Pembrolizumab Combo Generates High Response Rate in Refractory Myeloma

Jesus San Miguel, MD, PhD

The addition of the PD-1 inhibitor pembrolizumab (Keytruda) to an established multiple myeloma regimen elicited responses in 76% of 17 patients with relapsed/refractory disease in findings from one of several clinical trials presented at the 2015 ASH Annual Meeting that provide early signals that the immunotherapy agent may have an impact on hematologic malignancies.

In the KEYNOTE-023 trial,¹ patients with multiple myeloma who were treated with pembrolizumab, lenalidomide, and low-dose dexamethasone derived clinical benefit from the combination without experiencing excessive toxicities.

Among the 13 patients who responded to the combination therapy, 4 patients (24%) achieved a very good partial response and 9 patients (53%) exhibited a partial response. Additionally, 3 patients (18%) had stable disease, leaving only 1 patient whose disease progressed. The disease control rate, which measured any response plus stable disease lasting >12 weeks, was 88%.

Results were similarly strong among the 9 patients who were refractory to lenalidomide. Five of these patients were among the responders, including 2 participants with a very good partial response and 3 with a partial response.

At a median follow-up of 296 days, the median duration of response was 9.7 months and the median time to achieve the first objective response was 1.2 months (range, 1.0-6.5 months).

“Initial efficacy results show promising activity in heavily pretreated patients with relapsed/refractory multiple myeloma and support the continued development of pembrolizumab in patients with multiple myeloma,” said Jesus San Miguel, MD, PhD, of Clínica Universidad de Navarra in Pamplona, Spain, who presented the findings during an oral session.

Pembrolizumab, which the FDA has approved in melanoma and non—small cell lung cancer, is being explored extensively in multiple myeloma and other hematologic malignancies, according to Merck, the company developing the drug.

In October, Merck launched the phase III KEYNOTE-185 trial,² which calls for randomizing an estimated 640 patients with newly diagnosed, treatment-naïve multiple myeloma who are not eligible for a stem cell transplant either to a regimen similar to that used in the KEYNOTE-023 trial or to lenalidomide/dexamethasone alone.

In addition, pembrolizumab is being evaluated in patients in separate clinical trials in classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma.

“PD-1 blockade, through checkpoint inhibitors to unleash the immune system, has generated tremendous enthusiasm over the last few years in a number of cancers. This therapy, already approved in lung cancer, has also shown very promising results in highly refractory blood cancers,” Andre Goy, MD, chairman of John Theurer Cancer Center (JTCC) and chief of the Division of Lymphoma at Hackensack University Medical Center in New Jersey, said in a statement.

Key Multiple Myeloma Findings

JTCC researchers served as coauthors of the abstracts for the KEYNOTE-023 trial and for the phase I KEYNOTE-013 trial³ in patients with cHL.In multiple myeloma, San Miguel said scientific and preclinical studies have established a rationale not only for targeting PD-1, but also for combining a PD-1 inhibitor with an immunomodulatory agent, such as lenalidomide. He said that PD-L1 is expressed on the clonal tumor cell across all stages of multiple myeloma, but that levels are particularly high on the T cells of patients who are minimal residual disease positive.

“Lenalidomide reduces PD-L1 and PD-1 expression on multiple myeloma cells, and on T cells and myeloid-derived suppressor cells,” San Miguel said. “Lenalidomide enhances checkpoint blockade—induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against multiple myeloma cells.”

Meanwhile, pembrolizumab, a humanized monoclonal antibody of the IgG4/kappa isotype, directly blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

The 2 agents function synergistically when used together, San Miguel said. “Lenalidomide will increase the number of T cells and the T-cell activation, and anti-PD-1 [agent] will release the brake” so that the activated T-cells attack the tumor, he said.

In the KEYNOTE-023 study, researchers were seeking to determine the maximum tolerated dose (MTD) for the combination. Safety and tolerability were the primary endpoints of the study, while secondary endpoints included overall response rate, duration of response, progression-free survival, and overall survival.

After testing several doses, San Miguel said researchers established the MTD as a 200 mg fixed dose of pembrolizumab administered intravenously twice a month without premedication along with 25 mg of lenalidomide on days 1 to 21 of the cycle and 40 mg of dexamethasone weekly.

In all, 50 patients who had undergone a median of 4 therapies (range, 1-5), including 86% who had received a stem cell transplant, have participated in the study thus far. Half of the 38 patients (76%) who were refractory to lenalidomide were considered double, triple, or quadruple refractory to the drug.

For the efficacy analysis, San Miguel included the 17 patients who had participated in the dose determination and confirmation stages of the study. The safety analysis included all 50 participants.

The adverse events (AEs) manifested among the patients were consistent with the safety profiles of the individual drugs administered, San Miguel said. The most common all-grade AEs, defined as those experienced by ≥4 patients, were neutropenia (24%), thrombocytopenia (28%), diarrhea (16%), and fatigue (14%). The most frequent AEs of grade 3/4 severity were neutropenia (22%), thrombocytopenia (8%), anemia (8%), and hyperglycemia (6%).

Significantly, no cases of pneumonitis or colitis and no infusion-reactions were reported. There were several grade 1/2 cases of immune-related AEs, including 2 cases each of hyperthyroidism and hypothyroidism, and 1 case each of adrenal insufficiency and thyroiditis. However, there were no dose modifications or treatment discontinuations required because of immune AEs, San Miguel said.

Hodgkin Lymphoma Results

Although San Miguel stressed that the findings represented early data that warrant further study, he said the results far indicate that the combination has an “acceptable safety and tolerability profile.”In the KEYNOTE-013 trial, patients treated with pembrolizumab had relapsed or refractory cHL and had not undergone an autologous stem cell transplant because they either were not eligible or had refused to undergo the procedure. They also had progressed or failed to respond to treatment with brentuximab vedotin (Adcetris).

Of 31 evaluable patients, 65% responded to pembrolizumab therapy, including 5 patients (16%) who achieved a complete response, 15 patients with a partial response (48%), and 7 patients (23%) with stable disease, according to JTCC. The most common treatment-related AEs were hypothyroidism (16%), diarrhea (13%), nausea (13%), and pneumonitis (10%).

References:

1. San Miguel J, Mateos MV, Shah JJ, et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): Keynote-023. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 505.
2. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02579863.
3. Armand P, Shipp MA, Ribrag V, et al. PD-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: safety, efficacy, and biomarker assessment. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 584.

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