In the Literature - September 2016

September 2016, Vol 7, No 8

In This Article


Enzalutamide Superior to Bicalutamide in Patients with Prostate Cancer

Preclinical models suggested that enz­alutamide (Xtandi), an oral androgen receptor inhibitor, may provide clinical benefit compared with bicalutamide, a nonsteroidal antiandrogen, in patients with nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) who would normally receive bicaluta­mide as part of standard therapy. In the study known as STRIVE in men with nonmetastatic and metastatic CRPC, researchers compared progression-free survival (PFS) with enzalutamide and with bicalutamide (Penson DF, et al. J Clin Oncol. 2016;34:2098-2106).

STRIVE was a multicenter, randomized, double-blind, phase 2 trial that enrolled 396 chemotherapy-naïve men with metastatic or nonmetastatic CRPC. Patients were randomized in a 1:1 ratio to receive enzalutamide 160 mg daily or bicalutamide 50 mg daily. Androgen deprivation therapy was continued in both treatment arms. The median time of receiving treatment was longer with enzalutamide than with bicalutamide (14.7 months vs 8.4 months, respectively). The primary end point was PFS. Key secondary end points were time to prostate-specific antigen (PSA) progression, PSA response of ≥50%, and radiographic PFS for patients with metastatic disease.

Enzalutamide reduced the risk for disease progression or death by 76% (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.18-0.32; P <.001) compared with bicalutamide. Median PFS was also significantly longer with enz­alutamide compared with bicalu­tamide (19.4 months vs 5.7 months, respectively). In addition, enzalutamide was significantly superior to bicaluta­mide in secondary end points.

Enzalutamide was associated with an 81% reduction in the risk for PSA progression compared with a 31% reduction with bicalutamide (HR, 0.19; 95% CI, 0.14-0.26; P <.001). The median time to PSA progression was not reached with enzalutamide compared with 8.3 months with bicalutamide.

The proportion of patients with a ≥50% PSA response was 81% and 31% in the enzalutamide and bicalutamide groups, respectively. In the 139 patients with nonmetastatic disease, the median radiographic PFS was not yet reached in either arm. However, enzalutamide was associated with 76% reduced risk for radiographic PFS (HR, 0.24; 95% CI, 0.10-0.56) compared with bicalutamide.

In the 257 patients with metastatic CRPC, enzalutamide reduced the risk for radiographic PFS by 68% (HR, 0.32; 95% CI, 0.21-0.50; P <.001). The median radiographic PFS in patients with metastatic disease was not reached with enzalutamide compared with 8.3 months with bicalutamide.

The 2 drugs were well-tolerated, with enzalutamide demonstrating an adverse event profile consistent with phase 3 clinical trials.

In an accompanying editorial, Stein and Jang commented that “dramatic improvement in metastasis-free survival in those receiving enzalutamide compared with bicalutamide begs us to re-examine the role of hormonal therapy earlier in the disease continuum” (Stein MN, Jang TL. J Clin Oncol. 2016;34:2075-2078).

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Two-Drug Combination Shows Promise for Recurrent Small-Cell Lung Cancer

Patients with small-cell lung cancer (SCLC) frequently respond to first-line chemotherapy; however, disease progression is rapid, and outcomes with second-line treatments are poor. In a new study, researchers assessed the safety and activity of nivolumab (Opdivo) and the combination of nivolumab and ipilimumab (Yervoy) in patients with SCLC whose disease progressed after ≥1 previous regimens (Antonia SJ, et al. Lancet Oncol. 2016;17:883-895).

CheckMate 032 was a multicenter, open-label, 2-stage, multiarm, phase 1/2 trial that randomized 216 patients with progressive SCLC after ≥1 platinum-­based chemotherapy regimens to single-agent nivolumab or to the combination of nivolumab plus ipilimumab at 1 of 2 doses. In the monotherapy arm, patients received nivolumab 3 mg/kg intravenously every 2 weeks. In the combination arms, patients received nivolu­mab 1 mg/kg plus ipilimumab 3 mg/kg intravenously or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg intravenously every 3 weeks. After 4 cycles, patients in the combination arms received nivolumab monotherapy 3 mg/kg every 2 weeks.

The primary end point was objective response rate (ORR). The secondary end points included overall survival (OS), progression-free survival (PFS), duration of response, and treatment-related adverse events leading to treatment discontinuation.

The ORR was 10% in the nivolumab arm, 23% in the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg arm, and 19% in the nivolumab 3-mg/kg plus ipilimu­mab 1-mg/kg arm. Response generally consisted of partial responses, with 1 complete response observed in the nivolu­mab 1-mg/kg plus ipilimumab 3-mg/kg arm. The median OS was 4.4 months in the monotherapy arm, 7.7 months in the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg cohort, and 6.0 months in the nivolumab 3-mg/kg plus ipilimumab 1-mg/kg cohort. The corresponding 1-year OS was 33% for the nivolumab 3-mg/kg group, 43% for the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg group, and 35% for the nivolumab 3-mg/kg plus ipilimumab 1-mg/kg group.

The median PFS was 1.4 months in the monotherapy arm; in the combination arms, the PFS was 2.6 months in the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg group and 1.4 months in the nivolumab 3-mg/kg plus ipilim­umab 1-mg/kg group. The median duration of response was not reached with single-agent nivolumab; in the combination arms, the median duration of response was 7.7 months and 4.4 months, respectively.

Adverse events leading to treatment discontinuation were observed in 6% of patients in the monotherapy arm, 11% of patients in the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg arm, and 7% in the nivolumab 3-mg/kg plus ipilim­umab 1-mg/kg arm.

Nivolumab alone and in combination with ipilimumab showed antitumor activity with durable responses, encouraging OS, and manageable safety profiles in advanced SCLC. The findings suggest a potential new treatment approach for a population of hard-to-treat patients who have limited therapeutic options.

“Our findings show that nivolumab monotherapy and nivolumab plus ipi­limumab provide clinically meaningful activity and an acceptable safety profile for patients with limited-stage or extensive-stage SCLC and disease progression after at least one previous platinum-containing regimen,” the researchers concluded.

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Olanzapine Helps Prevent Chemotherapy-Related Nausea and Vomiting

Previous single-institution phase 3 trials showed that olanzapine (Zyprexa) could improve the efficacy of existing antiemetic treatments in patients receiving chemotherapy agents associated with a moderate-to-­severe risk for chemotherapy-induced nausea and vomiting (CINV). However, a larger trial was needed to confirm the efficacy and safety of adding olanzapine to standard therapies to prevent CINV. A new, randomized, double-­blind, placebo-controlled, phase 3 clinical trial of olanzapine in patients receiving highly emetogenic chemotherapy now showed that olanzapine significantly reduced the likelihood of nausea in the first 24 hours after chemotherapy compared with placebo (Navari RM, et al. N Engl J Med. 2016;375:134-142).

The current study included 380 patients aged ≥18 years who had not previously received chemotherapy, but were scheduled to receive cisplatin or cyclophosphamide-doxorubicin. Patients were randomly assigned to receive olanz­apine (N = 192) or placebo (N = 188) in combination with 3 other drugs immediately before and for 3 days after receiving their first round of chemotherapy; the doses of the 3 concomitant drugs were similar in the 2 treatment arms.

All participants received a 5-HT3–­receptor agonist (palonosetron 0.25 mg intravenously, granisetron 1 mg intravenously or 2 mg orally, or ondansetron 8 mg intravenously or orally) on chemotherapy day 1, dexamethasone (12 mg orally on day 1, and 8 mg orally on days 2, 3, and 4), and an NK1-receptor antagonist on day 1. The NK1-receptor antagonist was fosaprepitant or aprepitant. The 2 treatment groups received either olanzapine 10 mg orally or matching placebo on days 1 through 4.

The primary end point was nausea prevention at 3 assessment periods; a complete response (no emesis and no use of rescue medication) was the secondary end point.

Olanzapine significantly improved nausea prevention compared with placebo in the first 24 hours after chemotherapy (74% vs 45%, respectively), 1 to 5 days after treatment (42% vs 25%, respectively), and during the entire 5-day period (37% vs 22%, respectively). During the same 3 time periods, the olanzapine arm demonstrated a significantly increased complete response rate compared with the placebo arm: 86% versus 65%, 67% versus 52%, and 64% versus 41%, respectively. Overall, olanzapine combined with the 3 other agents appeared safe. Some patients receiving the drug experienced excessive tiredness, or sedation, with approximately 5% reporting severe sedation. This effect occurred on the second day of treatment but resolved on days 3, 4, and 5, even though patients continued to receive olanzapine on days 3 and 4.

This study demonstrates the efficacy of olanzapine combined with 3 standard antiemetic agents in preventing nausea and vomiting in patients who have not previously received chemotherapy but are currently receiving highly emetogenic chemotherapy.

“Our study showed that olanzapine combined with an NK1-receptor antagonist, a 5-HT3–receptor antagonist, and dexamethasone is more effective than placebo combined with these agents for the prevention of nausea and vomiting in patients with no previous chemotherapy who are receiving highly emetogenic chemotherapy,” the investigators concluded.

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Neratinib Demonstrates Efficacy for a Subgroup of Patients with Breast Cancer

The heterogeneity of breast cancer makes identifying effective therapies challenging. In a recent study, researchers reported the efficacy and safety results of the ongoing I-SPY 2 trial that evaluated the tyrosine kinase inhibitor neratinib among patients with HER2-positive, hormone-receptor (HR)-negative disease (Park JW, et al. N Engl J Med. 2016;375:11-22).

The I-SPY 2 trial is a multicenter, adaptive, phase 2 platform study that evaluates standard chemotherapy with an experimental regimen or with standard chemotherapy alone in patients aged ≥18 years with stage II or III breast cancer who are at high risk for early recurrence. In the current study, patients were randomized to standard neoadjuvant chemotherapy plus neratinib (240 mg/daily for the first 12 weeks) or to standard chemotherapy alone (the control group). Patients in the control group who had HER2-positive disease also received trastuzumab for the first 12 weeks. Patients were categorized according to 8 biomarker subtypes on the basis of HER2 status, HR status, and risk according to a 70-gene profile. Ten clinically relevant biomarkers were used to assess efficacy. The primary end point was pathological complete response (pCR).

A total of 127 patients were assigned to receive neratinib, of which 115 were evaluable; 84 patients were assigned to standard chemotherapy, of which 78 were evaluable. The only significant difference between the 2 groups was HER2 status, with a larger percentage of patients with HER2-positive disease in the neratinib group than in the control group (57% vs 28%, respectively).

Among patients with HER2-positive/HR-negative cancer, treatment with ner­atinib led to an estimated pCR of 56% compared with 33% in the control group. The neratinib regimen has 79% probability of being successful in a phase 3 trial among patients with HER2-positive/HR-negative breast cancer. Adverse events were similar to those in previous studies involving patients with advanced breast cancer, with diarrhea being the most common adverse event.

“The finding of the superiority of neratinib over trastuzumab in this tumor biomarker signature is notable given the experience in a number of trials that sought to improve on the efficacy of the current standard of care,” the researchers concluded.

Phase 3 clinical trials of neratinib as neoadjuvant therapy will be conducted in the I-SPY 3 program.

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