Checkpoint Inhibitor I-O drugs in the market
In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body’s immunological activity against tumors. CTLA-4, PD-1, and PD-L1 are the most widely studied and recognized inhibitory checkpoint pathways.
CTLA-4 mediates immunosuppression by indirectly diminishing signaling through the co-stimulatory receptor CD28. PD-1 is an inhibitory transmembrane protein expressed on T cells, B cells, Natural Killer cells (NKs), and Myeloid-Derived Suppressor Cells (MDSCs). PD-L1 is expressed on many tumor cells. Blockade of the PD-1 /PDL-1 pathway can enhance anti-tumor T-cell reactivity and promotes immune control over the cancerous cells.
Since 2011, seven checkpoint inhibitors have received regulatory approval in the United States: pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, and ipilimumab. The estimated percentage of patients with cancer eligible for checkpoint inhibitor drugs has increased from approximately 2% in 2011 to 44% in 2019, and the percentage of patients with cancer estimated to respond to checkpoint inhibitor drugs has risen, from under 1% in 2011 to approximately 13% in 20191.
The first wave of PD-1 checkpoint inhibitor Opdivo (nivolumab, Bristol-Myers Squibb) and Keytruda (pembrolizumab, Merck) demonstrated cure-like performance in select tumors such as NSCLC and melanoma. These two drugs have the widest range of approved uses and together account for more than 90% of the checkpoint inhibitor drug treated patients. Other PD-1 inhibitor Libtayo (Cemiplimab, Regeneron/Sanofi Genzyme) is approved for NSCLC and CSCC.
Several PD-L1 inhibitors are currently also in market including Tecentriq (Atezolizumab, Roche) approved for urothelial carcinoma, NSCLC, hepatocelluar carcinoma and melanoma, Bavencio (Avelumab, Pfizer) approved for merkel cell carcinoma, urothelial cancer, and renal cell carcinoma, and Imfinzi (Durvalumab, AstraZeneca) approved for NSCLC.
PD-1/PD-L1 checkpoint inhibitors are rapidly becoming the primary first-line treatments for patients in USA, with metastatic NSCLC, metastatic melanoma and metastatic renal cell carcinoma. These checkpoint inhibitors remain the most efficacious immuno-oncology therapies, and improvements in formulation or combinations with targeted therapies (e.g., Tyrosine Kinase Inhibitors) may lead to breakthroughs.
CTLA-4 inhibitor Yervoy (Ipilimumab, Bristol-Myers Squibb) is approved for melanoma, renal carcinoma, colorectal, hepatocellular carcinoma, and NSCLC.
Companies have increased their investment in immuno-oncology combination studies, with more than 200 mechanisms now being investigated as PD-L1 or CTLA-4 combination partners and immuno-oncology assets estimated to represent approximately half of top ten company pipelines
The immune checkpoint inhibitor approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways and drugs for other checkpoints such as LAG-3, TIM-3, TIGIT, BTLA, VISTA, CD-47 and B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, CD137 are under investigation.
Diagnostic tools for Checkpoint Inhibitor I-O drugs
Biomarkers that stratify patients likely to respond to therapy are now included in 39% of oncology trials, up from 25% in 2010, reflecting that precision medicine approaches are becoming more commonplace2.
Today, PD-1/PD-L1 immunohistochemistry tests (IHCs) are available as companion or complementary diagnostics to determine biomarker expression for many approved indications. Given the number and types of biomarkers explored (DNA, RNA, protein), multiple diagnostic modalities are being employed, including next-generation sequencing (NGS), quantitative polymerase chain reaction (qPCR), IHC and flow cytometry. NGS appears to address the majority of immuno-oncology biology and pathways. However, flow cytometry and IHC are also expected to be important immuno-oncology diagnostic tools given their ability to detect expressed proteins at the single-cell level.
Microsatellite instability (MSI) mutations impact the production of DNA mismatch repair enzymes, and cells harboring these mutations are less able to repair errors in DNA replication, increasing the risk of developing cancer. Many tumor types have these mutations, particularly in endometrial, colorectal, and other gastric cancers, which are among the most frequently tested for MSI-H/dMMR status. Keytruda (pembrolizumab) received the first approval for solid tumors with positive microsatellite instability–high (MSI-H) or mismatch-repair–deficient (dMMR) status in 2017. Both Keytruda (pembrolizumab) and Opdivo (nivolumab) have approvals for specific tumors that test positive for MSI-H/dMMR, such as endometrial or colorectal cancer.
The rapid rise of Tumor Mutational Burden (TMB) represents a paradigm shift. TMB is an observation that tumors with a relatively high frequency of mutations tend to respond better to checkpoint inhibitors (due to increased neo- antigen presentation). NGS is required to measure TMB, and as TMB becomes more routinely adopted, it will be an important driver to continued NGS adoption.
Checkpoint Inhibitor I-O Trial Trends
The number of immuno-oncology combination trials, those that include a treatment combination with more than one immuno-oncology therapy, has increased steadily since 2010. Combining checkpoint inhibitors with other types of cancer therapies may help to improve the efficacy of checkpoint inhibitors in certain tumors, certain patient populations, as well as help combat drug resistance.
Drugs being combined with checkpoint inhibitors include other immunotherapies, targeted therapies, chemotherapies, and radiotherapies, with the most common combinations being with chemotherapy or therapies that target the vascular endothelial growth factor (VEGF).
The randomized controlled trial (RCT) is the gold standard design for clinical trials. However, in the era of precision oncology, targeted agents are being studied in smaller, heterogeneous, but molecularly defined subpopulations, which has led to a rise in the use of novel trial designs. In some cases, novel trials designs are better suited for precision oncology than RCT.
Basket or bucket trials can be used in early-stage development for tissue-agnostic or multi-indication development and are designed to allow a targeted therapy to be evaluated across multiple diseases with similar traits, such as tumors that share mutations.
Umbrella trials can be used to evaluate multiple targeted therapies within a single type of cancer stratified into subgroups of patients by molecular alternation.
Adaptive trials allow for pre-specified modifications in the protocol or statistical procedures based on data collected that helps to avoid costly protocol amendments. Fewer patients are required in an adaptive trial, dose selection can be much more efficient, and stakeholders can quickly identify and discontinue unsuccessful trials.
The number of adaptative, umbrella, and basket trials in oncology has more than tripled since 2010, and 6% of late-stage pipeline oncology therapies in 2019 use one of these new trial types. The percentage of novel trial types incorporating precision biomarkers has also increased, from approximately 50% of novel trials including a precision biomarker in 2010 to over 70% in 20193.
Pitfalls of Checkpoint inhibitor I-O therapies
Despite their performance, checkpoint therapies have a number of shortcomings. For instance, response rates are still only 20 to 30% on average. Checkpoint inhibitors also come with significant side effects, especially when used in the combination regimens. Checkpoint inhibitors cost at up to $150,000 per year for monotherapy, and represent a significant burden to healthcare systems and payers. Furthermore, prior exposure to checkpoint therapy may render patients ineligible for other immune-oncology clinical trials.
Reimbursement can be a challenge, as demonstration of clinical efficacy within regulatory approval trials has been limited by the small numbers of subjects within the trials, which in turn limits the amount of data available for interpretation by payers and health technology assessment (HTA) bodies. Additionally, the innovative trial designs used to demonstrate efficacy and receive regulatory approval may be problematic for some HTAs, such as lack of active comparators or use of surrogate endpoints. Finally, the cost of these agents, along with the cost of diagnostics such as next-generation sequencing (NGS), may be prohibitive to some patients.
Image Credit: MattLphotography / Alamy Stock Photo
Source:
- Iqvia MIDAS, Evaluate.com
- Globaldata
- clinicaltrials.gov