Checkpoint Inhibitor Previews in Breast Cancer to Mixed Reviews

Neil Osterweil

December 10, 2014

SAN ANTONIO, Texas — Immunotherapy has been slow to catch on in breast cancer, and the first results with an immunomodulator drug in women with heavily pretreated triple-negative breast cancer suggests that there is still a long way to go.

The results, reported here at the San Antonio Breast Cancer Symposium (SABCS), come from a phase 1 trial with the checkpoint inhibitor pembrolizumab (Keytruda, Merck & Co) in patients with heavily pretreated breast cancer whose tumors tested negative for HER-2, estrogen, and progesterone receptors (triple-negative). The overall response rate was 18.5%, with only one complete response, four partial responses, and seven cases of stable disease. An equal number of evaluable patients (n = 12) had progressive disease. One patient developed fibrinogen depletion and died of disseminated intravascular coagulation (DIC).

These results contrast with the high response rates seen with pembrolizumab in the treatment of advanced malignant melanoma and, more recently, in patients with relapsed, refractory Hodgkin's lymphoma.

But this is just the beginning of Act 1 for immunomodulators in breast cancer, and investigators are moving forward with phase 2 trials of the drug. They expect to begin enrollment early in 2015, in the hope that they can improve on the early results.

"The responses were quite durable, with three of the five responders remaining on therapy for greater than or equal to 11 months, and the acceptable safety and tolerability profile, coupled with a promising antitumor activity, supports the further development of pembrolizumab in patients with advanced triple-negative breast cancer," said lead author Rita Nanda, MD, associate director of Breast Medical Oncology at the University of Chicago, Illinois.

A breast cancer investigator who was not involved in the study pointed out that clinical experience with the drug in breast cancer is still very early and that heavily pretreated patients have compromised immunity that may dampen the efficacy of a checkpoint inhibitor, especially when it is used as a single agent.

"This is just an insight into where we're going, and this isn't going to be a single-agent home-run drug. We need to figure out how to get immune infiltrate into the tumors," said Jennifer Litton, MD, assistant professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, in an interview with Medscape Medical News.

Dr Litton, who is currently investigating programmed death-1 (PD-1) inhibitors in breast cancers, moderated a media briefing where the data were presented.

"I'm excited to see patients with some response, at this point," she said.

PD-1 is expressed primarily on activated T cells, and binding of PD-1 to its ligands PD-L1 and PD-L2 acts as a brake or checkpoint on the immune system. This checkpoint and other immune checkpoints are exploited by some malignant tumors, allowing them to evade immune system surveillance.

Pembrolizumab is a fully humanized monoclonal antibody that binds with high-affinity to the PD-1 receptor to block PD-L1 and PD-L2, thereby releasing the brakes. Clinical evidence to date suggests that pembrolizumab and other checkpoint inhibitors such nivolumab and ipilimumab (Yervoy) are most effective in malignancies with high immune-cell infiltrates, such as melanoma, renal cell carcinoma, and Hodgkin's lymphoma, Dr Litton said.

Phase 1 Study

In the phase 1 study, Rita Nanda, MD, from the University of Chicago, and colleagues enrolled 32 patients with recurrent or metastatic triple-negative breast cancer positive for PD-1 and administered pembrolizumab 10 mg/kg intravenously every 2 weeks until they had either a complete response, partial or stable response, or confirmed disease progression. Patients who had a complete response were allowed to discontinue the drug, while those with partial response or stable disease could continue on treatment for up to 24 months or until disease progression or intolerable toxicity. Tumors were assessed every 8 weeks according to response criteria in solid tumors (RECIST).

Of the 27 patients evaluable for efficacy, 19 had received two or more prior lines of therapy for metastatic disease.

Among all 32 patients treated, 18 experienced a treatment-related adverse event. Four patients had grade 3 events, which included anemia, headache, aseptic meningitis, and pyrexia. One patient had a grade 4 event (the previously mentioned patients who died of DIC).

Ultimately, said invited discussant Mary L .(Nora) Disis, MD, professor of oncology at the University of Washington in Seattle, the real role of PD-1 inhibitors is likely to be in combination with other therapies and provided earlier in the course of disease.

She noted that the 18.5% response rate seen in KEYNOTE-012 is "in the ballpark" with response rates seen with PD-1 inhibitors in other solid tumors.

"It's immunogenic, we're seeing 20% response rates with triple-negative breast cancer. It's important to know that in some of these diseases, like melanoma, people are already going to combination therapy. Where used in combination with standard therapies, other immune therapies, we're seeing response rates of 50%, 60%, so let's not wait — let's move this forward so we can benefit our breast cancer patients," she said.

Let's not wait — let's move this forward so we can benefit our breast cancer patients. Dr Mary L .(Nora) Disis

Dr Litton told Medscape Medical News that the true promise of immunotherapy in breast cancer, particularly the notoriously treatment-refractory triple-negative cancers, has yet to be seen.

"These tumors mutate and become more unlike us, and that's actually why we think that immunotherapies may potentially have a role, and it tends to be in these tumors that are very high grade and growing quickly," she said.

The study was supported by Merck & Co. Dr Nanda, Dr Litton, and Dr Disis have disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium (SABCS) 2014. Abstract S1-09. Presented December 10, 2014.


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