Anti-PD-L1 therapy yielded durable responses in early NSCLC trials

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A potential breakthrough for metastatic lung cancer

Dr. Lary Robinson

The PD-L1/PD-1 ligand complex is a natural suppressive pathway used by cells to inhibit IL-2 production and T-cell proliferation so that inflammation is kept under control. However, some remarkably clever cancers including renal cell, ovarian, and non–small cell lung cancer exploit this pathway by up-regulating PD-L1 to evade and hide from the host’s immune system by suppressing inflammation. Four different monoclonal antibodies, such as MPDL3280A, that block PD-L1 have been developed. By blocking this anti-inflammatory pathway, these agents expose the cancer to the host’s activated immune system – the activated "killer" (cytotoxic) T cells.

Early results in a number of phase I clinical trials of anti-PD-L1 agents have shown remarkable and exciting responses using these minimally toxic agents in patients with highly chemoresistant stage IV lung cancer. Somewhat higher responses rates are seen with these agents, and the results are rapid and durable even when treatment is discontinued. This novel immunotherapy approach to systemic treatment of lung cancer is regarded by thoracic oncologists as a potential breakthrough in treatment, and it may soon become the preferred first-line, well-tolerated therapy for this very large group of metastatic lung cancer patients who express high levels of PD-L1, as well as PD-L1–negative tumors. Numerous trials with these agents are ongoing in order to ascertain the most appropriate dosages, potential use with other chemotherapy drugs, and most suitable patient population.

Dr. Lary A. Robinson is professor of thoracic surgery and interdisciplinary oncology at the University of South Florida, Tampa.



SAN DIEGO – Results from studies conducted to date indicate that anti-PD-L1 therapy is well tolerated in patients with non–small cell lung cancer, with rapid response rates.

In fact, responses are "not only very rapid, they’re also very durable," Dr. Leora Horn said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

"We’re seeing continued responses even when treatment is discontinued. The response rates appear to be somewhat higher in tumors that express PD-L1, and we see no pneumonitis or treatment-related grade 5 adverse events to date."

The four anti-PD-L1 agents that have been investigated or are currently being investigated in patients with non–small cell lung cancer (NSCLC) are BMS-936559, MPDL3280A, MEDI-4736, and MSB0010718C, according to Dr. Horn, clinical director of the thoracic oncology research program at Vanderbilt University, Nashville, Tenn.

BMS-936559, developed by Bristol Myers-Squibb, was part of a phase IA dose study at 0.3, 1, 3, and 10 mg/kg in patients with multiple tumor types including NSCLC. Of the 207 patients enrolled, 75 had NSCLC (N. Engl. J. Med 2012;366:2455-65).

More than half of all patients (61%) had treatment-related adverse events, with fatigue the most common (16%), followed by infusion reaction (10%) and diarrhea (9%). Grade 3 and 4 adverse events occurred in 9% of patients. "One of the themes with anti-PD-L1 therapy is that we’re not seeing grade 3-5 pneumonitis in these like we have seen with anti-PD-1 agents," said Dr. Horn. "This may have to do with different expression of PD-1 and PD-2 within the body and the targets of PD-1 compared to anti-PD-L1 antibodies."

The response rate among NSCLC patients treated in the trial reached about 10%, and responses were seen in squamous and nonsquamous NSCLC. "This agent is not being further developed in NSCLC patients," Dr. Horn said. "Nivolumab, a PD-1 blocking antibody, has really taken over as far as development for Bristol-Myers Squibb."

The next agent she discussed, MPDL3280A, is being developed by Roche and Genentech. A phase I trial presented at the 2013 European Society for Medical Oncology (ESMO) Congress examined different doses in 85 patients with NSCLC ranging from 10 to 20 mg/kg once every week for just under 1 year. Key eligibility criteria were measurable disease per Response Evaluation Criteria in Solid Tumors v1.1 and Eastern Cooperative Oncology Group Performance Status 0 or 1. Dr. Horn said that the majority of adverse events were grade 1-2 and did not require intervention. "There was also no maximum tolerated dose or dose-limiting toxicities, and no grade 3-5 pneumonitis was observed," she said.

In a study of MPDL3280A presented by Dr. Horn and her associates at the 2013 World Conference on Lung Cancer, the clinical impact was assessed in 53 patients with NSCLC. Patients first dosed at 1-20 mg/kg by Oct. 1, 2012, with data cutoff on April 30, 2013. The response rate was 83% among patients who had an immunohistochemistry (IHC) score of 3, 46% among those who were IHC 2 and 3, and 31% among those who were IHC 1, 2, and 3. "In all-comers the response rate was 23%," Dr. Horn said. "The responses in these patients are very rapid. We see them by their first or second CT [computed tomography] scan. The responses are also very durable regardless of their IHC status and in patients who are PD-L1 negative. They’ve also been responding even after treatment has been discontinued."

She and her associates examined the response rate to MPDL3280A based on smoking status and mutational status. The response rate was higher in patients who were current or former smokers compared with never smokers (26% vs. 10%, respectively). By molecular status, the response rate in EGFR [epidermal growth factor receptor] wild-type patients was 26%, compared with 17% in EGFR mutant patients. In addition, there was a 30% response rate in patients who were KRAS wild-type and a 10% response rate in KRAS mutant patients, although the numbers are very small, she noted.

According to Dr. Horn, there are three separate, ongoing studies looking at MPDL3280A in NSCLC patients: one in patients with PD-L1–positive NSCLC, one in combination with bevacizumab and/or chemotherapy, and one randomized phase III trial comparing the agent with docetaxel in patients after platinum failure.

Data on the next agent Dr. Horn discussed, MEDI4736 from MedImmune, are limited. A study of this agent was presented at the 2013 ESMO Congress and included 11 patients who received doses of 0.1, 0.3, and 1.0 mg/kg. The most common treatment-related adverse events were diarrhea, vomiting, and dizziness (18% each), and no grade 3 or 4 adverse events or pneumonitis have been reported to date.


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