The new cancer drugs based on the PD-1 inhibitors have not been approved for clinical use overnight and their introduction into oncology clinical practice has been possible only after a long series of preclinical investigations and early- as well as late-phase clinical trials, biomarker development, approval by regulatory authorities and postmarketing surveillance.
Here, we review the long journey of the PD-1 inhibitor, from the first experimental studies on cancer immunology, through the early phases of human clinical trials, large randomized Phase III clinical trials, marketing approval and, finally, the clinical uses in daily oncology practice, also underlining the main areas of research which are still under investigation.
Understanding the Scientific Foundation
The work on PD-1 inhibitor started with research into immune checkpoint biology, i.e. the study of signaling pathways that are involved in stimulating or inhibiting an immune response and which, in physiological conditions, maintain immune homeostasis and prevent excessive activation of an immune response.
The protein Programmed Death-1 (PD-1) is expressed by activated T cells. Under normal circumstances, it interacts with its ligands, PD-L1 and PD-L2 to down-regulate immune responses and maintain self-tolerance and tissue homeostasis.
Many tumor cells can exploit the above-mentioned immune checkpoint pathway by expressing PD-L1, in order to reduce T-cell activity and thereby avoid destruction by immune cells. These studies provided the biological basis for the development of therapeutic strategies that would counteract cancer cell-induced immune suppression by targeting the PD-1 pathway and restoring T cell antitumor function.
Early Clinical Development
Early clinical trials were then set up to assess the safety and antitumor activity of these compounds in patients with advanced tumors who had relapsed after standard treatments.
Several of the early clinical trials investigating the use of PD-1 inhibitors for the treatment of advanced cancers included patients who had received prior therapy for their disease.
These early clinical investigations evaluated:
- Safety profiles
- Dose escalation
- Pharmacokinetics
- Pharmacodynamics
- Immune-related adverse events
- Preliminary response rates
- Duration of response
These early clinical investigations provided evidence of clinical activity in selected patient populations, thus providing continued basis for clinical development of these compounds in multiple types of cancer. Further, results from these initial studies not only established safety of these drugs, they also highlighted the difference in their actions compared to conventional chemotherapy.
Expansion Across Multiple Solid Tumors
In addition, as more evidence was generated, larger multicenter clinical trials were subsequently conducted to investigate the use of PD-1 inhibitors in a variety of solid tumors.
Clinical investigations expanded to include selected patients with:
- Non-small cell lung cancer
- Melanoma
- Renal cell carcinoma
- Head and neck squamous cell carcinoma
- Esophageal cancer
- Gastric cancer
- Hepatocellular carcinoma
- Cervical cancer
- Urothelial carcinoma
These studies addressed key clinical endpoints such as overall survival, progression-free survival, overall response rates, duration of response, and patient reported outcomes.
Research in these areas continues and this growing evidence base is enabling approval of these cancer drugs for use in an increasing number of clinical settings. This evidence is also being incorporated into clinical practice guidelines for the treatment of cancer.
The Role of Biomarker Research
As clinical experience with these therapies is gathered, it is increasingly recognized that individual patients are going to respond to treatment in different ways. Current biomarker evaluation may include:
- PD-L1 expression
- Microsatellite instability
- Mismatch repair deficiency
- Tumor mutational burden in selected settings
- Molecular profiling when clinically appropriate
Ongoing research may uncover more biomarkers to predict treatment outcome. These can be used for individualized treatment decisions. The integration of biomarker assessment has become an important component of precision oncology.
Evolution of Combination Treatment Strategies
Building on the success of single agents, such as PD-1 inhibitors, that are approved as monotherapies for selected patient populations, clinical studies have been performed to evaluate the addition of other therapies to PD-1 inhibitors. Clinical studies have evaluated combinations with:
- Chemotherapy
- Radiation therapy
- Targeted therapies
- Anti-angiogenic therapies
- CTLA-4 inhibitors
- Investigational immunotherapies
- Cancer vaccines
- Cellular therapies
The main rationale for combining a PD-1 inhibitor with another type of treatment, including chemotherapy, is that each type of treatment can work through different mechanisms and thus activate different arms of the immune system, and attack tumor progression by different means. Ongoing clinical trials investigate the efficacy safety sequences and optimal treatment durations of the various tumors.
Advancing Safety Knowledge
The introduction of the first PD-1 inhibitor also required new approaches to recognize and manage immune related adverse events. These adverse effects are distinct from typical chemotherapy toxicities because they are inflammatory in nature and can affect many different organ systems.
Areas of ongoing investigation include:
- Early recognition of toxicity
- Risk prediction models
- Organ-specific management strategies
- Long-term safety monitoring
- Biomarkers associated with toxicity
- Survivorship following immunotherapy
Multidisciplinary collaboration is critical for the management of toxicity from immune checkpoint inhibitors and for the oncologist managing patients on these medications throughout the entire treatment course. Ongoing pharmacovigilance is necessary to better understand the long-term effects of treatment in an increasingly diverse population of patients.
Integration Into Standard Oncology Practice
Transition to clinical practice is based on an increasing amount of evidence from randomized clinical trials, clinical guidelines and non-interventional studies. These cancer therapies are now being considered for use in certain patient populations with a variety of cancers. Clinical decision-making generally involves consideration of:
- Tumor histology
- Disease stage
- Biomarker status
- Prior treatment history
- Performance status
- Comorbid conditions
- Patient preferences
- Current clinical practice guidelines
The integration of immunotherapy into a multidisciplinary treatment plan is continually evolving based on emerging evidence.
Ongoing Research Shaping Future Practice
Although PD-1 inhibitors are now established treatments for a number of cancers, further research is required to optimize their use in clinical practice.
Current priorities include:
- Earlier treatment intervention
- Personalized immunotherapy strategies
- Novel predictive biomarkers
- Mechanisms of treatment resistance
- Artificial intelligence-assisted biomarker discovery
- Combination of immunotherapy approaches
- Optimization of treatment duration
- Long-term survivorship outcomes
Advances in the field of molecular biology, computational medicine and translational oncology will in the future enable a better understanding of immune check point functions, and of ways to improve upon current forms of cancer immunotherapy. As further work with immunotherapy is developed, healthcare professionals will need to update their knowledge on the latest clinical evidence, treatment guidelines and ongoing clinical trials.
Key Takeaways
The pd-1 inhibitor has come a long way from the early days of clinical investigation. Decades of scientific discoveries, clinical studies, and collaboration among different specialties have finally led to their inclusion as one of the treatment options for different types of cancer.
For healthcare professionals, knowledge of the PD-1 inhibitors’ history provides useful insight into current evidence, biomarker guided treatment, immune-related adverse events and multidisciplinary cancer treatment. Continued research will allow for improved selection of patients for treatment with PD-1 inhibitors, optimization of current treatments and evidence to support use of these drugs in the various types of cancer.
