Guest Post: Advancing Next-Generation Combo Therapy in Oncology

By Aidan Finley, Consultant, Health Advances

We are all well aware that oncology is rapidly undergoing significant changes. Encouraged by recent FDA guidance, we've begun a transition from empirical combinations developed post-approval to rational combinations co-developed in the clinic. In this month's IN VIVO, Health Advances addresses the past and future of combination therapy for oncology.

As demonstrated by the recent launches of Xalkori and Zelboraf, the right ingredients are finally in place: more comprehensive genetic and biologic understanding of tumors, better tumor pathway definitions, availability of companion diagnostics, and a burgeoning armamentarium of clean targeted single and multi-kinase inhibitors. To transform these ingredients into successful drugs is no mean task: both clinical trial design and dealmaking need to change.

Fortunately, clinical trials are changing. We see an increase in combination trials, not just of established assets, but of novel agents early in development. For example Novartis recently combined its novel mTOR inhibitor Afinitor with Pfizer’s aromatase inhibitor Aromasin to great effect in breast cancer, showing PFS and OS survival benefits. And Syndax Pharmaceuticals released findings at AACR showing beneficial combination of its HDAC inhibitor entinostat with exemestane in breast cancer, and published a trial of entinostat in combination with Vidaza in NSCLC.

We also see more development of precisely dual targeted kinases, like Roche’s dual PI3k/MTOR inhibitor (GDC-0980) or Novartis’s competing dual P13k/MTOR inhibitor (BEZ235), or VEGF/FGF inhibitor dovitinib. Clinicians are also embracing the potential of new agents and combinations to affect resistance, a durable unmet need: At this moment at the MGH there are 4 trials opening for patients resistant to BRAF inhibitor in melanoma and 10 trials for patients with resistance to targeted agents in lung cancer. Collectively, these trials and abstracts represent the growing consensus around next generation combination therapy and the route by which sponsors, clinicians, regulatory authorities, and patients can advance care.

But biopharma partnership strategies need to evolve to allow for testing of more and better drug combinations (and we see more room for improvement here). Ultimately, developers need to balance the control of intramural development with the flexibility and risk-sharing of partnerships and joint ventures. AstraZeneca and Merck famously began their ALK and MEK collaboration in 2009 in part because their research directors bumped into one another at a security queue while traveling to a conference. Despite growth in cancer-specific partnerships since (e.g. Merck-Serono and Sanofi in 2010, Roche and BMS in 2011), has a better mechanism for identification and execution of partnership been identified?

One necessary change is a tighter coordination between R&D and BD. R&D efforts can no longer be siloed, or pursued in isolation without consistent reference to corporate strategic goals. BD efforts need to be partially focused on identifying both potential strategic partnerships and as well as agent-extending in-licensing efforts. Staying on top of the literature, BD can work to bring in complementary agents to better achieve dual inhibition of a target (e.g. to achieve something like the demonstrated benefits of trastuzumab and pertuzumab in Her2+ breast cancer) or actively seek agents targeting newly validated targets like EML4-ALK rearrangements after high-profile publications.

Given these factors, it makes perfect sense that oncology deal-making is aggressively moving earlier (pointed out by Campbell Alliance, here). But in-licensing alone cannot satisfy Pharma and Biotech’s need to mitigate risk. Companies need to get better at working together, using the Merck/AstraZeneca joint venture as a template. Sharing risk by sharing assets, development costs, trial designs, and ultimately regulatory risk will be necessary to capture full value for these complex oncology assets.

The situation gets even more complicated when biomarkers are considered. Using an established biomarker developer like Roche or Abbott will make negotiations between the existing two members of the partnership more complex, but these players may be the only ones capable of arbitraging the clinical and economic risk of companion diagnostic development. Pfizer and Abbott had their own difficulties developing their partnership over crizotinib, though the companies surmounted these difficulties with a successful joint application. Unfortunately for Abbott, they will receive only $1,500 per patient, compared with Pfizer’s $9,600 per month.

The market is already focusing on modular, diagnostic-aware, targeted therapies that can be slotted into multiple therapeutic lines and extended by combination or mechanism into adjacent indications. We want to see both intelligent in-licensing driven by R&D/BD alignment and data-driven opportunism as well as more structured joint ventures and collaborations focused on mitigating risk and better delivering complex, multi-company, multi-agent trials of out-of-the-box combination therapies. These are exciting times in oncology, and it is important to create the types of agents and combinations capable of dramatically advancing standard of care.