Tucatinib Lead Researcher Explains Significance of FDA Approval in HER2+ Breast Cancer

Rashmi Murthy, MD, MBE

The approval of tucatinib (Tukysa) for use in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) offers an attractive option for heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, according to Rashmi Murthy, MD, MBE, especially because of its favorable safety profile and ability to cross the blood-brain barrier.

The FDA gave the green light to the combination on April 17, 2020, based on data from the pivotal phase II HER2CLIMB trial, which showed that the tucatinib triplet resulted in a 34% reduction in the risk of death versus trastuzumab and capecitabine alone in this patient population.^1,2 Specifically, the median overall survival (OS) in the tucatinib arm was 21.9 months versus 17.4 months in the control arm (HR, 0.66; 95% CI, 0.50-0.88; P =.0048). The 1- and 2-year OS rates in the tucatinib and control arms were 76% versus 62% and 45% versus 27%, respectively. Notably, the OS benefit was observed across all prespecified subgroups.

Importantly, the triplet combination also reduced the risk of disease progression or death by 52% (HR, 0.48; 95% CI, 0.34-0.69; P <.00001) in patients who had brain metastases at baseline, a subgroup with a significant unmet medical need. The median progression-free survival (PFS) in this subgroup was 7.6 months with the tucatinib triplet versus 5.4 months with trastuzumab/capecitabine alone. One-year PFS rates between the tucatinib and control arms were 25% versus 0%, respectively. An OS benefit with the small molecule TKI was also observed in this important subgroup (HR, 0.58; 95% CI, 0.40-0.85).

“The key take-home message is that tucatinib, when added to the backbone of trastuzumab and capecitabine, reduced the risk of death by one-third in heavily pretreated patients, including those with brain metastases; it also reduced the risk of progression or death by one-half in this heavily pretreated patient population,” said Murthy, the lead investigator on the HER2CLIMB trial. “The strong efficacy data, as well as the tolerability profile, really make it a great treatment option to consider for patients with metastatic HER2-positive breast cancer, in those who have brain metastases and those who do not.”

Tucatinib is also being examined in the phase III HER2CLIMB-02 trial in combination with T-DM1 to see whether the combination is more effective than T-DM1 alone in the treatment of patients with unresectable locally advanced and metastatic HER2-positive breast cancer who have had prior treatment with a taxane and trastuzumab in any setting. Patients in the study will be randomized to receive either tucatinib or placebo in combination with T-DM1.³ Other future research efforts will focus on whether tucatinib can provide benefit in earlier lines of treatment, according to Murthy.

In an interview with OncLive, Murthy, assistant professor in the Department of Breast Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the data that led to the approval of the tucatinib triplet, the clinical implications of the approval on practice, and the next steps for research with the agent.

OncLive: What was the rationale for the tucatinib triplet and what were the previous data with tucatinib in this space?

Murthy: Tucatinib is a HER2-specific TKI; it's an oral drug and it has 2 very important features that I'd like to highlight. The first is its HER2 selectivity, and then the second is its ability to cross the blood-brain barrier; these 2 features really make it a great addition to trastuzumab and capecitabine. What we know from in vitro assays is that tucatinib is highly selective for HER2. In fact, tucatinib has a greater than thousand-fold selectivity for HER2 over EGFR, which really translates to a more favorable toxicity profile. We know that blocking EGFR often causes additional toxicity, such as rash and diarrhea, but it doesn't seem to improve upon the efficacy of HER2 blockade, as we've seen in prior studies in the field. As such, this feature of tucatinib is really important and it differentiates [this agent] from the other small molecule inhibitors; this all translates into a significant clinical impact from the perspective of tolerability and quality of life for our patients.

The second feature is its ability to cross the blood-brain barrier, and we know that the active metabolite of tucatinib does, in fact, do this. This is supported by preclinical work that has shown that tucatinib treatment significantly enhanced survival in HER2-driven intracranial tumors mouse models. This key potential for tucatinib has really been critical in our minds since early development of the drug, as brain metastases represents a really significant problem for patients with HER2-positive breast cancer. We've had an urgent need to develop systemic therapies that target the disease when it does spread to the brain.

Finally, results from the phase Ib dose-escalation study really set the foundation for the HER2CLIMB randomized trial and the results from the dose-escalation study showed that the combination of tucatinib at the phase II dose of 300 mg twice daily combined with capecitabine and trastuzumab resulted in really easily managed toxicities and very encouraging antitumor activity in patients with and without brain metastases. These clinical data from the early trials really set the foundation for the HER2CLIMB study.

Could you expand on the data reported from the HER2CLIMB trial? How did these findings pave the way for the FDA approval?

HER2CLIMB was a relatively large trial of over 600 patients. All patients were treated with trastuzumab and capecitabine as their backbone therapy and then they were randomized to either the addition of tucatinib or placebo. All patients enrolled had prior exposure to trastuzumab, pertuzumab (Perjeta), and trastuzumab emtansine (T-DM1; Kadcyla). There are one key eligibility criteria that I would like to highlight that really sets this trial apart, which is that patients were allowed to enroll if they had brain metastases; this was not limited to those who had stable and treated brain metastases. Patients who had new disease or previously treated progressing disease in the brain, who did not require urgent local therapy, were also allowed to enroll on the trial. Thus, it's really important to highlight that the trial allowed for a very high-risk patient population to enroll; patients who are heavily pretreated and those who potentially had active brain metastases.

The trial met all 4 of its end points, so PFS, OS, PFS in the brain metastases population, as well as objective response rate (ORR). We saw that when tucatinib was added to trastuzumab and capecitabine, this resulted in a 2-month improvement in PFS, in patients with and without brain metastases. Furthermore, an unprecedented 4.5-month improvement in OS was observed in, as I mentioned before, a very high-risk patient population. The benefits from tucatinib were noted across all the clinically relevant subgroups. Finally, the confirmed ORR nearly doubled with the addition of tucatinib.

Focusing a little bit on the patient population with brain metastases, approximately 50% of the trial population had brain metastases; this is really reflective of what we see in the clinic, as well. Of the patients with brain metastases, approximately 40% had either new or progressing disease in the brain. One of the most striking results from the HER2CLIMB study was that among patients with brain metastases who received tucatinib, one-quarter of them remained on trial at the 1-year time point whereas none of those with brain metastases who did not receive tucatinib remained on trial at 1 year. We certainly need to do better than 25%, but this is a really huge step forward for our patients. These trial results really paved the way for the FDA approval that we recently heard about.

This was the first investigational therapy in a pivotal trial to include patients with HER2-positive metastatic breast cancer with active brain metastases. Could you elaborate on the significance of that?

HER2CLIMB is the first randomized trial that I'm aware of that has included this very high-risk patient population. Where most trials allow patients to enroll if they have a history of brain metastases, most of them require these brain metastases to be stable and treated. HER2CLIMB had very unique eligibility criteria in that it allowed patients with new disease or progressing disease. I must note that this decision to allow this high-risk patient population to enroll was very well supported by robust preclinical and early clinical data that demonstrated a significant potential for tucatinib to cross the blood-brain barrier and positively impact patients with this significant problem.

This is really important because brain metastases are very frequently seen with HER2-positive breast cancer, and thus, they represent a very significant problem. Up to half of patients may develop disease in the brain and there is, we know, continuous risk for this over time, in patients with metastatic HER2-positive breast cancer. As patients live longer with advances made in targeted therapies that may control their systemic disease, they still remain at risk for disease spread to the brain. Also, we have not really seen that advances in neoadjuvant or adjuvant targeted therapy have really been able to address this problem. As such, a very great medical need to develop such therapies that can cross the blood-brain barrier remains. Hopefully, we will have many more such trials and more drugs that will follow this example.

Are any other trials including this population in their analyses in light of this research?

The HER2CLIMB-02 study is currently ongoing, and it is evaluating the addition of tucatinib or placebo to T-DM1 in patients with advanced HER2-positive breast cancer who previously progressed on trastuzumab and a taxane. This trial has a very similar eligibility with regard to the patients with brain metastases as the first HER2CLIMB study that we've just discussed. There is much need for further development beyond tucatinib and hopefully we will see more drugs in the coming years that may help this population of patients.

What we have realized is that, as a community, one of the keys to developing drugs for a high-risk population such as this is really to start with preclinical efforts to identify drugs that have the scope to cross the blood-brain barrier, and then move these compounds into early-phase trials that can really set the foundation and give us a confidence to then enroll patients into randomized trials. The development of tucatinib over the years has been a great example of starting from a preclinical setting, moving into early clinical, and then really has set the foundation for the impressive results that we've now seen in HER2CLIMB, the randomized study.

Regarding safety, what does the toxicity profile for the triplet regimen look like?

What we saw is that tucatinib did not really add much more in terms of toxicity. The combination is a very attractive treatment option for patients with metastatic disease because it does not potentially affect the quality of life of our patients in a negative way. The randomized study was really able to confirm the safety of tucatinib when added to trastuzumab and capecitabine.

The most common adverse events (AEs) that we saw were diarrhea, hand-foot syndrome, nausea, fatigue, and vomiting; these were all mostly low grade. All AEs were determined to be manageable with supportive therapy. Often, we see many of these AEs in patients who are on capecitabine plus trastuzumab alone. Potentially, some of this is also related to capecitabine in particular. No significant EGFR-related toxicities that we couldn't manage were reported and this is something that we had expected given the drug's unique property of being HER2 selective. In summary, the regimen was confirmed to be very safe and tolerable for patients.

You mentioned that diarrhea was the most common AE associated with the triplet. Do you have any advice for managing the toxicities associated with this regimen in practice?

Diarrhea was the most common AE, but this was the case in both the tucatinib group as well as the placebo group; most of these events were really low grade. Antidiarrheal prophylaxis was not mandated on this study; however, it was introduced as needed, and the median duration of use was short in both arms, about 3 days per cycle. As such, the diarrhea that was seen on this study could certainly be well managed. I would recommend that patients who develop diarrhea while receiving this treatment go ahead and get started with antidiarrheal treatment to help manage that event.

As far as the elevations in liver transaminase levels, these were again, all mostly low grade. When these events occurred, they were transient and were reversible. It’s really important to highlight that the most common reason for treatment discontinuation on this study was not because of AEs, but because of disease progression. Very few patients had to discontinue treatment due to AEs, only approximately 6% in the tucatinib arm and 3% in the placebo arm.

Are there any unanswered questions with the combination that future research efforts should address?

Certainly, a great number of unanswered questions exist with this very important data set that we now have. I know many of us are looking forward to see what the intracranial response rate and the duration of response was [with the combination] in the patients with brain metastases at baseline. Also, it will be really interesting to see the rates of progression in the brain among patients who did not have a history of brain metastases at the start of study entry.

Furthermore, patients were allowed to receive local therapy if they had isolated disease progression in the brain, so it will be really interesting to see the outcomes for those patients. A key question is, “What is the activity of tucatinib after patients have been exposed to other TKIs, such as neratinib (Nerlynx) or lapatinib (Tykerb)?” Then, several ongoing efforts are examining whether tucatinib may have a potential role in earlier lines of therapy, such as the HER2CLIMB-02 study I mentioned. Also, we want to see whether tucatinib could be brought in even earlier lines of treatment, such as the adjuvant setting, to potentially prevent patients who are at higher risk from developing metastatic disease or disease spread to the brain.

Are there any ongoing research efforts examining tucatinib that you wanted to highlight?

Certainly, one very interesting ongoing clinical trial is examining whether the combination may be helpful for patients with leptomeningeal disease. In some unfortunate situations, breast cancer can actually spread into the leptomeninges. When this happens, we know that prognosis is often very poor for these patients and treatment options are quite limited. After seeing the unprecedented results of the HER2CLIMB study really, we are hopeful that this might be a great treatment option to also help patients with leptomeningeal disease. Currently, an ongoing trial is enrolling at several sites across the country through the Translational Breast Cancer Research Consortium. I certainly would encourage physicians to refer patients who may have leptomeningeal disease to that study.

As far as moving the drug to the frontline setting, with these results, the natural next step would be to see whether we can introduce tucatinib even earlier on. As I mentioned, an ongoing study is already being conducted. Efforts in the curable setting are also being made to see whether we can actually prevent patients from developing metastatic disease.

How will this approval impact the treatment paradigm for HER2-positive breast cancer?

The approval of tucatinib provides a key treatment option for patients with HER2-positive metastatic breast cancer; its favorable toxicity profile and its activity across the blood-brain barrier really make this a very attractive option in my mind. The OS benefit is really unprecedented in this heavily pretreated patient population, and so, its approval allows us to improve outcomes for patients and really expand the options that we have available for patients with and without brain metastases.

References

1. Murthy R, Loi S, Okines A, et al. Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases (HER2CLIMB). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-01.
2. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer [published online December 11, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1914609
3. A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Patients With Advanced or Metastatic HER2+ Breast Cancer. https://clinicaltrials.gov/ct2/show/NCT03975647. Updated February 27, 2020. Accessed April 18, 2020.