The 2019 annual meeting of the American Society of Clinical Oncology (ASCO19) has now come and gone. Over 40,000 people attended the conference, and much of the excitement in Chicago involved immunotherapy. In addition to our daily recaps—Day 1, Day 2, Day 3, Day 4, and Day 5—that covered these immuno-oncology updates, we also wanted to share some overall insight into several of the most important immunotherapy trends that were unveiled over the last week.
Long-Term Survival after Checkpoint Immunotherapy
As more time passes since immunotherapy was first introduced into the clinic, its long-term benefits are becoming more and more clear. Perhaps most impressively, a follow-up of patients with advanced non-small cell lung cancer—which was previously considered essentially untreatable—found that nearly one-quarter of them were still alive five years later. This number rose to 30% for patients whose tumors expressed high levels of PD-L1. In melanoma, too, immunotherapy’s long-term benefits continue to come to light. In one study, two-thirds of patients who initially had complete responses were still relapse-free years later, and roughly 80% of them survived at least five years. Among melanoma patients who received the combination of PD-L1 immunotherapy along with BRAF and MEK inhibition, 40% had complete responses, and roughly half have gone at least two years without disease progression. Lastly, in patients with advanced liver cancer, combining PD-1 and CTLA-4 checkpoint immunotherapy doubled the response rate compared to PD-1 alone, and roughly half of the patients survived at least two years.
The Benefits of Immunotherapy Earlier in the Course of Treatment
In several cancers, the benefits of immunotherapy earlier in the course of treatment—ether as a first-line treatment or even before surgery—were clear. In advanced head and neck cancer, the first-line combination of PD-1 immunotherapy and chemotherapy was shown to double three-year survival. The combination of PD-1 and CTLA-4 immunotherapy also appeared promising in these patients. In melanoma, patients treated with PD-1 immunotherapy after their tumors were removed surgically experienced a greater than 40% reduction in the risk of recurrence. In kidney cancer, combining PD-1 immunotherapy with either CTLA-4 immunotherapy or VEGF/VEGF-R-blocking therapy after surgery also helped protect patients against recurrence, with 84% of these patients surviving at least two years.
Biomarkers to Guide and Improve Checkpoint Immunotherapy
In patients with advanced lung cancer, blood-based tumor mutational burden measurements as well as PD-L1 expression levels helped predict which patients would respond to either single or dual checkpoint immunotherapy versus chemotherapy. In head and neck cancer patients who received dual checkpoint immunotherapy prior to their tumors being surgically removed, an increase in “killer” T cells found within patients’ tumors was shown to be linked to a greater likelihood of pathologic complete response, which in turn is associated with improved overall survival.
Additionally, in advanced melanoma there were a number of biomarker insights revealed at the conference. Levels of the circulating biomarkers IL-6 and CRP were linked to outcomes, and CRP was also shown to inhibit the activation of T cells by dendritic cells. Tumor mutational burden and interferon gamma-related gene signatures were also found to be good predictors of patient responses: in one study, of the patients who possessed both biomarkers, all responded to checkpoint immunotherapy. Levels of PD-L1 expression, an important biomarker for PD-1/PD-L1 immunotherapies, were also shown to differ between primary and metastatic lesions, and variations in PD-L1 expression were found to be associated with either the presence of, or lack of, certain genetic mutations. Assessing PD-L1 expression via circulating exosomes might also provide a potentially better and less invasive way to measure this biomarker. Body composition was another factor that appeared to affect how likely patients were to respond to PD-1 immunotherapy, with the patients who had both a high fat and high muscle content having the best outcomes. In patients who received dual PD-1 and CTLA-4 immunotherapy prior to surgical resection, low-grade (1-2) immune-related side effects were associated with improved therapeutic benefits.
Cellular Immunotherapy Advances
Cellular immunotherapies, such as CAR T cells, have proven very effective in blood cancers such as leukemia and lymphoma. In addition to continued signs of success in these cancers, two therapies that involve taking tumor-infiltrating T cells from patients also appeared promising for patients with solid tumor types. First, the LN-145 T cell therapy led to responses in roughly half the patients with advanced cervical cancer who were treated, and helped stabilize disease in many of the others. Second, in melanoma patients who had previously received PD-1 immunotherapy, a therapy called Lifileucel that used cryopreserved T cells appeared beneficial, leading to responses in almost 40% of patients, whereas only about 20% had disease progression. Lastly, mesothelin-targeting CAR T cells also appeared safe and effective, in combination with PD-1 immunotherapy, when they were delivered into the chest cavity of patients with pleural cancers. Overall, more than half these patients responded, including several who had complete tumor elimination, and none had CAR T cell-related side effects greater than grade 1.
Other New Immune-Based Approaches & Combinations
Of the newer therapies with promising results at ASCO19, four stood out. One targeted CD47, which cancer cells use as a “don’t eat me!” signal to protect themselves against macrophages. In combination with therapy targeting either PD-1 or HER-2, this CD47-blocking immunotherapy led to responses in patients with head and neck cancer, stomach cancer, esophageal cancer, and lung cancer, and was also shown to increase the infiltration of macrophages into tumors. Another approach targeted the 4-1bb pathway that acts as a co-stimulatory switch for T cells, and appeared to synergize with PD-1 immunotherapy in patients with recurrent glioblastoma. Third, a vaccine targeting survivin—which aids cancer cell survival—was able to generate immune responses in a majority of patients with newly diagnosed glioblastoma. Lastly, a bispecific antibody that targeted both the EGFR and cMET pathways on cancer cells led to responses in patients with non-small cell lung cancer who were previously resistant against other EGFR-blocking therapies.
Want to Keep the Conversation Going?
Join us for “Cancer Immunotherapy Insights from ASCO,” a Twitter chat (#CIMchat) on Tuesday, June 11, from 12pm-1pm ET, moderated by Sharon Begley, senior science writer for STAT News.