Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, comprising 85% of all diagnosed cases of lung cancer. Treatment of NSCLC is dependent on the stage of the disease. In stage III NSCLC, the primary (original) tumor is large and the cancer has spread to lymph nodes in the center of the chest or other lymph nodes that are on the same side as the primary tumor. This stage of NSCLC is often referred to as locally advanced lung cancer and is divided into stages IIIA, IIIB, and IIIC, based on which lymph nodes have been affected and the size of the primary tumor. (Read more about lung cancer staging here.)
In 2018, the US Food and Drug Administration approved an immunotherapy drug, durvalumab (also known by its brand name, Imfinzi®), for the treatment of locally advanced stage III NSCLC following definitive chemoradiation, based on the results of the PACIFIC trial. Unlike other immunotherapies that have been approved for stage IV/metastatic NSCLC, durvalumab is the first immunotherapy approved for this subset of NSCLC patients.
We sat down with Patrick Forde, MD (MB, BCH), Associate Professor of Oncology at the Johns Hopkins School of Medicine, to discuss the results of the PACIFIC trial and what it means for our survivor community. Dr. Forde is an expert on immunotherapies for lung cancer and has led several global phase 3 immunotherapy clinical trials. We produced a webinar of our conversation, which you can watch below.
How has stage III NSCLC been traditionally treated? What is definitive concurrent chemoradiation?
Approximately one-third of NSCLC patients have stage III, locally advanced, disease at diagnosis. Stage III is highly heterogeneous, and treatment may involve surgery with chemotherapy or chemoradiation, or definitive concurrent chemoradiation without surgery. The choice of treatment for a patient should be jointly made by the patient and their healthcare team (which include a medical oncologist [who provides cancer treatment with drugs], a surgical oncologist [who provides cancer treatment with surgery], and a radiation oncologist [who provides cancer treatment with radiation]). Definitive concurrent chemoradiation is defined as a chemotherapy-radiation therapy combination treatment during which the patients receive radiation therapy on the same day as the chemotherapy infusion. Our understanding of radiation therapy has significantly advanced over the past few decades. Now, radiation therapy is often administered through intensity-modulated radiation therapy (IMRT)—the intensity of the radiation is adapted to match the precise shape and size of the tumor and minimize the damage to surrounding tissues, such as the heart and the other lung.
What is the PACIFIC trial? How have the results of the PACIFIC trial changed our approach to treating stage III NSCLC?
Though some stage III patients respond to chemoradiation, the chances of the cancer recurring is quite high. The PACIFIC trial was designed to test whether the addition of the immunotherapy drug durvalumab after a patient has completed chemoradiation decreases the chance of recurrence. Results of the PACIFIC trial indicate that patients receiving durvalumab after chemoradiation had both a higher progression-free survival (PFS) and overall survival (OS). The addition of durvalumab almost tripled PFS, and 66.3% of patients were alive after 24 months of treatment. Based on these highly promising results, treatment with durvalumab has become standard of care for those stage III patients who have received definitive concurrent chemoradiation. While testing for the immunotherapy biomarker, PD-L1, is not required in the US, there are ongoing studies to determine which patients may derive more benefit than others from this drug.
How does durvalumab work? How does it enhance chemoradiation, which was traditionally used alone for the treatment of stage III NSCLC?
Durvalumab is a human monoclonal antibody that blocks the programmed death ligand 1 (PD-L1) protein on tumor cells.
When a patient receives chemoradiation, the treatment leads to gradual killing of the lung cancer. Tumor antigens are released into blood circulation and attract immune cells to the cancer. However, cancer cells can escape from the immune system by producing high levels of PD-L1 protein. Durvalumab blocks PD-L1 and unmasks the cancer cells, providing an additional attack on the tumor after chemoradiation.
Image courtesy of Dr. Forde.
Immunotherapy and chemoradiation are very different: immunotherapy harnesses the patient’s own immune system to fight the cancer, whereas chemoradiation directly kills the cancer cells. In stage III NSCLC, chemoradiation followed by durvalumab delivers a one-two punch to the lung cancer.
What side effects can patients expect after starting durvalumab?
Side effects from durvalumab are comparable to those of other PD1 and PD-L1 blocking antibodies. However, unlike the other immunotherapies, durvalumab is administered after a patient has completed chemoradiation treatment. There may be residual side effects from the chemoradiation. The patient’s healthcare team will discuss how best to manage these residual side effects. In general, serious side effects from durvalumab are rare, and the common side effects we see in the clinic can be managed easily. Among these may be fatigue, musculoskeletal pain, changes in hormone levels, decreased appetite, nausea, and the accumulation of fluid, causing swelling in the lower legs or hands.
For stage III NSCLC patients who may be candidates for chemoradiation, it may be useful to discuss that durvalumab may be a treatment option at the start of treatment.
We also invite you to check out our new free downloadable patient education booklet on stage III NSCLC.
This educational activity was made possible by a grant from Astra Zeneca.
Dr. Basu Roy is LUNGevity's Senior Director of Research .