatment, a much faster rate than with imatinib (ie, 12-18 months for maximum response). Furthermore, this study shows that the standard response criteria established by the ELN are not appropriate for use with these second generation agents. The authors also propose that for patients receiving nilotinib or dasatinib, achieving a CCyR by 3 months is considered an optimal response, and that a partial cytogenetic response is suboptimal.
High-Risk Myelodysplastic Syndrome Outcomes after Azacitidine Treatment Failure
Background: Treatment with azacitidine is the current standard of care for high-risk myelodysplastic syndrome (MDS), despite frequent primary or secondary treatment failure in many patients. The absence of data on outcomes after treatment failure limits the development of clinical trials and the interpretation of their data. An analysis of 4 clinical trial data sets aimed to describe those outcomes.
Design: Outcomes data from 435 patients with highrisk MDS or acute myeloid leukemia (AML) with 20% to 30% blasts who demonstrated treatment failure after receiving azacitidine therapy between 2000 and 2009 were compiled from 4 clinical trial cohorts: the Johns Hopkins University J9950 and J0443 trials; the AZ001 trial; and the French azacitidine compassionate use program database. Therapy was administered for 8 weeks in the J9950, J0443, and AZ001 trials and for 12 weeks in the French azacitidine compassionate use program. Patients in all cohorts continued their azacitidine regimen until their disease progressed or intolerance to therapy led them to discontinue it. OS rates were estimated using the Kaplan-Meier method, and prognostic factors of OS were determined from univariate analyses.
Summary: A total of 302 (74%) patients received therapy for MDS, and 133 (26%) received therapy for AML. The median follow-up after azacitidine failure was 15 months. The median OS was 5.6 months, and the 1-year and 2-year survival probability was 28.9% and 15.3%, respectively. Factors correlated with a shorter OS included increasing age (P = .002), male sex (P = .04), high-risk cytogenetics (P = .002), higher bone marrow blast count before azacitidine treatment (P = .04), and the absence of previous hematologic response to azacitidine (P = .007). In addition, among initial responders to azacitidine, high-risk cytogenetics were associated with a shorter OS after treatment failure (P = .03). Post-failure treatment data were available for 270 patients. Among this group, the prognosis was worst for patients who received unknown salvage (OS, 3.6 months) or best supportive care (OS, 4.1 months) but was best for those who received investigational agents (overall response rate [ORR], 11%; OS, 13.2 months) or allogeneic stem-cell transplantation (ORR, 68%; OS, 19.5 months). Poor outcomes were also observed in patients who received low-dose chemotherapy (ORR, 0%; OS, 7.3 months) or intensive AMLlike chemotherapy (ORR, 14%; OS, 8.9 months).
Takeaway: This study shows that there is no standard second-line chemotherapy treatment for high-risk MDS after azacitidine failure. Best supportive care or cytotoxic chemotherapy (ie, hydroxyurea, mercaptopurine, low-dose cytarabine, low-dose melphalan, or intense AML-like chemotherapy) were not of any substantial benefit to these patients. A variety of investigational agents—DNA methyltransferase enzyme inhibitors alone or in combination with histone deacetylase inhibitors, thalidomide-derivative (ie, lenalidomide or thalidomide), treatments for patients in clinical trials evaluating nonregistered drugs (including immunotherapy, bryostatin, triapine, farnesyl transferase inhibitors, and mammalian target of rapamycin inhibitors)—produced better OS than best supportive care or cytotoxic chemotherapy. The best outcomes were observed in patients receiving allogeneic bone marrow transplant. The authors suggest that the results of this study can be used as a basis for comparing new agents to be used in palliative care in future trials.