Immunotherapy induces ‘striking’ responses in non–small cell lung cancer



AMSTERDAM – Almost a quarter of patients with advanced and heavily pretreated lung cancer responded to treatment with the novel immunotherapy MPDL3280A in an ongoing phase I study.

The objective response rate was 23% in 53 patients with non–small cell lung cancer (NSCLC) evaluated for clinical activity, with 17% of patients achieving stable disease for 24 weeks or longer, and a progression-free survival rate of 45%. The best responses were seen in patients with the highest expression of the targeted protein, PD-L1; current or past smokers seemed to gain the greatest benefit from the novel immunotherapy.

MPDL3280A was well tolerated by the 85 patients with NSCLC who were evaluated for safety, which was the main aim of the early clinical study.

"Most adverse events seen in the trial were grade 1 or 2 and did not require intervention," Dr. Jean-Charles Soria said at the multidisciplinary European cancer congresses.

Dr. Soria, director of the Institut Gustave Roussy’s integrated cancer research center in Villejuif, France, noted that were no dose-limiting toxicities with doses of up to 20 mg/kg, and no cases of grade 3-5 pneumonitis. There was, however, a single, severe grade 3-4 adverse event in a patient with large-cell neuroendocrine NSCLC, and one death due to cardiac arrest in a patient with sinus thrombosis and a large tumor mass invading the heart at baseline.

Dr. Soria explained that MPDL3280A inhibits PD-L1 in such a way that it leaves some immune homeostatic functions intact, which could potentially prevent the development of autoimmunity.

The phase I trial he presented included patients with nonsquamous (76%) and squamous (24%) histology who were treated with an intravenous (10, 15, or 20 mg/kg) infusion of MPDL3280A every 3 weeks for up to 1 year. The patients’ median age was 60 years; 56% were male. Most (81%) were current or former smokers, and more than half (55%) of the patients had received three or more systemic regimens. Almost all (95%) patients had metastases involving the central nervous system, and 60% had EGFR wild-type.

Sara Freeman/IMNG Medical Media

Dr. Paul Baas

Objective response rates (ORRs) were 21% and 27%, respectively, in patients with nonsquamous and squamous histology. Interestingly, the ORR increased with PD-L1 expression, which was determined using immunohistochemistry (IHC), suggesting this might be a potential biomarker for response. The ORR was 83% when 10% or more of the tumor cells were positive for PD-L1 (IHC 3), 46% when 5% or more of the tumor cells were PD-L1 positive (IHC 2 and 3), and 31% when 1% or more of tumor cells were PD-L1 positive (IHC 1/2/3). The respective rates of progressive disease by IHC status were 17%, 23%, and 38%.

Responses to the investigational drug were "outstandingly" durable, and all but one of the 12 patients who had responded to the drug continued to respond at the time of the data cutoff, Dr. Soria said. The longest duration of treatment response seen at this time point was 84 weeks, he added.

As it had been recently suggested that there might be a relationship between the mutational tumor load and the immunogenicity of the tumor (Clin. Cancer Res. 2012;18:6580-7), Dr. Soria and his associates decided to determine if there was any difference in the response to MPDL3280A according to patients’ smoking status. The results were striking: ORRs in smokers versus never-smokers were 26% and 10%, respectively.

"This is extremely important because most advances achieved over the past 10 years with molecularly targeted agents have benefited never-smokers," he said.

"It is very good to now have something for patients who were former smokers," said Dr. Paul Baas of the Netherlands Cancer Institute, Amsterdam. "It works in adenocarcinoma and squamous cell carcinomas, and I think the importance of this [study] is that [MPDL3280A] is already very active in phase I."

Roche is now pushing ahead with its clinical development program for MPDL3280A in a larger population of patients with NSCLC to see if the novel immunotherapeutic fulfills this early promise.

"Based on these data, we are moving quickly into late-stage clinical studies that will also include a Roche companion diagnostic to potentially identify those who are more likely to respond to treatment," Dr. Hal Barron, Roche’s chief medical officer and head of global product development, said in a statement.

Phase II studies of MPDL3280A in patients with NSCLC (NCT01846416 and NCT01903993) have already been initiated, and further studies are planned. The investigational drug is also being tested in combination with vemurafenib (Zelboraf) in the treatment of BRAFV600-mutation positive melanoma (NCT01656642), in combination with bevacizumab (Avastin) in patients with advanced solid tumors (NCT01633970), and as a single agent in patients with locally advanced or metastatic solid tumors or hematologic malignancies (NCT01375842).


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