PD-1 Immunotherapy Makes Strong Showing in Three Tumor Types

Suzanne L. Topalian, MD

An immunotherapy agent that targets the programmed death-1 (PD-1) pathway demonstrated response rates as high as 28% in an early-phase study involving patients with different tumor types, according to data released Friday at the American Society of Clinical Oncology (ASCO) annual meeting.

The study of BMS-936558, an investigational drug that Bristol-Myers Squibb is developing, marks another noteworthy result for cancer immunotherapy, particularly among patients with non-small cell lung cancer (NSCLC), where such therapies typically have not succeeded, researchers indicated during a press briefing.

“One of the remarkable features about this therapy is that it can induce very durable responses in otherwise treatment-refractory patients with advanced disease,” said lead investigator Suzanne L. Topalian, MD, professor of Surgery and Oncology at the Johns Hopkins University School of Medicine in Baltimore, Maryland.

The phase I trial enrolled 296 patients who already had been heavily treated for melanoma, colorectal, NSCLC, prostate, or renal cell carcinoma (RCC). Participants received the drug intravenously in an outpatient setting every two weeks, for a cycle of four treatments every eight weeks, and were eligible to continue treatment for up to two years.

Of the 236 patients for whom mature results were available, objective response rates were 28% (26/94 patients) in patients with melanoma, 27% (9/33 patients) in participants with RCC, and 18% (14/76 patients) in those with NSCLC. Objective response consisted of complete and partial responses.

In addition, six patients (6%) with melanoma, five patients (7%) with NSCLC, and nine patients (27%) with RCC exhibited stable disease ≥24 weeks. Twenty of 31 patients experienced responses lasting more than a year.

By contrast, objective responses were not observed in the 19 patients with colorectal cancer or the 13 patients with prostate cancer included in the group.

Overall, the adverse event profile was favorable, although there were three treatment-related deaths due to pneumonitis (lung inflammation), said Topalian. She said investigators have developed ways to identify patients at risk of pneumonitis, detect the side effect earlier, and “treat it aggressively.”

In all, adverse events of grades 3/4 occurred in 14% (41 patients) of the total cohort , and only 5% of all patients treated in the trial discontinued treatment. The most frequently reported grades 1/2 adverse events were fatigue, rash, and diarrhea. “Many of these side effects were consistent with an immune-related causality,” Topalian said.

BMS-936558 is a monoclonal antibody that targets PD1 proteins, which are expressed on the surface of tumor-fighting T cells but which will turn off the body’s immune system if they join with PD ligand 1 (PD-L1). “The interaction between these two molecules creates a protective shield that shields the tumor from immune attacks,” said Topalian.

By attacking PD1, BMS-936558 takes the brakes off the immune system through a checkpoint blockade strategy, similar to the mechanism that the melanoma drug ipilimumab (Yervoy; Bristol-Myers Squibb) employs against CTLA-4, Topalian explained in an interview.

Through subset analysis, researchers also identified PD-L1 as a potential biomarker that could predict how patients would respond to treatment. Tissue samples from the tumors of 42 patients were analyzed prior to initial treatment with BMS-936558. Thirty-six percent of patients with PD-L1-positive tumors responded to the drug (9/25 patients) while none of the patients whose tumors were negative exhibited a response.

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Dr. Topalian on the PD-1 Targeted Therapy BMS-936558

In a separate study, an anti-PD-L1 agent, BMS-936559, was evaluated in 207 patients. Five of 49 (10%) patients with NSCLC, nine of 52 (17%) of patients with melanoma, and two of 17 (12%) of patients with RCC responded to treatment, according to a press release from Johns Hopkins Medicine.

“We feel that these two studies are, in a sense, bookends,” said Topalian. “They both point to the importance of the PD1 pathway in cancer therapy across multiple histologies.”

Topalian said controlled clinical registration trials of BMS-936558 in melanoma, NSCLC, and RCC are planned, as are additional studies assessing the potential of PD-L1 as a predictive marker of response.

The findings from the two trials were scheduled for publication online in The New England Journal of Medicine Saturday.

Topalian SL, Brahmer JR, Hodi FS, et al. Anti-PD1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: clinical activity, safety, and a potential biomarker of response. J Clin Oncol. 2012;30(suppl; abstr CRA2509).

Tykodi SS, Brahmer JR, Hwu W, el al. PD-1/PD-L1 pathway as a target for cancer immunotherapy: safety and clinical activity of BMS-936559, an anti-PD-L1 antibody, in patients with solid tumors. J Clin Oncol. 2012;30(suppl; abstr 2510).

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