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BREAKING NEWS: Daratumumab pushes forward toward FDA approval

Home/News, Research, Side effects, Supplements/Drugs, Tips/BREAKING NEWS: Daratumumab pushes forward toward FDA approval

BREAKING NEWS: Daratumumab pushes forward toward FDA approval

Important news as the promising new immunotherapy, daratumumab, continues to move swiftly toward FDA approval.

My friends at Genmab and Jannsen in the Netherlands emailed me details last evening, along with some helpful background information to review:

Daratumumab is an investigational human anti-CD38 monoclonal antibody that received Breakthrough Therapy Designation from the FDA in May, 2013, as a treatment for patients with multiple myeloma who are refractory to both a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who have received three or more prior lines of therapy, including a PI and an IMiD.

Here’s the email:

Hi Pat,
Today, data from the Phase 1/2 GEN501 study of daratumumab in heavily pre-treated patients with multiple myeloma was published in The New England Journal of Medicine. A few key points to note:
• Single-agent daratumumab demonstrated a 36 percent overall response rate with responses improving over time.
• Study results also showed 65 percent of responding patients remained in remission at 12 months.
• Patients enrolled in the study had a median of four prior lines of therapy, and 64 percent were refractory to both PIs and IMiDs.
• Data from the study were included in the rolling Biologic License Application submitted to the U.S. FDA.

The Phase 1/2 GEN501 study precedes the Phase 2 MMY2002 (SIRIUS) trial of daratumumab recently presented at ASCO 2015. Interim GEN501 data was presented at ASCO 2014.

Multiple myeloma, an incurable disease, is the third most common blood cancer in the U.S., following only leukemia and lymphoma.

[i] Approximately 26,850 new patients will be diagnosed with multiple myeloma, and approximately 11,240 people will die from the disease in the U.S. in 2015.[ii]

See below for full press release. I would be happy to put you in touch with Peter F. Lebowitz, Global Oncology Head at Janssen or lead author Henk M. Lokhorst, M.D., Ph.D., Department of Haematology, VU University Medical Center, Amsterdam, Netherlands, should you have any further queries.

Best, Jerica

Thanks, Jerica! Here’s the lead part of the press release; I’m not including all of the company information and disclaimers:

Data Published in The New England Journal of Medicine Show Single-Agent Daratumumab Demonstrated a 36 Percent Overall Response Rate and Tolerable Safety Profile in Heavily Pre-Treated Multiple Myeloma Patients

Study results also showed 65 percent of responding patients remained in remission at 12 months

RARITAN, N.J., August 26, 2015 – Janssen Research & Development, LLC announced today data from the multicenter, two-part, open-label Phase 1/2 GEN501 study published in The New England Journal of Medicine show daratumumab, an investigational, human anti-CD38 monoclonal antibody, demonstrated a tolerable safety profile as a monotherapy in patients with multiple myeloma who had relapsed after or were refractory (resistant) to at least two or more prior lines of therapy, including proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), chemotherapy and autologous stem cell transplantation. Daratumumab also demonstrated a 36 percent overall response rate (ORR) in patients treated with a 16 mg/kg dose, with responses improving (or “deepening”) over time. Patients enrolled in the study had a median of four prior lines of therapy and 64 percent were refractory to both PIs and IMiDs.

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by excess growth and survival of malignant plasma cells.[1] Patients who are refractory to both PIs and IMiDs have a poor prognosis, with an estimated median overall survival of nine months.[2]

“What is impressive about this study is that daratumumab monotherapy induced durable responses that improved, or deepened, over time and 65 percent of responding patients remained in remission at 12 months,” said lead author Henk M. Lokhorst, M.D., Ph.D., Department of Haematology, VU University Medical Center, Amsterdam, Netherlands. “These findings speak to the potential of daratumumab as an option for patients with multiple myeloma who no longer respond to existing therapies.”

The GEN501 trial had a two-part study design. In Part 1, 32 patients were treated with escalating doses and no maximum tolerated dose was identified. In Part 2, 72 patients were enrolled in a dose expansion cohort and received either 8 mg/kg (30 patients) or 16 mg/kg (42 patients) of daratumumab at various schedules until disease progression or unmanageable toxicity to optimize doses identified in Part 1. Following this study, 16 mg/kg was chosen as the dose to be used in all daratumumab clinical trials.

Patients had a median of four prior lines of therapy and 79 percent were refractory to their last therapy, including both lenalidomide and bortezomib (64 percent). Additionally, 76 percent of patients previously received an autologous stem cell transplant. The primary endpoint for this trial was safety. Secondary endpoints were pharmacokinetics, objective response according to the International Myeloma Working Group (IMWG) uniform response criteria for myeloma, relative reductions in the levels of M protein and free light chains, time to disease progression, duration of response, progression-free survival and overall survival.

In the 16 mg/kg cohort, the ORR was 36 percent (11 partial responses, two very good partial responses and two complete responses) and 10 percent in the 8 mg/kg cohort (three partial responses). The two complete responses were confirmed with the use of a novel assay. Median progression-free survival was 5.6 months (95% CI: 4.2, 8.1) and 65 percent (95% CI: 28, 86) of responders remained in remission at 12 months.

“These data were part of our recent submission package to the FDA for daratumumab. Our hope is that daratumumab will offer a new treatment for patients with multiple myeloma who are greatly in need of new options,” said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen. “We are confident in our comprehensive development plan for daratumumab, which includes studying the medicine in earlier lines of therapy, both as a single agent and in combination with existing therapies.”

In the 16 mg/kg cohort, serious adverse events (AEs) occurred in 33 percent of patients. Infusion-related reactions (IRRs) occurred in 71 percent of patients in both the 8 mg/kg and 16 mg/kg cohorts, and all were grades 1 and 2, except for the occurrence of grade 3 reactions in one patient. The majority of IRRs occurred during the first infusion, with notably fewer during subsequent infusions. No patient discontinued treatment due to an IRR. The most common AEs in either treatment group were fatigue, allergic rhinitis and pyrexia (fever). The most frequent hematologic AE was neutropenia (abnormally low levels of neutrophils, a type of white blood cell), which occurred in 12 percent of patients (n=5) in the 16 mg/kg cohort. Grade 3 or 4 AEs were reported in 26 percent of patients in the 16 mg/kg cohort, with pneumonia (n=5) and thrombocytopenia (abnormally low levels of platelets in the blood; n=4) as the most common in both the 8 mg/kg and 16 mg/kg cohorts.

On July 9, 2015, Janssen completed the rolling submission of its Biologic License Application (BLA) for daratumumab to the FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an IMiD, or who are double refractory to a PI and an IMiD. Daratumumab received Breakthrough Therapy Designation from the FDA for this patient population in May 2013. The regulatory submission for daratumumab will be primarily supported by data from the Phase 2 MMY2002 (SIRIUS) monotherapy study presented in May/June 2015 at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO), along with additional data from four other studies, including GEN501.

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab. If approved, daratumumab would be commercialized in the U.S. by Janssen Biotech, Inc.

So we already had a feeling that daratumumab is safe to use, especially when compared to powerful IMiDs and proteasome inhibitors (PIs). And we all know an active compound like dara will work better when combined with another, big hitter. But if a patient is refractory to Revlimid (IMiD) and Velcade (PI), what will doctors choose to pair dara with?

DR RichardsonLet’s review. Coincidentally (or not), a helpful analysis was published in Medical Xpress yesterday, featuring Dana-Farber’s myeloma guru, Dr. Paul Richardson. Unfortunately, the article also focuses on dara as a single agent (with dex, of course):

Immunotherapy agent benefits patients with drug-resistant multiple myeloma

If it was the other, soon to be approved immunotherapy agent, elotuzumab, it would be paired with pomalidomide. Not sure if dara works best with IMiDs or PIs. I know they’re working on it and we’ll have more results at ASH.

As it sits now for a patient like me, dara would probably be diagnosed alone to start. Assuming it helps (30-40% chance), I’m guessing it would be boosted by adding pomalidomide (Pomalyst) or carfilzomib (Kyprolis) as it started to weaken in four to six months; hopefully longer.

By the way, dara is available to us now through larger myeloma centers like Dana-Farber, UAMS and Dana-Farber. Check with your specialist and see if you think it could help you right away. If you can wait a while, should be approved by the end of the year or early in 2016.

Hopeful news, don’t you think? My thoughts about what the 65% of us that are left behind–that dara doesn’t work for–in the next week or so. Jumping to a combo therapy should push those numbers up another 20-30%. That’s good news, too.

Feel good and keep smiling! Pat