AACR: Lung Cancer Therapy Innovations

Julie R. Brahmer, MD

Today, ahead of the American Association for Cancer Research Annual Meeting, held this year April 6–10 in Washington, DC, we speak with Dr. Julie Brahmer, associate professor of oncology at Johns Hopkins School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, about lung cancer therapy. Dr. Brahmer is giving a presentation on immunotherapy in lung cancer at the meeting, and is one of the clinical investigators of the extensive phase I trial of the anti–PD-1 antibody, BMS-936558, or nivolumab, that was presented last June at the annual American Society of Clinical Oncology meeting and also published in the New England Journal of Medicine. Dr. Brahmer was involved in the lung cancer portion of the trial, and her research focuses both on clinical practice and research for lung cancer, and specifically, the development of new therapies for its treatment and prevention.

-Interviewed by Anna Azvolinsky, PhD

Cancer Network: Dr. Brahmer, let’s start with immunotherapy for lung cancer. You were heavily involved in the phase I trial with the anti–PD-1 agent nivolumab. Can you describe the lung cancer results for this trial?

Dr. Brahmer: Yes. Of the 122 patients with non–small-cell lung cancer who were enrolled in the multi-dose phase I trial of nivolumab, where nivolumab was given once every 2 weeks, we have approximately 39% of patients that had squamous cell carcinoma and 61% had non-squamous histology. Also, 55% of these patients had three or more prior therapies, so this was a group of heavily pretreated lung cancer patients. In general the nivolumab was easy to tolerate for our patients with non–small-cell lung cancer; the rate of any adverse event related to nivolumab was very similar in the total population and the lung cancer population. The grade 3 and 4 adverse event rate was lower in the non–small-cell lung cancer population, with a rate of 9% grade 3 and 4 side effects, compared with 15% in the total patient population. The most common side effect in general of any grade was fatigue. Also of note, in general, pneumonitis was relatively rare. Only 2% of patients overall had grade 1 and 2 pneumonitis, and only three drug-related deaths occurred. These were due to pneumonitis. Two patients with lung cancer had pneumonitis, and one patient with colorectal carcinoma had pneumonitis. This was a relatively rare side effect mainly seen early on.

In the activity in lung cancer, overall, the response rate, as reported at ESMO in 2012-we have not had an update since-was 16%, so 20 of 122 patients had an objective response based on RESIST. Patients also had stable disease over 6 months; this was 9% of patients. The progression-free survival rate at 6 months was 33%. Responses were seen at each dose level but particularly at the 3 mg/kg dose, where 27% of patients had a response, and the 10 mg/kg dose, where 17% of patients had a response. Again, at those levels, stable disease was seen as well. There were six patients who had an unconventional pattern of response that was not included in those numbers that I just mentioned, because their tumors originally progressed, and then responded over time. We also saw activity in both the squamous and non-squamous histologies. The response rate in the squamous carcinoma patients at the 3 mg/kg dose was 27%, so 4 of 15 patients had a significant response. We also saw responses in the non-squamous cell histology group. At the 3 mg/kg dose, the response rate was 28%. We saw stable disease in both histologies and very promising progression-free survival. We have several patients that have made it to 2 years of treatment and are now being followed without evidence of progression. We hope to hear more information about them over the next 6 months to get a better idea of how durable these responses are, but we have seen patients who stopped therapy at 2 years based on that clinical trial, and their disease has remained under control for a long period of time.

Cancer Network: Based on these promising results, there are now two phase III trials testing this antibody in two different lung cancer patient populations. Could you describe the trials, and specifically the dosing schedules and how long patients remain on the therapy?

Dr. Brahmer: There are two phase III trials, mainly in second-line treatment. Patients in one of the trials can only have squamous cell histology and previously been treated with one prior chemotherapy treatment. These are patients who have metastatic disease, have progressed through their first-line treatment, and are now looking for therapy options. This particular phase III trial takes patients with squamous histology and randomizes them to the standard chemotherapy in the second-line setting, which is docetaxel given once every 3 weeks, or they are randomized to nivolumab, which is given at 3 mg/kg once every 2 weeks. These therapies are given until progression or for 2 years, particularly for the patients in the anti–PD-1 group-they are stopped at 2 years and followed. The goal of the trial is looking at objective response and overall survival. We are expecting to enroll approximately 264 patients. This trial is open and available for accrual. I think that, in general, it has been easy to enroll patients. Again, they have to have one prior platinum-based chemotherapy, and we also have to have tumor tissue available to evaluate as well.

The second phase III trial is one of just non-squamous cell patients who have been previously treated-one prior platinum-containing chemotherapy is required, and patients who have an EGFR mutation can also have had an EGFR tyrosine kinase inhibitor. This trial will take EGFR-mutated patients as third-line patients. The non-squamous patients are randomized to either single-agent docetaxel every 3 weeks or the anti–PD-1 antibody given at 3 mg/kg once every 2 weeks. Again, this is given until progression or 2 years of treatment. This trial is looking at improvement in overall survival.

Cancer Network: Are there other ongoing lung cancer immunotherapies that are currently in development that you would like to highlight?

Dr. Brahmer: Yes, there is actually a large phase I lung trial that is ongoing of nivolumab in the first-line setting, combining it with ipilimumab in patients with squamous and non-squamous cell histology. Also, there are other anti–PD-1 and anti–PD-L1 antibodies that are being studied. Merck has an anti–PD-1 antibody that is finishing up a phase I expansion trial. They are also looking to develop a larger trial specifically in lung cancer. There is an antibody that has been developed by Genentech, an anti–PD-L1 antibody. I believe the phase I trial will be presented at the AACR meeting this year, so we hope to hear some information on the activity in lung cancer patients in the reporting of that trial as well. Certainly there are other companies that are developing very similar antibodies and could be phase I treatment options for patients with lung cancer.

Cancer Network: Lung cancer has not historically been an immunologic cancer. Was it partly surprising that nivolumab has activity in lung cancer patients, and how do you see immunotherapy being used compared with targeted therapy in lung cancer?

Dr. Brahmer: In the past, immunotherapy has not really found its niche in lung cancer. I think that at least now we have a hint of activity, and activity that is sustained. Compared with patients who are getting chemotherapy, the response for the majority of patients on chemotherapy is not long-lived, and they cannot tolerate the side effects, but for patients who respond to nivolumab, that response can be sustained for months and even years. That is quite unprecedented. In the past, vaccines have not gotten a stronghold in lung cancer either, but we hope that with some of the trials that are ongoing with vaccines, that that will also be true.

Cancer Network: Thank you so much for joining us today, Dr. Brahmer.

Dr. Brahmer: You’re welcome, thank you!