publication date: May. 31, 2019

Drugs & Targets

FDA approves first mesothelioma treatment in 15 years

FDA has approved a tumor-treating fields device in combination with pemetrexed plus platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced, or metastatic malignant pleural mesothelioma.

The device, the NovoTTF-100L System (Novocure), is the first treatment for MPM approved by the FDA in 15 years, since pemetrexed was approved in 2004.

TTF therapy uses electric fields to disrupt solid tumor cancer cell division. Previously, FDA approved Optune, another TTF delivery system from Novocure, for the treatment of glioblastoma in 2011.

MPM is a rare but aggressive cancer strongly associated with asbestos exposure. Prior to the new approval, pemetrexed plus cisplatin was the only FDA-approved therapy for patients with unresectable MPM, according to a company statement.

The new device for MPM was approved under the Humanitarian Device Exemption, which was created to encourage innovation in rare diseases.

FDA approval is based on the results of the STELLAR trial, a prospective, single-arm trial of NovoTTF-100L plus chemotherapy first-line in patients with unresectable MPM.

In the trial, 80 unresectable MPM patients treated with TTF plus chemotherapy experienced a median overall survival of 18.2 months. However, Novocure acknowledged “the effectiveness of this device for this use has not been demonstrated.”

Median OS was 21.2 months for patients with epithelioid MPM (n = 53) and 12.1 months for patients with non-epithelioid MPM (n = 21). More than half (62%) of patients were alive at 1 year.

The overall response rate was 40%, all were partial responses. In addition, 57% had stable disease; the remaining 3% of patients had progressive disease. At least one follow-up CT scan was performed in most patients (n = 72).

Median progression-free survival was 7.6 months.

Trial results show NovoTTF-100L can be combined with chemotherapy, as there was no increase in serious systemic adverse events when the two modalities were joined. Mild-to-moderate skin irritation was the most common device-related side effect.


FDA approves Piqray + fulvestrant in breast cancer

FDA has approved Piqray (alpelisib, formerly BYL719) in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor positive, human epidermal growth factor receptor-2 negative, PIK3CA-mutated, advanced or metastatic breast cancer, as detected by an FDA-approved test following progression on or after an endocrine-based regimen.

Piqray is sponsored by Novartis.

Approximately 40% of patients living with HR+/HER2- breast cancer have PIK3CA. PIK3CA mutations are associated with tumor growth, resistance to endocrine treatment, and a poor overall prognosis. Piqray targets the effect of PIK3CA mutations and may help overcome endocrine resistance in HR+ advanced breast cancer.

FDA approval is based on the results of the phase III trial, SOLAR-1, that showed Piqray plus fulvestrant nearly doubled median progression-free survival compared to fulvestrant alone in HR+/HER2- advanced breast cancer patients with a PIK3CA mutation (median PFS 11.0 months vs. 5.7 months; HR=0.65, 95% CI: 0.50-0.85; p<0.001). Piqray provided consistent PFS results across pre-specified subgroups, including among patients previously treated with a CDK4/6 inhibitor.

Overall response rate more than doubled when Piqray was added to fulvestrant in patients with a PIK3CA mutation (ORR= 35.7% vs 16.2% for fulvestrant alone, p=0.0002).

Piqray and its associated companion diagnostic test from QIAGEN N.V. was the first combination product approved under the FDA Oncology Center of Excellence Real-Time Oncology Review pilot program.

“Today’s approval is expected to change the way we practice medicine in advanced breast cancer. For the first time, physicians can test for PIK3CA biomarkers and develop a treatment plan based on the genomic profile of a patient’s cancer,” said Fabrice André, global SOLAR-1 principal investigator, research director and head of INSERM Unit U981, professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France.

“In the SOLAR-1 phase III trial, alpelisib plus fulvestrant nearly doubled median PFS and more than doubled overall response rate in patients with a PIK3CA mutation, offering them new hope for longer life without progression.”

Patients with HR+/HER2- advanced breast cancer can be selected for treatment with Piqray based on the presence of PIK3CA mutations. Concurrent with the approval of Piqray, the therascreen PIK3CA companion diagnostic test from QIAGEN was also approved by the FDA and is now available for patient testing.      

SOLAR-1 is a global, phase III randomized, double-blind, placebo-controlled trial studying Piqray in combination with fulvestrant for postmenopausal women, and men, with PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor. SOLAR-1 is the pivotal phase III trial that supported this approval.

The trial randomized 572 patients. Patients were allocated based on central tumor tissue assessment to either a PIK3CA-mutated cohort (n=341) or a PIK3CA non-mutated cohort (n=231).

Within each cohort, patients were randomized in a 1:1 ratio to receive continuous oral treatment with Piqray (300 mg once daily) plus fulvestrant (500 mg every 28 days + Cycle 1 Day 15) or placebo plus fulvestrant.

Stratification was based on visceral metastases and prior CDK4/6 inhibitor treatment. Patients and investigators are blinded to PIK3CA mutation status and treatment.

The primary endpoint is local investigator assessed PFS using RECIST 1.1 for patients with a PIK3CA mutation. The key secondary endpoint is overall survival. Secondary endpoints include, but are not limited to, overall response rate, clinical benefit rate, health-related quality of life, efficacy in PIK3CA non-mutated cohort, safety, and tolerability. SOLAR-1 is ongoing to assess overall survival and other secondary endpoints.


FDA approves lenalidomide for follicular and marginal zone lymphoma

FDA approved lenalidomide (Revlimid) in combination with a rituximab product for previously treated follicular lymphoma and previously treated marginal zone lymphoma.

The drug is sponsored by Celgene Corp.

Approval was based on two clinical trials: AUGMENT (NCT01938001) and MAGNIFY (NCT01996865). In AUGMENT, 358 patients with relapsed or refractory FL or MZL were randomized (1:1) to receive lenalidomide and rituximab or rituximab and placebo. In the single-arm component of MAGNIFY, 232 patients with relapsed or refractory FL, MZL, or mantle cell lymphoma received 12 induction cycles of lenalidomide and rituximab.

In AUGMENT, the primary endpoint was progression-free survival in the intent-to-treat population, as determined by an independent review committee. Median PFS was 39.4 months (95% CI: 22.9, NE) in the lenalidomide arm and 14.1 months (95% CI: 11.4, 16.7) in the placebo-containing arm (HR 0.46; 95% CI: 0.34, 0.62; p<0.0001).

The objective response rate by IRC assessment for patients with follicular lymphoma was 80% (118/147; 95% CI: 73%, 86%) in the lenalidomide arm compared with 55.4% (82/148; 95% CI: 47%, 64%) in the control arm.

For patients with marginal zone lymphoma, the ORR by IRC assessment was 65% (20/31; 95% CI: 45%, 81%) compared with 44% (14/32; 95% CI: 26%, 62%), respectively.

In MAGNIFY, the ORR by investigator assessment was 59% (104/177; 95% CI: 51%, 66%) for patients with follicular lymphoma. Median response duration was not reached with a median follow-up of 7.9 months (95% CI: 4.6, 9.2). For patients with marginal zone lymphoma, the ORR by investigator assessment was 51% (23/45; 95% CI: 36%, 66%). Median response duration was not reached with a median follow-up of 11.5 months (95% CI: 8.0, 18.9).

The recommended lenalidomide dose for FL or MZL is 20 mg once daily orally on days 1-21 of repeated 28-day cycles for up to 12 cycles.


FDA approves gilteritinib for refractory AML

FDA approved the addition of overall survival data in labeling for gilteritinib (Xospata), which is indicated for adult patients who have relapsed or refractory acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test.

The drug is sponsored by Astellas Pharma US, Inc.

Approval was based on the ADMIRAL trial (NCT02421939), which included 371 adult patients with relapsed or refractory AML having a FLT3 ITD, D835, or I836 mutation identified by the LeukoStrat CDx FLT3 Mutation Assay.

Patients were randomized (2:1) to receive Xospata 120 mg once daily (n=247) over continuous 28-day cycles or prespecified salvage chemotherapy (n=124). Salvage chemotherapy included either intensive cytotoxic chemotherapy or a low-intensity regimen.

For the analysis, OS was measured from the randomization date until death by any cause. The median OS was 9.3 months for patients receiving gilteritinib and 5.6 months for those on the chemotherapy arm (HR 0.64; 95% CI: 0.49,0.83; 1 sided p-value=0.0004).

The results were consistent in the intensive chemotherapy stratum (HR 0.66; 95% CI: 0.47-0.93) and the low-intensity regimen stratum (HR 0.56; 95% CI: 0.38-0.84).

The recommended gilteritinib dose is 120 mg orally once daily.

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