With Commentaries by
University of California, San Francisco
Professor of Pharmacy
College of Pharmacy
Mare Island, Vallejo, CA
- Adding Antiandrogen to Radiation Therapy Extends Survival in Relapsed Prostate Cancer
- Venetoclax plus Rituximab an Attractive Treatment Option for Relapsed or Refractory CLL
- Aggressive Local Consolidative Therapy Shows Benefit in Patients with Oligometastatic Non–Small-Cell Lung Cancer
- Lutetium-177-Dotatate Extends Progression-Free Survival in Patients with Midgut Neuroendocrine Tumors
Adding Antiandrogen to Radiation Therapy Extends Survival in Relapsed Prostate Cancer
BACKGROUND: Patients with prostate cancer who undergo radical prostatectomy and have disease relapse often require salvage radiation therapy, which leads to disease progression in 50% of patients. Combining radiation therapy with antiandrogen therapy has prolonged survival in certain men with intact prostates. A new study evaluated whether adding antiandrogen therapy (bicalutamide) to radiation therapy could extend overall survival after radical prostatectomy.
METHODS: This double-blind, placebo-controlled clinical trial randomized 760 patients with prostate cancer that relapsed after radical prostatectomy with lymphadenectomy to receive radiation therapy combined with 24 months of antiandrogen therapy (bicalutamide tablets, 150 mg daily) or placebo. Patients were given salvage radiation therapy within 12 weeks of randomization, with a total dose of 64.8 Gy administered in 36 daily fractions of 1.8 Gy. Placebo or bicalutamide 150 mg was administered daily since the start of radiation therapy for 24 months. The primary end point was overall survival. Secondary end points included disease-specific death, distant metastases (ie, metastatic prostate cancer), local disease progression, non–disease-specific death, any prostate cancer progression, including a second biochemical recurrence, and adverse events.
RESULTS: The median follow-up was 13 years. Adding antiandrogen therapy to radiation therapy resulted in a higher overall survival rate (76.3%) at 12 years in patients with persistent or recurrent postoperative disease compared with those who received placebo plus radiation therapy (71.3%). At 12 years, the cumulative incidence of distant metastatic prostate cancer was 14.5% in the bicalutamide group versus 23% in the placebo group; the cumulative incidence of a second biochemical recurrence was 44% compared with 67.9%, respectively. The rates of local disease progression and disease progression of any type (ie, a second biochemical recurrence) were lower in the patients who received bicalutamide than in patients who received placebo.
Multivariate analyses demonstrated that negative prognostic factors that significantly affected overall survival included receiving placebo, having a prostate-specific antigen level >1.5 ng/mL at study entry, a prostate cancer Gleason score of 8 to 10, a Karnofsky performance status of 80 or 90, and age ≥65 years. Adverse events were similar between the 2 groups; however, grade 1 to 3 gynecomastia occurred in 69.7% of patients who received bicalutamide versus 10.9% of those who received placebo.
The addition of antiandrogen therapy to radiation therapy resulted in increased overall survival, as well as disease-specific, and metastasis-free survival, with the higher rate of overall survival becoming more apparent in the second decade after therapy.
Source: Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med. 2017;376:417-428.
Venetoclax plus Rituximab an Attractive Treatment Option for Relapsed or Refractory CLL
BACKGROUND: Monotherapy with venetoclax has demonstrated robust responses and complete remission in patients with relapsed or refractory BCL-2–positive chronic lymphocytic leukemia (CLL). Encouraging synergy results from preclinical models combining venetoclax with rituximab led to this new study.
METHODS: This phase 1b dose-escalation clinical trial included 49 patients with relapsed or refractory CLL or small lymphocytic lymphoma, all of whom received oral venetoclax in a daily, stepwise increase to target doses ranging from 200 mg to 600 mg, plus monthly infusions of rituximab (375 mg/m² in month 1, and 500 mg/m² in months 2-6). The primary end points included an assessment of the safety profile, defining a maximum tolerated dose, and determining the recommended phase 2 venetoclax dose when used in combination with rituximab. The secondary end points were an evaluation of the pharmacokinetic profile, and an analysis of efficacy (ie, overall response, duration of response, and time to tumor progression).
RESULTS: The overall response rate with venetoclax plus rituximab was 86% (42 patients); 51% of patients had a complete response (CR), and 57% of patients achieved negative marrow minimal residual disease in their bone marrow, with acceptable safety. The 2-year estimates for ongoing response and progression-free survival (PFS) were 89% and 82%, respectively. Overall, 11 patients had disease progression during therapy; 6 of these patients achieved a partial response before their CLL progressed.
The adverse event profile and pharmacokinetics of venetoclax were not significantly altered by the addition of rituximab. Grade 3 or 4 adverse events occurred at similar rates as reported in previous studies of venetoclax monotherapy, with no significant increase in the incidence or severity of neutropenia, and without an increase in the percentage of patients who had a severe infection. The most common serious adverse events included pyrexia, febrile neutropenia, lower respiratory tract infection, and pneumonia. The most common grade 3 or 4 peripheral blood cytopenias included neutropenia, thrombocytopenia, anemia, febrile neutropenia, and leukopenia.
Overall, the combination of venetoclax and rituximab was found safe and effective in this patient population and does not compromise the venetoclax dose. These results suggest that rituximab can be safely administered with venetoclax at a dose of 400 mg daily. The maximum tolerated dose of venetoclax was not defined.
Source: Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18:230-240.
|COMMENTARY BY ROBERT J. IGNOFFO|
According to the National Comprehensive Cancer Network (NCCN) guidelines, the current standards of care for relapsed B-cell CLL with high-risk features, such as 17p deletion (del17p), are ibrutinib monotherapy or idelalisib plus rituximab.1 In a phase 1b/2 clinical trial, ibrutinib monotherapy produced an estimated 75% PFS and 83% overall survival (OS) at 26 months, and an objective response rate of 68%.2 In a follow-up phase 3 clinical trial, ibrutinib significantly prolonged PFS and reduced mortality risk by 57%, with a partial response of 43%.3 After the first planned interim analysis of a phase 3 placebo-controlled clinical trial of idelalisib plus rituximab, the study was stopped early as a result of a significant difference in the efficacy of the active combination versus rituximab plus placebo.4 At 12 months, the PFS and OS were significantly improved in the idelalisib arm compared with the placebo arm—81% versus 13%, and 92% versus 80%, respectively.
Venetoclax has been studied as a single drug, showing impressive activity in patients with relapsed B-cell CLL with del17p,5 leading to the US Food and Drug Administration (FDA) approval of venetoclax (Venclexta) in April 2016. Venetoclax is indicated for patients with CLL with del17p as detected by an FDA-approved test who received previous therapy. Venetoclax received accelerated approval for this indication based on overall response rate, and continued approval is dependent on confirmatory results of the drug’s clinical benefit. Major precautions listed in the prescribing information include tumor lysis syndrome, neutropenia, immunosuppression, and embryo-fetal toxicity.
The purpose of the current study by Seymour and colleagues was to determine whether venetoclax in combination with rituximab could improve the results of venetoclax given as monotherapy. This phase 1b study of venetoclax plus rituximab showed a comparable response rate and PFS to the standard regimens above. CRs were seen in an impressive 51% of patients. The median duration of treatment was approximately 10 months for those achieving a CR. OS was not evaluated because of additional therapies that were allowed after disease relapse associated with venetoclax. These results support the outcomes of earlier studies. Currently, the NCCN guidelines recommend venetoclax as a first-line treatment for patients with refractory CLL.1
Finally, because of the risk for tumor lysis syndrome, especially in high-risk patients, the dosing regimen for venetoclax must be followed closely and prophylaxis for tumor lysis syndrome must be given with allopurinol or rasburicase.1
1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): chronic lymphocytic leukemia/small lymphocytic lymphoma. Version 1.2017. www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed February 16, 2017.
In the March 2017 issue of Journal of Hematology Oncology Pharmacy, in the From the Literature section, an error was made in the article “Venetoclax plus Rituximab an Attractive Treatment Option for Relapsed or Refractory CLL.” In his commentary, Robert J. Ignoffo, PharmD, FASHP, FCSHP, mentioned ibrutinib and idelalisib for the treatment of relapsed or refractory chronic myeloid leukemia (CLL) with high-risk features. The current National Comprehensive Cancer Network guidelines now list venetoclax as the second agent for CLL; therefore, venetoclax should have been included in his description.
Aggressive Local Consolidative Therapy Shows Benefit in Patients with Oligometastatic Non–Small-Cell Lung Cancer
BACKGROUND: Although several small and retrospective prospective clinical trials have demonstrated the potential benefit of local therapy in patients with stage IV oligometastatic non–small-cell lung cancer (NSCLC) and limited metastases, such an advantage has yet to be shown in randomized, well-controlled clinical trials.
METHODS: This controlled, multicenter, phase 2 clinical trial randomized 49 patients with stage IV NSCLC and ≤3 metastases in a 1:1 ratio to receive local (chemoradiotherapy or local surgery of all metastases), with or without subsequent maintenance therapy (n = 25) or maintenance therapy alone (n = 24). Standard-of-care maintenance options consisted of pemetrexed and bevacizumab (for nonsquamous NSCLC), erlotinib (for patients with EGFR mutations), crizotinib (for patients with ALK rearrangement), and observation, defined as close surveillance but without any cytotoxic treatment. In addition to other criteria, eligible patients had to have received standard first-line systemic therapy, defined as ≥4 cycles of platinum doublet chemotherapy, or an epidermal growth factor receptor (EGFR) inhibitor or an anaplastic lymphoma kinase (ALK) inhibitor in patients with EGFR or ALK mutations, respectively, for ≥3 months. The primary end point was progression-free survival (PFS). The secondary end points included overall survival, safety and tolerability, time to progression of previous metastatic lesions, time to appearance of new metastatic lesions, and quality of life.
RESULTS: In patients with oligometastatic NSCLC, local consolidative therapy was practical, tolerable, and significantly prolonged PFS in patients with ≤3 metastases compared with maintenance therapy or observation. Overall, 13 patients had disease progression or died in the consolidative therapy group compared with 17 patients in the maintenance therapy group. The median PFS was significantly longer with consolidative therapy than with maintenance treatment (11.9 months vs 3.9 months, respectively), and at 1 year, PFS was 48% in the consolidative therapy group versus 20% in the maintenance treatment group.
No grade 4 adverse events or treatment-related deaths occurred in either treatment groups, and adverse events were similar between the 2 groups. Grade 3 adverse events in the consolidative therapy group were esophagitis, anemia, pneumothorax, and abdominal pain. Grade 3 adverse events in the maintenance therapy group included fatigue and anemia.
Source: Gomez DR, Blumenschein GR Jr, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17:1672-1682.
Lutetium-177-Dotatate Extends Progression-Free Survival in Patients with Midgut Neuroendocrine Tumors
BACKGROUND: Limited treatment options exist for patients with advanced midgut neuroendocrine tumors that progressed during therapy with a first-line somatostatin analog. Since 1992, radiolabeled somatostatin analog treatment has demonstrated considerable therapy potential in patients with advanced, well-differentiated neuroendocrine tumors. Investigators in the multicenter NETTER-1 clinical trial sought to compare the safety and efficacy of lutetium-177 (177Lu) with that of high-dose octreotide long-acting repeatable (LAR) in patients with advanced, progressive, somatostatin-receptor–positive neuroendocrine tumors of the midgut.
METHODS: NETTER-1 was an open-label, randomized, international, phase 3 clinical trial that randomized 229 patients with inoperable, metastasized, or locally advanced midgut neuroendocrine tumors that progressed during treatment with octreotide LAR to receive 177Lu-Dotatate 7.4 GBq every 8 weeks plus best supportive care or high-dose octreotide LAR 60 mg monotherapy every 4 weeks in a 1:1 ratio. The best supportive care for the 177Lu-Dotatate group comprised octreotide LAR 30 mg every 4 weeks for symptom control. Progression-free survival (PFS) was the primary end point. The secondary end points included the objective response rate, safety, side-effect profile, and overall survival.
RESULTS: 177Lu-Dotatate demonstrated longer PFS and was associated with fewer adverse events than octreotide LAR monotherapy. A primary analysis revealed that PFS at 20 months was an estimated 65.2% in the 177Lu-Dotatate group versus 10.8% in the octreotide LAR monotherapy group. Response rates were 18% in the 177Lu-Dotatate group compared with 3% in the octreotide LAR group, and regardless of stratification and prognostic factors (eg, tumor grade, age, tumor marker levels), 177Lu-Dotatate was associated with consistent treatment benefits. Overall survival was assessed in a planned interim analysis; 14 deaths occurred in patients who received 177Lu-Dotatate, whereas 26 deaths occurred in patients who received octreotide LAR, representing an estimated risk for death that was 60% lower in the 177Lu-Dotatate group than in the octreotide LAR group.
Overall, 129 patients had ≥1 adverse events associated with the trial therapy (86% of patients in the 177Lu-Dotatate group vs 31% of patients in the octreotide LAR group). Fatigue, asthenia, abdominal pain, and diarrhea were among the most common adverse events reported in the 177Lu-Dotatate group, and ≥97% were grade 1 or 2. Grade 3 or 4 adverse event rates were similar between the treatment groups, but 1%, 2%, and 9% of patients in the 177Lu-Dotatate group had grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia, respectively, compared with no patients in the octreotide LAR group. No renal toxic effects were reported during the observation period.
Source: Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125-135.