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What's Intriguing And Concerning About Early Results For Keytruda In Breast Cancer

This article is more than 9 years old.

At first glance, it’s hard to get excited about the preliminary results of an early phase trial study of pembrolizumab (Keytruda, MK-3475) in women with triple-negative breast cancer (TNBC). The non-randomized study has, so far, yielded an overall response rate of 18.5 percent – only 5 among 27 evaluable patients.

The findings drew attention at the San Antonio Breast Cancer Symposium, in part because TNBC is a notoriously hard-to-treat form of the disease. The work* was presented by Dr. Rita Nanda, of the University of Chicago, who led a multinational list of authors including academics and several Merck employees.

Keytruda is a monoclonal antibody given by infusion. When it binds PD-1, as it’s engineered to do with high affinity, it can unleash the body’s normal immune cells to fight a tumor. Recently, the FDA approved Keytruda for use in advanced melanoma. Last week, at the annual meeting of the American Society of Hematology, investigators reported preliminary findings that the drug is well-tolerated and may be helpful in Hodgkin’s lymphoma.

The KEYNOTE-12 study, sponsored by Merck, recruits patients with several types of malignancies including advanced head and neck cancer, bladder cancer, gastric cancer and a cohort of women with advanced TNBC. The phase 1b trial is designed to measure the safety, side effects and possible anti-tumor activity of Keytruda. Among the women with breast cancer who received the drug in this trial, the median age was 51.9 years.

A limitation of the findings is that among 32 women with refractory breast cancer who received Keytruda, only 27 could be evaluated for a response at the time of analysis. As reported, five of the women had sustained, measurable responses by RECIST criteria lasting over 40 weeks in three cases. One woman had a complete response. In addition, seven women (26 percent) had stabilized disease.

One woman died while on this study. Her death was attributed to disseminated intravascular coagulation (DIC), a severe blood disorder with impaired clotting. Otherwise, apart from one patient with hepatitis whose doctor did not ascribe that liver problem to the medication, the overall toxicity profile was fairly good. Several patients experienced high fevers. Other reported adverse events included anemia and headache. A total of four “serious” side effects, including the DIC case, were noted. For 27 of the 32 patients with TNBC who received Keytruda, only low-grade side effects were reported.

In some ways – despite all those adverse events including a death – the results are somewhat promising for a group of patients with an extremely poor prognosis. As emphasized by the study’s authors and discussants at the meeting, the trial involved a heavily-treated group: Among the five patients with TNBC who demonstrated complete and partial responses, all had been treated previously with Capecitabine, all had received a taxane drug; four had received an anthracycline; three had received a platinum drug and one had failed Eribulin.

An 18-20 percent response rate (complete and partial), for a single agent among women with heavily-treated, refractory TNBC, is potentially helpful – if the patients understand the risks of the trial and can provide meaningful, informed consent for receiving the experimental immune modulator. The fact that a significant fraction experienced stabilization of their disease is not to be dismissed, either. If you count the seven patients with stable disease, the progression-free response rate approximates 44 percent.

But it’s hard to read much, either way, about the patients’ responsiveness to the immune modulator; the number with TNBC who’ve received Keytruda in this non-randomized trial is just too small.

What concerns me, perhaps most, about these preliminary findings is that the median time to response was 18 weeks (range 7 – 32 weeks). For patients to wait four months or longer to see if there's a benefit, all-the-while taking an experimental or, if approved, costly drug by intravenous infusion every two weeks – seems like a lot; these are women without much time to spare.

It’s not just the toxicity and finances of this protocol that are problematic, but the lost opportunity for those with TNBC who want to try, and might benefit from, another experimental treatment, something that’s not a “sexy” immune modulator.

If the responses to Keytruda could be seen sooner (which seems unlikely), or if the patients enrolled could be checked for a surrogate marker of likely PD-1 blockade responsiveness (which needs be discovered), that would make a Phase II study of this drug in breast cancer, as is planned, more promising.

*Abstract #S1-09: "A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer" presented at the SABCS on Dec 10, 2014.

 

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