AMSTERDAM—The engineered monoclonal antibody MPDL3280A showed promise as intravenous monotherapy in 85 patients with refractory squamous or non-squamous non-small cell lung cancer as part of a large Phase I clinical trial looking at a range of cancers, according to data reported here at the European Cancer Congress (Abstract 3408, accessible via http://eccamsterdam2013.ecco-org.eu/Scientific-Programme/Abstract-search.aspx#).
Professor Jean-Charles Soria, MD, PhD, Director of the Site de Recherche Intégrée sur le Cancer (SIRIC) Socrate project at Institut Gustave Roussy in Villejuif, France, explained that he and his colleagues undertook the study because the antibody targets the programmed death 1 protein PD-1 and its signaling ligand PD-L1, which suppress the patient's immune system and thus allow cancer to grow. Because MPDL3280A blocks PD-L1 from binding to its receptors and restores the patient's normal tumor-specific T-cell immunity, it was logical to target this pathway with a specific drug, he said.
Unusually, PD-L1 inhibition was found selectively to achieve better objective responses rates among smokers than in never smokers. The objective response rate (ORR) in the former or current smokers group was 25 percent (8 of 31 patients) compared with 16 percent (1/6) in patients who had never smoked. When all patients were included, the overall ORR was 24 percent (nine out of 37 evaluable patients) and response durations ranged from one to 214 days.
The PD-L1 molecule was also found to be a biomarker for response: Patients with the marker had an ORR of 100 percent (4/4), while those whose tumors tested negative for PD-L1 had an ORR of only 15 percent (4/26).
In an interview, Soria called the PDL-1 molecule the cancer cell's equivalent of having a diplomatic passport: it gives “diplomatic immunity” to the body's immune system, he said. “An anti-PD-L1 is a compound that will take away the ‘diplomatic immunity’ and allow the ‘cops’—the immune cells—to do their job and take the bad guys away.”
The lung cancer findings were part of a larger overall Phase I study of PD-L1 inhibition to assess both efficacy and safety data in several solid tumors and hematologic malignancies. There were objective responses in all cancers, and in the case of lung cancer there were theoretical grounds for expecting better responses among smokers, he said: “We hypothesized that smoking was associated with tumors that harbor more genetic mutations, and that the immune systems of these patients might therefore be more likely to respond and attack the tumors once PD-L1 had been blocked.”
Toxicities were considered acceptable, he reported: A third of patients had grade three to four adverse events including pericardial effusion (six percent of patients), dehydration (four percent), dyspnea (four percent), and fatigue (four percent), and there were no grade three to five pneumonitis or diarrhea reported.
Soria said he considered the good response rate and low toxicity among heavily pretreated patients to be very significant and confirmed that the differential benefit in smokers was the result of these patients' higher “mutational load”—i.e., that their cancers were prime candidates for immunological attack.
“This is the first time in the last 10 years that a molecular targeted agent brings more hope for smokers than for never smokers,” he said. He was nonetheless quick to say that quitting smoking was of course best, but that there was at least some good news for smokers: “Smoking people have the possibility to benefit from a new compound with mild toxicity and clear activity, which is potentially a ‘game changer.’”
He said he used to be an “immunoskeptic” as far as lung cancer treatments were concerned—“but no longer.”
He noted, though, that although the best results were seen in smokers or former smokers, the findings show that PD-L1 blockade was also an important strategy for non-smokers.
“This is changing the paradigm,” he said: “We used to consider that these were very expensive initiatives with zero results. Now immunology has entered the thoracic world—immunology brings promise.”
At a news briefing, Cora Sternberg, MD, Chief of Medical Oncology at the San Camillo and Forlanini Hospitals in Rome, was also upbeat about PD-L1 blockade, as well as other novel immunotherapies, for treating lung and other cancers: “To have a drug that works in more than 20 percent of heavily pretreated non-smokers is really big news for patients. It's extremely important,” she said.
In an interview, she said that she thought that combination therapies including PD-L1 inhibition were also possible, although she thought that regimens including steroids—which lower immunity—might not be right. She said she was optimistic about the scope in lung cancer: “We now have a chance of giving a non-toxic therapy that can work where we had nothing but chemotherapy to offer patients with lung cancer, so I think there's great hope for patients in the future.”
European Cancer Organization President Cornelis van de Velde, MD, PhD, Professor of Surgery at Leiden University, agreed that the study had important implications for patients with non-small-cell lung cancer for whom, he said, millions of euros had been spent testing immunotherapies that had proved disappointing. “These early findings on the effect of the anti-PD-L1 monoclonal antibody, MPDL3280A, suggest that it has the potential to open new therapeutic approaches, particularly for smokers and former smokers,” he concluded.
On the iPad edition of this issue, Jean-Charles Soria, MD, PhD, discusses more about his findings in a podcast interview at the Congress with Peter Goodwin and Sarah Maxwell. Also expanding on her comments about the implications is Cora Sternberg, MD.
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