publication date: Aug. 31, 2018
Drugs & Targets
Imbruvica + rituximab becomes first non-chemo combination for Waldenström’s macroglobulinemia
The Janssen Pharmaceutical Companies of Johnson & Johnson announced the FDA approval of Imbruvica (ibrutinib) in combination with rituximab for the treatment of Waldenström’s macroglobulinemia.
The approval expands the label for Imbruvica in WM beyond its approved use as a monotherapy to include combination use with rituximab. The approval represents the first approved non-chemotherapy combination option for the treatment of WM.
Imbruvica first received FDA approval in WM as a monotherapy in January 2015 via the Breakthrough Therapy Designation pathway, making it the first FDA-approved therapy for the disease. The expanded label marks the ninth FDA approval for Imbruvica since 2013. Imbruvica is a first-in-class Bruton’s tyrosine kinase inhibitor jointly developed and commercialized by Janssen Biotech Inc. and Pharmacyclics LLC, an AbbVie company.
This approval is based on results from the randomized, double-blind, placebo-controlled iNNOVATE study (PCYC-1127), the largest phase III study of a non-chemotherapy combination in WM patients. The iNNOVATE study evaluated Imbruvica in combination with rituximab versus placebo plus rituximab in 150 patients with either relapsed/refractory disease or previously untreated WM.
At a median follow up of 26.5 months, a significant improvement in the Independent Review Committee-assessed primary endpoint of progression-free survival was seen with Imbruvica plus rituximab when compared with placebo plus rituximab (30-month PFS rates were 82% vs. 28%, respectively). Patients in the Imbruvica plus rituximab treatment arm experienced an 80% reduction in relative risk of disease progression or death compared with patients treated with placebo plus rituximab (hazard ratio=0.20; confidence interval, 0.11-0.38, p<0.0001).
FDA approves lenvatinib for unresectable hepatocellular carcinoma
FDA approved lenvatinib capsules (Lenvima) for first-line treatment of patients with unresectable hepatocellular carcinoma.
The drug is sponsored by Eisai Inc.
Approval was based on an international, multicenter, randomized, open-label, non-inferiority trial (REFLECT; NCT01761266) conducted in 954 patients with previously untreated, metastatic or unresectable HCC. 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 (400 mg orally twice daily). Treatment continued until radiological disease progression or unacceptable toxicity.
REFLECT demonstrated that lenvatinib was non-inferior but not statistically superior to sorafenib for overall survival (HR 0.92; 95% CI: 0.79, 1.06). Median OS in the lenvatinib arm was 13.6 months 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 PFS 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<0.001) per modified RECIST for HCC; findings were similar according to RECIST 1.1. The overall response rate was higher for the lenvatinib arm as compared to sorafenib (41% vs. 12% per mRECIST and 19% vs. 7% per RECIST 1.1).
Lenvima gets European approval for advanced, unresectable hepatocellular carcinoma
Eisai and Merck said the European Commission granted a marketing authorization for the oral receptor tyrosine kinase inhibitor Lenvima (lenvatinib), as a single agent for the first-line treatment of adult patients with advanced or unresectable hepatocellular carcinoma who have received no prior systemic therapy.
Lenvima is the first new, first-line treatment for advanced or unresectable HCC in a decade to show an overall survival treatment effect by statistical confirmation of non-inferiority against standard of care.
Lenvima is marketed in Japan for the treatment of HCC and in the United States for the treatment of first-line unresectable HCC, and applications seeking approval for this indication have been submitted to additional countries.
FDA approves pembrolizumab + chemo for first-line metastatic non-squamous NSCLC
FDA approved pembrolizumab (Keytruda) in combination with pemetrexed and platinum as first-line treatment of patients with metastatic, non-squamous non-small cell lung cancer, with no EGFR or ALK genomic tumor aberrations.
Keytruda is sponsored by Merck & Co.
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 pembrolizumab administered with pemetrexed and carboplatin as compared with pemetrexed and carboplatin alone in the KEYNOTE-021 study.
The approval represents fulfillment of a postmarketing commitment demonstrating the clinical benefit of this product. This action is based on the results of KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active controlled study enrolling 616 patients receiving first-line treatment for metastatic NSqNSCLC.
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 (RECIST 1.1.)
The trial demonstrated a statistically significant improvement in OS for patients randomized to pembrolizumab and chemotherapy (HR 0.49; 95% CI: 0.38, 0.64; p<0.00001) in a pre-specified interim analysis.
The median OS was not reached at the time of the data cut-off in the pembrolizumab plus chemotherapy arm and was 11.3 months for those in the chemotherapy arm. The trial also demonstrated an improvement in PFS for patients randomized to pembrolizumab plus chemotherapy (HR 0.52; 95% CI: 0.43, 0.64; p<0.00001). The median PFS 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=0.0001) for those in the pembrolizumab plus chemotherapy arm and the median response duration was 11.2 months and 7.8 months, respectively.
FDA updates prescribing information for Keytruda, Tecentriq
FDA has updated the prescribing information for Keytruda (pembrolizumab) and Tecentriq (atezolizumab) 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 cisplatin-ineligible. FDA approved two different companion diagnostic tests, one for use with Keytruda and one for use with Tecentriq, as described below.
FDA approved the Dako PD-L1 IHC 22C3 PharmDx Assay (Dako North America, Inc.) as a companion diagnostic to select patients with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible for treatment with Keytruda. The 22C3 assay determines PD-L1 expression by using a combined positive score assessing PD-L1 staining in tumor and immune cells.
The updated indication for Keytruda is: Keytruda 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 [Combined Positive Score ≥ 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.
FDA approved the Ventana PD-L1 (SP142) Assay (Ventana Medical Systems, Inc.) as a companion diagnostic test to select patients with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible for treatment with Tecentriq. The SP142 assay determines PD L1 expression in immune cells.
The updated indication for Tecentriq is: TECENTRIQ 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 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. The tests used in the trials to determine PD-L1 expression are listed in Section 14 of each drug label.
Nivolumab gets accelerated approval for third-line metastatic small cell lung cancer
FDA granted an accelerated approval to nivolumab (Opdivo) for patients with metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy.
The drug is sponsored by Bristol-Myers Squibb Co. Inc.
Approval was based on demonstration of a durable overall response rate in a subgroup of patients from CheckMate-032 (NCT01928394), a multicenter, open-label trial in patients with metastatic solid tumors. This subgroup comprised 109 patients with metastatic SCLC, with disease progression after platinum-based therapy and at least one other prior line of therapy, regardless of tumor PD-L1 status. All patients received nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks.
The major efficacy outcome measures were overall response rate and duration of response according to RECIST v1.1 as assessed by blinded independent central review. The ORR was 12% (95% CI: 6.5, 19.5). Responses were durable for 6 months or longer in 77%, 12 months or longer in 62%, and 18 months or longer in 39% of the 13 responding patients. PD-L1 tumor status did not appear to be predictive of response.
Safety data was evaluated in 245 patients with metastatic SCLC with disease progression following platinum-based chemotherapy and received at least one dose of nivolumab.
FDA approves Kyowa Kirin’s Poteligeo for mycosis fungoides and Sézary Syndrome
Kyowa Hakko Kirin Co. Ltd. said FDA has granted approval for Poteligeo (mogamulizumab-kpkc) for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy. FDA granted Priority Review and Breakthrough Therapy Designation in late 2017.
Poteligeo is a humanized monoclonal antibody directed against CC chemokine receptor 4, which is frequently expressed on leukemic cells of certain blood cancers including CTCL. Using the proprietary Potelligent technology, the amount of fucose in the sugar chain structure of Poteligeo is reduced, which enhances the antibody dependent cellular cytotoxicity.
“Mycosis fungoides and Sézary syndrome can be disfiguring, and debilitating. MAVORIC, the largest study of systemic therapy ever conducted in MF and SS, showed that mogamulizumab prolonged progression-free survival compared to vorinostat in patients with relapsed or refractory MF or SS,” said Jeffrey Humphrey, president of Kyowa Kirin Pharmaceutical Development, Inc. “We look forward to the publication of MAVORIC’s primary results and to ongoing scientific exchange within the medical and academic communities.”
Because CTCL manifests itself in skin lesions, it is often mistaken for other non-critical skin conditions, which can delay conclusive diagnosis and treatment options. MF and SS are the two most common subtypes of CTCL. MF is the most common subtype, accounting for 50-70% of cases. It is a slow progressing form of lymphoma that can involve the skin, blood, lymph nodes and organs, and may be associated with severe infections. SS accounts for approximately 3% of CTCL cases and is a more aggressive, leukemic form of CTCL.
FDA approval of Poteligeo is supported by the MAVORIC (Mogamulizumab anti-CCR4 Antibody Versus Comparator In CTCL) study, which is the largest randomized trial in MF and SS and the first pivotal trial in CTCL to use PFS as a primary endpoint.
MAVORIC was a phase III open-label, multi-center, randomized study of mogamulizumab versus vorinostat in patients with MF and SS who have failed at least one prior systemic treatment. The study was conducted in the U.S., Europe, Japan and Australia, and randomized a total of 372 patients to mogamulizumab or vorinostat. The results showed that mogamulizumab demonstrated significantly superior PFS at a median of 7.6 months [95% CI: 5.6, 10.2] compared to 3.1 months with vorinostat [95% CI: 2.8, 4.0], [hazard ratio 0.53: 95% CI: 0.41, 0.69; p<0.001]. The confirmed overall response rate for mogamulizumab and vorinostat was 28% and 5%, respectively (p<0.001).
FDA granted Poteligeo Breakthrough Therapy Designation for the treatment of MF and SS in adult patients, and evaluated Poteligeo with Priority Review, which is reserved for drugs that treat a serious condition and, if approved, would provide a significant improvement in treatment safety or effectiveness.