Incyte Corporation, a biopharmaceutical company, and AstraZeneca, a global, innovation-driven biopharmaceutical business, announced a new collaboration to evaluate the efficacy and safety of Incyte’s Janus-associated kinase (JAK) 1 inhibitor, INCB39110, in combination with AstraZeneca’s next generation epidermal growth factor receptor (EGFR) inhibitor, Tagrisso (osimertinib).

The combination will be assessed as a second-line treatment for patients with EGFR mutation-positive non-small cell lung cancer (NSCLC), who have been treated with a first generation EGFR tyrosine kinase inhibitor (TKI) and subsequently developed the T790M resistance mutation.

There is increasing evidence that signaling through the JAK-STAT (signal transducer and activator of transcription) pathway could be a contributing factor in resistance to EGFR TKI treatment in patients with EGFR mutation NSCLC. Blocking both JAK and EGFR activity may therefore offer an improved targeted treatment benefit in some patients.

Under the terms of the agreement, AstraZeneca and Incyte will collaborate on a phase 1/2 study, to be conducted by Incyte. The phase 1 part of the trial is expected to establish a recommended dose regimen for the combination of INCB39110 and Tagrisso while the phase 2 part of the study will assess the safety and efficacy profile. Results from the study will be used to determine whether further clinical development of this combination is warranted.

“The expansion of our research collaboration with AstraZeneca will allow us to further our understanding of these two compounds and explore their potential synergies both of which support our goal of delivering innovative medicines that will benefit patients with cancer or other diseases,” said Rich Levy, MD, chief drug development officer, Incyte. “We look forward to adding to our ongoing clinical research for INCB39110 and exploring the potential of this combination.”

“We are pleased to be building on our existing relationship with Incyte and exploring a potentially exciting combination for lung cancer patients who have developed a resistance to first generation EGFR inhibitor treatment,” said Antoine Yver, head of oncology, global medicines development at AstraZeneca. “This collaboration allows us to explore further ways in which Tagrisso, our first-in-class T790M-directed tyrosine kinase inhibitor, can help meet urgent unmet patient need, following its accelerated approval in the US and the recent positive CHMP opinion, recommending approval in Europe.”

This agreement builds on an existing collaboration between the two companies, announced in May 2014, to explore AstraZeneca’s anti-PD-L1 immune checkpoint inhibitor, durvalumab, in combination with Incyte’s oral indoleamine dioxygenase-1 (IDO1) inhibitor, epacadostat (INCB24360).

INCB39110 is an orally bioavailable, isoform-selective inhibitor of Janus-associated kinase 1 (JAK1). JAK1 activity is believed to play an important role in both autoimmune and oncologic diseases. JAK1 forms heterodimeric complexes with JAK2, JAK3 or TYK2 and functions as an immunomodulatory and inflammatory signalling kinase. Selective JAK1 inhibition prevents STAT signaling downstream of a number of cytokines, including IL-6, IL-10 and interferon-gamma. Consistent with the dominant role for JAK1 in mediating heterodimeric JAK/STAT signaling, JAK1 inhibition has been shown to result in equivalent efficacy compared to balanced JAK1/JAK2 modulation in a variety of preclinical solid and liquid tumor models. INCB39110 will be investigated in clinical trials as monotherapy in graft versus host disease (GvHD) and in several combination-based therapeutic regimens, including with PI3Kd (INCB50465), IDO1 (epacadostat) and EGFR (Tagrisso) inhibitors.

Tagrisso is the only approved medicine indicated for adult patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer. This indication is approved under the FDA’s accelerated approval process based on tumour response rate and duration of response (DoR). Osimertinib is being compared with platinum-based doublet chemotherapy in the confirmatory AURA3 phase III study in patients with EGFR T790M-positive, locally advanced, or metastatic NSCLC who have progressed after EGFR-TKI therapy. It is also being investigated in the adjuvant and metastatic first-line settings, including in patients with brain metastases, and in combination with other compounds.

Non-clinical in vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against mutant EGFR phosphorylation across the range of clinically relevant EGFRm and T790M mutant NSCLC cell lines, with significantly less activity against EGFR in wild-type cell lines.