WILMINGTON, Del.—AstraZeneca and MedImmune, AstraZeneca’s global biologics research and development arm, presented encouraging results from their novel combination-focused immuno-oncology portfolio at the American Society of Clinical Oncology (ASCO) Annual Meeting 2015.
“We are particularly encouraged by the data indicating that these complementary agents can be combined to increase T-cell activity and improve the clinical activity among the broader patient population of non-small cell lung cancer [NSCLC] patients whose tumors are PD-L1 negative and are therefore in need of better treatments,” the companies said in a prepared statement.
Overall, data indicated clinical activity with manageable safety profiles for the anti-programmed cell death ligand 1 (PD-L1) monoclonal antibody MEDI4736, both as monotherapy and in combination with other immuno-oncology and small molecule therapies across different tumor types and tumor biology.
Results from the combination study of MEDI4736 and tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) monoclonal antibody, in the treatment of advanced NSCLC, demonstrated clinical activity in heavily-pretreated patients with a manageable safety profile, establishing appropriate doses to move forward into Phase 3 combination trials.
MEDI4736 and tremelimumab target two different tumor escape pathways; engaging the immune system to fight the cancer’s immune-evading tactics and maintaining tumor specific T-cell responses.
Data from the Phase 1b open label, dose escalation study of patients with advanced NSCLC, showed that the combination of the PD-L1 and CTLA-4 blockade helped to increase response rates in both PD-L1 biomarker positive and negative patients. Sixty-three patients with 16 weeks or more of follow up were evaluable for clinical activity, 102 patients were evaluated for safety. Notably, the data demonstrated specific clinical activity and tolerability in PDL-1 negative patients, who make up approximately 70 percent of NSCLC patients and who are less likely to respond to monotherapy. In the PD-L1 negative patient subset, overall response rate (ORR) was 27 percent (9/33) and disease control rate (DCR)—defined as complete response (CR), partial response (PR) or stable disease (SD) for 16 weeks or more—was 48 percent (16/33). Overall, nearly half of patients in the study achieved a partial response or stable disease, with ORR of 27 percent (17/63) and DCR of 41 percent (26/63). (Antonia et al, abstract #3014)
Overall adverse events (AEs) were manageable and generally reversible using standard treatment guidelines. The most frequently reported treatment related grade 3/4 AEs across all dose cohorts were colitis, diarrhea, elevated lipase and elevated liver function tests. Twenty of 102 patients discontinued the study due to drug-related AEs in this heavily-pretreated disease setting.
The combination data presented at ASCO builds on preliminary results from 18 patients presented at the European Society of Medical Oncology Congress in September 2014.
“The maturing data presented today on the combination of MEDI4736 and tremelimumab are truly exciting—we are starting to see the potential of combination therapy become a reality,” said Dr. Ed Bradley, senior vice president and head of the Oncology Innovative Medicines unit, MedImmune. “We are particularly encouraged by the data indicating that these complementary agents can be combined to increase T-cell activity and improve the clinical activity among the broader patient population of non-small cell lung cancer patients whose tumors are PD-L1 negative and are therefore in need of better treatments.”
A range of doses was identified that provided clinical benefit with acceptable tolerability, with a specific dose and schedule of MEDI4736 20mg every four weeks (12 total doses) and tremelimumab 1mg/kg every four weeks (four total doses) selected for future Phase 3 combination trials in NSCLC. This decision was supported by data from the trial, which evaluated key indicators of best outcomes for patients (clinical efficacy, tolerability and biologic activity) to ensure that each molecule contributes optimally in the combination. Data indicated that the selected dose of tremelimumab is well tolerated and enhances clinical activity as efficaciously as the other doses studied.
Bahija Jallal, executive vice president, MedImmune, said “We are encouraged by the immunotherapy data being presented here at ASCO 2015, but this is just the tip of the iceberg as we continue to follow the science and build on the diversity of our portfolio with smart combinations. We believe the most powerful combinations will likely target multiple mechanisms in the immune system where cancer wages its battles—T-cell activation, antigen presentation and innate immunity, and the tumor microenvironment. AstraZeneca and MedImmune are uniquely positioned to lead in this area, through our biologics and small molecule portfolio and through targeted collaborations, which allow us to explore novel combinations across this cycle of anti-tumor immunity.”
The study design for the ongoing Phase 3 ARCTIC trial, designed to evaluate the efficacy and safety of the combination of MEDI4736 and tremelimumab in NSCLC patients with PD-L1-negative tumors, as well as MEDI4736 versus standard of care in NSCLC patients with PD-L1-positive tumors, was also presented at ASCO. (Planchard et al, abstract #TPS8104) A Phase II study of MEDI4736 and tremelimumab as monotherapies and in combination in patients with recurrent squamous cell carcinoma of the head and neck was also recently started.
AstraZeneca’s pipeline of next-generation investigational medicines is focused on four main disease areas—ovarian, lung, breast, and hematological cancers. These are being targeted through four key platforms—immuno-oncology, the genetic drivers of cancer and resistance, DNA damage repair and antibody drug conjugates.
MedImmune is the worldwide biologics research and development arm of AstraZeneca focused on innovative research and exploring novel pathways across key therapeutic areas, including respiratory, inflammation and autoimmunity; cardiovascular and metabolic disease; oncology; neuroscience; and infection and vaccines. The MedImmune headquarters is located in Gaithersburg, Md., one of AstraZeneca’s three global R&D centers.