On July 24, 2015 Novartis reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (Press release, Novartis, JUL 24, 2015, View Source [SID:1234506618]). The Company also announced that the US Food and Drug Administration (FDA) has granted priority review for the same patient population.

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"The CHMP positive opinion and FDA priority review of Tafinlar and Mekinist validate the importance of this targeted therapy combination for patients with the most serious form of skin cancer," said Bruno Strigini, President, Novartis Oncology. "This good news for the combination of Tafinlar and Mekinist in metastatic melanoma follows on the FDA’s recent Breakthrough Therapy designation for the combination in BRAF V600 mutation-positive non-small cell lung cancer. We look forward to working with the US and EU regulatory authorities to help bring this targeted therapy combination to more patients who may benefit."

The CHMP positive opinion is based on results from the Phase III COMBI-d and COMBI-v studies. The COMBI-d study showed that the combination of Tafinlar and Mekinist achieved a statistically significant overall survival (OS) benefit compared to Tafinlar monotherapy (median of 25.1 months vs 18.7 months; Hazard Ratio [HR] 0.71 [95% Confidence Interval (CI), 0.55-0.92], p=0.011). In those who received Tafinlar in combination with Mekinist, OS was 74% at 1 year and 51% at 2 years versus 68% and 42% for those who received Tafinlar only, respectively[1]. The COMBI-v study showed that the combination of Tafinlar and Mekinist achieved a statistically significant OS benefit compared to vemurafenib monotherapy (median for the combination not reached vs 17.2 months; HR 0.69 [95% CI, 0.53-0.89], p=0.005). In the COMBI-v study, the rate of OS at 1 year was 72% with the combination of Tafinlar and Mekinist and 65% for those receiving vemurafenib only[2]. The safety results from these studies were consistent with the profile observed to date for the combination; no new safety concerns were observed[1],[2]. The most common adverse reactions seen for combination therapy in both studies at >=20% include pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, arthralgia, vomiting, hypertension, and cough[1]. Adverse events or toxicities were generally manageable with appropriate intervention, as described in the product labelling submitted with the application.

The European Commission will review the CHMP recommendation and is expected to deliver its final decision within three months. The decision will be applicable to all 28 EU member states plus Iceland, Norway and Liechtenstein.

The US FDA granted Priority Review in metastatic melanoma for the supplemental New Drug Application (sNDA) for the combination of Tafinlar and Mekinist, which included data from the COMBI-d and COMBI-v studies. Since January 2014, the combination of Tafinlar and Mekinist has been approved for use in the US in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma as detected by an FDA-approved test. The combination was approved through the FDA’s Accelerated Approval program and reviewed under a Priority Review designation. The approval was contingent on the results of the COMBI-d study, which was designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma with a BRAF V600 mutation. A PDUFA date is in November 2015.

Metastatic melanoma is the most serious and life-threatening type of skin cancer[3] and is associated with low survival rates with a five-year survival of about 20% for those with late-stage disease[4]. There are about 200,000 new cases of melanoma diagnosed worldwide each year[5], approximately half of which have BRAF mutations[4],[6]. Gene tests can determine whether a tumor has a BRAF mutation, and results can play a key role in prognosis and determining appropriate treatment[4].

The FDA Breakthrough Therapy designation in BRAF V600 mutation-positive non-small cell lung cancer (NSCLC) is based on interim analysis results from an ongoing single-arm, two-stage, Phase II trial investigating the Tafinlar and Mekinist combination in patients with metastatic NSCLC who had the BRAF V600E mutation and failed at least one line of chemotherapy. The data, which were presented at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), showed an overall response rate (ORR) of 63% [95% CI: 40.6, 81.2%] based on investigator assessment; the analysis by independent review was consistent with an ORR of 68% [95% CI: 45.1, 86.1%]. The most common adverse events (incidence >=20%) among patients included in this analysis were pyrexia, diarrhea, nausea, vomiting, decreased appetite, asthenia, cough, peripheral edema, and rash[7].

Breakthrough Therapy designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint. The designation includes all of the fast track program features, as well as more intensive FDA guidance. It is a distinct status from both Accelerated Approval and Priority Review, which can also be granted to the same drug if relevant criteria are met[8].

Tafinlar and Mekinist in combination for NSCLC is the sixth Breakthrough Therapy designation for Novartis, continuing the company’s trajectory as a leader in developing innovative therapies to help treat diseases in which there remains significant unmet medical need.

About the COMBI-d Study
COMBI-d is a pivotal Phase III, randomized, double-blinded study comparing the combination of the BRAF inhibitor, Tafinlar, and the MEK inhibitor, Mekinist, to single agent therapy with Tafinlar and placebo in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study randomized 423 patients at investigative sites in Australia, Europe and North and South America. The primary endpoint of this study was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DoR), and safety. There was no crossover between treatment arms[1].

Updated results from the COMBI-d study showed that the combination of Tafinlar and Mekinist achieved a statistically significant OS benefit compared to Tafinlar monotherapy (median of 25.1 months vs 18.7 months; HR 0.71 [95% CI, 0.55-0.92], p=0.011). In those who received the Tafinlar and Mekinist combination, OS was 74% at 1 year and 51% at 2 years versus 68% and 42% for those who received Tafinlar only, respectively. The analysis for the combination also showed median PFS of 11.0 months, ORR of 69%, and median DoR of 12.9 months. The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for Tafinlar monotherapy; no new safety concerns were observed. The most common adverse events (>=20%) in the combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, joint pain (arthralgia), hypertension, vomiting, cough, and peripheral edema. More patients had AEs leading to dose modifications in the combination arm compared to Tafinlar monotherapy. Increased incidence (57% vs 33%) and severity (grade 3, 7% (n=15) vs 2% (n=4)) of pyrexia occurred with combination treatment as compared to Tafinlar monotherapy. There was a lower incidence of cutaneous squamous cell carcinoma (cuSCC) (link is external) including keratoacanthoma with the combination arm (3% (n=6)) compared to the Tafinlar monotherapy arm (10% (n=22)). Discontinuation of treatment due to adverse events occurred in 11% (n=24) vs 7% (n=14) of patients in the combination group and the monotherapy group, respectively[1].

About the COMBI-v Study
COMBI-v was a two-arm, open-label, Phase III study comparing the combination of Tafinlar and Mekinist combination therapy with vemurafenib monotherapy in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The primary endpoint of this study was OS[2].

Results from the COMBI-v study showed a 31% decrease in the risk of death for patients treated with Tafinlar and Mekinist combination therapy compared to vemurafenib monotherapy (HR 0.69 [95% CI, 0.53-0.89], p=0.005). At 12 months, the rate of OS was 72% for the combination of Tafinlar and Mekinist and 65% for vemurafenib monotherapy. The analysis for the combination also showed median PFS of 11.4 months, ORR of 64%, and median DoR of 13.8 months. The most frequent adverse events in the Tafinlar and Mekinist combination arm (>=30%) were pyrexia, nausea, diarrhea, and chills. More patients had AEs leading to dose modifications in the combination arm compared to the vemurafenib monotherapy arm. For the combination group compared to the vemurafenib group, there was a lower incidence of rash, 22% (n=76) vs 43% (n=149); photosensitivity reaction, 4% (n=13) vs 22% (n=78); hand-foot syndrome, 4% (n=14) vs 25% (n=87); skin papillomas, 2% (n=6) vs 23% (n=80); squamous-cell carcinomas and keratoacanthomas, 1% (n=5) vs 18% (n=63); and hyperkeratosis, 4% (n=15) vs 25% (n=86). Adverse events occurring more frequently in the combination arm compared with the vemurafenib arm included pyrexia, 53% (n=184) vs 21% (n=73), respectively, and bleeding events, 18% (n=62) vs 7% (n=25), respectively. Discontinuation of treatment due to adverse events was similar between the treatment groups: 13% (n=44) for the combination group compared to 12% (n=41) for the monotherapy group[2].

On July 24, 2015 I FUJIFILM KYOWA KIRIN BIOLOGICS Co., Ltd. (President and CEO: Hideaki Nomura; hereinafter "Fujifilm Kyowa Kirin Biologics") reported that it has entered into an agreement with AstraZeneca plc (hereinafter "AstraZeneca") to establish a joint venture for the development and commercialisation of FKB238 in development for the treatment of multiple solid tumours (Press release, Kyowa Hakko Kirin, JUL 24, 2015, View Source [SID:1234506617]).

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FKB238 is a biosimilar version of bevacizumab, an anti-VEGF1 humanized monoclonal antibody with established efficacy across a range of cancers including colorectal and non-small cell lung cancer2. Fujifilm Kyowa Kirin Biologics commenced its Phase I clinical trial for FKB238 in Europe in November 2014.

Under the terms of the agreement, the new joint venture that is equally co-funded by the two companies and will use FKB238’s non-clinical, clinical development data compiled by Fujifilm Kyowa Kirin Biologics thus far. Fujifilm Kyowa Kirin Biologics will transfer the rights to FKB238 to the new joint venture, and will receive a lump-sum payment of USD45 million in return.

"Together with Kyowa Hakko Kirin, Fujifilm has been developing high-quality, cost-competitive biosimilars, by adopting to Fujifilm Kyowa Kirin Biologics its technological expertise in precise production control and strict quality assurance, cultivated over the years in photographic film business." said Takatoshi Ishikawa, Director, Senior Vice President, General Manager Pharmaceutical Products Division of Fujifilm. "We hope that FKB238 will help patients as soon as possible by the joint venture accelerating the drug development."

"Since 2012, we have put effort in biosimilar business with Fujifilm through Fujifilm Kyowa Kirin Biologics." said Wataru Murata, Executive Officer, Director, Corporate Strategy & Planning Department of Kyowa Hakko Kirin. "We expect that this joint venture with AstraZeneca will accelerate the global development of FKB238 as a potential companion to other oncology medicines for the treatment of a range of cancers."

Fujifilm Kyowa Kirin Biologics was established by FUJIFILM Corporation (President and CEO: Shigehiro Nakajima; hereinafter "Fujifilm") and Kyowa Hakko Kirin Co., Ltd. (President and CEO: Nobuo Hanai, hereinafter "Kyowa Hakko Kirin") on March 27, 2012 as a company for developing, manufacturing and marketing biosimilars. In its pipeline are FKB238 as well as biosimilar of the fully human anti-TNF-A monoclonal antibody, adalimumab (Development No. FKB327) a drug with dramatic therapeutic effects for rheumatoid arthritis. FKB327 is under Phase III clinical trial in the United States and other countries.

By merging the technologies in advanced production, quality control and analysis which Fujifilm has developed over many years through its photographic film business, with the proprietary technologies and know-how which Kyowa Hakko Kirin has accumulated through its biopharmaceutical R&D and manufacturing, Fujifilm Kyowa Kirin Biologics creates revolutionary production processes and reduces costs for the production of biosimilars. Through this partnership, the company will develop and manufacture reliable, high quality, cost-competitive biosimilar products and commercialize these products in a timely manner. With this strategy, Fujifilm Kyowa Kirin Biologics aims to hold a leading position in the expanding biosimilar market.

* VEGF is an abbreviation for Vascular Endothelial Growth Factor. VEGF is a glycoprotein which promotes mitogenic activity in vascular endothelial cells, which in turn stimulates angiogenesis.
** Lung cancer can be broadly divided into small cell lung cancer and non-small cell lung cancer, with 85% of lung cancers falling into the latter category. Non-small cell lung cancers include squamous cell cancer, adenocarcinoma and large cell carcinoma