OREANDA-NEWS. July 20, 2015. AstraZeneca and MedImmune, the company’s global biologics research and development arm, today presented encouraging results from their novel combination-focused immuno-oncology portfolio at the American Society of Clinical Oncology (ASCO) Annual Meeting 2015.

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 tumour types and tumour biology.

MEDI4736 and tremelimumab combination shows clinical activity and tolerability in both PD-L1 positive and PD-L1 negative advanced non-small cell lung cancer (NSCLC) patients; dose confirmed for future studies

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 III combination trials.

MEDI4736 and tremelimumab target two different tumour escape pathways; engaging the immune system to fight the cancer’s immune-evading tactics and maintaining tumour specific T-cell responses.

Data from the Phase Ib 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. 63 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% 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% (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% (16/33). Overall, nearly half of patients in the study achieved a partial response or stable disease, with ORR of 27% (17/63) and DCR of 41% (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. 20/102 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 tumours are PD-L1 negative and are therefore in need of better treatments.”

A range of doses were 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 III 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 tumour 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-tumour immunity.”

The study design for the ongoing Phase III ARCTIC trial, designed to evaluate the efficacy and safety of the combination of MEDI4736 and tremelimumab in NSCLC patients with PD-L1-negative tumours, as well as MEDI4736 versus standard of care in NSCLC patients with PD-L1-positive tumours, 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 (SCCHN) was also recently started.

Data reinforce the potential of MEDI4736 as a cornerstone for combinations with other immunotherapies and small molecule treatments in multiple tumour types

Other data at ASCO underpinned the potential for MEDI4736 in combination with other immuno-oncology and small molecules in melanoma and lung cancer:

  • Preliminary results from the first ever Phase I triple combination study of MEDI4736 with BRAF (dabrafenib) and/or MEK (trametinib)1 inhibitors in patients with advanced melanoma showed clinical activity with acceptable tolerability, with all three agents at full doses. In patients with advanced BRAF-mutation positive melanoma, confirmed partial responses were seen in 69% of patients (18/26) receiving MEDI4736 plus dabrafenib and trametinib. The disease control rate (CR, PR or SD) was 100% and 89% of responding patients (16/18) had ongoing responses after a median follow-up duration of 7.1 months. Overall, AEs were consistent with the known safety profiles of the combination components, and no exacerbation of immune-related AEs was apparent. (Ribas et al, Abstract #3003; Oral Abstract Session: Developmental Therapeutics – Immunotherapy, Monday, June 1, 2:15 pm)
  • Dose escalation data from a Phase I study of MEDI4736 in combination with Iressa (gefitinib), AstraZeneca’s epidermal growth factor receptor (EGFR) mutation positive tyrosine kinase inhibitor (TKI) in advanced NSCLC showed that treatment was generally well tolerated, with early treatment activity in heavily pre-treated patients. (Creelan et al, abstract #3047)
  • Preliminary results from TATTON, a multi-arm Phase Ib trial of AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer patients who have progressed following therapy with an EGFR-TKI, indicated that MEDI4736 and AZD9291 were tolerated at their Phase III doses in the combination arm. (Oxnard et al, Poster #2509)

MEDI4736 monotherapy: data indicate durable responses in multiple tumour types

Increasingly mature data from an ongoing Phase I/II, multicentre, open-label study of MEDI4736 in patients with solid tumours continue to demonstrate durable anti-tumour activity and a manageable safety profile. Analysis of data from 200 response evaluable patients with NSCLC treated with MEDI4736 and with 12 weeks or more of follow-up showed ORR of 16% (27% in PD-L1 positive patients), and DCR (CR, PR or SD for 12 weeks or more) of 42% (48% in PD-L1 positive). ORR was higher in patients with squamous (21%) than non-squamous (13%) disease. Responses were durable with 66% (21/32) ongoing. Drug-related AEs at grade 3 or higher were reported in 8% of patients. (Rizvi et al, Poster #340).

Additional results were also presented on MEDI4736 monotherapy in patients with SCCHN. Of 62 response evaluable patients with 24 weeks or more of follow up, ORR was 11% (18% in PD-L1 positive patients), and DCR (CR, PR or SD for 24 weeks or more) was 15% (18% in PD-L1 positive patients). Responses are ongoing in 71% (5/7) of responding patients. Drug related AEs at grade 3 or higher were reported in 10% of patients. (Segal et al, Poster #337)

Positive progress with companion diagnostic test to help identify patients who are more likely to respond to MEDI4736, reinforcing personalised healthcare approach

A PD-L1 companion diagnostic test that is being developed jointly by Ventana Medical Systems and MedImmune has demonstrated robust, reproducible results as a biomarker to predict response to MEDI4736. Three separate pathologist reviews of 81 patients with NSCLC and 100 patients with SCCHN from MEDI4736 clinical trials showed an overall accuracy of 97% and 91% in the NSCLC and SCCHN samples respectively. The consistency of the results across the pathologist reviews shows that the selected scoring algorithm is precise, reproducible and practical in the clinical setting. In the MEDI4736 monotherapy trials, both NSCLC and SCCHN patients identified as PD-L1 positive by the scoring algorithm had a higher response to MEDI4736 than those identified as PD-L1 negative. (Rebelatto et al, abstract #8033)

NOTES TO EDITORS

1 Novartis medicines for treatment of patients with metastatic melanoma.

About AstraZeneca in Oncology

Oncology is a therapeutic area in which AstraZeneca has deep-rooted heritage. It will be potentially transformational for the Company’s future, becoming the sixth growth platform. Our vision is to help patients by redefining the cancer treatment paradigm and one-day eliminate cancer as cause of death. By 2020, we are aiming to bring six new cancer medicines to patients.

Our broad pipeline of next-generation investigational medicines is focused on four main disease areas - ovarian, lung, breast, and haematological 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.

About MedImmune

MedImmune is the worldwide biologics research and development arm of AstraZeneca. MedImmune is pioneering 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 centres. For more information, please visit www.medimmune.com.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit:www.astrazeneca.com.