Immunotherapies Continue to Impress in NSCLC Trials With Several Forecast for Approval

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.

This slightly different approach to producing immune system response has also produced very encouraging results in early-stage trials against lung cancer and other tumor types.

Trials of both types of compound show that patients whose tumors express large amounts of PD-L1 are several times more likely to respond than those whose tumors appear to express little or none of ligand on their surfaces. Their responses also tend to last longer.

That said, predicting who will benefit from which treatment remains an inexact science. Fewer than half of all people with high ligand expression respond to any given treatment, and as many as 10% of all people with little detectable ligand expression respond to some treatment.

Right now, each drugmaker is developing a unique assay for each treatment, but all of those assays are essentially testing the same thing. Herbst briefly discussed ongoing efforts at his lab and others to develop additional screening methods that will predict response with even greater accuracy.

“The good news is that, although there is certainly some benefit overlap, the trials suggest that different treatments probably benefit different patient populations with different tumor biologies,” said Herbst, who is particularly happy to report that immunotherapy benefits many people with tumors that will not respond to any therapy targeted at particular genetic mutations.

“The bad news is that instead of collaborating on a single assay that would predict which treatment will work best for which patient—an assay that could be expanded as we learn more about screening patients—the maker of each treatment is making a proprietary assay.”

Turning to the issue of toxicity, Herbst said that immunotherapy is generally better tolerated than chemotherapy, but that it creates a unique set of toxicities that oncologists must learn to manage.

Researchers, on the other hand, must learn how best to combine immunotherapies with other types of medications and each other, said Herbst, who believes the Lung MAP (Lung Cancer Master Protocol) and innovative trial design will inform this process.

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