Keytruda, Imprime PGG Combo Increases Overall Survival in Metastatic Triple-negative BC, Data Show

Keytruda, Imprime PGG Combo Increases Overall Survival in Metastatic Triple-negative BC, Data Show

Treatment with Biothera Pharmaceutical‘s Imprime PGG appears to increase the sensitivity of chemotherapy-resistant metastatic triple-negative breast cancers (mTNBC) to the immune checkpoint inhibitor Keytruda (pembrolizumab), interim data from a Phase 2 study show.

The combination nearly tripled treatment responses and extended survival by about seven months in this patient population, which is unlikely to benefit from immune checkpoint inhibitors,

The findings were presented at the 2019 San Antonio Breast Cancer Symposium, in Texas, in a poster titled “Response and clinical benefit assessment of the combination of the dectin-1 agonist imprime PGG and anti-PD-1 pembrolizumab in chemotherapy-resistant metastatic triple negative breast cancer (TNBC).”

Immune checkpoint inhibitors like Keytruda (developed by Merck, known as MSD outside the U.S. and Canada) work by preventing interactions between cancer cells and immune cells that dampen immune responses. The approach boosts the body’s own immune system, increasing survival outcomes in many tumor types.

In triple-negative breast cancers, however, immune checkpoint inhibitors have only led to minimal benefit. Patients who failed to respond to their first-line chemotherapy regimen have low response rates (5-6%), and only about 37-40% live longer than one year.

The reason behind this is that people with triple-negative breast cancers typically lack T-cells within their tumors, and these cells are needed for checkpoint inhibitors to work. Thus, approaches that recruit T-cells to tumors should increase clinical responses to these therapies.

Imprime PGG is an investigational dectin receptor agonist that acts as an immunological “ignition switch.” It triggers a cascade of events throughout the innate immune system that culminates in T-cell activation and cancer cell elimination.

By increasing T-cell recruitment and activation, Imprime PGG increases the efficacy of immune checkpoint inhibitors, as seen in mouse models of cancer.

The IMPRIME-1 Phase 2 trial (NCT02981303) is investigating a combination of Imprime PGG and Keytruda in people with metastatic triple-negative breast cancer who failed to respond to first-line chemotherapy. It also is testing the combination in advanced melanoma.

The trial is being conducted in two parts. The first part enrolled 12 triple-negative breast cancer patients to assess the combination’s safety. Then, with fewer than four severe or life-threatening adverse events reported, an additional 32 participants were included.

IMPRIME-1’s main goals are overall response rate and safety — but researchers also will assess duration of responses, time to disease progression or death, and overall survival as secondary measures.

Participants received Imprime PGG as an intravenous (into-the-vein) injection on days 1, 8, and 15 of each 21-day cycle, while Keytruda was administered on day 1 of each cycle, also as an IV injection. Computed tomography (CT) scans were used to assess treatment response, and were taken at the study’s start and every six weeks thereafter until the cancer progressed.

At the time of the analysis, all 44 patients had been enrolled and receiving therapy for at least 12 weeks. After a median follow-up of 19.1 months, a total of 15.9% of patients (7 participants) had responded to the combination, with one complete response and six partial responses. An additional 40% had their disease stabilized — meaning tumors didn’t grow or shrink significantly — for longer than 12 weeks. Four participants had stable disease for 24 weeks or longer.

The median overall survival is 16.4 months, with 57.6% of patients living past the one-year mark.

A majority of patients (62.5%) had a reduction or stabilization of their target lesions. More than half of patients (53.7%) stopped the treatment due to new lesions or the increase of non-target lesions, even if the measured lesion was shrinking or stable. Patients with this mixed response pattern, however, showed increased overall survival.

Overall survival benefits were seen in three subgroups of patients: those with shrinkage of any measured lesion, whose risk of death was reduced by 67%; those with a more than 10% reduction in total tumor burden at 12 weeks, whose risk was reduced by 86%; and those whose total tumor burden dropped below baseline levels at any time — who saw a 56% reduction — regardless of the effects on new lesions and non-measured lesions.

“Patient response patterns and clinical benefit revealed extended [overall survival] even in those patients not classified as responders by RECIST criteria [the mixed responders],” Jeremy Graff, PhD, Biothera’s president and chief scientific officer, said in a press release. “The extended [overall survival] was most evident in patients with any reduction in target tumor burden.”

Biopsies and blood samples were used to assess immune activation within tumors and in circulation. The researchers saw higher numbers of innate immune cells and T-cells within the tumor tissue after just six weeks of therapy. At the study’s start, the participants were predominately devoid of activated T-cells. But 16 patients showed activated T cells as early as three weeks into therapy, and this was associated with better survival outcomes.

“The maturing clinical data show compelling evidence for the clinical benefit from the combination of Imprime PGG and Keytruda in chemo-refractory metastatic TNBC patients,” Graff said.  “Importantly, the translational data not only provide proof of concept at the molecular and cellular level, but also provide incredibly valuable insight that informs the next steps for Imprime PGG’s clinical development.”