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Recent Drug Approvals and Revisions in Prescribing Information


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THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) issued the following approvals and prescribing information revisions in August 2018.

Lenvatinib Approved for Unresectable Hepatocellular Carcinoma

THE FDA approved lenvatinib (Lenvima) for the first-line treatment of patients with unresectable hepatocellular carcinoma. Approval was based on the international, multicenter, randomized, open-label, noninferiority REFLECT trial conducted in 954 patients with previously untreated, metastatic, or unresectable hepatocellular carcinoma.

In the REFLECT trial, patients were randomized 1:1 to receive lenvatinib (12 mg orally once daily for patients with a baseline body weight of ≥ 60 kg and 8 mg orally once daily for patients with a baseline body weight of < 60 kg) or sorafenib (Nexavar; 400 mg orally twice daily). Treatment continued until radiologic disease progression or unacceptable toxicity.

REFLECT demonstrated that lenvatinib was noninferior but not statistically superior to sorafenib for overall survival (hazard ratio [HR] = 0.92; 95% confidence interval [CI] = 0.79–1.06). Median overall survival was 13.6 months in the lenvatinib arm and 12.3 months in the sorafenib arm. REFLECT also demonstrated a statistically significant improvement in progression-free survival with lenvatinib as compared to sorafenib.

Median progression-free survival was 7.3 months in the lenvatinib arm and 3.6 months in the sorafenib arm (HR = 0.64; 95% CI = 0.55–0.75; P < .001) per modified Response Evaluation Criteria in Solid Tumors (RECIST) for hepatocellular carcinoma; findings were similar according to RECIST, version 1.1. The overall response rate was higher for the lenvatinib arm as compared to sorafenib (41% vs 12% per modified RECIST and 19% vs 7% per RECIST 1.1).

The most common adverse reactions observed in the lenvatinib-treated patients with hepatocellular carcinoma (≥ 20%) in order of decreasing frequency were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea.

The recommended lenvatinib dosage for patients with hepatocellular carcinoma is 12 mg orally once daily in patients 60 kg or greater actual body weight or 8 mg orally once daily in patients less than 60 kg actual body weight. Full prescribing information for lenvatinib can be found at www.accessdata.fda.gov.

Nivolumab Approved for Certain Patients With Small Cell Lung Cancer

NIVOLUMAB (OPDIVO) has received FDA approval for patients with metastatic small cell lung cancer (SCLC) whose cancer has progressed after platinum-based chemotherapy and at least one other line of therapy. Approval for this indication has been granted under accelerated approval based on overall response rate and duration of response.

This approval for nivolumab had been granted Priority Review from the FDA. It was based on data from the SCLC cohort of the ongoing phase I/II CheckMate-032 study evaluating nivolumab monotherapy in patients who experienced disease progression after platinum-based chemotherapy.

Of 109 patients receiving nivolumab after platinum-based chemotherapy and at least 1 other prior line of therapy, 12% (n = 13/109; 95% CI = 6.5%–19.5%) responded to treatment based on assessment by a blinded independent central review, regardless of programmed cell death ligand 1 (PD-L1) expression. Twelve patients had a partial response (11%), and one patient had a complete response (0.9%). Among these responders, the median duration of response was 17.9 months (range = 3.0–42.1 months).

Nivolumab was discontinued in 10% of patients, and 1 dose was withheld in 25% of patients for an adverse reaction. Serious adverse reactions occurred in 45% of patients. The approved dosing for nivolumab in this indication is 240 mg administered every 2 weeks by intravenous infusion until disease progression or unacceptable toxicity.

The most frequent serious adverse reactions reported in ≥ 2% of patients were pneumonia, dyspnea, pneumonitis, pleural effusion, and dehydration. The most common adverse reactions (reported in ≥ 20% of patients) were fatigue (45%), decreased appetite (27%), musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%), constipation (20%), and cough (20%).

Pembrolizumab Plus Chemotherapy Approved for Nonsquamous NSCLC

THE FDA approved pembrolizumab (Keytruda) in combination with pemetrexed (Alimta) and platinum as first-line treatment of patients with metastatic, nonsquamous non–small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations. This most recent approval represents fulfillment of a postmarketing commitment demonstrating the clinical benefit of this product. This action is based on the results of KEYNOTE-189, a randomized, multicenter, double-blind, active controlled study enrolling 616 patients receiving first-line treatment for metastatic, nonsquamous NSCLC.

Pembrolizumab was previously granted accelerated approval for this indication in May 2017 based on improvements in overall response rate and progression-free survival for patients randomized to receive pembrolizumab administered with pemetrexed and carboplatin as compared with pemetrexed and carboplatin alone in the KEYNOTE-021 study.

In KEYNOTE-189, patients were randomized (2:1) to receive pembrolizumab (or placebo) in combination with pemetrexed and investigator’s choice of either cisplatin or carboplatin every 3 weeks for 4 cycles followed by pembrolizumab (or placebo) and pemetrexed. Treatment with pembrolizumab continued until disease progression, unacceptable toxicity, or a maximum of 24 months. The primary efficacy outcome measures were overall survival and progression-free survival as assessed by a blinded independent committee review (using RECIST, version 1.1).

The trial demonstrated a statistically significant improvement in overall survival for patients randomized to receive pembrolizumab and chemotherapy (HR = 0.49; 95% CI = 0.38–0.64; P < .00001) in a prespecified interim analysis. Median overall survival was not reached at the time of the data cutoff in the pembrolizumab-plus-chemotherapy arm and was 11.3 months for those in the chemotherapy arm.

The trial also demonstrated an improvement in progression-free survival for patients randomized to receive pembrolizumab plus chemotherapy (HR = 0.52; 95% CI = 0.43–0.64; P < .00001). The median progression-free survival was 8.8 months for patients receiving pembrolizumab plus chemotherapy and 4.9 months for those receiving chemotherapy alone. The overall response rate was significantly higher (48% vs 19%; P = .0001) for those in the pembrolizumab-plus-chemotherapy arm. The median response duration was 11.2 months and 7.8 months, respectively.

The most common adverse reactions reported in ≥ 20% of patients in KEYNOTE-189 were fatigue/ asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.

The recommended pembrolizumab dose and schedule for nonsquamous NSCLC is 200 mg as an intravenous infusion over 30 minutes every 3 weeks.

Updated Prescribing Information for Pembrolizumab and Atezolizumab in Urothelial Carcinoma

THE FDA has updated the prescribing information for pembrolizumab and atezolizumab (Tecentriq) to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin therapy. The FDA approved two different companion diagnostic tests—one for use with each agent—as described below.

On August 16, 2018, the FDA approved the Dako PD-L1 IHC 22C3 PharmDx Assay as a companion diagnostic to select patients with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible for treatment with pembrolizumab. The 22C3 assay determines PD-L1 expression by using a combined positive score (CPS) assessing PD-L1 staining in tumor and immune cells. The updated indication for pembrolizumab is described in the prescribing information as follows:

Pembrolizumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥ 10) as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

On July 2, 2018, the FDA approved the Ventana PD-L1 (SP142) Assay as a companion diagnostic test to select patients with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible for treatment with atezolizumab. The SP142 assay determines PD-L1 expression in immune cells. The updated indication for atezolizumab is described in the prescribing information as follows:

Atezolizumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

• Are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1–stained tumor-infiltrating immune cells covering ≥ 5% of the tumor area), as determined by an FDA-approved test, or

• Are not eligible for any platinum-containing therapy regardless of level of tumor PD-L1 expression.

The FDA updated the prescribing information for both drugs to require use of an FDA-approved test for the selection of patients being treated in the first-line setting who are cisplatin-ineligible. The second-line indications in urothelial carcinoma for both drugs remain unchanged. View the updated label information at https://labels.fda.gov. ■


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