INIPARIB FOR TRIPLE NEGATIVE BREAST CANCER

October 10, 2010 (Milan, Italy) — An investigational agent appears to extend survival in women with metastatic triple-negative breast cancer, according to new data.

Patients who received iniparib (Sanofi-aventis) plus gemcitabine (Gemzar; Eli Lilly) and carboplatin survived an average of almost 5 months longer than those treated with chemotherapy alone.

In the iniparib plus chemotherapy group, the median overall survival was 12.3 months compared with 7.7 months for patients who received chemotherapy alone (P = .014).

The results of the phase 2 trial were presented here at the 35th European Society for Medical Oncology Congress.

"The overall survival data was probably the most striking finding in the study," commented study coauthor John Pippen, MD, during a press briefing that highlighted the study results. "The addition of iniparib to gemcitabine–carboplatin significantly improved clinical outcomes in patients with metastatic triple-negative breast cancer."

Dr. Pippen, a medical oncologist from Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, emphasized that triple-negative breast cancer is a difficult diagnosis. "[Patients with this disease] have a high rate of symptomatic visceral and brain metastasis, and the median survival is only 13 months after the patients develop metastases," he said. "Treatment options are limited, and the progression-free survival for patients with metastatic disease is short."

Thus, there is a great need for more optimal therapy and a wider range of treatment options for this population. "These results are showing the efficacy of a new class of drugs," said Fortunato Ciardiello, MD, PhD, professor at the Division of Medical Oncology, Seconda University of Naples, Italy. "They may be opening a new avenue of treatment for triple-negative metastatic breast cancer."

Dr. Ciardiello moderated the press briefing and was not involved in the study.

High Response Rate

Progression-free survival was also improved in the group who received iniparib, at 5.9 months vs 3.6 months (hazard ratio, 0.59; 95% confidence interval, 0.39 - 0.9; P = .012). The authors also note that more than the half of the patients (55.7%) in the iniparib group experienced a complete or partial response, or stable disease, for at least 6 months. This was compared with about one third (33.9%) of patients in the chemotherapy-alone group.

Iniparib is a small molecule, novel agent that inhibits PARP1, a nuclear enzyme that promotes DNA repair through the base-excision repair pathway. Triple-negative breast cancer is associated with DNA repair defects, including BRCA1 dysfunction, the authors note. Malignant cells with this type of defect have demonstrated sensitivity to PARP1 inhibition.

Iniparib also potentiates the effects of gemcitabine–carboplatin, which is an active combination in metastatic breast cancer, Dr. Pippen noted.

In this phase 2 study, Dr. Pippin and colleagues randomly assigned 123 women with metastatic triple negative breast cancer (1:1) to receive gemcitabine–carboplatin alone or gemcitabine–carboplatin plus iniparib. Gemcitabine (1000 mg/m2) and carboplatin (area under the curve, 2) were given on days 1 and 8, and iniparib (5.6 mg/kg; intravenously) on days 1, 4, 8, and 11 every 21 days.

All of the participants had undergone at least 2 prior cytotoxic regimens, and in this study, they were restaged every 2 cycles. The primary objectives were the clinical benefit (objective response rate + stable disease ≥ 6 months) and safety and tolerability. Secondary objectives were progression-free survival and objective response rate, as well as toxicity associated with each study group.

Although it was not specified in the study protocol, overall survival was also analyzed and reported.

Approximately half (48%; n = 30) of the patients receiving gemcitabine–carboplatin alone crossed over to the iniparib plus chemotherapy group.

Adverse Events Similar

The authors also found that the addition of iniparib to combination chemotherapy was well tolerated and did not potentiate chemotherapy-related toxicities. There was little or no increase in adverse events between the 2 groups, Dr. Pippen pointed out.

The most frequent grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, fatigue, leukopenia, and ALT increase, and these were seen in both groups (81% vs 86%).

There was a greater than 5% increase in the incidence of both grade 3/4 anemia and thrombocytopenia in patients who received iniparib, but the differences were not statistically significant. Serious adverse events were also similar between the 2 groups (29% vs 28%).

Going Forward...

The strategy of combining iniparib with gemcitabine and carboplatin "seems to have worked," commented Richard Bell, MD, director of cancer services at Geelong Hospital, Australia.

There is a caveat with that, he emphasized. "This is an investigational report of responses," said Dr. Bell, who served as a discussant of the paper. "It's a small study, and it's a phase 2 trial."

However, Dr. Bell notes that "we have confirmation at hand" that a phase 3 trial has accrued, and "we will get that information soon."

Another important issue is whether this agent will work in other types of breast cancer or in other types of cancer, he said.

It is also very important that there is correlative biology in all studies that are investigating targeted agents, he emphasized. "I think within this room there are probably 50 or 60 people with designs for trials using Parp inhibitors. We need to do very careful studies, as we go forward, to get the information that it is also biologically relevant."

There are currently 2 phase 3 studies of iniparib ongoing — one in triple-negative breast cancer and a second in squamous cell non–small cell lung cancer. Iniparib is also being investigated in other malignancies that have proven difficult to treat, including ovarian, pancreatic, and brain cancers.

Editorial support was funded by Sanofi-aventis. Coauthors C. Bradley, B.M. Sherman, and C. Rocha are employed by Bipar Sciences. Dr. Bell has disclosed no relevant financial relationships.

35th European Society for Medical Oncology Congress: Abstract LBA11. Presented October 10, 2010.