The HER2CLIMB-02 Trial Design, Results and Implications
Insights From: Erika P. Hamilton, MD, Sarah Cannon Research Institute
Erika P. Hamilton, MD: HER2CLIMB-02 was a relatively large trial; there were 600 patients, and it put patients on the capecitabine/trastuzumab backbone and then randomized them to the addition or not of tucatinib. This was really a so-called third-line setting trial, meaning patients had already received taxane, pertuzumab, etc, and already received T-DM1 [trastuzumab emtansine]. Patients on this trial were allowed to have brain metastases, and this was defined in a way that was much different from other historical trials. It’s often quite common that patients with brain metastases are treated and stable and allowed to come on trial. But almost never do we allow patients who have progressive brain metastases.
I really have to give credit to, initially, Oncothyreon Inc.—later called Cascadian Therapeutics, Inc., and now it’s actually Seattle Genetics, Inc.—for including these patients. They not only allowed patients who had treated stable brain metastases, but they also allowed patients who had untreated asymptomatic brain metastases, or a third category of patients who had been treated, and had progressive brain metastases. They knew tucatinib crossed the blood-brain barrier; they knew this was a high unmet clinical need, and they allowed these patients; I think it really paid off.
You have to think about the results. This was really a high-risk population. This wasn’t even the population that traditionally was allowed on the clinical trials before. It did come out that about 50% of patients on the trial did have brain metastases, so about half and half. And what we saw was an improvement in all the end points: an improvement in progression-free survival of a little over 2 months, and an improvement in overall survival for all-comer patients on the trial of 4½ months. And in the subset of patients with brain metastases, an improvement in progression-free survival there.
There’s 1 statistic that really stands out to me: patients with brain metastases at 1 year, if they did not receive tucatinib, did not remain on the trial—everyone had progressed. For those patients who did receive tucatinib with brain metastases, a quarter of patients still remained on trial. The improvement from 0% to 25%—although we would like it better—is a huge step forward for patients with brain metastases.
I actually participated in a phase I clinical trial of tucatinib back when it was called ONT-380. We started this trial in 2014, so 5 years ago. At that point in the phase I, we had 2 separate trials. We had the combination that you’re familiar with in the HER2CLIMB trial, the capecitabine with trastuzumab plus or minus tucatinib. We also had another trial that looked at the so-called second-line regimen in combination with T-DM1 [trastuzumab emtansine]. Ultimately, tucatinib was well tolerated with both these regimens, thus the company made the decision to move forward with a third-line regimen into the HER2CLIMB trial. But I do believe that the company will go back and look at tucatinib in combination with T-DM1 [trastuzumab emtansine] and move this up into the earlier-line setting as well.
Tucatinib is a HER2 tyrosine kinase inhibitor—so not unlike something like neratinib or lapatinib—an oral pill that you take daily. However, what’s special about tucatinib is it doesn’t block HER2 and EGFR or HER2 and HER1; neratinib and lapatinib block both of these. Tucatinib is specific just for HER2, and what this translates to is decreased rash and diarrhea, which are the most common and problematic adverse effects with lapatinib and neratinib. What that also translates to is better tolerability for patients. They tolerated the capecitabine-trastuzumab and the tucatinib regimen quite well. Capecitabine is known to cause hand-foot syndrome or redness, peeling hands and feet, etc, and it can also cause some elevations in the liver function tests—maybe a little bit of nausea from the oral pills, etc. But tucatinib really didn’t add a whole lot of toxicity to this regimen. To be able to add a drug that not only gets into the brain and helps those patients but does not add a whole lot of toxicity is a huge one.
The patients who were allowed to come on to the HER2CLIMB trial were those traditional third-line patients, those who had had chemotherapy in combination with trastuzumab and pertuzumab normally and then T-DM1 [trastuzumab emtansine]. These patients traditionally would have been treated with another chemotherapy combination, capecitabine-lapatinib, a chemotherapy backbone with trastuzumab, etc.
Obviously, the patients had to have good organ function, etc—the things we normally see in clinical trials. But what really sets this trial apart was their inclusion of patients with brain metastases and specific populations that are normally not included on clinical trials. I really have to credit the company—which was initially Oncothyreon and then was Cascadian and is now Seattle Genetics—for allowing these patients with a high unmet clinical need onto the trial. Trials traditionally include patients who]have treated and stable brain metastases. They also allowed patients with asymptomatic untreated brain metastases and patients who had brain metastases that had been treated and then progressed. So that was really quite a high-risk population.
I actually do have quite a bit of personal experience with tucatinib. Again, I participated in this trial in 2014 where we dosed the first patient in the phase I with this combination with capecitabine-trastuzumab, and what then was ONT-380 and later became known as tucatinib. I’ve treated quite a few patients on this. I actually still have patients alive who I treat who were on this regimen that long ago. There is 1 patient who really stands out in my mind, who was on this regimen, because I still treat her. She had progressive brain disease and came onto trial and did quite well. She ultimately ended up being on the trial for over 3 years. So I think, as an investigator, when we’re testing new trials, new drugs in the clinic, it’s quite exciting to actually see your patients really benefit. I knew back then that this drug was a winner, so I’m very excited to see the results of HER2CLIMB today.