AstraZeneca Says 'IDO' To Incyte For Imfinzi Marriage
Executive Summary
As the major immuno-oncology players seek out the best combination therapies, AstraZeneca and Incyte are starting a Phase III trial evaluating Imfinzi and the IDO inhibitor epacadostat in Stage III NSCLC.
AstraZeneca PLC's bid to establish its PD-1/L1 inhibitor Imfinzi (durvalumab) as a standard treatment in the future for early-stage lung cancer has been boosted by plans to start a late-stage trial of the drug in combination with Incyte Corp.'s closely-watched indoleamine 2, 3-dioxygenase (IDO) checkpoint inhibitor epacadostat.
The two companies will co-fund a Phase III trial in patients with locally-advanced (ie Stage III), unresectable non-small cell lung cancer (NSCLC) whose disease has not progressed following platinum-based chemotherapy concurrent with radiation therapy. The study is expected to begin enrolling patients in the first half of 2018 and builds on an existing clinical collaboration for Imfinzi and epacadostat announced back in May 2014.
Incyte has not been coy in seeking out other partners for epacodostat and 2014 also saw the US biotech sign deals with Merck & Co. Inc., Bristol-Myers Squibb Co. and Roche, as well as AstraZeneca to investigate combos of the IDO inhibitor with their respective immune checkpoint inhibitors. With this new study, however, the partners stressed that it is an "exclusive collaboration for the study population."
Sean Bohen, AstraZeneca's chief medical officer, said the company's therapy has shown "exciting clinical potential in treating patients with locally-advanced lung cancer. We are pleased to build on recent data from the PACIFIC trial to further explore how Imfinzi, in combination with an IDO inhibitor could provide additional benefit."
The full set of results from PACIFIC, presented at the European Society for Medical Oncology (ESMO) congress in Madrid in September, showed that Imfinzi improved progression-free survival (PFS) in patients with unresectable stage III NSCLC after standard chemoradiation by just over 11 months - 16.8 months in the Imfinzi arm compared to 5.6 months with placebo. PACIFIC represented something of a turnaround in the drug's prospects in lung cancer, especially given the bitter blow suffered in July with data from the large MYSTIC trial, where a combination of Imfinzi and AstraZeneca's investigational CTLA-4 inhibitor tremelimumab failed to show a PFS benefit in patients with previously-untreated stage IV metastatic NSCLC. (Also see "MYSTIC Misses: Devastation For AstraZeneca As Imfinzi Fails PFS Endpoint In NSCLC" - Scrip, 27 Jul, 2017.)
Imfinzi got accelerated approval from the US Food and Drug Administration earlier this year for previously-treated patients with advanced bladder cancer but AstraZeneca sees most opportunity for the drug in Stage III lung cancer. The latter represents approximately one-third of NSCLC incidence and was estimated to affect around 105,000 patients in the seven leading markets in 2016.
In Stage III, AstraZeneca is way ahead of the more established checkpoint inhibitor competition - Merck ’s Keytruda (pembrolizumab) and B-MS' Opdivo (nivolumab). It will be hoping the Imfinzi/epacadostat combo will consolidate that lead at a time when the combination with tremelimumab is being scrutinized following the MYSTIC failure.
As for Incyte, chief medical officer Steven Stein said "we look forward to beginning an additional pivotal trial for epacadostat, as we seek to position IDO1 enzyme inhibition as a key component of combination immunotherapy.” The most advanced partnership for the drug is with Keytruda, and the combo is in a Phase III trial (ECHO-301) for the treatment of patients with unresectable or metastatic melanoma, with initial data expected around May next year.
Incyte and Merck have also expanded their clinical development program by initiating Phase III studies of epacadostat in combination with Keytruda in four additional tumors: NSCLC, renal cell carcinoma, bladder cancer and squamous cell carcinoma of the head and neck.
Other than Keytruda studies, epacadostat is also currently in combination trials with Opdivo. In April, Incyte and B-MS unveiled plans for Phase III studies in first-line NSCLC across the spectrum of PD-L1 expression and in first-line head and neck cancer. On the negative side, a Phase I trial of epacadostat in combination with Roche’s Tecentriq (atezolizumab) to treat patients with previously treated stage IIIB or IV NSCLC was discontinued in July this year after slow study enrolment.
Analysts at Pharmavitae Analytics believe epacadostat will be a key growth driver for Incyte, saying in a recent report that "with impressive clinical data amounting," it currently forecasts that epacadostat could generate over $300m by 2026 in metastatic melanoma alone. They also see the company and its pipeline as an attractive candidate for M&A in the near future, claiming that "Merck, Pfizer Inc., Gilead Sciences Inc. and Celgene Corp. all would find epacadostat and Incyte’s market position an enticing target."
Edward Thomason, an analyst at Datamonitor Healthcare, told Scrip that “Incyte is reliant on strong partnerships for the clinical development and future success of epacadostat as it lacks efficacy as a monotherapy and must be used in combination with PD-1 inhibitors for anti-tumor efficacy. It is an important part of Incyte’s strategy to be promiscuous in its epacadostat partnering as it will secure epacadostat as the chosen combinational checkpoint inhibitor regardless of which PD-1 drug it partners with."
He added that with Merck, B-MS and AstraZeneca all investigating epacadostat in combination with their respective PD-1 targeted therapies in pivotal trials in multiple solid tumors, "Incyte looks set to partner with the eventual winner in the PD-1 class." Thomason concluded by saying "the fact that these companies continue to expand partnerships supports epacadostat’s clinical potential and claim as the leading checkpoint combinational agent for all PD-1 therapies in solid tumors.“
News of the Imfinzi/epacadostat study comes days after Incyte struck a deal with MacroGenics Inc. to in-license the latter's investigational PD-1 drug MGA012. Incyte is paying $150m upfront to get hold of a checkpoint inhibitor of its own to test with epacadostat. (Also see "Incyte Adds PD-1 Inhibitor To Its Promising IDO With MacroGenics Deal" - Scrip, 26 Oct, 2017.)
Amid all the talk of Incyte's promiscuity, it is only fair to point out that AstraZeneca is also playing the IDO field. Last month, it inked an agreement with NewLink Genetics Corp. to study the combination of Imfinzi with the latter’s IDO inhibitor indoximod in Phase II trials for metastatic pancreatic cancer.