1. Introduction
A focal point of our special issue on biliary tract cancer is a series of interviews with experts from industry and academia who are dedicated to this field of research. First up is Dr Susan Pandya of Agios Pharmaceuticals who crystallizes her knowledge, thoughts, and anticipations regarding drug targets, precision therapeutics, diagnostics, and key research activities at Agios and how current advances may impact patients in years to come.
2. What led you to work in precision oncology and rare cancers?
My motivation stems from my clinical training and expertise in medical oncology. Having practiced caring for patients and leading first-in-human studies with novel targeted agents as a principal investigator, I have a long-standing appreciation for the study and clinical application of targeted therapies across numerous cancers. I am fascinated by cancer biology and the intricacies of deciphering the actionable molecular features of a cancer as it evolves over time. As a drug developer in rare cancers that have yet to be impacted by an approved targeted therapy, I am driven by the tremendous unmet need and the potential impact of a first-in-class therapy targeting cancer metabolism.
3. Tell us about the key oncology research activities at Agios
Agios is a world leader in developing therapies targeting mutant isocitrate dehydrogenase (IDH) 1 and 2 enzymes, which are involved in tumor metabolism. We have an oral therapy, ivosidenib (TIBSOVO®), which is approved for the treatment of certain subsets of acute myeloid leukemia (AML) with an IDH1 mutation. We determined that inhibiting the mutant protein could lead to cellular differentiation in AML, and now we are applying our knowledge in solid tumors, including cholangiocarcinoma (CCA) with ivosidenib, and glioma with our brain-penetrant, dual mutant IDH1/2 inhibitor vorasidenib. In solid tumors, we are beginning to understand the intracellular and extracellular impact of mutant IDH inhibition through suppression of the oncometabolite D-2-hydroxyglutarate (2-HG) from various biomarker studies led by our internal translational science team and through external collaborations. We hope to apply this knowledge when considering which novel combination treatment approaches to study with our IDH inhibitors. We continue to investigate the mechanism of action of IDH inhibitors across these various cancers.
4. Cholangiocarcinoma is a quickly progressing, aggressive cancer with a poor prognosis. Can you highlight the unmet needs in terms of new therapeutics, drug targets and diagnostics and how Agios is tackling these unmet needs?
The genomic landscape of CCA has evolved over the past decade, and there are several actionable mutations that have been identified, including IDH1 mutations. Unlike other cancers that have benefitted from the explosion of immunotherapy approvals, CCA unfortunately is not particularly sensitive to this type of therapy, which appears to be effective in a very small percentage of patients in clinical studies. Despite our evolving understanding of the disease biology, the vast majority of CCA patients will receive chemotherapy as first-line therapy. Few chemotherapy options are available in the second-line setting, and outcomes associated with second-line chemotherapy are not particularly encouraging, making clinical trial participation a critical consideration for patients. Some of the downsides of chemotherapy are the potential for cumulative toxicity, which can be dose limiting, and the burden on patients and families to have frequent clinical visits for intravenous infusions and blood draws.
There had been no chemotherapy or targeted therapy approvals in CCA until last year when a drug [pemigatinib] targeting a small subset of patients with fibroblast growth factor receptor (FGFR)-altered CCA was approved for patients who had progressed following chemotherapy. Our pivotal ClarIDHy study represents the first phase 3 study conducted in a biomarker-selected population of IDH1-mutant CCA. With the study having met its primary endpoint and other supportive endpoints of clinical benefit favoring the treatment arm, we are hopeful that ivosidenib will be another oral, tolerable, noncytotoxic option available to patients with previously treated IDH1-mutant CCA. Based on this very recent progress, molecular profiling of tumor tissue will hopefully be the standard approach to diagnostics when considering treatment options for patients. This will open the door to new therapy options and additional research efforts to move the field forward. At Agios, we are thrilled and honored to be in a position to move the needle in this disease. We continue to evaluate the science to understand other combination approaches that could be considered in this disease and hope to work with the clinical experts in the field to make additional in-roads in future additional research initiatives.
5. Please elaborate on the importance of targeting IDH1 and other mutations in cholangiocarcinoma. What are the key targets currently and what is your takeaway message on targeting these mutations?
As mentioned above, molecular profiling is a necessity in this disease to provide patients with the best options for treatment that can be effective beyond the general chemotherapy approaches. Currently, IDH1 mutations and FGFR alterations represent the greatest subset of actionable mutations in patients with CCA, followed by the less frequent tumors with neurotrophic tropomyosin receptor kinase (NTRK) fusions or microsatellite instability (MSI-high) that can be targeted with tumor-agnostic approved therapies. Other targetable mutations of interest in CCA include human epidermal growth factor receptor 2/neu (Her2/neu) and B-Raf. These molecular aberrancies rarely co-occur and little is known about the emergence of other targetable mutations at the time of disease recurrence in these biomarker-selected populations. Thus, sequential or combination approaches are worthy of further exploration. Ideally, having targeted sequential options would afford patients the greatest chance of targeting the relevant mutation at the right time in an effort to outsmart, or at least keep up with, the cancer’s evolving genome. The currently approved therapies mark important progress in this disease, but more work certainly needs to be done to keep the cancer under control effectively for as long as possible.
6. Ivosidenib is an investigational drug for the treatment of cholangiocarcinoma that is in phase III clinical trials. Can you update our readers on the ClarIDHy study?
ClarIDHy was the first phase 3 study ever conducted in a biomarker-selected population of IDH1-mutant CCA. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), safety/tolerability, and patient-reported outcomes. The study design evaluated ivosidenib vs placebo in patients who had received at least 1 and no more than 2 prior treatments. Patients randomized to placebo were given the option to cross over and receive ivosidenib at the time of disease progression. The study met its primary endpoint with a highly statistically positive result, demonstrating that ivosidenib reduced the risk of progression or death by 63% compared with placebo. The secondary endpoint of OS was recently analyzed at data maturity and indicated that ivosidenib was associated with a consistent improvement in OS, though the results were not statistically significant. We believe that the final OS data are likely confounded by the high crossover rate of ~70%. The available safety and patient-reported outcomes data indicate a positive benefit/risk assessment of ivosidenib, and we look forward to sharing these results at an upcoming scientific congress and with regulators.
7. The benefit of this drug was not determined to be statistically significant, so how can this be explained?
The PFS endpoint, which was the primary endpoint, was statistically significant; however, the mature OS data were not. These results were likely impacted by the high rate (~70%) of patients in the placebo arm crossing over to receive ivosidenib. The totality of the data supports the clinical benefit associated with ivosidenib.
8. How will you work with regulators to advance this potential targeted treatment option for patients? How do you see the clinical development unfolding and what will be the key milestones to achieve?
Our first priority is to review the final ClarIDHy data with the FDA before the end of 2020 and discuss the regulatory path forward for ivosidenib’s US approval in IDH1-mutant CCA. If all goes well, we intend to submit our supplemental new drug application in 2021. In parallel, we continue to support combination efforts through our investigator-led programs and look forward to the data generated from those studies over the next few years.
9. Are there other agents outside Agios in the clinical development pipeline that have caught your eye? Which investigational agents do you see as the front runners in this therapeutic area?
In my view, the field is waiting to see how immunotherapy responses can be enhanced since the monotherapy data thus far with checkpoint inhibitor therapies are not very compelling. So, data from rational immunotherapy combinations or targeted agents may be informative. The poly(ADP-ribose) polymerase (PARP) inhibitor class of drugs has broad applications in a variety of cancer settings with known genetic susceptibility due to DNA repair deficiency, so it will be interesting to see whether this applies to CCA.
10. What are your hopes for the diagnosis and treatment of patients with cholangiocarcinoma over the next 5 to 10 years?
Heart disease, the leading cause of death in the US, has several screening programs and lifestyle modifications as part of the prevention, detection, and treatment paradigm. My hope and aspirations are that, as a society, we will similarly tackle known causes of cancer in a concerted effort at prevention, and continue to explore other pathways of prevention, including keeping our cancer-fighting immune cells healthy in number and function. I also hope that patients with CCA will be diagnosed at a time when their disease can be treated early and cured. Hopefully, there will be noninvasive and accurate methods for early detection across a variety of cancers like CCA for which screening is not currently in place. This type of progress might be further than 5 − 10 years out but is worthy of intense exploration considering the massive toll cancer as an overarching disease has taken on society on multiple levels.
In the near term, I hope every patient with suspected CCA will have a specialized diagnostic approach, consisting of standard histopathology performed by a pathologist trained in hepatobiliary tumors coupled with genetic profiling. Having diagnostic certainty is critical in this aggressive disease, which requires timely treatment decisions. Finally, I hope every eligible patient with an IDH1-mutant CCA will have the option to receive ivosidenib.
Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Taylor & Francis.
Declaration of interest
S Pandya is an employee and stockholder of Agios Pharmaceuticals, Inc.