Targeted PD-1 Therapy Offers Opportunity to Sequence Agents

Jeffrey S. Weber, MD, PhD

Director, Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center and Research Institute, Tampa, FL

Drugs that target the programmed death-1 (PD-1) pathway hold considerable promise for the treatment of patients with melanoma, particularly in integrating the agents into the sequence of therapy, according to Jeffrey S. Weber, MD, PhD.

Weber said the PD-1 inhibitor BMS-936558, which caused considerable excitement at the American Society of Clinical Oncology (ASCO) annual meeting in June, can be an effective part of a treatment regimen that includes ipilimumab (Yervoy).

BMS-936558 is a monoclonal antibody that targets PD-1 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).

By attacking PD-1, BMS-936558 takes the brakes off the immune system through a checkpoint blockade strategy, similar to the mechanism that ipilimumab, an immunotherapeutic agent, employs against CTLA-4.

The study presented at ASCO found that BMS- 936558 was effective in heavily pretreated patients exhibiting one of three tumor types: non-small cell lung cancer, renal cell carcinoma, and melanoma.¹

Of those three types, the highest objective response rate—which included patients who achieved complete or partial responses—was observed in melanoma, with 26 of 94 patients (28%) responding to the treatment. Additionally, six of those melanoma patients (6%) achieved stable disease for at least 24 weeks (Table).

Table. Key Data in BMS-936558 Study¹

Tumor Type

No. patients

ORR (CR/PR)

No. patients (%)

SD ≥24 wk

No. patients (%)

Melanoma

94

26 (28)

6 (6)

Non-small Cell Lung Cancer

76

14 (18)

5 (7)

Renal Cell Carcinoma

33

9 (27)

9 (27)

ORR indicates objective response rate; CR, complete response;

PR, partial response; SD, stable disease.

Weber said the PD-1 antibody offers a flexible option for patients with advanced disease.

“We’re finding that we can give the PD-1 antibody to patients who fail ipilimumab, but we’re also finding that the reverse is true, and that we can give ipilimumab to patients who fail the PD-1 antibody,” said Weber.

Weber said that the drug has shown a durable response in these patients, adding to an ever-growing armamentarium of options in advanced melanoma. There had been no new options for many years before the FDA approved ipilimumab in March 2011.

“We’re seeing a major response by the second and third weeks of treatment,” said Weber. “These drugs represent some of the biggest advances we’ve made in treating melanoma in many years.”

Bristol-Myers Squibb developed both BMS-936558 and ipilimumab. Weber noted that research into other PD-1 inhibitors also is under way.

A phase I study presented at ASCO indicated that MK-3475 generated antitumor activity in three different dosages administered to nine patients with advanced solid tumors, including two patients with melanoma.² MK-3475 is a humanized monoclonal IgG4 antibody that Merck is developing.

AMP-224, a fusion protein that blocks the interaction between PD-1 and the protein B7-H1, is being assessed in a two-stage phase I study with an estimated enrollment of 63 patients, according to ClinicalTrials.gov (NCT01352884). The study will evaluate escalating doses in relapsed or refractory solid tumors or cutaneous T-cell lymphoma, and safety in ovarian cancer and melanoma.

Amplimmune, a Maryland-based company, is developing AMP-224 under an agreement with GlaxoSmithKline.

References

1. 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. Presented at: The American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, Illinois. Abstract CRA2509.
2. Patnaik A, Kang SP, Tolcher AW, et al. Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. J Clin Oncol. 2012;30(suppl; abstr 2512).