Patients in KEYNOTE-012 had an overall response rate of 18%, with 3% achieving a complete response, 15% achieving a partial response, and 20% achieving stable disease. There was also a correlation between PD-1 expression in tumor cells and improved survival. A subsequent Phase III trial of pembrolizumab, KEYNOTE-040, did not meet its primary endpoint of a 20% decrease in death compared to patients receiving chemotherapy, but median survival for the pembrolizumab patients was 8.4 months, compared to 7.1 months for those receiving chemotherapy, a significant response nonetheless, said Dr. Kim. In 2018, an updated presentation on KEYNOTE-040 showed that the drug did meet its overall survival goal.
Explore This IssueNovember 2018
In a 2017 Phase III trial of nivolumab, CheckMate-141, the immunotherapy agent had a better survival rate than the investigators’ chemotherapy of choice: methotrexate, docetaxel, or cetuximab. The study and a later follow-up showed that patients on nivolumab had a 30% decrease in risk of death, and patients with a higher expression of PD-L1 had a better response. Also, patients with P16-positive disease had a much better response to nivolumab than those with P16-negative disease. One reason may be that “because P16 tumors are induced by HPV, a foreign virus, the expression of the viral particles on the surface of the tumor cells may make them more antigenic, allowing the nivolumab to be more effective,” said Dr. Kim.
Mechanisms of Resistance
The tumor microenvironment can help physicians understand the resistance mechanisms of immune checkpoint blockade, said Yoon Woo Koh, MD, a professor of otolaryngology at Yonsei Head and Neck Cancer Center in Seoul, South Korea.
“What are the key characteristics of the immune system? One is memory,” said Dr. Koh. T cells and immune cells mount a stronger, faster response to secondary challenges. Other characteristics are balance and regulation. “Overactivation of the immune system will incur autoimmune diseases or, sometimes, allergy or asthma. Oversuppression will sometimes result in cancer or infection.” Both innate and adaptive immunity play strong roles in how immunotherapy works, as well as potential resistance to it, he said.
“We have to understand the cancer-immunity cycle,” including its aspects as both a regulator and a diverse stimulator, and develop it as a cancer immunotherapy. Diverse mechanisms are involved in this cycle, said Dr. Koh. Two important mechanisms are positive and negative co-stimulation. Molecules like CD28 are constitutively expressed on naïve T cells and augment TCR [T cell antigen receptor]-mediated activating signals. CD28 is a stimulatory molecule. CTLA-4, expressed in the T cells, is an inhibitory molecule that attenuates TCR-mediated activating signals. Anti-CTLA-4 therapies include ipilimumab (Yervoy).