Roy S. Herbst, MD, PhD
Roy S. Herbst, MD, PhD, led some of the first trials of gefitinib, the EGFR inhibitor that helped introduce targeted therapies of this important mutation into the treatment landscape of non–small cell lung cancer.
But Herbst believes that many of today’s experimental immunotherapies will soon provide even greater benefit to even more patients.
Herbst, professor of medical oncology and pharmacology at the Yale Cancer Center, explained his reasoning November 8 during a presentation at the 9th Annual New York Lung Cancer Symposium.
“The trial results for some of these therapies rank among the most exciting things I’ve ever seen,” Herbst said in an interview with OncologyLive
. “Several of these treatments are almost certain to win rapid approval and quickly become the standard of care for a large percentage of all patients with lung cancer.”
Herbst’s presentation covered both the theory behind immunotherapy and the performance to date of medications such as nivolumab (Opdivo) and pembrolizumab (Keytruda).
Lung cancer specialists are waiting eagerly for results from Bristol-Myers Squibb on phase III nivolumab trials, which are expected any time now, but early trial results explain Herbst’s optimism.
Results from the CheckMate-063 study, a phase II, single-arm, open-label study of nivolumab administered as a single agent in patients with advanced non–small cell lung cancer (NSCLC) who have progressed after at least two prior systemic treatments, were announced last month in conjunction with the 2014 Chicago Multidisciplinary Symposium on Thoracic Oncology. After approximately 11 months of minimum follow up, the objective response rate was 15%, the estimated 1-year survival rate was 41%, and median overall survival was 8.2 months, the company reported.
Pembrolizumab is also being tested against many tumor types. Indeed, it is already approved to treat pretreated melanoma, and Merck hopes to secure an indication against lung cancer in the near future.
Like nivolumab, pembrolizumab shows activity against both squamous and non-squamous NSCLC. Overall response rates to the compound are just under 20%, but they are higher in some subgroups, and those who respond tend to have durable responses. Progression-free survival in one trial topped 80 weeks for 40% of the patients whose tumors appeared likely to respond.
“The durability of the response is one of the most promising aspects of this type of immunotherapy,” Herbst said. “When it works at all, it tends to work for a long time because the immune system, unlike targeted therapies, is designed to attack any foreign cell rather than a single thing that may disappear as tumors mutate.”
Herbst argued during his presentation that official trial results may be understating the benefits of immunotherapies by using the wrong endpoints to evaluate their efficacy. Treatments that work on substantially less than half of all trial patients rarely produce huge improvements in median results, yet those same treatments can greatly increase long-term survival rates, if they provide the durable benefits that immunotherapy seems to offer.
Trials may also be understating patient response rates, Herbst said, by failing to detect some instances of “pseudoprogression,” when tumors grow larger even though treatment is working. Successful immunotherapy can initially induce tumor growth in many patients, Herbst said, perhaps because of an inflow of lymphocytes.
The new therapies that Herbst discussed all work by making it harder for tumors to escape attack from the T cells of the body’s immune system.
T cells are covered with receptors that help them distinguish normal cells from foreign invaders. Among the most important of those is programmed death receptor 1 (PD-1).
When T cells encounter normal human cells, PD-1 binds with the programmed death receptor-ligand 1(PD-L1) that’s expressed on the outside of healthy human cells, and that connection signals the T cell to stand down. When T cells encounter cells that lack PD-L1, they attack those cells and call other T cells for backup. Two agents currently in development targeting PD-L1 are MPDL3280A (Genentech) and MEDI4736, being developed by Medimmune, AstraZeneca’s biologics research and development arm.
Many tumors evade that immune response, Herbst said, because they express PD-L1 and thus convince T cells to accept them as normal.
Both nivolumab and pembrolizumab are anti-PD-1 antibodies that encourage the immune system to attack cancer by preventing receptors on T cells from binding with ligands on tumors. Other experimental treatments work on tumors rather than T cells, blocking the ligands to prevent them from binding with the PD-1 on the T cells.