FDA Approvals in November 2017: Novel Drugs, New Indications

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THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) approved a number of novel drugs and new indications in November 2017. Several of them are listed here. 

Fulvestrant/Abemaciclib Combination in Breast Cancer 

ON NOVEMBER 15 , the FDA approved fulvestrant (Faslodex) in combination with abemaciclib (Verzenio), a cyclin-dependent kinase (CDK) 4/6 inhibitor, for the treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy. The approval is based on data from the phase III MONARCH 2 trial (Clinical Trials. gov Identifier NCT0217703), which met the study’s primary endpoint of progression-free survival. The trial included 669 women with hormone receptor–positive, HER2-negative advanced breast cancer whose disease progressed on or after neoadjuvant or adjuvant endocrine therapy, within 12 months from the end of adjuvant endocrine therapy, or while receiving first-line endocrine therapy for metastatic disease. 

Study Design 

Participants were randomly assigned to receive intramuscular injection of fulvestrant at 500 mg with abemaciclib or placebo orally twice daily in a 2:1 ratio. Pre/ perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin acetate (Zoladex) for at least 4 weeks prior to and for the duration of the study. Patients remained on treatment until the development of progressive disease or unmanageable toxicity. 

Approximately 59% of patients in each of the treatment arms— fulvestrant in combination with abemaciclib and fulvestrant with placebo—received endocrine therapy as their first therapy for advanced breast cancer; the remaining 38% of patients in the experimental and control treatment arms received this regimen as their second endocrine therapy for advanced breast cancer. Overall, 55.8% had visceral disease and 26.9% had bone-only disease; 25% of patients had primary endocrine resistance, and 2.7% had locally advanced disease. 

Key Findings 

The results showed a statistically significant increase in investigator-assessed median progression-free survival of 7.1 months (16.4 vs 9.3 months) in patients who received fulvestrant/abemaciclib over fulvestrant/placebo (hazard ratio [HR] = 0.553, 95% confidence interval [CI] = 0.449–0.681; P < .0001). 

Detailed results of MONARCH 2 were published by Sledge et al in the Journal of Clinical Oncology.1 

Brentuximab Vedotin in Primary Cutaneous Anaplastic Large Cell Lymphoma 

ON NOVEMBER 9, brentuximab vedotin (Adcetris) received regular approval for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma or CD30-expressing mycosis fungoides who have received prior systemic therapy. Approval was based on the phase III, randomized, open-label, multicenter ALCANZA trial (NCT01578499) of brentuximab vedotin in patients with mycosis fungoides or primary cutaneous anaplastic large cell lymphoma who had previously received one prior systemic therapy and required systemic treatment. Data are expected to be presented at the upcoming meeting of the American Society of Hematology in December. 

The trial randomized 131 patients (1:1) to receive either brentuximab vedotin or the physician’s choice of methotrexate or bexarotene. Efficacy was established based on improvement in objective response rate lasting 4 months, complete response rate, and progression-free survival assessed by an independent review facility. 

Key Findings 

ALCANZA demonstrated an improvement (P < .001) in objective response rate lasting 4 months in the brentuximab vedotin arm vs the physician’s choice arm, 56% (95% CI = 44%–68%) vs 12% (95% CI = 4%–21%), respectively. The complete response rate was also superior (P = .007) in the brentuximab vedotin arm vs the physician’s choice arm, 16% (95% CI = 8%–27%) vs 2% (95% CI = 0%–8%). 

ALCANZA also demonstrated improvement in progression-free survival with an estimated hazard ratio of 0.27 (95% CI = 0.17–0.43, P < .001). The median progression-free survival was 17 months in the brentuximab vedotin arm vs 4 months in the physician’s choice arm. 

The most common adverse reactions occurring in > 20% of patients receiving brentuximab vedotin were anemia, peripheral sensory neuropathy, nausea, diarrhea, fatigue, and neutropenia. The most common adverse event leading to treatment discontinuation was peripheral neuropathy. 

The recommended dose of brentuximab vedotin is 1.8 mg/kg up to a maximum of 180 mg as an intravenous infusion over 30 minutes every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity. 

Letermovir for CMV Prophylaxis 

ON NOVEMBER 9, the FDA approved letermovir (Prevymis) once-daily tablets for oral use and injection for intravenous infusion for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT). 

In the phase III clinical trial that supported approval (NT02137772), significantly fewer patients in the letermovir group (38%, n = 122 of 325) compared to the placebo group (61%, n = 103 of 170) developed clinically significant CMV infection, discontinued treatment, or had missing data through week 24 posttransplant, the primary efficacy endpoint. All-cause mortality in patients receiving letermovir was lower compared to placebo—12% vs 17%, respectively, at week 24 posttransplant. 

Adverse Events 

The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in patients receiving letermovir than placebo (13% vs 6%). The rate of adverse events occurring in at least 10% of letermovir-treated transplant recipients and at a frequency at least 2% greater than placebo were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%). The most frequently reported adverse event that led to study drug discontinuation was nausea (occurring in 2% of letermovir patients and 1% of placebo patients). Hypersensitivity reaction, with associated moderate dyspnea, occurred in one patient following the first infusion of intravenous letermovir after switching from oral letermovir, leading to treatment discontinuation. 

The recommended dosage of letermovir is 480 mg administered once daily, initiated as early as day 0 and up to day 28 posttransplantation (before or after engraftment), and continued through day 100 posttransplantation. 

Alectinib for Metastatic NSCLC 

ON NOVEMBER 6, the FDA granted regular approval to alectinib (Alecensa) for treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non–small cell lung cancer (NSCLC), as detected by an FDA-approved test. 

Alectinib received accelerated approval for treatment of patients with ALK-positive metastatic NSCLC whose disease progressed on or who were intolerant of crizotinib (Xalkori) in December 2015, based on an independent review committee–assessed overall response rate of 38% and 44% among 87 and 138 patients, respectively, in 2 single-arm trials. 

This current approval is based on data from the ALEX trial (NCT02075840), a randomized, multicenter, open-label, active-controlled trial conducted in 303 patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease. All patients were required to have evidence of ALK rearrangement identified by the Ventana ALK (D5F3) CDx Assay performed through central laboratory testing. Patients were randomized 1:1 to receive alectinib at 600 mg orally twice daily (n = 152) or crizotinib at 250 mg orally twice daily (n = 151). 

ALEX demonstrated an improvement in progression-free survival as assessed by blinded independent review committee, with a hazard ratio of 0.53 (95% CI = 0.38–0.73; P < .0001). The estimated median progression-free survival for patients randomized to alectinib was 25.7 months (95% CI = 19.9 to not estimable [NE]) compared with 10.4 months (95% CI = 7.7–14.6) for those randomized to crizotinib. The time to cause-specific central nervous system (CNS) progression as assessed by independent review committee was also significantly improved; there was a lower incidence of disease progression in the CNS as the first site of disease progression, alone or concurrent with systemic disease progression, in the alectinib arm (12%) compared to the crizotinib arm (45%). The confirmed overall response rate was 79% (95% CI = 72%–85%) and 72% (95% CI = 64%–79%) in the alectinib and crizotinib arms, respectively. Among the 120 responders in the alectinib arm and the 109 responders in the crizotinib arm, the proportion of patients with a response duration of ≥ 12 months was 64% and 36%, respectively. 

CNS involvement was assessed in all patients. Among the 43 patients with measurable CNS lesions on baseline brain scans, the CNS overall response rate, assessed by blinded independent review committee neuroradiologist, was 81% (95% CI = 58%–95%) in the alectinib arm and 50% (95% CI = 28%–72%) in the crizotinib arm. Among patients with measurable CNS lesions and a CNS response, the proportion of patients with a CNS response duration of ≥ 12 months was 59% in the alectinib arm and 36% in the crizotinib arm. 

The most common adverse reactions (occurring in ≥ 20% of patients taking alectinib in ALEX) were fatigue, constipation, edema, myalgia, and anemia. Serious adverse reactions occurred in 28% of patients treated with alectinib. Adverse reactions leading to alectinib discontinuation occurred in 11%. Adverse reactions that led to alectinib discontinuation in 1% or more of patients were renal impairment, hyperbilirubinemia, increased alanine aminotransferase, and increased aspartate aminotransferase. Dose interruption due to adverse reactions occurred in 19% of alectinib-treated patients, while dose reductions were required in 16%. 

The recommended dose of alectinib is 600 mg orally twice daily with food. ■


1. Sledge GW, Masakazu T, Neven P, et al: MONARCH 2: Abemacicilib in combination with fulvestrant in women with HR+/ HER2-negative advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 25:2875-2884, 2017.