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Medicine Matters oncology

So the HER2CLIMB trial was a randomized, blinded, placebo-controlled clinical trial that tested the value of adding tucatinib, the HER2 selective tyrosine kinase inhibitor, to a backbone of trastuzumab and capecitabine in patients with metastatic HER2-positive breast cancer. And what was unique about HER2CLIMB is that it allowed patients with brain metastases on not just stable treated brain metastases, which is fairly typical nowadays, but also, patients with a newly diagnosed or "progressive at the time of study entry" brain metastases, and that's very unique for this particular trial.



The topline results of HER2CLIMB have already been published, which showed an improvement in both progression-free survival and overall survival for the overall population of patients with and without brain metastases enrolled in the study. And this analysis focuses on the subset of 291 patients in HER2CLIMB who had brain metastases at study entry.



And what we found is that when we looked at time to CNS progression-- that is CNS as progression-free survival defined as time from randomization until CNS progression or death-- that the addition of tucatinib significantly prolonged CNS PFS in patients with brain metastases. And in addition, there was a significant prolongation of overall survival in these patients with a hazard ratio of 0.5 h. And that translated into a six-month absolute improvement in median overall survival.



What do these findings mean for patients?

So about half of patients with HER2-positive metastatic breast cancer will develop brain metastases over the course of their disease, so having effective treatments, not only to treat patients with brain metastases, but also, to prolong the time to CNS progression, is a really important benefit for patients. And I think that really, that's where these results need to be taken into context. Tucatinib has been recently approved by the FDA for use in patients with HER2-positive metastatic breast cancer, and I think that these results further solidify the value of tucatinib in patients with HER2-positive disease.



Is it unusual for an agent in this setting to be able to cross the blood–brain barrier?

Yeah, so there are a number of other compounds that have demonstrated activity in terms of CNS objective response. In the case of tucatinib, within the HER2CLIMB trial, we looked at the subset of patients with measurable active brain metastases at baseline, and nearly half of those patients achieved a CNS objective response. Other studies with other tyrosine kinase inhibitors, including loratinib and lapatinib, have also shown CNS activity. But what was unique about HER2CLIMB trial is the randomized nature of the study and the fact that the addition of tucatinib actually produced not only objective responses, but an overall survival advantage for these patients.



Is there a role of tucatinib and trastuzumab, without chemotherapy, in this setting?

Yeah, so we actually had previously conducted a phase-1b study that was led by a colleague, Dr. Otto Metzger at Dana Farber, that combined just tucatinib and trastuzumab without any chemotherapy. And the trial actually enrolled only patients with active brain metastases.



We did show that there was a modest rate of CNS objective response, although it was quite modest. And there were several patients with prolonged clinical benefit. That is, defined a stable disease for 16 weeks or longer. And what was unique about that phase-1b is it actually allowed patients who had had prior lapatinib and loratinib because one question that's not fully answered at this point is, what is the benefit of successive lines of HER2 TKIs. Interestingly, in our phase-1b study, which is recently published online at Annals of Oncology, we found that of the patients with clinical benefit, 80% had had prior lapatinib or neratinib exposure. So we think that's very encouraging.



What are the next steps to take this research forward?

So tucatinib is now being evaluated a number of different settings. For example, the HER2CLIMB-02 trial is randomizing patients to T-DM1 alone or T-DM1 plus tucatinib in the second-line setting, and really understand whether tucatinib has a role earlier in the treatment of HER2-positive metastatic breast cancer. And HER2CLIMB-02, just like the initial HER2CLIMB trial, does allow patients, either with or without brain metastases, to enroll. In addition, the TBCRC is conducting a study of the trastuzumab/cape citabine/tucatinib regimen in patients who have HER2-positive leptomeningeal disease because those patients were excluded from the original HER2CLIMB study, and it's important to understand whether the regimen has activity in LMD.



And finally, there are plans to incorporate tucatinib in the early-stage setting, essentially, a KATHERINE-like design of patients with residual disease after standard trastuzumab-containing chemotherapy who will be randomized to T-DM1 with or without tucatinib in the post-operative adjuvant setting.