Is the gold rush in immunotherapy trials good?

Although the concept of immunotherapy has been around for more than a century, it only gained prominence as a method of targeted cancer therapy in the early 2000s. In 2015, Merck’s Keytruda (pembrolizumab), a checkpoint inhibitor drug, made headlines as a breakthrough therapy for melanoma after former U.S. president Jimmy Carter was treated with it. Keytruda had just received approval from the U.S. Food and Drug Administration (FDA) as the first anti-PD-1 therapy, and its highly-publicized success created a frenzy in the media; followed by the initiation of scores of immuno-oncology (I-O) clinical trials.

Only three years later, the situation resembles a “gold-rush,” according to an editorial in The Lancet. Estimated to be worth $50 billion a year, the cancer immunotherapeutics market is booming, and more than 800 drug trials are currently underway in the U.S., involving upwards of 100,000 patients.

With the Rise of AI, What IP Disputes in Healthcare Are Likely to Emerge?

Munck Wilson Mandala Partner Greg Howison shared his perspective on some of the legal ramifications around AI, IP, connected devices and the data they generate, in response to emailed questions.

With the revelation that, in some circumstances, checkpoint inhibitors like pembrolizumab and nivolumab can be extraordinarily efficacious in modulating the immune system to fight cancer, it’s no surprise that so many drug companies want to develop their own version. As immunotherapies present a compelling therapeutic paradigm across the broad oncology patient market, both new and established drug companies are intensely focused on being part of the immunotherapy solution.

Can There Be Too Many Immunotherapy Trials?

Can the saying “too much of a good thing” really apply to the newly enlivened immuno-oncology field? According to The Lancet’s editorial, many opinion leaders claim a large number of these 800 clinical trials are hastily-planned and poorly-executed, consuming valuable resources, in particular, patient volunteers. In the scramble to bring drugs to market, some sponsors neglect to conduct thorough preclinical investigations and do not obtain appropriate patient samples (before, during treatment, and at progression). The resulting clinical trials will not sufficiently increase knowledge around mechanisms of action and reasons for therapy resistance.

In addition, the intense competition in the immuno-oncology field could result in a rush to larger registrational trials and programs without sufficient early phase safety and efficacy data leading to costly failures, as observed in the much-anticipated ECHO-301/KEYNOTE-252 trial. This trial studied the IDO1 inhibitor epacadostat in combination with pembrolizumab in advanced melanoma, and its failure to improve progression-free survival (PFS) versus single-agent pembrolizumab has led to numerous other IDO1 inhibitor clinical trials being terminated across several oncology indications.

One question that comes to mind is: would these trials garner the interest of top researchers? Most top institutions will steer clear of this “fool’s gold.” On the other hand, if some of these clinical trials have protocols that have a rational design backed by solid scientific data, there may be real gold in those hills, and such trials will have no problem attracting investigators and patients.

Another concern regarding this gold rush is the difficulty in finding eligible patients, as typified by this New York Times article. But the high patient demand is over-exaggerated because the numbers found in public databases such as clinicaltrials.gov are based on the maximum number of patients planned for enrollment. The majority of active immuno-oncology trials are dose-escalation and expansion trials, which are often adaptive in nature, and test various regimens in multiple patient populations. Enrollments to these expansion arms are often gated, allowing for rapid go/no-go decisions depending on safety and a minimum efficacy, and many trials don’t move beyond the first enrollment stage, meaning that fewer patients are enrolled than estimated. Additionally, 60 percent of the ongoing trials are sponsored by non-industry entities (e.g., nonprofits, government, academic institutions). These are typically single-site trials and enroll smaller patient numbers than a multicenter biopharma sponsored trial.

What Are the Pros To An Escalated Number Of Trials?

Cancer – and immunotherapy – is extremely complex. Although targeted immunotherapy approaches are arguably some of the best tools we have on hand to treat certain cancers, there is much we don’t know. For instance, immunotherapies as monotherapies only work on a small subset of patients; in the case of non-small cell lung cancer (NSCLC), it is only 30 percent. Thus, it stands to reason that the more well-planned trials that are run, the more quickly a unifying hypothesis on how immuno-oncology works on the population as a whole can emerge.

For example, there are key questions related to PD-L1 inhibitors that can benefit from multiple trials in the same patient population:

Are there better biomarkers that can predict response to immunotherapy?
Can we interrogate patient tumor and blood samples from trials to understand the mechanisms of primary and secondary resistance?
Are PD-1 and PD-L1 inhibitors equivalent?
When do you stop treating responders? What are the best schedules of treatment? (Note that these can be very expensive therapies, depending on treatment duration)
How do you most effectively sequence combination therapies?
What are the factors affecting the tumor microenvironment in each patient?

To address these questions, drug sponsors are trying a variety of clinical development strategies to build a more complete and nuanced picture of the cancer immune model, and looking at a multitude of ways in which immunotherapies can be deployed. Some companies are making in-roads by investigating therapeutic targets alternative to the main signaling pathways of PD-L1 and CTLA-4 (e.g. TIM-3, VISTA, LAG-3, IDO, and KIR), and exploring variations on antibodies (e.g. bispecific T-cell engagers, bispecific PD-L1 antibodies). Other researchers are working on different approaches to manipulate the immune system: instead of inhibiting the proteins that stop the immune system from attacking tumor cells, they are activating proteins that trigger an immune attack. Some of these antibodies target CD40, GITR, OX40, CD137, and ICOS, and are being developed as mono-and combination therapies.

Another benefit to having a hundred immuno-oncology trials versus ten is that even failures can provide valuable information. A case in point is the failure of Bristol-Myers Squibb’s Checkmate-026 Phase III clinical trial of Opdivo (nivolumab) as a monotherapy in patients with previously untreated advanced NSCLC. Opdivo failed to meet its primary endpoint of PFS in this patient group whose tumors showed greater than 5 percent PD-L1 expression. So, the drug company used that information to chart a new course and combined Opdivo with another immunotherapeutic. They also made a change in their endpoint: instead of looking at PD-L1 status, they turned to a different biomarker, tumor mutation burden, which showed better correlation of efficacy. The resulting IO/IO combination therapy with a new endpoint was able to produce statistically significant PFS in first-line patients with NSCLC.

Driving Immuno-Oncology Forward

Although the field of immuno-oncology is advancing rapidly, with many variations of current therapies being tested in clinical trials, there are still uncharted territories and room for innovation. Developing a unique strategy backed by a strong scientific background, robust preclinical and early phase clinical data, and well-designed clinical trials will go a long way in this crowded race. The field will advance, both through successful studies and by failures that elucidate hidden “golden nuggets”: important bits of information that can be used to develop better immunotherapies.

Photo: NeilLockhart, Getty Images