NOTE: We will keep the I/O landscape dashboard updated as best we can. Check in periodically to see the latest progress in the field.2016 proved to be a pivotal year for cancer immunotherapies, with nearly 20 new drug and diagnostic approvals and label expansions across the U.S. and Europe, and sales expected to reach ~$7B. By year’s end, there will be at least 9 immunotherapies approved for, combined, >25 cancer indications with an estimated ~250K eligible patients across the U.S. and Europe according to currently-approved labels. The interactive Tableau dashboard below shows the current state of the cancer immunotherapy landscape, including all approved immuno-oncology (I/O) drugs and indications, sales, and approval histories. To interact with the dashboard, click on one or more company logos at the top to filter the data for those companies; use Crtl + Click to make multiple selections.

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2016 was marked by some important milestones and a few surprises for I/O. While there’s still time for major developments before year’s end, we’ve highlighted some of the key takeaways from the world of I/O in 2016:

Opdivo comes up short as monotherapy in first-line (1L) NSCLC; Merck’s Dx strategy pays offProbably the biggest shock to the I/O market landscape this year was the failure of BMS’ Opdivo to show improvement in progression-free survival (PFS) compared to chemotherapy as a first-line treatment for metastatic non-small cell lung cancer (mNSCLC) in patients that express PD-L1 on ≥5% of tumor cells in its CheckMate-026 trial. Prior to this announcement, Opdivo enjoyed market leader position in 2L mNSCLC, buoyed by its approval for all patients regardless of PD-L1 expression status. This news was followed a few weeks later by the FDA’s approval of Merck’s Keytruda, Opdivo’s primary competitor, for 1L mNSCLC for strongly PD-L1 expressing (on >50% of tumor cells) patients and following progression on ALK- and EGFR-targeted drugs for patients with those genetic aberrations. While only ~30% of patients are expected to be PD-L1 high expressers, Keytruda’s position as the only immunotherapy option for 1L mNSCLC gives it a leg-up as more and more oncologists will become familiar with the drug and its associated tests, potentially lowering the barrier to adoption of the drug in later lines or for other indications. While Opdivo will get additional shots at 1L mNSCLC as a combination treatment (e.g., CheckMate-227), Keytruda will enjoy its advantage for now.

Roche’s Tecentriq joins the partyWith its approval for metastatic urothelial carcinoma and 2L mNSCLC, Roche’s Tecentriq (atezolizumab) became the third checkpoint inhibitor targeting the PD-1/L1 pathway to be approved for use in the U.S., and the first targeting PD-L1 specifically. Like BMS, Roche thus far has taken a “complementary diagnostic” strategy with Tecentriq, opting to target patients regardless of PD-L1 expression status. Similar to both BMS and Merck, Roche is casting a wide net with its clinical trials for Tecentriq, with an initial focus on mNSCLC, both as monotherapy and in combination, as well as bladder cancer and triple-negative breast cancer. As of this writing, Tecentriq is only approved for use in the U.S.

While the availability of new cancer drugs is always good news, the addition of Tecentriq to the checkpoint inhibitor lineup adds complexity to an already complicated landscape. In 2L mNSCLC, for example, there are now three drugs available that target the PD-1/L1 pathway: two of them target PD-1 while the other targets PD-L1; two of them have “complementary” diagnostic tests for this indication, while the other has a “companion” diagnostic test; two of the diagnostic tests stain tumor cells while the other stains both tumor and immune cells; all three tests have different thresholds for PD-L1 expression to indicate who might benefit from treatment; two of the drugs are administered every 3 weeks while the other is administered every 2 weeks. As labels for these drugs expand and new drugs are approved (more on that later) the PD-L1 landscape will become increasingly complicated to navigate.

Agilent stakes it claim as the leader in I/O diagnostics; Roche and others in hot pursuitAgilent manufactures the PD-L1 diagnostic (Dx) tests for both Keytruda and Opdivo, which were the only tests approved for use with PD-L1 checkpoint inhibitors for the first half of 2016. With the recent approval of Keytruda for PD-L1-high 1L mNSCLC, PD-L1 testing will essentially be standard for all metastatic NSCLC patients, which will be a boon to Agilent’s CDx business. Agilent has not yet released sales figures for its PD-L1 business, but the company has been “very pleased” with the performance of its tests and believes the PD-L1 testing market could eventually be as large as the HER2 testing market. Competition, however, is increasing quickly. The FDA approved Roche Ventana’s test for use alongside Tecentriq, and many other companies (e.g., Foundation Medicine, NanoString, HalioDx, Adaptive Biotechnologies, HTG Molecular) are pursuing new diagnostic modalities for immuno-oncology drugs, focusing on multiplex and genomic analysis techniques.

Juno’s ROCKET trial grounded; CAR-Ts hit a speedbumpJuno Therapeutics is one of the leading players in the chimeric antigen receptor T-cell (CAR-T) immunotherapy space. In July of this year, the FDA halted Juno’s phase II trial, known as ROCKET, for its lead candidate, JCAR015, for adult B-cell Acute Lymphoblastic Leukemia after 3 patient deaths due to cerebral edema. At the time, Juno hypothesized that the adverse events were due to a reaction to fludarabine, a chemotherapy that had been recently added to the preconditioning regimen. Days later, the FDA decided to lift its hold on the ROCKET trial, allowing it to proceed without fludarabine in preconditioning regimen. However, in late November, Juno announced that it was voluntarily halting its ROCKET trial due to 2 more cerebral edema-related deaths. Meanwhile, in August, Novartis announced plans to shutter it’s Cell and Gene Therapy unit and “re-integrate activities conducted by the Cell & Gene Therapies Unit into the larger Novartis organization”. While Novartis insists that its CAR-T program will remain on-track, investors were spooked about the prospects for CAR-T therapies nonetheless.

While the immunotherapy landscape progressed and changed at an almost unprecedented rate in 2016, we expect even greater evolution of the marketplace in 2017. Here are some things to keep an eye out for in the next year:

Expansion into 1L settingWe expect to see more approvals for immunotherapies in the first-line setting for metastatic disease in 2017. Currently, most solid-tumor immunotherapy indications are in the 2L+ setting; we believe that there is room to grow the eligible immunotherapy patient volume to ~425,000 annually by expanding to the first line setting within existing indications. Much of this opportunity will be in 1L mNSCLC, where Keytruda is already approved, but for a relatively small share of patients due to the high-PD-L1 expression requirement. Early trial results for checkpoint inhibitors in combination with chemotherapies for 1L mNSCLC have looked promising (e.g., KEYNOTE-021, CheckMate-012); with multiple phase III 1L mNSCLC trials underway and expected to give readouts and/or file in 2017 (e.g., Roche: IMpower 110/111, 130, 131, 120; BMS: CheckMate-227; Merck: KEYNOTE-189, -407, -042, AstraZeneca: MYSTIC, ARTIC, PACIFIC, Pfizer: JAVELIN Lung 100), there’s a good chance a greater share of 1L mNSCLC patients will get access to immunotherapies by the end of the year.

Competition heats upCompetition within the immuno-oncology landscape is expected to increase in 2017. In addition to label expansion for immunotherapies already on the market, we expect at least two new PD-L1 checkpoint inhibitors and two CAR-T therapies to file for approval in 2017. Below is a table of select expected regulatory submissions in 2017:

*Labelled as priority review (FDA) or accelerated assessment (EMA) **Received “priority medicines” designation from the EMA

Pfizer and Merck KGaA’s Avelumab was awarded a “priority review” designation by the FDA for Merkel cell carcinoma in late November while AstraZeneca’s Durvalumab received “fast track” designation in February for 3L+ mNSCLC. As a result of a recent temporary hold placed on two trials for advanced head and neck cancers, AstraZeneca decided to scrap plans for an early regulatory review for Durvalumab in head and neck cancer. Like the currently approved PD-1/L1 drugs, diagnostic tests for PD-L1 expression will be developed for use alongside both of these new drugs.

In the CAR-T race, both Kite and Novartis are on track to submit for review their CD19-directed CAR-T therapies for non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia, respectively. Both drugs have received “breakthrough therapy” designations from the FDA. Kite states that clinical data for its BLA has already been submitted to the FDA on a rolling basis and should be finished by the end of Q1 2017. Kite also plans to file in Europe in 2017. Novartis, despite the shuttering of its Cell and Gene Therapy unit, maintains an early 2017 filing for CTL019 in the U.S. and expects a late 2017 filing for Europe.

I/O turns to AIExpect to see greater application of artificial intelligence (AI) and machine learning to immuno-oncology research and development in 2017. Due to the inherent complexity of tumor-immune-microenvironment interactions and the vast number of potential combination therapies, I/O research is an ideal target for optimization using artificial intelligence. As such, multiple companies have begun to utilize AI to transform their research strategies and effectively navigate the I/O space. Earlier this month, Pfizer announced a partnership with IBM Watson Health for use of its cognitive computing capabilities to accelerate the identification of potential new I/O therapies. Using Watson’s AI system, Pfizer can more quickly analyze and test hypotheses from massive volumes of data, including laboratory and data reports as well as medical literature to identify potential biomarkers and / or combinations of biomarkers for I/O therapies. Other companies, including Insilico Medicine and Globavir Biosciences, have also turned to machine learning platforms to reduce drug discovery times. Companies have also begun to use AI to inform I/O patient care decisions. In October, NantWorks announced its plan to use the New England Cancer Specialists (NECS) supercomputing genomics engine to better understand the cancer genome and achieve real-time predictive modeling and clinical outcomes that can continually improve physicians’ ability to make more effective care decisions. With the ever-increasing complexity of the I/O space and the strong advancements in AI, we expect to see the number of I/O AI efforts to grow in 2017.

I/O gets personalWhile checkpoint inhibitors have dominated the I/O market to-date, we expect to see increasing activity around more personalized I/O therapies in 2017, primarily in the form of neoantigen-based cancer vaccines (also referred to as personalized vaccines). Neoantigens arise from mutations in tumor DNA and are recognized by the immune system as non-self. By using NGS and sophisticated bioinformatics, neoantigen sequences can be identified from patient tumor DNA and used to design patient-specific vaccines to stimulate the immune system to attack tumor cells. While the personalized cancer vaccine field is relatively nascent, two companies have initiated clinical trial activity: Neon Therapeutics is currently recruiting for a Phase 1b clinical trial for its NEO-PV-01 vaccine + Opdivo combo, and Gristone Oncology expects to begin a clinical trial for its vaccine + checkpoint inhibitor in 2017. Recent collaborations also highlight strides in personalized cancer vaccine research. In October, NantWorks’ partnership with NECS emphasized using genomic data for neoepitope antibody research to accelerate personalized vaccine development. Additionally, earlier this month, the Parker Institute for Cancer Immunotherapy and CRI announced a collaboration, called the Tumor neoantigEn SeLection Alliance (TESLA), that includes 30 of the world’s leading cancer neoantigen research groups from both academia and industry. As the checkpoint inhibitor space gets increasingly crowded, we expect to see increasing focus on alternative types of immunotherapies, such as personalized vaccines.

As what many are considering a new “pillar” of cancer care, immunotherapies look poised to fundamentally alter the way cancer is treated across a broad range of cancer types. Despite the impressive progress made to date, we have likely only scratched the surface of the potential of cancer immunotherapies.We will continue to track the progress of the I/O market landscape throughout 2017, so check back in for future updates.Disclaimer: Some of the companies listed above may be DeciBio Consulting clients or customers.---

Authors:Andrew Aijian, Project Leader at DeciBio Consulting, LLC, aijian@decibio.comMadison Jones, Senior Analyst at DeciBio Consulting, LLC, jones@decibio.comSally Chen, Analyst at DeciBio Consulting, LLC, chen@decibio.comConnect with Andrew, Madison, and Sally on LinkedInhttps://www.linkedin.com/in/andrew-aijianhttps://www.linkedin.com/in/madison-joneshttps://www.linkedin.com/in/sallybchen