A new analysis of immuno-oncology (IO) by the nonprofit Cancer Research Institute (CRI) has found that the field is rapidly expanding globally—so fast that it is difficult for clinicians to keep up with progress. While cause for celebration, this rapid expansion has led to fragmentation, lack of coordination, overlap, and duplication in clinical trials, which the study authors state could be alleviated if professionals in academia, industry, regulatory agencies, and nonprofit organizations work together collaboratively toward common goals in the IO field.
Drawing on its database of 2,004 IO agents, the authors sought to track all the current IO agents in clinical development and the clinical trials in which they are being tested. The worldwide, independent analysis—believed to be the first of its kind—found that as of September 2017 (the study cutoff date) 26 IO therapies have been approved, and 17 types of cancer have at least one approved IO drug as a treatment option. Some 940 IO agents were in clinical development, with another 1,064 in preclinical studies. Some 3,042 active clinical trials are evaluating clinical-stage IO agents, with a target of enrolling 577,076 study subjects. And in 2017 alone, 469 new studies were started, with a target enrollment of 52,539 patients. In most cases, approved IO drugs are designed to treat advanced, refractory, or relapsed cancers that did not respond to standard-of-care treatments.
In this fast-moving field, the analysis noted, “...it has become challenging for oncology physicians conducting clinical trials, industry veterans developing IO drugs, and even regulators reviewing novel IO agents to keep track of the rapidly evolving landscape.” The authors warn that “the fast-expanding and ever-changing IO field could overwhelm even the most experienced clinical investigators as they seek treatment options for their patients.”
The new CRI analysis is titled “Comprehensive analysis of the clinical immuno-oncology landscape.” The CRI is the leading worldwide nonprofit organization dedicated exclusively to IO. The new report was published in Annals of Oncology (2017; https://doi.org/10.1093/annonc/mdx755). Highlights of the report's findings were presented at ESMO's Immuno-Oncology Congress in Geneva, Switzerland, in December 2017.
The rapid growth in scientific advances in IO is changing the prognoses for many cancer patients, so much so that the report states that “it is probably the best time for progress in oncology in the past decades.” Its authors assert that “the large numbers of promising experimental therapies, active clinical trials, and planned patient enrollment suggest that we are entering a new era that could change the standard of care in even more cancer types.”
CRI Chief Medical Officer and report co-author Aiman Shalabi, PharmD, MBA, BCOP, said the independent analysis is the first “that quantifies and confirms the level of excitement and potential of immuno-oncology.
“By using these landscape data, we aim to better inform the field and find solutions to several meaningful and actionable trends in the current IO landscape.”
Shalabi is also Director of the Anna-Maria Kellen Clinical Accelerator, CRI's clinical program, which is a nonprofit, philanthropic venture capital fund that supports the testing of IO agents from multiple companies by global academic experts across multiple treatment centers.
So bright is the promise of IO that—as previously reported in Oncology Times—ASCO named immunotherapy 2.0 (a term indicating maturation in the field) as its top advance for 2017. It was the second year in a row that ASCO chose immunotherapy for this distinction. ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO, has described immunotherapy as the hottest area in oncology.
“The new breakthroughs are really exceptional—things we could not have imagined decades ago,” he noted. Clinical Cancer Advances 2017: ASCO's Annual Report on Progress Against Cancer cites progress with immune checkpoint inhibitors as especially effective in extending the lives of patients with different cancers.
The new CRI analysis shows that the 940 clinical-stage IO agents are owned by 462 different companies or academic centers, and they modulate 271 different targets. Almost half of the 940 agents modulate just 40 targets, a finding which confirms the authors' “assumption of significant duplication” in the IO field. Fully 164 agents target the PD-1 or PD-L1 pathways, leading the authors to warn that “the concentration of IO development and patient resources on a few targets, some with already approved drugs, could potentially be stalling future innovation.” Their observation about fragmentation and lack of coordination in the IO field applies especially to PD-1/PD-L1 agents, particularly those being studied in combination trials.
Of the 164 PD-1/PD-L1 agents under study, 50 are currently in clinical-stage development, and five are FDA-approved. Combination trials for anti-PD-1/PD-L1 agents are flourishing; the 50 agents are being studied in 1,502 studies, of which 1,105 are combination trials. Combinations being evaluated include other IO therapies, targeted therapies, chemotherapies, or chemoradiotherapies. Some 49 of the combination trials are testing agents that have not been approved, whereas most of the combination trials focus on the five approved agents. The authors commented, “Many of these studies we observed have significant overlap and duplication of the combination partner targets.”
The new analysis identified a notable and rapid shift in study sponsorship from companies to investigator-initiated trials in the early development cycle, especially in combination trials. Of the 1,105 anti-PD1/PD-L1 combination trials, 60 percent were sponsored by non-industry sources, such as individual academic centers, government agencies, collaborative groups, or nonprofit entities. These investigator-initiated studies are deemed “more exploratory,” and typically have a small patient enrollment—76 per trial on average. The report's authors propose more multi-center collaboration.
In addition to the rapidly evolving landscape in PD1/PD-L1 research, the new report found a rapid proliferation of studies on CAR T-cell therapy. CD19 is the most common CAR-T target, with 56 clinical-stage therapies focused on it. In this area of IO research, China clearly leads the way; 98 clinical-stage CAR-T agents are owned by 46 companies from China, compared to 51 clinical-stage agents owned by 22 companies in the U.S.—with much smaller numbers for all other countries combined.
Mindful of fragmentation, overlap, and duplication in the IO field, the authors of the CRI report suggest that new trial designs should be considered for IO development, which might lead to breakthrough treatments sooner.
One such example is KEYNOTE-001, a phase I trial which led to two FDA approvals, one in melanoma and the other in advanced NSCLC. This large trial recruited 1,245 patients; it used an adaptive trial design. The trial led to the approval of pembrolizumab for ipilimumab-resistant melanoma, and 1 year later results from the same trial led to the second approval, for advanced NSCLC. (Note: on Sept. 22, 2017, the FDA granted accelerated approval to pembrolizumab for patients with recurrent locally advanced or metastatic, gastric, or gastroesophageal junction adenocarcinoma whose tumors express PD-L1. Approval was based on the results of KEYNOTE-059, an open-label, multi-center trial).
Adaptive trial designs cited in the new report include umbrella, basket, or platform designs. These, the CRI report notes, could “create a unique opportunity to drive collaboration, coordination, and accelerated innovation.”
The CRI, which has been cultivating the IO field for 65 years, hopes to become a key educational resource for the IO community. The report authors stated that in “working with the IO community, we aim to build an unbiased, neutral, comprehensive information hub for clinical IO.” The new analysis, which is available in an interactive format, and additional resources can be found on the CRI website, www.cancerresearch.org/IO-landscape.
Peggy Eastman is a contributing writer.