shutterstock_145903538.jpgMarie Yurkovich and Malik Kaman co-authored this blog post with Vikas Verma.

Antibodies that target immune checkpoints, like those against programmed cell death-1 (PD-1) or its ligand (PD-L1), have rapidly changed the oncology treatment landscape for multiple tumor types including melanoma, bladder cancer and non-small-cell lung cancer (NSCLC). Opdivo and Keytruda, the flagbearers for anti-PD-1 therapy, have collective sales of more than $8 billion alongside a presence in more than six oncology indications.

Despite considerable success, only a subset of patients treated respond to immune checkpoint inhibitors (ICI). Analysis of clinical trial data has identified three broad patient populations:

  • Responders: patients who respond initially to ICI therapies and continue to respond
  • Innate resistance: patients whose tumor fails to ever respond
  • Acquired resistance: patients who, despite initially responding, acquire resistance and eventually progress

As discussed in previous blog posts, identifying potential “responder” patients from those with innate resistance has been an ongoing challenge since around 60% of patients who currently receive anti-PD-1 therapy fail to ever respond, although recent progress has been made in using complex genomic signatures as markers to better predict ICI response. In June 2017, Keytruda received the first “tissue agnostic” label for MSI-H tumors, and in February 2018, Opdivo’s phase III trial in combination with Yervoy demonstrated a superior PFS for 1L NSCLC patients identified as TMB-high—regardless of PD-L1 expression. While these advances are encouraging, their ultimate utility is dependent on more comprehensive diagnostic tools being integrated into treatment algorithms.

An emerging problem—the focus of this post—is acquired resistance to ICI agents. As the use of immuno-oncology agents is predicted to continue to increase across tumor types, acquired resistance represents a significant, and growing, challenge. While it’s a challenge that leaders in immuno-oncology are already making moves to address, the scale of current activities seems to neglect the potential size and unmet need of this underserved population.  

A Complex Problem 

The underlying science: While the mechanisms of acquired resistance are heterogeneous and yet to be fully elucidated, patients refractory to anti-PD-1 therapy demonstrate an upregulation in certain biomarkers, including the secondary T-cell immunoglobulin mucin-3 (TIM-3), LAG-3 and CTLA-4, in both CD4 and CD8 T-cells, implying that these biomarkers could be detected in patients who have acquired resistance.

The scope: As ICI therapies are still entering the market for several indications, the ultimate size and cost of this problem is still emerging, although a recent study showed that around 25% of melanoma patients who initially responded to anti-PD-1 therapies ultimately developed acquired resistance (with a median follow up of 21 months). The potential costs implicated in treating patients with acquired resistance is also of concern: One study found that for patients with advanced lung cancer, immunotherapy treatment past progression accounted for 29% of total treatment costs.

Moves in Immuno-oncology to Address Acquired Resistance

To address ICI acquired resistance, two treatment strategies have emerged:

  • The use of therapies that will re-sensitize a tumor to immune checkpoint inhibitors
  • The use of therapies that target the secondary markers upregulated through initial ICI treatment

Clinical trial landscape: Surveying the clinical trial landscape reveals a recent surge in trials (there are more than 15 in progress) for anti-PD-1 refractory patients. Of these, 80% are in phase I/II and nearly all are testing an agent in combination with an ICI. Agents with several different mechanisms of action are being tested in combination with an ICI, including tumor-infiltrating lymphocyte technology (LN-144, Iovance Biotherapeutics), HDAC1/2/3 protein inhibitors (4SC-202, 4SC AG), CXCR4 receptor antagonists (X4P-001, X4 Pharmaceuticals), and IL12 stimulants (pIL-12, OncoSec Medical Inc.). While melanoma and NSCLC are still the major indications, more than 10 tumor types are being evaluated across trials.

Players in this space: Perhaps unsurprisingly, Merck and BMS are sponsoring roughly one-third of these trials. After these two, there are many other manufacturers with at least one trial in the space, including 4SC AG, Prometheus Laboratories, AstraZeneca, Checkmate Pharmaceuticals, Celgene, Roche and Incyte Corp. While a majority of the studies are ongoing, impressive preliminary results in refractory melanoma patients include a 50% best overall response rate demonstrated by OMS-I102 (an IL 12 stimulant) in combination with pembrolizumab, and a 44% overall response rate displayed by IMO-2125 (TLR9 agonist) in combination with Yervoy. Still to be determined are what regulators would consider as benchmarks for approval.

Recently, the validity of ORR as a surrogate for PFS and overall survival (OS) has been challenged as ICI’s have unique patterns of response that differ from those of chemotherapy or molecular targeted agents. Therefore, despite a majority of the refractory phase II trials selecting ORR as the primary endpoint, regulators may demand additional endpoints for approval.

Commercial Implications

To date, ICI manufacturers have concentrated their efforts on being first to a variety of indications either as a monotherapy or in novel combinations. As these spaces become increasingly crowded, many of our clients are asking two questions: “Where are the remaining white spaces in oncology?” and, “How can we differentiate in such hotly competitive markets?” The acquired resistance population could be the answer to both questions, hiding in plain sight. 

  1. Where are the remaining white spaces in oncology? Early studies have indicated that around 25% of anti-PD-1 treated patients can acquire resistance. Considering the rise in patient exposure to PD-1 therapies across a wide array of tumor types, a clinical strategy around acquired resistance should seem obvious. Yet, when you compare the number of acquired resistance trials (around 15) to the total number of ICI trials currently running (around 2,300), the untapped potential within this patient population is surprising. Granted, the technical challenges are non-trivial and the probabilities of clinical success are smaller. However, the math becomes more forgiving if we consider a tissue-agnostic approach spanning all exposed patients. Recent advances in genomic profiling and big data (RWE) make this opportunity feasible to pursue.

Of course, pulling off an opportunity like this would require a significant commitment to personalized medicine and ongoing patient monitoring. While this might seem like an albatross, we believe it has the potential to be the answer to question No. 2. 

  1. How can we differentiate in such hotly competitive markets? Today’s cancer drug value proposition often leaves providers, payers and patients feeling frustrated and transactional. This is because the incentives are misaligned. Manufacturers provide very expensive drugs that only benefit a minority of patients, but they rarely have a meaningful role to play in the ongoing lives of patients treated (despite efforts to the contrary). Occasionally, these incentives do become aligned, and here pharma plays a significant role and adds significant value. Celgene’s REMS program in the U.S. is a good example. As a result of the regulatory requirement, Celgene has an ongoing incentive to stay involved throughout treatment, and the conversations tend to focus on the patient and not the drug. This has become a well-known “secret weapon” in terms of customer centricity and differentiation in the multiple myeloma market. Many orphan drugs/rare disease companies have managed to create a similar effect.

In this same regard, we believe that significant differentiation could be achieved if manufacturers make a serious commitment to developing an ongoing patient registry for the active surveillance of patients’ disease. To be able to detect and identify patients who have acquired resistance and swiftly move them to the appropriate treatment would demonstrate substantial disease leadership. This could shift the conversation away from one focused on relatively incremental differences in drug profiles to one that’s meaningfully focused on the patient. We encourage manufacturers in this space to embrace this worthy goal.


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Topics: competitive differentiators, immuno-oncology, checkpoint inhibitors, pharma manufacturer, meaningful patient experience, Vikas Verma, acquired resistance, ICI therapies