Impressive Results Shown for Immune Checkpoint Inhibitors: Anti-PD1 and Anti-PD-L1 Antibodies 


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Antibody-mediated blockade of the programmed death 1 protein (PD-1) and its ligand (PD-L1) resulted in potent and durable tumor regression and prolonged stabilization of disease in patients with advanced solid tumors, according to early data on these drugs presented at the 2013 ASCO Annual Meeting. While these investigations are phase I studies, the promising findings earned a slot for the investigators at the first Annual Meeting press briefing, where they were peppered with questions by journalists.

The anti-PD-1 and anti-PD-L1 antibodies potentiate immune responses by blocking the interaction between the PD-1 protein, a T-cell co-inhibitory receptor, and one of its ligands, PD-L1—critical players in the ability of tumor cells to evade the host’s immune system (see sidebar on page 11). The anti-PD-L1 antibody MPDL3280A yielded impressive single-agent activity against a variety of solid tumors. The anti-PD-1 antibody nivolumab (BMS-936558) was part of a two-pronged immunologic strategy, paired with ipilimumab.

Dual Immunomodulation in Melanoma

Concurrent treatment with nivolumab plus ipilimumab, which targets the cytotoxic T-lymphocyte antigen 4 (CTLA-4), led to objective responses in 40% of patients with previously treated stage III or IV melanoma, reported Jedd D. Wolchok, MD, PhD, Associate Attending Physician at Memorial Sloan-Kettering Cancer Center and Associate Member of the Ludwig Institute for Cancer Research in New York.1

“What was unique in our experience was that most responding patients had rapid and deep regression by the time of the first CT scan,” Dr. Wolchok announced.

The agents were given concurrently or in sequence in varying doses. Of 86 patients, 52 received concurrent therapy for four cycles, then nivolumab every 3 weeks for four cycles; at week 24, patients received concurrent treatment every 3 months. Sequential treatment involved administration of nivolumab alone to patients who had previously received ipilimumab.

Responses were observed in 40% of patients in the concurrent group, including tumor reductions ≥ 80% in 31% of patients. The most active regimen was ipilimumab at 3 mg/kg plus nivolumab at 1 mg/kg, which produced responses in 53%. The inclusion of patients with delayed responses and stable disease increased the clinical benefit rate to 65%, Dr. Wolchok reported. “The majority of patients had a decrease in tumor burden, with a surprisingly high number showing more than 80% regression,” he commented.

Activity was less robust in the sequential group, in which 38% patients treated with 1 mg/kg of nivolumab had ≥ 50% tumor shrinkage, but no responses were observed with 3 mg/kg. “Responses were noted even in patients with previous progression on ipilimumab, which tells us that patients can respond to another immune modulator,” he said.

Side effects were manageable and reversible using standard protocol algorithms. Concurrent treatment was associated with a rate of grade 3/4 adverse events of 53%, primarily immune-related inflammation. About 13% of patients had asymptomatic laboratory abnormalities.

New Perspective on Melanoma Therapy

Dr. Wolchok told The ASCO Post that the findings “do change the way we think about melanoma treatment,” in that this concurrent immune strategy produces a “more predictable onset of action with more straightforward kinetics” than are typically seen with immunotherapeutic approaches. “The rapidity of response with this combination reminds us of the kinetics we are accustomed to seeing with BRAF inhibitors, so if the combination becomes FDA-approved, this would change how we think about things. If responses can be achieved in a short period, with the kind of durability we see with immune therapies, this regimen would be advantageous.”

A phase III trial evaluating concurrent therapy vs either agent alone will be conducted, he said. “This combination is being investigated in non–small cell lung cancer and renal cell cancer, too.”

MPDL3280A Robust as Single Agent

When MPDL3280A attaches to the PD-L1 protein, which is frequently overexpressed on cancer cells, the cancer cells can no longer hide and the body’s T cells are able to attack the cancer. Development of MPDL3280A arose from the theory that blocking expression or activity of PD-L1 would restore immune cells’ ability to detect and kill cancer cells.

This hypothesis was tested in a multicenter phase I trial of patients with metastatic solid tumors, including cancers of the lung, kidney, colon, stomach, and head and neck, and melanoma. Findings were reported for 171 patients who had received a median of three prior therapies and were given MPDL3280A intravenously every 3 weeks until disease progression.2

Overall, 29 of 140 (21%) patients responded to MPDL3280A, including 36% of patients whose tumors tested positive for PD-L1 and, somewhat surprisingly, 13% of those who were PD-L1-negative. This response rate may, in fact, be an underestimate, due to additional delayed responses and the immune-related (nontumor) masses sometimes seen with immunotherapy, said Roy Herbst, MD, PhD, Ensign Professor of Medicine and Chief of Medical Oncology at Yale University School of Medicine, New Haven, Connecticut.

“Importantly, these responses tended to occur quickly in many cases, and they were also quite durable. I have been impressed by this in our patients here at Yale,” Dr. Herbst told the media.

Responses were observed across tumor types but were greatest for non–small cell lung cancer, renal cancer, and melanomas. At their last assessment, 26 of 29 responders were continuing to respond to treatment after 3 to 15 or more months on study, Dr. Herbst reported.

Enhanced Safety and Efficacy

Although 43% of patients developed grade 3/4 adverse events, most events (all but 13%) were unrelated to treatment. The most common grade 3/4 adverse events were hyperglycemia, fatigue, elevated liver function tests, dyspnea, and hypoxia, each of which occurred in 3% to 5% of patients.

Dr. Herbst explained to The ASCO Post that MPDL3280A was specifically engineered for enhanced safety and efficacy compared to earlier PD-L1 or PD-1 targeted agents. In a study presented at the ASCO Annual Meeting last year, the anti-PD-1 antibody BMS956338 was associated with three treatment-related deaths, including two due to pneumonitis.3

“MPDL3280A should not activate antibody-dependent cell-mediated cytotoxicity, which is important because we don’t want to kill T cells, just block the interaction,” Dr. Herbst explained. “We have seen only low-grade pneumonitis with this drug, and no deaths from it. Does that mean this is a better/safer drug [than previous anti-PD-1 antibodies]? No, but it’s consistent with that. So far we are impressed with the safety profile, but further studies are needed.” ■

Disclosure: Dr. Wolchok reported no potential conflicts of interest. Dr. Herbst received research support from Genentech.

References

1. Wolchok JD, Kluger HM, Callahan MK, et al: Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9012. Presented June 2, 2013.

2. Herbst RS, Gordon MS, Fine GD, et al: A study of MPD3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. 2013 ASCO Annual Meeting. Abstract 3000. Presented June 3, 2013.

3. Topalian SL, Brahmer JR, Hodi FS, et al: Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: Clinical activity, safety, and a potential biomarker for response. 2012 ASCO Annual Meeting. Abstract CRA2509. Presented June 2, 2012.


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