A Silver Lining to the Immuno-Oncology “Gold Rush”

immunotherapy oncology trials, standing out among the crowd, yellow umbrella among white umbrellasWith the recent clinical success of cancer immunotherapeutics, such as checkpoint inhibitors, there has been a dramatic influx of public, academic, and industrial interest in the immuno-oncology (IO) field. Many pharmaceutical companies are looking for the next breakthrough drug and investing significant time and money into IO development. For patients, this is great as investment and competition creates more therapeutic options, yet on the other hand, professionals in the biopharma industry have begun to question whether the industry has gone too far and if an overly crowded market is actually a good thing.

The Immunotherapy ‘Gold Rush’

A recent editorial in The Lancet asserted that it is time to end this immuno-oncology “gold rush,” in which many drug companies are jumping into the immunotherapy market which could be worth $50 billion annually. Within the IO space, there are 50 checkpoint inhibitors alone currently in development worldwide, and more than 800 ongoing US cancer immunotherapy trials involving more than 100,000 patients. Many large companies have invested in the development of therapies in the same class as pembrolizumab, nivolumab and other checkpoint inhibitors that target PD-(L)1, seeking to develop ‘me too’ versions of these established treatments. This rush to emulate success has led to some hastily planned trials, executed without sufficient preclinical investigation or research funds, and an increased potential for toxicity risks which may impact patient safety. These trials consume valuable resources, none more important than the critical patient volunteers, all to retread familiar ground.

If there are already five PD-(L)1 inhibitors in the marketplace, does the industry need another 50 clinical-stage agents to find more?

One argument in favor of additional PD-(L)1 inhibitor development is financial in nature: any company developing an immunotherapy-based pipeline will be at a competitive disadvantage if they lack their own PD-(L)1 inhibitor. Checkpoint inhibitors are becoming the backbone therapy for a growing number of indications, and developing partnerships to gain access to them can slow vital clinical research. As therapeutic regimens receive approval, ownership of each component of the regimen will allow greater pricing freedom and options.

On the other hand, resources, both money and patient volunteers, could be instead funneled toward answering the many outstanding issues that must be addressed to better care for patients with cancer. Despite the success of checkpoint inhibitors, the reality remains that in some indications, upwards of 75% of patients still receive no benefit.  Fundamental to the development of expensive new therapies are accurate biomarkers that can precisely predict which patients will respond to therapy. A meta-analysis of patients with non-small-cell lung cancer (NSCLC) who are PD-L1 negative showed some patients still see a benefit with nivolumab (a PD-1 inhibitor) treatment, and vice versa. This is just one example that points to what has yet to be discovered about the fundamental way in which specific cancer types respond to immunotherapies. Given the complexity of our immune system and cancer’s characteristic and nefarious ability to alter and suppress a patient’s immune response in a variety of ways, there will be questions continually uncovered that will need to be answered in greater detail. Many of these questions can only be answered through clinical research, as preclinical research may not accurately predict outcomes in humans.

The Silver Lining

Despite the existence of the plethora of ‘follow-on’ immunotherapies and hastily planned clinical trials, there is a silver lining to all this attention. The focus on the field has led science-driven biopharma companies to identify new therapeutic targets, experiment with sequencing combination therapies, and create new variations of established therapies, all of which drives immunotherapy forward. Layering the complexity of the immune response on top of the high risk of clinical research, there will inevitably be many failures (such as the recent ECHO-301/KEYNOTE-252 Phase 3 clinical trial), thus necessitating a greater number of well-planned and scientifically-driven attempts.

The Cancer-Immunity Cycle is a conceptual model that continues to benefit from the added attention of the “gold rush.” It is a conceptual framework developed by scientists Dan Chen and Ira Mellman that works to explain how the immune system recognizes and kills cancer. This includes how T-cells get primed to attack cancer, how they travel through the body to reach the tumor, and what they do once they get into the tumor microenvironment. Through this process, there are a variety of bottlenecks where the immune system’s ability to wipe out cancer is hindered and shut down. The true complexity of this multifactorial process is still being elucidated and new targets and strategies for increasing the immune response against cancer are being identified regularly.

There is an element of a “gold rush” when looking at the number of trials that are studying the same patient populations with the same therapeutic regimens. However, not all trials equally displace resources: for example, smaller, investigator-initiated single site trials make up the majority of ongoing trials, or 60 percent. Further, estimates of patient demand are over estimations, based on maximum number of patients allowed to enroll in a trial. The majority of the active IO trials are dose-escalation and expansion trials that are often adaptive in nature. Given the difficulty in determining which patient population will be most responsive to treatment in preclinical studies, sponsors often test the investigational regimen in multiple patient populations, routinely including six or more indications in a single clinical trial. Enrollments to these expansion arms are often gated, allowing for rapid go or no-go decisions depending on safety and a minimum efficacy. If the threshold is met in the first set of 15 or 20 patients, then a larger group of patients can be enrolled to obtain more data and verify initial results – or a protocol amendment to add a registrational arm may follow. However, most of the indications explored in the first expansion arms will not move beyond the first 15 or 20 patients enrolled, and thus the trial enrolls fewer patients than estimated from ClinicalTrials.gov or other public sources.

Another positive effect of the “gold rush” is that a large number of innovative and science-guided companies, including our customers, are exploring various unique strategies and variations to alleviate the immunosuppressive forces in the tumor microenvironment and stimulate the patient’s immune response against cancer. Some of these innovators are building off the success of checkpoint inhibitors and leapfrogging currently approved strategies beyond the main checkpoint signaling pathways of PD-(L)1 and CTLA-4. Through this approach, many innovative twists on immunotherapy that could pay off in the future have emerged, with great potential for future treatment.

Second- and third- generation therapies are currently being developed to help improve response rates and safety by treating the more than 75 percent of patients who do not respond to current cancer immunotherapeutics, or helping to overcome secondary resistance mechanisms.

This includes the development of novel immuno-oncology modulators, both antibodies and small molecules, focused on targets such as TIM-3, VISTA, LAG-3, IDO, and KIR that take a very different approach: while these drugs inhibit molecules that prevent the immune system from killing cancer cells, there is active research into molecules that stimulate T-cells to kill cancer cells. Several of these stimulatory antibodies target CD40, GITR, OX40, CD137, and ICOS, and are under development as mono- and combination therapies.

A growing number of innovations on the successful chimeric antigen receptor-T cell (CAR-T) therapeutics are also in preclinical and clinical development. The new crop of CAR-T and T-Cell Receptor (TCR) therapeutics are geared toward developing therapies with greater safety and efficacy by targeting new antigens, creating bispecific CAR-Ts, kill switches, localized expression of cytokines or PD-(L)1 inhibitors, combinations with targeted therapies, defining the T-cell composition (i.e., CD4+:CD8+ composition), and many other strategies. In addition, when one accounts for the pursuit of these alternative strategies in both allogeneic and autologous therapeutic categories and other T-cell focused adoptive cell therapy strategies, the number of biopharma companies and research programs entering the clinic grows dramatically.

Strong Science and Data Beat All

While many of these “gold rush” trials leverage the success of previous trials, creating follow-on therapies, and could pejoratively be labeled as fool’s gold, other companies have devised a way to tread new ground and find innovation in novel places.

And regardless of the number of trials underway, experience suggests if your protocol is scientifically supported and you have robust preclinical data showing your trial has a strong scientific rationale, you will increase your odds of success in finding a standout place in this crowded field for your potential golden nugget.

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