On January 12, 2018, Endpoints News sponsored a breakfast panel at the 2018 JP Morgan Healthcare Conference (JPM18) in San Francisco, CA. The focus of this panel was the current state of clinical cancer immunotherapy development. The full panel is recorded as a video on YouTube. The panel is also discussed in a special Web article on Endpoint News.
The impetus for this panel was a published research report (dated 1 January 2018) by Aiman Shalabi and his colleagues at The Anna-Maria Kellen Clinical Accelerator, Cancer Research Institute (CRI), New York, NY USA. A slide presentation based on this report [including the role of the CRI in immuno-oncology (IO) innovation] is also included at the bottom the Endpoint News special article.
The panelists in the Endpoint News program (which was entitled “How many PD-1/L1 drugs do we need? Where is immunotherapy headed?”) were Jay Bradner (Novartis Institutes for BioMedical Research) Hervé Hoppenot (Incyte), Ellen Sigal ( Friends of Cancer Research), David Berman (AstraZeneca), Gideon Blumenthal (FDA Office of Hematology and Oncology Products), and Aiman Shalabi. The moderator of the panel was John Carroll, the Co-founder and Editor of Endpoints News.
The major conclusion of the published research report and of the panel discussion was that anti-PD-1/PD-L1 studies (including studies of combinations of anti-PD-1/PD-L1 therapies with other agents) will continue to deliver many breakthroughs, with the strong potential to change the standard of care for many types of cancer. However, there is an urgent need for efficiencies. Specifically, a large number of companies and academic groups are testing the same combinations, often using inefficient trial designs. In particular, there has been a great increase in the number of small, investigator-initiated studies.
The CRI team discussed some initiatives aimed at addressing these challenges. In particular, there is the need to move toward novel, collaborative trial designs that allow more questions to be answered more efficiently in a single multicenter trial. Many biotechnology and pharmaceutical companies are adopting these types of study designs. (For example, see Merck’s KEYNOTE-001 adaptive trial of pembolizumab/Keytruda, which led to accelerated approval for metastatic melanoma and NSCLC, as well as a companion diagnostic.) However, such clinical studies sponsored by a single company tend to include drugs only from their own portfolio.
The nonprofit and public sectors, however, can facilitate and conduct these innovative trials across multiple companies and research centers. There are now several examples of nonprofit organizations leading such novel study designs. One example, which was discussed in the Endpoint News panel, is the LUNG-MAP study for lung cancer. LUNG-MAP is a collaboration between Friends of Cancer Research, Foundation for NIH, National Cancer Institute, the Southwest Oncology group, and various biopharmaceutical and diagnostic companies. (Panelist Ellen Sigal of Friends of Cancer Research was especially active in discussing LUNG-MAP.) The study is now open with multiple arms at hundreds of sites.
Dr. Shalabi and his colleagues conclude that now—with the strong emergence of IO therapies—is probably the best time for progress in oncology in several decades. This historic opportunity would be maximally capitalized if people from academia, industry, regulatory agencies, and nonprofit organizations work together, especially in adopting novel collaborative study design, aimed at bringing the promise of cancer immunotherapies to patients, sooner rather than later.
Are there enough patients for IO clinical trials in 2018?
One factor that is often cited as severely limiting the ability of researchers to conduct all the clinical trials in progress and planned for IO agents and combinations is a shortage of patients. The panelists cited a number of 52,000 patients now in trials, with many more needed. However, the panelists estimated that there are 2 million patients per year that are dying of cancer. The best chance for these patients’ survival is for them to be enrolled in a clinical trial, often an IO trial. However, most cancer patients are treated in community settings, and are not even offered clinical trials—let alone the clinical trials that would be the most appropriate for each patient’s disease. From the point of view of patients, their caregivers, and of the research community, these patients need access to clinical trials.
Several panelists (notably Jay Bradner of Novartis) cited the need to move toward patient-driven IO clinical research, and to enlist the patient as a collaborator in clinical trials (for example, via conducting on-treatment tumor biopsies). In support of moving towards patient-driven IO clinical research, the CRI website includes a “Patients” page, that links to a “clinical trial finder”. In our own Biopharmconsortium Blog, the January 12, 2015 article included a section entitled “Implications for patients with terminal cancers”. That section featured links to CRI web pages on immunotherapy trials for pancreatic cancer and glioblastoma, which we used as examples of deadly cancers that have become the subject of IO clinical trials. Now—in 2018—it is even more imperative that IO trials become patient-driven.
Why so many IO combination clinical trials?
Many of the IO trials currently in progress are combination trials with a checkpoint inhibitor and a second agent. The rationale for these trials is that there is a significant unmet need in IO, since (depending on the type of cancer) some 80% of patients do not respond to checkpoint inhibitors. As we discussed at length in our 2017 book-length report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes”, and more briefly in our September 20, 2017 article on this blog, checkpoint inhibitors work by reactivating intratumoral T cells, especially CD8+ cytotoxic T cells. Checkpoint inhibitors are therefore ineffective in treating “cold” tumors (which lack T cell infiltration), and immunosuppressed tumors that inhibit infiltrating T cells. Researchers and companies are therefore attempting to develop agents that render cold or immunosuppressed tumors “hot”. When such agents are given in combination with checkpoint inhibitors, they may improve their effectiveness, thus resulting in tumor shrinkage. This type of strategy, as discussed in our report, is a major theme of “second wave” immuno-oncology, or “immuno-oncology 2.0.” Many of these agents are discussed in our 2017 report.
Many of these complementary “immunotherapy 2.0” agents are being developed by small or medium-sized biotechnology companies. (One such medium-sized company, Incyte, was represented on the JPM18 panel.) Large pharmaceutical companies that have been developing checkpoint inhibitors are thus seeking to collaborate with or acquire smaller companies that are developing “immunotherapy 2.0” agents. Interestingly, Jay Bradner of Novartis stated that he was more concerned about competition from the “500 biotechs within a 20 mile radius around Novartis Institutes for BioMedical Research (NIBR)-Cambridge” than from another Big Pharma in IO. However, in terms of conducting clinical trials, Novartis has a big advantage over small biotechs because of its global reach—it can expand a clinical trial by opening up sites in Europe. Nevertheless, NIBR-Cambridge is actively recruiting the participation of biotech companies in IO combination studies, and wishes to become the “partner of choice” for such collaborative studies.
The JPM18 panel is optimistic for the prospects of IO therapies
The JPM18 panel was very optimistic that IO clinical studies will result in breakthrough therapies that will change the practice of treatment of important types of cancer, and that such breakthroughs should start to emerge within the next two years.
This is in contrast to the pessimism of many people in the biotech/pharma industry, and in parts of the venture capital community. For example, a January 4, 2018 article in Forbes by venture capitalist Bruce Booth suggests that the crowding of the IO field is making it difficult for small biotechs to compete with the clinical and post-marketing programs of the larger companies, and that starting new IO companies is difficult. Researchers, entrepreneurs and funders would be better off focusing on areas like neuroscience, according to this article.
1. Potentially important IO deals between small and large companies are being done. For example, on February 14, 2018 Nektar Therapeutics (San Francisco, CA) and Bristol-Myers Squibb (BMS) announced that they had concluded a $3.6 billion collaboration deal for a minority share of Nektar’s early-stage T-cell modulator NKTR-214, a CD122 agonist. The collaboration will study combinations of NKTR-214 with BMS’ checkpoint inhibitors Opdivo and Yervoy, in 20 indications involving 9 types of tumors. We covered NKTR-214 in the chapter on immune agonists in our 2017 Cancer Immunotherapy report.The Opdivo/NKTR-214 combination has been evaluated in Phase 1/2 studies. Nektar and BMS now are initiating clinical trials with the potential for registration data that could start coming in in about 18 to 24 months.
2. New IO companies are being started and funded. Tmunity Therapeutics, a CAR-T based cellular immunotherapy company, was founded by Carl H. June, MD and his collaborators at Penn Medicine in January 2016. On January 23, 2018, Tmunity announced that it was raising $100 million from a group of investors including Gilead Sciences, the Parker Institute for Cancer Immunotherapy, Ping An Ventures, and Be The Match, a patient advocacy group. The company will use the funding in part to finance two clinical trials that will attempt to use genetically modified T-cells to treat solid tumors. As we discussed in our 2017 Cancer Immunotherapy report, using CAR-T and related types of T cells to treat solid tumors has proven to be more difficult than treating blood cancers. Tmumity researchers are attempting to overcome these difficulties.
Meanwhile, CAR-T company Juno Therapeutics (Summit, NJ) is being acquired by Celgene for approximately $9 billion.
3. Researchers continue to make discoveries with the potential to improve the efficacy and safety of IO therapies for increasing numbers of patients. For example, the February 2018 issue of Nature Biotechnology reported on two such discoveries: a model to determine which tumor neoepitopes (or neoantigens) are likely to result in tumor response to checkpoint inhibitor therapy, and studies on the effects of gut bacteria on patent response to IO treatments. The tumor neoepitope research was originally published in the 22 November 2017 issue of Nature . We discussed neoantigen modeling and other aspects of neoantigen science in three types of IO therapies (checkpoint inhibitor, cancer vaccine, and cellular immunotherapy) in our 2017 Cancer Immunotherapy report.
The gut bacteria/tumor IO research was originally published in the 2 November 2017 issue of Science, and was reviewed in a News article in Nature.
A third recent discovery concerns the role of TGF-beta in resistance to checkpoint inhibitor therapy. In mouse models, a TGF-beta inhibitor enables T cells to get into IO resistant tumors. Checkpoint inhibitor therapy (given together with the checkpoint inhibitor) then becomes more effective in shrinking the tumor. Several TGF-beta inhibitor/checkpoint inhibitor combinations are now in clinical studies. However, to date, TGF-beta inhibitors have been suffering from various safety and/or efficacy issues.Therefore, some researchers have suggested the need for developing improved TGF-beta pathway inhibitors for use in combination with checkpoint inhibitors.
As research on IO continues, some of these discoveries will make their way into improved therapies with increased patient benefit.
Our report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes”
Our 2017 Cancer Immunotherapy report can help you achieve a deep understanding of the IO field. This especially applies to immuno-oncology 2.0, which is the basis for IO combination trials. Our report covers the three major areas of IO R&D—checkpoint inhibitor therapy (including combination therapies), cancer vaccines, and cellular immunotherapies. Immunotherapy 2.0 strategies, agents, and companies discussed in our report may well make the news over the next several years, in terms of corporate deals and product approvals. This has already been happening, as illustrated by the BMS/Nektar collaboration discussed earlier, the emergence of strategies and clinical trials aimed at developing CAR-T therapies for solid tumors at Tmunity, and the continuing development of neoantigen science aimed at improved IO therapies. Our report is thus well worth purchasing and reading for those who are interested in the further development of IO.
For more information on our report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, or to order it, see the CHI Insight Pharma Reports website.
As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.