HER2+ mBC: Systemic Therapies and HER2CLIMB-02 Trial

Transcript:

Sarah A. Hurvitz, MD: A few systemic therapies have been evaluated for the management of CNS [central nervous system] metastases in the HER2-positive realm. These include lapatinib when combined with capecitabine, or neratinib plus capecitabine. Both of these agents have demonstrated some activity, anywhere from 20% up to 50%, depending on the line of therapy in terms of CNS response rate. Certainly, it’s not a home run yet. Both of these drugs are tyrosine kinase inhibitors that hit both HER2 as well as HER1, or EGFR. Since it’s not selected for HER2 and it is hitting EGFR, there are toxicities including diarrhea and rash that are associated with these agents at a not insignificant rate.

Recently a new drug called tucatinib, which is unique in its HER2 selectivity, has been developed. This, too, is an oral agent. Since it’s selective against HER2 and is not specifically hitting HER1, the hope has been that this drug will have lower rates of adverse effects, including diarrhea. In fact, the phase I study demonstrated not only reasonable tolerability when combined with capecitabine and trastuzumab, but interestingly in 12 patients who had CNS metastases, over 40% of them had a response in the brain with this drug.

This led to the development of a randomized placebo-controlled registrational strategy large phase II trial that many of us would consider similar to phase III.

This led to the development of a placebo-controlled randomized clinical trial for patients with HER2-positive metastatic breast cancer who had received prior therapy with trastuzumab, taxane, etcetera. Patients were assigned to receive capecitabine plus trastuzumab with either tucatinib or placebo. It was a 2-to-1 randomization scheme. What was unique about the structure and design of this clinical trial is that patients who had progressive or untreated CNS metastases were allowed to participate in the trial. I can’t remember a trial in my career before this that would allow a patient to come on who had progressing CNS disease.

About 50% of the patients in this trial actually had CNS metastases, about 40% of whom had progressive or untreated metastases at the time of enrollment. This trial bravely went into this realm of evaluating whether their drug could impact patients who have this area of unmet need and that their disease is progressing.

The stratifications for this trial included whether patients had CNS metastases, as well as performance status and world region. It was very exciting at the 2019 San Antonio Breast Cancer Symposium because the results were presented, both for progression-free survival [PFS] in the overall population, as well as the population of patients with CNS metastases and importantly, the overall survival data. When they looked at the data, PFS was significantly improved in both the overall population as well as in the population of patients who had CNS metastases. What was extraordinary was that at this first look, overall survival was significantly improved. This is unique to have a study meet all those important end points at the same time.

What is also important is the tolerability of this drug did appear to be rather good. The therapeutic index in my opinion is quite good for this. There was a slightly higher rate of grade 3 diarrhea, around the 13% rate, compared to capecitabine, trastuzumab, but this is a rate that when you compare it to other studies of other tyrosine kinase inhibitors that are not selective for HER2, compares favorably.

In all I think this is potentially practice-changing. Hopefully in the short term we’ll have this available as a standard of care.

HER2CLIMB combined tucatinib with capecitabine and trastuzumab based on very promising phase I data. Tucatinib has also been pared with T-DM1 [ado-trastuzumab emtansine] in a phase Ib study that has shown promising efficacy data, as well as phase II data. Based on these data, tucatinib is going to be evaluated in that second-line setting in a study that is going to be called HER2CLIMB-02. It’s enrolling now, and patients will be randomly assigned to receive T-DM1 or T-DM1 plus tucatinib in the second-line setting.

Transcript Edited for Clarity