Zosia Chustecka

March 27, 2014

GENEVA — Lung cancer researchers continue to be excited over the potential for immunotherapy, and the subject was given a top billing here in a keynote lecture on the first day of the European Lung Cancer Conference 2014.

Reviewing early clinical data with several investigational immunomodulatory drugs that have been tested in advanced lung cancer, Julie Brahmer, MD, MSc, associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, said the results show a similar pattern for all the new agents. About 20% of patients respond to these therapies, and the responses are durable, even when the drug is stopped.

The investigational drugs include nivolumab (Bristol-Myers Squibb) and MK-3475 (Merck & Co.; now known as pembrolizumab and formerly known as lambrolizumab), which act as programmed death inhibitors, and also BMS-936559 and MPDL-3280A (Genentech/Roche), which are antiprogrammed-death ligand inhibitors. Although they act at slightly different points, they both function as checkpoint inhibitors in the interaction between T-cells and cancer cells.

Dr. Julie Brahmer

In an interview with Medscape Medical News, Dr. Brahmer predicted that "for the immunomodulatory agents that are being tested in lung cancer, there is a subset of patients who will be able to be treated and have their disease controlled for a long period of time, but we have yet to find a way of identifying those patients, other than to try them on the drug to see if they respond."

"Most of the patients who are benefiting are benefiting for a long period of time, and their disease does not seem to be progressing," Dr. Brahmer said.

She mentioned 2 patients in her clinic who are still alive 3 years after starting on nivolumab in a clinical trial; these were patients who had progressed on several previous therapies, with an expected survival of around 4 to 6 months.

Similar extended survival in lung cancer has been seen recently in patients with EGFR mutations treated with targeted agents such as erlotinib (Tarceva) or gefitinib (Iressa), she said, but in those cases, the patients continue on the therapy, and they eventually become resistant to it.

With these new immunomodulators, the response persists even when patients stop taking the therapy, and has been seen even in patients who have taken only 1 dose of the drug. This suggests that there has been some resetting of the immune system, perhaps creating some sort of immune memory, she said.

This type of response has already been reported with immunotherapy, in a different disease with a different drug. Some patients with metastatic melanoma treated with the CTLA-4 inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb) are still alive 10 years later, suggesting that their immune system has been reset in a way that allows them to live with the disease.

Although those data for lung cancer are less mature, the pattern of response is similar, giving hope that here, too, the immunotherapies may allow patients to live on for years.

"This is extremely exciting. This is the first time that something has worked early on and been consistent.... It's not just a flash in the pan, I don't think, as all of these antibodies have similar results," Dr. Brahmer said.

However, she added that survival data in lung cancer are needed from the comparative trials that are now ongoing.

Only a Subset of Patients Respond

A frustration in this field is the response rate, which is around 20% to 25% with the various immunotherapies currently being investigated in lung cancer. While this is comparable or even better than is seen with chemotherapy, it is much lower that the responses seen with targeted agents in patients with mutations, which can be 60% or more.

But with the targeted agents, the patients are selected for the drug therapy by testing for mutations, and there are great efforts underway to develop similar ways of identifying patients who might respond to immunotherapy.

There is some indication that antiprogrammed-death ligand-1 (PDL-1) expression is correlated with response to these programmed-death inhibiting drugs, but "that is not the whole story; there seems to be something else involved," Dr. Brahmer said.

In addition, there are many questions about how best to use these therapies, she said. Most of the trials so far have used immunomodulators alone in metastatic lung cancer. But how would they perform upfront in less advanced disease? Would combination with other therapies would improve the response rates, as well as survival rates? Ongoing trials are exploring the use of these drugs in combination with chemotherapy, radiotherapy, and targeted agents.

Targeted Therapy Plus Immunomodulator

One presentation here at the meeting suggests that the combination of an immunomodulator with targeted therapy could be particularly active.

Armida D'Incecco, MD, and colleagues from the Istituto Toscano Tumori in Livorno, Italy, investigated the expression of PDL-1 and programmed cell death-1 (PD-1) in tissue samples taken from a group of 123 non-small cell lung cancer patients. They also analyzed the cancers for EGFR and KRAS mutations.

They found that 43 of 122 patients were positive for PD-1, and 68 of 123 patients were positive for PDL-1.

In addition, of the 125 patients tested for mutations, 56 were found to have an EGFR mutation, 29 had a KRAS mutation, and 10 had an ALK transformation. They found a significant correlation between PD-1 expression and KRAS mutations, and also with current smokers, and a significant correlation between PDL-1 expression and EGFR mutation, and also with not smoking (although that did not reach significance.)

In addition, clinical data showed that among the 99 patients whose tumors carried EGFR mutations and who were treated with targeted therapies (erlotinib or gefitinib), the outcomes were better for patients who were PDL-1-positive. These patients had a longer disease-free progression, and tended toward longer overall survival, than PDL-1-negative patients. These results suggest a strong correlation between PDL-1 expression and EGFR mutation and between PD-1 expression and KRAS mutations, supporting further investigation of anti-PDL-1 or anti-PD-1 agents in combination with targeted therapies, the authors conclude.

Commenting on the finding, Jean-Charles Soria, MD, PhD, from the Institute Gustave Roussy in Paris, said: "This study suggests that PDL-1 expression is correlated with EGFR mutation. If this is true, then the immunocheckpoint blockade combination with EGFR tyrosine kinase inhibitors is a major path toward improving the outcome of patients who have EGFR-mutant non-small cell lung cancer. Trials to explore this relationship are underway."

Dr. Soria was a principal investigator on one of the first trials of MPDL3208A in lung cancer, and reported responses that were "outstandingly durable" at the 2013 European Cancer Congress. At the time, he said he used to be an "immunoskeptic," but the results with the new agents have converted him.

Now, he says, "immunotherapy is heralding a new era of lung cancer treatment."

"Blocking PD-1 and PDL-1 can result in striking and durable responses, with global overall response rates of 20% to 25% as monotherapy in metastatic non-small cell lung cancer," Dr. Soria said in a statement.

"These impressive results have yet to be confirmed in other trials" he cautioned, but added: "Nonetheless, immune checkpoint inhibitors will most likely become part of daily practice for non-small cell lung cancer in the near future."

The study was supported by the Italian Association for Cancer Research and the Instituto Tumori Toscano. Dr. Brahmer reports receiving research support from Bristol-Myers Squibb and consultation fees from Merck. Dr. D’Incecco and colleagues have disclosed no relevant financial relationships.

European Lung Cancer Conference (ELCC) 2014: Abstract 380. Presented March 27, 2014.


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