Experimental Immunotherapy Makes Headway in Lung Cancer

CHICAGO – The experimental immunotherapeutic anti-PD-1 agent known as BMS-936558 appears active in non–small cell lung cancer, a malignancy notoriously resistant to immunotherapy.

Among 76 evaluable patients with advanced NSCLC who were enrolled in a multidose phase I trial, 14 patients (18%) had a response. The progression-free survival rate at 24 weeks was 26%.

^{Patrice Wendling/IMNG Medical Media}

Dr. Julie Brahmer

The responses were durable, lasting anywhere from 2 to 21 months, Dr. Julie R. Brahmer, an oncologist at Johns Hopkins Hospital in Baltimore, reported at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a fully human IgG4 antibody that blocks the programmed death–1 (PD-1) protein. PD-1 is highly expressed by regulatory T cells and tumor-infiltrating lymphocytes in many tumor types, and plays a key role – along with one of its ligands, PD-L1 – in the ability of tumor cells to evade the host’s immune system. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response, Dr. Brahmer noted.

When responses to BMS-936558 were evaluated by histology, the overall response rate was 33% (6 of 18) in patients with squamous histology, and 12.5% (7 of 56) in those with nonsquamous histology.

"Both of these responses are higher than the drugs we have for patients who fail chemotherapy," said discussant Dr. Giuseppe Giaccone of the Medical Oncology Branch at the National Cancer Institute. Moreover, there are no effective targeted agents for NSCLC patients with squamous cell histology.

He pointed out that tumor-infiltrating lymphocytes were associated with better survival in squamous cell carcinomas in a large retrospective analysis of patients with resected lung neoplasms (Ann. Thorac. Surg. 2009;87:365-71), suggesting that there are differences in immunogenicity and that squamous cell histology might be more immunogenic than other types.

Dr. Giaccone went on to highlight a recent phase II study reporting that first-line treatment with another immunomodulatory agent, ipilimumab (Yervoy), added in a phased fashion with paclitaxel (Taxol) and carboplatin chemotherapy, was superior to paclitaxel and carboplatin plus placebo in chemotherapy-naive patients with advanced NSCLC (J. Clin. Oncol. 2012;30:2046-54). Survival was much higher in patients with squamous cell vs. nonsquamous histology, which again suggested a difference between the two types with regard to immunogenicity.

Patients in the current phase I trial with advanced NSCLC and other solid tumors that had progressed after one to five systemic therapies received intravenous BMS-936558 at varying doses until disease progression or clinical deterioration or unacceptable toxicity. Patients who responded or had stable disease, or who had progressive disease but were clinically stable, were treated until they achieved a complete response, worsening progressive disease, or unacceptable toxicity for up to 12 cycles (96 weeks).

In all, 122 patients with NSCLC were evaluable for safety and 76 for clinical activity. At baseline, 60% of the 122 patients had nonsquamous histology, 96% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and 55% had received at least three prior therapies including platinum-based chemotherapy in 94%, tyrosine-kinase inhibitors in 34%, and radiotherapy in 33%.

The overall response rate was 18% in the 39 patients who were enrolled at the 10-mg/kg dose of BMS-93558, 32% in 19 patients who were given the 3-mg/kg dose, and 6% in 18 patients given the 1-mg/kg dose. The percentage of patients who were free of progression at 24 weeks was 24%, 41%, and 16%, respectively, Dr. Brahmer reported. Three NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions, but were not classified as responders for the overall response rate.

Serious adverse events occurred in 14% of the 296 patients in the entire cohort, according to Dr. Suzanne L. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore, who presented the results of the main study at the ASCO meeting.

Grade 3/4 adverse events occurred in 10 patients (8%) with NSCLC. There were three drug-related deaths in the study resulting from pneumonitis in two patients with NSCLC and one patient with colorectal cancer, said Dr. Brahmer, who presented the results for patients with NSCLC in a separate session. Investigators saw no apparent relationship between drug dose and adverse event frequency in all treated patients or NSCLC patients.

Dr. Giaccone said the severe pneumonitis was worrisome, but that there is no comparison between the toxicity of BMS-936558 and ipilimumab.

"These represent similar mechanisms, but the side effects are clearly lower with the PD-1 compound," he said, adding that randomized studies will be needed to prove that BMS-936558 is better than the standard of care.