The development of targeted therapies brought new progress to lung cancer treatment and research in the past 20 years, and new options will continue to be available in the future. Roy Herbst, MD, PhD, director of thoracic oncology research program at the Yale Comprehensive Cancer Center at Yale School of Medicine in New Haven, CT, spoke at the 43rd Annual Congress in Washington, DC, on new standards of care for non-small cell lung cancer (NSCLC), immunotherapy for NSCLC, and development of rational drug combinations using biomarkers.
In the American Association for Cancer Research/ONS joint session, Herbst cited that the first continuous phase I study for gefitinib began in 1998, and the drug became the first U.S. Food and Drug Administration-approved targeted therapy for NSCLC in May 2003. Since then, lung cancer has seen continued progress in treatments that involve the immune system. According to Herbst, the immune system has three key attributes:
Although activating the immune system has shown to be a successful goal for cancer treatment, Herbst did note that it can result in immune-related adverse effects (irAEs) in various body systems:
- Endocrine (e.g., thyroiditis, hypothyroidism, hyperthyroidism, hypophysitis, hypopituitarism, adrenal insufficiency)
- Pulmonary (e.g., pneumonitis, respiratory failure)
- Gastrointestinal (e.g., nausea, emesis, diarrhea, colitis, perforation, pancreatitis)
- Neurologic (e.g., neuropathy, meningitis, Guillain-Barre syndrome)
- Ocular (e.g., iritis, uveitis, conjunctivitis)
- Cardiac (e.g., pericarditis)
- Dermatologic (e.g., mucositis, rash, vitiligo)
- Hepatic (e.g., transaminitis, hepatitis)
- Renal (e.g., nephritis, renal insufficiency)
One of the studies Herbst discussed is the large phase I study on overall survival and long-term safety of nivolumab in patients with NSCLC. In the trial, 129 patients with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg via IV once every two weeks in eight-week cycles for up to 96 weeks. The trial showed encouraging survival rates in patients with NSCLC, as well as durable responses.
Another study that Herbst noted, a phase II trial of pembrolizumab for patients with melanoma or NSCLC and untreated brain metastases, showed that pembrolizumab may have a role in systemic immunotherapy.
Although treatments for lung cancer have improved, unmet needs still remain; Herbst noted that combination therapies are likely to be required to improve patient outcomes. One of the issues related to immunology in general is with the programmed death ligand-1 (PD-L1) biomarker; PD-L1 expression can be used as a predictive biomarker in cancer immunotherapy. The following cutoffs are used in defining a positive result:
- Cell type expressing PD-L1 (immune cell versus tumor or both)
- Location of expression (cell surface, intracellular, or stromal)
- Intensity, percentage of positive cells
- Distribution (patchy versus diffuse, intratumoral versus peripheral)
Herbst noted that multiple immune mechanisms are involved in understanding immuno-oncology:
- Checkpoint inhibitors (anti-PD-L1, anti-PD-1)
- Active T cells (CD137/4-1BB, OX-40 agonist antibody)
- Abrogate suppression from macrophages and MDSCs (M-CSF, IDO1 inhibitor)
- Transfer engineered T cells (CAR-T)
- Vaccines, oncolytic viruses, bispecific
When trying to understand the best treatment for lung cancer, combinations of immunotherapy, targeted therapy, chemotherapy, and radiotherapy will be needed. However, anti-PD-1/PD-L1 is currently considered a backbone to combination treatment, and various pharmaceutical companies want to develop their own anti-PD1 to use with their own secondary drug. This is causing a huge influx of new immunotherapy trials without enough patient participants.
One of the most important aspects of evolving cancer care is how to bring more science to immune therapy studies, which is what the Lung-MAP is attempting to do. This study, which has many organizations currently collaborating and partnering on it, will assess the type of cancer trait (biomarker) in the patient and that will determine to which sub-study, within this protocol, a participant will be assigned to compare new targeted cancer therapy, designed to block the growth and spread of cancer, or combinations to standard of care therapy with the ultimate goal of being able to approve new targeted therapies in this setting.