New Immunotherapy Could Be 'Game Changer' in NSCLC

Zosia Chustecka

September 30, 2013

AMSTERDAM — A new immunotherapy, MPDL3280A (under development by Genentech), has shown impressive results in a small group of patients with heavily pretreated nonsmall-cell lung cancer (NSCLC) who were taking part in a phase 1 clinical trial.

All but 1 of the 53 NSCLC patients responded, and the responses are "outstandingly durable," Jean-Charles Soria, MD, from the Institut Gustave Roussy in Villejuif, France, told journalists here at the European Cancer Congress 2013.

Responses were higher in patients who were smokers than in nonsmokers — the first time that this has been seen with any therapy.

Dr. Soria suggested that the new product would be a "game changer" in the treatment of NSCLC, and moderator of the press conference, Cora Sternberg, MD, chief of the Department of Medical Oncology and chair of the division of medical oncology at the San Camillo and Forlanini Hospitals in Rome, agreed.

Discussant for the study at the meeting, Paul Bass, MD, PhD, from the Cancer Institute Amsterdam, said these were impressive results, showing "very high response rates [and] limited, very acceptable toxicity, with hardly any side effects."

Blocks Programmed Death Pathway

MPDL3280A is a monoclonal antibody that acts on the programmed death (PD) pathway, and targets the signaling ligand to the PD protein. This pathway blocks the immune system's response to cancer, and the product's anti-PDL1 action removes this block, thereby increasing the patient's immune response to cancer.

Another investigational agent acting on the same pathway, nivolumab (Bristol-Myers Squibb), has also shown promising activity in NSCLC, as well as unprecedented response rates in melanoma. However, this product has a slightly different mechanism of action; it is an anti-PD-1 antibody that blocks the binding of PD-1 to PDL1, as well as PDL2.

Dr. Jean-Charles Soria

In his presentation, Dr. Soria noted that in the small phase 1 study with MPDL3280A, there were no cases of grade 3 to 5 pneumonitis, which has previously been reported with PDL1/PDL2 blockade. All of the adverse events seen with MPDL3280A were grade 1/2 and did not require any intervention, with the exception of 1 case of immune-related grade 3/4 adverse events observed in 1 patient with large-cell neuroendocrine NSCLC.

This may theoretically suggest less toxicity, but there are too few data at present to make any comparison between these 2 drugs with their slightly different mechanisms of action, said Luis Paz-Ares MD, PhD, from the University Hospital Virgen del Rocío in Seville, Spain. "So far we are not sure that there are differences," he told Medscape Medical News in an interview.

The results with both compounds in NSCLC are "very early, but these early results are very good," and they show that immunotherapy in lung cancer "is a clear path to follow," Dr. Paz-Ares said. It is a big change in lung cancer research — if he had been asked 5 years ago about this, he would have not bet on immunotherapy, he said.

Dr. Soria also said that he had been an "immunoskeptic" but has now been convinced that immunotherapy works in lung cancer

"Hundreds of millions of euros have been spent chasing the dream of immunotherapy for lung cancer patients, but with zero results," commented Cornelius van de Velde, MD, from the Leiden University Medical Center in the Netherlands, and president of the European CanCer Organisation. He said in a statement that these early findings "are extremely important for patients NSCLC," as they have few treatment options that make much impact on their disease.

High Response Rate, Long Duration

The results for MPDL3280A come from a phase 1 study in 175 patients with many tumor types, including renal cell carcinoma, melanoma, gastric cancer, sarcoma, and lymphoma. The drug was administered by intravenous infusion every 3 weeks, and this study tested several doses (10, 15, and 20 mg/kg).

Dr. Soria presented efficacy results from 53 patients with metastatic NSCLC, about half of whom had already been treated with 3 previous lines of therapy. The overall response rate was 23% (12 of 53 patients).

Such a response rate is a significant finding, commented Dr. Paz-Ares, as the usual response rate among pretreated NSCLC patients with chemotherapy is lower than 10%.

The median time to first response was 11.9 weeks, Dr. Soria said, and all of the patients who responded are still responding (with treatment duration ranging from 170 to 534 days). This is also unusual, Dr. Paz-Ares noted, as with chemotherapy only half of the patients are still responding after 6 months.

Better Responses in Smokers

Dr. Soria and colleagues then analyzed the responses on whether or not the patients had smoked, and found that the response rate rose to 26% in smokers (n = 43), compared with 10% in nonsmokers (n = 10)

"Usually it's the other way around," Dr. Paz-Ares commented, with both chemotherapy and targeted agents showing better responses in nonsmokers. "This is good news for lung cancer patients who smoke or used to smoke," he added.

The tumors in smokers are more complex, with more genetic and molecular abnormalities as compared with the tumors from neversmokers, he explained. Dr. Soria suggested that this higher mutational load may result in a higher immunoreactivity, so that these tumors in smokers present more of a target for the activated immune system to home in on.

Dr. Soria and colleagues also analyzed the tumors (using immunohistochemistry [IHC]) for PDL1 expression. About half of the patients had tumors with some PDL1 expression (IHC1, 2, 3), and in this group, the overall response rate was 31% (8 of 26 patients). In the small subset of patients who showed the highest rates of PDL1 expression (IHC3), the objective response rate was 83% (in 5 of 6 patients). This may be a way of selecting those patients who are most likely to benefit from treatment, he suggested.

Further clinical trials of both MDPL3280A and nivolumab are underway.

Dr. Soria reports serving on the advisory board for Genentech. Two of his coauthors are employees of Genentech.

European Cancer Congress 2013 (ECCO-ESMO-ESTRO): Abstract 3408. Presented September 29, 2013.

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