A new Phase I/II clinical program in which Bristol-Myers Squibb collaborates with AbbVie will evaluate the safety, tolerability and efficacy of the investigational biomarker-specific antibody-drug conjugaterovalpituzumab tesirine, also known as Rova-T (SC16LD6.5; Stemcentrx/AbbVie), in combination with nivolumab (Opdivo; Bristol-Myers Squibb), designed to alleviate immune suppression as a treatment for relapsed extensive-stage small cell lung cancer (SCLC).

The new study, expected to start patient enrollment later this year, will determine if the targeted cell killing and antigen release caused by rovalpituzumab tesirine may further enhance the effect of immunotherapy and  evaluate if it drives improved and sustained efficacy and tolerability above the current standard of care.

Rovalpituzumab tesirine, is a novel, investigational, antibody drug conjugate developed by Stemcentrix that targets and eliminates tumor initiating cells and other bulk tumor cells.  The drug targets the cancer-stem cell-associated target delta-like protein 3 (DLL3) which is expressed in more than 80% of small cell lung cancer (SCLC) patient tumors, where it is prevalent on tumor cells, including cancer stem cells, but not present in healthy tissue.

Minimizing toxicity to healthy cells
As an antibody-drug conjugate, rovalpituzumab tesirine is comprised of the D6.5 Pyrrolobenzodiazepine (PBD) payload conjugated to cysteine residues on the SC16 antibody via a maleimide-containing linker with an eight-carbon polyethylene glycol spacer, cathepsin B–cleavable valine-alanine dipeptide, and self-immolating group, with a mean drug-to-antibody ratio (DAR) of 2. [1] Since the drug delivers a cytotoxic agent directly to the DLL3-expressing cancer cells it minimizing toxicity to healthy cells. [1]

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Based on the agreement between the two companies, AbbVie will initiate a first-line clinical study for rovalpituzumab tesirine in SCLC and several other types of tumors in the near term.

The investigational agent, is currently is under investigation as a third-line treatment in SCLC. Studies evaluating rovalpituzumab tesirine as a first-line SCLC regimen will be starting in the near term. The expression of DLL3 suggests rovalpituzumab tesirine may be useful across multiple tumor types, including metastatic melanoma, glioblastoma multiforme and some prostate, pancreatic and colorectal cancers.

The trial evaluates rovalpituzumab tesirine in combination with nivolumab the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 54 countries including the United States, Japan, and in the European Union as a single agent for the treatment of patients with BRAF V600 wild-type or mutation-positive unresectable or metastatic melanoma.

The drug is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy, for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy and for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin.

In the United States these indication are approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Checkpoint pathways
In order to survive, cancer cells may exploit ‘regulatory’ pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Nivolumab, a PD-1 immune checkpoint inhibitor, binds to the checkpoint receptor PD-1 expressed on activated T-cells and blocks the binding of PD-L1 and PD-L2.  This in turn, prevents the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

A targeted approach
“We are excited to explore the potential benefits of combining Bristol-Myers Squibb’s immunotherapies with a targeted approach like Rova-T in small cell lung cancer where the need for new therapies is particularly acute for this aggressive form of lung cancer,” said Jean Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb.

“As the science around cancer research continues to rapidly evolve, we are building on our leadership in Immuno-Oncology with numerous collaborations that may help advance new therapies for cancers in need of better options,” Valett added.

Priming the immune system
“We believe the combination of these cancer-fighting agents may offer patients a new treatment option in a disease with limited therapies,” said Scott J. Dylla, Ph.D., vice president, research and development, AbbVie. “By combining immune-checkpoint inhibitors that prime the body’s immune system to fight cancer cells with Rova-T’s approach to target cancer stem cells, we hope to build on our goal to develop differentiated treatments with therapeutic benefit that elevate the standard of care for small cell lung cancer patients.”

Difficult to treat
High-grade pulmonary neuroendocrine tumors, which include Small Cell Lung Cancer is a difficult-to-treat form of cancer that accounts for approximately 15% of all lung cancers. SCLC is an aggressive disease that is commonly metastatic at the time of diagnosis and is rarely amenable to surgery. [2][3] The disease predominantly develops in older patients with a history of smoking. The five-year survival rate for extensive-stage SCLC is less than 5% and treatment options are limited for the more than 234,000 people diagnosed annually.  Because novel treatment options have not emerged for more than 30 years, SCLC belongs to the most deadly malignancies known. The current standard of care is chemotherapy with etoposide (Toposar™; Pfizer ) , a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases, and a platinating agent such as cisplatin (Platinol/Platinol AQ® ;Bristol-Myers Squibb) or carboplatin (Paraplatin® ;Bristol-Myers Squibb). [4]

The combined clinical trials fits in the Bristol-Myers Squibb vision for the future of cancer care that is focused on immuno-oncology, now considered a major treatment choice alongside surgery, radiation, chemotherapy and targeted therapies for certain types of cancer.

The company’s ongoing immuno-oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering clinical trials for overall survival and other important measures like durability of response. Hence, the collaboration with academia, as well as small and large biotech and pharmaceutical companies, to research the potential of immuno-oncology and non-immuno-oncology combinations is designed to investigate new treatment options in clinical practice.

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