Development of immunotherapies that can alter the activity of T cells by targeting checkpoint pathways and determining their level of activity is well under way.
David R. Spigel, MD
Development of immunotherapies that can alter the activity of T cells by targeting checkpoint pathways and determining their level of activity is well under way.1Tumor cells include evolved mechanisms to evade attack by the immune system, and one such tactic is high cell-surface expression of the programmed death receptor-ligand 1 (PD-L1).2The PD-1 receptor is expressed on the surface of tumor-invading T cells, and when activated by the ligand, sends a signal leading to decreased T-cell proliferation and reduction of cytokine synthesis, inducing a degree of immunosuppression within the tumor.
Under normal circumstances, this inhibitory checkpoint pathway is thought to protect healthy tissue from T-cell attack and the induction of autoimmunity,3but when tumor-invading T cells interact with PD-L1, they are inactivated, permitting tumor cell replication and tumor growth. The microenvironment within a tumor may also stimulate invading T cells to increase expression of PD-1 versus T cells in normal tissue and peripheral blood.4Additionally, PD-L1 is a ligand for B7-1 (CD 80), which also inhibits T-cell proliferation and cytokine synthesis.5
“Early data from multiple studies suggest to us that PD- L1 expression can predict for a higher response (particularly to an anti-PD-L1 therapy),” said David R. Spigel, MD, director of the lung cancer research program at the Sarah Cannon Research Institute in Nashville, Tennessee. “However, these same studies show that patients without PD-L1 overexpression can still benefit from these agents, so it remains unclear that their PD-L1 expression by immunohistochemistry is going to be the optimal biomarker and a way to select patients for immunotherapy treatment.”
The high levels of expression of PD-L1 in lung cancer tumor cells has led to the development of monoclonal antibodies that prevent the ligand from binding to its receptors, including PD-1 and B7.1, thereby facilitating a vigorous T-cell immune response against the tumor.6Two agents are in the advanced stages of development: MPDL3280A, an antibody that has been modified to remove its antibody-dependent cell-mediated cytotoxicity function, and MEDI4736, a human IgG1 monoclonal antibody.
A phase I study of MPDL3280A (NCT01375842) in patients with locally advanced or metastatic solid tumors demonstrated Response Evaluation Criteria In Solid Tumors (RECIST) responses in patients with NSCLC and other tumor types, and the treatment was well tolerated. Patients with PD-L1positive tumors showed an overall response rate (ORR) of 39%, and a progressive disease (PD) rate of 12%. Patients with PD-L1–negative tumors had an ORR of 13% with a PD rate of 59%. The results suggested a correlation between response to the agent and PD-L1 status.6,7
In an ongoing multicenter dose-escalation study of MEDI4736 (NCT01693562) in patients with advanced solid tumors (13 NSCLC, 8 melanoma, 5 other), treatment resulted in a disease control rate of 46% and 4 partial responses (3 NSCLC, 1 melanoma). The safety profile was acceptable and tumor shrinkage occurred at all doses tested, was durable, and was seen as early as 6 weeks.8Currently recruiting, the ATLANTIC (NCT02087423) is a single-arm, phase II global study of efficacy and safety of MEDI4736 in patients with locally advanced or metastatic NSCLC who have received at least 2 prior chemotherapies, one of which had to be platinum-based. The primary outcome measure is ORR. The estimated primary completion date is April 2015.
In May 2014, AstraZeneca announced the start of a phase III study9for its anti-PD-L1 monoclonal antibody, MEDI4736, versus placebo, in concert with the global double-blind PACIFIC trial (NCT02125461). The primary outcome measures are PFS and OS. It is expected that 880 patients will be randomized, and the trial will use more than 100 sites. It will recruit patients with locally advanced, unresectable NSCLC, with no evidence of progression after completion of treatment with a course of chemoradiotherapy. Estimated primary completion date is May 2017.
A phase III trial of MPDL3280A (NCT02008227) is recruiting patients. This open-label, multicenter, global trial expects to enroll 850 patients and is designed to evaluate the efficacy and safety of MPDL3280A (1200 mg IV on day 1 of each 21-day cycle) versus an active comparator, docetaxel (75mg/m2IV on day 1 of each 21-day cycle) in patients with locally advanced or metastatic NSCLC following failure on a platinum-containing chemotherapy. The primary outcome measure is OS. The estimated primary completion date is June 2018.
“To date, the efficacy and safety profiles are very encouraging for the anti-PD-1 and PD-L1 therapies. In terms of efficacy, so far there appear to be higher response rates in heavily pretreated patients than we would expect with single-agent systemic therapy,” said Spigel.
In terms of safety, results have been encouraging, according to Spigel. “The agents appear to be well tolerated across the board, although there have been rare serious events, including pneumonitis (with nivolumab in the initial phase I experience, leading to 2 fatalities). However, so far, this does not appear to be a general problem for any one agent or for the class. Immune-related toxicities have occurred, including thyroid abnormalities, but most of the toxicities have been mild and reversible.”
Inducing a robust T-cell response against NSCLC tumors using antibodies directed at PD-L1 is a promising approach to improving outcomes, and clinical data clarifying the benefits of this approach are expected from active clinical trials over the next 4 to 5 years.