On November 7, 2014 MorphoSys reported that the Food & Drug Administration (FDA) has granted fast track designation to MOR208, MorphoSys’s humanized Fc engineered monoclonal antibody against CD19, for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (Press release MorphoSys, NOV 7, 2014, View Source [SID:1234500937]). The FDA’s fast track program aims to expedite the development and review of drugs that have the potential to fill an unmet medical need in serious or life-threatening conditions.

“First results of our ongoing Phase 2 trial, which we will present at this year’s ASH (Free ASH Whitepaper) conference in December, have helped to identify diffuse large B-cell lymphoma as a valuable development opportunity for MOR208. We are therefore delighted to have received the fast track designation for further development of MOR208 in DLBCL. The more frequent interactions with the FDA that this enables will help us to expedite the development of MOR208 in this particular subset of non-Hodgkin’s lymphoma patients,” commented Dr. Arndt Schottelius, Chief Development Officer of MorphoSys AG.

DLBCL is the most common lymphoma and accounts for approximately 25 percent of all NHLs in the developed world. The disease occurs primarily in older individuals, though it can also occur in children and young adults in rare cases.

MOR208 is a humanized monoclonal antibody targeting the antigen CD19, which is being developed for the treatment of B-cell malignancies. The program is currently in phase 2 clinical development in chronic lymphocytic leukemia (CLL), acute lymphoblastic B-cell leukemia (B-ALL) and non-Hodgkin’s lymphoma (NHL). MOR208 was in-licensed from Xencor Inc. in 2010.

On November 7, 2014 Boehringer Ingelheim reported data from a pre-specified subgroup-analysis of the pivotal Phase III LUX-Lung 3 trial which demonstrated that Asian non-small cell lung cancer (NSCLC) patients with the most common type of EGFR mutation, (exon 19 deletion; del19), lived significantly longer after receiving first-line treatment with afatinib compared to chemotherapy (33.3 vs 22.9 months, respectively) (Press release Boehringer Ingelheim, NOV 6, 2014, View Source [SID:1234500936]). This equated to a significant 43% reduction in the risk of death. The data were presented today at the 2014 IASLC Asia Pacific Lung Cancer Conference (APLCC), in Kuala Lumpur.

Overall survival results from this pre-specified Asian subgroup-analysis are consistent with the overall del19 population in LUX-Lung and with the previously reported Asian Phase III LUX-Lung 6 trial, in which patients with the del19 mutation lived a median of more than one year longer if they started treatment with afatinib rather than standard chemotherapy. No significant difference in overall survival was seen for Asian patients with the L858R mutation in the LUX-Lung 3 and LUX-Lung 6 subgroup-analyses, respectively.

Professor Yi-Long Wu from the Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China and principal investigator of the LUX-Lung 6 trial commented: “Afatinib is the first treatment to demonstrate a significant overall survival benefit for NSCLC patients with the del19 mutation, the most common EGFR mutation. More than half of the world’s lung cancer cases occur in Asia. Therefore, EGFR testing for NSCLC patients is important in order to identify the patients eligible for targeted therapy.”

Demonstrating an overall survival benefit is a key advancement for NSCLC treatments and an important outcome for patients. In Asia, more than 900,000 new cases of lung cancer are diagnosed each year.4 The prevalence of EGFR mutations in Asian NSCLC patients is approximately 40%, and del19 accounts for 50% of these mutations, representing a substantial group of lung cancer patients who could potentially benefit from treatment with afatinib.

Previously reported data from the LUX-Lung 3 trial showed afatinib provided further benefits to NSCLC patients with common EGFR mutations (del19 and L858R), which account for 90% of all EGFR mutations. Patients with common EGFR mutations taking afatinib lived for over a year without their tumour growing (progression free survival; PFS of 13.6 months; primary endpoint) versus just over half a year (PFS of 6.9 months) for chemotherapy. In addition, more patients taking afatinib, experienced an improvement in lung cancer-related symptoms (cough, shortness of breath, chest pain) and a significantly better quality of life, when compared with chemotherapy.

Furthermore, in a combined exploratory analysis of the LUX-Lung 3 and LUX-Lung 6 trials, afatinib prolonged overall survival (secondary endpoint) of patients with common EGFR mutations compared with standard chemotherapy by a median of 3 months (27.3 compared to 24.3 months, respectively).

Adverse events for afatinib in the LUX-Lung 3 and 6 trials were as expected with EGFR inhibition, and were predictable, manageable and reversible. Diarrhoea and rash/acne were the most frequently reported side effects with afatinib therapy.

Professor James Chih-Hsin Yang, Director of the Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan and principal investigator of the LUX-Lung 3 trial commented: “Overall survival benefit in trials involving advanced lung cancer patients has rarely been observed up until now. Data from the LUX-Lung 3 and LUX-Lung 6 trials, individually demonstrating an overall survival benefit of more than 12 months in the subgroup of NSCLC patients with the del19 mutation taking afatinib versus chemotherapy, is very encouraging. These studies suggest that various EGFR mutations should be studied or treated differently in the future.”

On November 6, 2014 Novartis reported that the US Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) did not recommend the investigational compound LBH589 (panobinostat), a pan-deacetylase (pan-DAC) inhibitor, for patients with previously treated multiple myeloma when used in combination with bortezomib and dexamethasone (Press release, Novartis, NOV 6, 2014, View Source [SID:1234500932]).

The Committee’s vote will be considered by the FDA in its review of the LBH589 new drug application (NDA), but the FDA is not bound to follow the Committee’s guidance. The final decision regarding US approval is made by the FDA.

“We are disappointed by this voting outcome and believe the results from our clinical trials provide strong evidence to support LBH589 as a potential first-in-class treatment option for multiple myeloma, a cancer where an unmet patient need exists,” said Bruno Strigini, President, Novartis Oncology. “We will continue to work with the FDA as it completes its review of the US application.”

Data presented at today’s meeting included two clinical studies evaluating LBH589 in combination with bortezomib and dexamethasone for patients with relapsed or relapsed and refractory multiple myeloma: a Phase III randomized, double-blind, placebo-controlled, multicenter global registration trial called PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) and a Phase II US multicenter, single-arm, open-label study called PANORAMA-2[1].

About multiple myeloma and LBH589
Multiple myeloma is a cancer of the plasma cells, a kind of white blood cell present in bone marrow-the soft, blood-producing tissue that fills the center of most bones. The cancer is caused by the production and growth of abnormal cells within the plasma, which multiply and build up in the bone marrow, pushing out healthy cells and preventing them from functioning normally[2]. Multiple myeloma is an incurable disease with a high rate of relapse (when the cancer returns) and patients often become refractory (unresponsive to therapy), despite currently available treatments[3]. It typically occurs in individuals 60 years of age or older, with few cases in individuals younger than 40[4].

Epigenetics is the cell programming that governs gene expression and cell development[5]. In multiple myeloma, the normal epigenetic process is disrupted (also called epigenetic dysregulation) resulting in the growth of cancerous plasma cells, potential resistance to current treatment and ultimately disease progression[6],[7].

LBH589 is a potent pan-deacetylase (pan-DAC) inhibitor that if approved will be a first-in-class therapy for patients with previously treated multiple myeloma[8]. As an epigenetic regulator, LBH589 may help restore cell programming in multiple myeloma[9].

Because LBH589 is an investigational compound, the safety and efficacy profile has not yet been established. Access to this investigational compound is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the compound. Because of the uncertainty of clinical trials, there is no guarantee that LBH589 will ever be commercially available anywhere in the world.