For the treatment of triple-negative breast cancer, the PARP inhibitor iniparib improved overall survival, and cetuximab (Erbitux) showed benefit as well, in two randomized phase II studies presented at the 35th ESMO Congress in Milan, Italy.

Eagerly Awaited Data

The data on overall survival with iniparib (BSI-201) have been eagerly awaited after encouraging results were presented at the 2009 ASCO Annual Meeting in Chicago.1

Joyce O'Shaughnessy, MD, of US Oncology and Baylor Sammons Cancer Center, Houston, reported the final results of the multicenter phase II open-label study of 123 patients at ESMO, showing that iniparib (5.6 mg/kg) plus gemcitabine (1,000 mg/m2) and carboplatin (AUC 2) every 3 weeks produced not only a longer time to disease progression but also a longer survival time, compared with a regimen of gemcitabine/carboplatin only.2

"Overall survival was not a prespecified endpoint in the protocol, but is reported as a clinically relevant endpoint," Dr. O'Shaughnessy said. A survival benefit was shown in spite of a 30% rate of crossovers from the control to the experimental arm, although the activity of iniparib appeared limited in this setting, she added.

Median overall survival time was 12.2 months with the combination, compared with 7.7 months with chemotherapy, amounting to a 43% reduction in risk (P = .014). Median progression-free survival (PFS) was 5.9 vs 3.6 months (P = .012), overall response rate was 52.5% vs 32.3% (P = .023), and clinical benefit rate was 55.7% vs 33.9% (P = .015).

Approximately 60% of the patients had received no prior treatment in the metastatic setting. Most had three sites of metastases.

There were no significant differences in adverse events between chemotherapy alone or in combination with iniparib. Grade 3-4 adverse events, mainly hematologic toxicity, were seen in 81% vs 86%, respectively, and serious events in 29% and 28%. Treatment discontinuation due to toxicity occurred in 27% with chemotherapy alone and in 14% when iniparib was added.

Cetuximab Doubles Response Rate

In a second presentation, Jose Baselga, MD, reported that targeting the epidermal growth factor receptor (EGFR) may be beneficial in triple-negative disease, because about half the tumors of this aggressive subtype express EGFR.3
"This is the first randomized trial assessing this target in breast cancer, and we are excited by these results," said Dr. Baselga, who is now Associate Director of the Massachusetts General Hospital Cancer Institute, Boston. "Although EGFR had been considered a potential target for therapy in breast cancer, this is the first proof that this is the case."

The phase III BALI-1 trial, conducted in six countries, included 173 women with triple-negative metastatic disease who were randomized to cetuximab (400 mg/m2 as the initial dose, then 250 mg/m2 weekly), plus up to six 3-weekly cycles of cisplatin, or to cisplatin alone.

Responses were observed in 20% of the cetuximab/cisplatin arm, which was twice as high as the rate with cisplatin alone 10.3% (P = .11), although the difference was not statistically significant. Adding cetuximab to cisplatin more than doubled the median PFS, from 1.5 to 3.7 months, which was a statistically significant 33% reduction in risk for this secondary endpoint (P = .03), Dr. Baselga reported.

However, the study just failed to meet its primary endpoint, which mandated that a response rate of more than 20% be achieved with the combination. "Despite the doubling of response, the study did not meet the prespecified assumptions," he said.

Dr. Baselga acknowledged that cisplatin might not be the best control arm. "This is a tough group to treat, and I am concerned about how poorly these patients responded to cisplatin. We are wondering if perhaps we should move forward with a more robust control group, such as gemcitabine/carboplatin," he said.

Nevertheless, Dr. Baselga sees the findings as quite positive, he emphasized in a press briefing. "We see a doubling in response and a hazard ratio for progression of 0.67. In my mind, the study is vastly positive," he said. "I am convinced that an anti-EGFR agent has a role in triple-negative breast cancer, without question. We just have to design the appropriate trial." ■

References

1. O'Shaughnessy J, Osborne C, Pippen J, et al: Efficacy of BSI-201, a poly(ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin in patients with triple-negative breast cancer: Results of a randomized phase II trial. 2009 ASCO Annual Meeting. Abstract 3. Presented May 30, 2009.

2. O'Shaughnessy J, Osborne C, Pippen J, et al: Final efficacy and safety results of a randomized phase II study of the PARP inhibitor iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple negative breast cancer. 35th ESMO Congress. Abstract LBA11. Presented October 10, 2010.

3. Baselga J, Gomez P, Awada A, et al: The addition of cetuximab to cisplatin increases overall response rate and progression-free survival in metastatic triple-negative breast cancer: Results of a randomized phase II study. 35th ESMO Congress. Abstract 2740.  Presented October 11, 2010.