Highlights From the 2021 SABCS Symposium

HER2CLIMB: Phase II, Tucatinib Plus Trastuzumab/Capecitabine in HER2+ MBC

Sara Tolaney, MD, MPH:
HER2CLIMB is a phase II, placebo-controlled, active comparator trial. It evaluated the addition of tucatinib to capecitabine and trastuzumab for the treatment of patients with HER2-positive MBC, including 291 patients with active or stable brain metastases.^16-18 Previous data from this trial found an improvement in PFS and OS for the overall patient population.¹⁶ This trial is the first registration trial that did not exclude patients with progressive brain metastases (a population often excluded from these trials), because investigators observed that this drug had central nervous system (CNS) penetration and activity.

HER2CLIMB: OS in All Patients With Brain Metastases

Sara Tolaney, MD, MPH:
The HER2CLIMB analysis presented at SABCS 2021 focused specifically on OS in patients who had brain metastases. It showed a 9‑month improvement in OS for these patients, a striking improvement.¹⁹

HER2CLIMB: OS in Patients With Active or Stable Brain Metastases

Sara Tolaney, MD, MPH:
With the longer follow-up period, even patients with stable, treated brain metastases, who did not show a benefit in earlier data, had a survival benefit of more than 5 months with tucatinib.

Joyce O’Shaughnessy, MD:
The updated survival result from this HER2CLIMB trial is very impressive—more than a doubling in the percentage of patients with active brain metastases alive at 2 years. Approximately one half of the patients with active brain metastases who received tucatinib were still alive at 2 years, compared with only 21% of patients who received placebo.

HER2CLIMB: CNS-PFS in Patients With Brain Metastases

Sara Tolaney, MD, MPH:
A significant CNS-PFS benefit with tucatinib continued with longer follow-up.

HER2CLIMB: Intracranial Overall Response and Duration of Response in Patients With Active Brain Metastases

Sara Tolaney, MD, MPH:
The intracranial ORR was 47% with tucatinib vs 20% for placebo.

HER2CLIMB: Conclusions

Sara Tolaney, MD, MPH:
I think these data strongly support the current indication for tucatinib in combination with capecitabine and trastuzumab, particularly in patients with brain metastases. Almost one half of patients with HER2-positive disease end up with brain metastases, and we do not have other agents with known OS benefit for progressive brain metastases. I think these results and the way this trial was designed are going to change the way future drugs are developed for these patients.

But one thing that we need to consider is that we have several drugs for metastatic HER2‑positive disease. Data from the DESTINY-Breast03 trial presented at SABCS showed that T-DXd was better than T-DM1 for patients with brain metastases.²⁰ Dr. O’Shaughnessy, from the clinical perspective, if you have a patient who has brain metastases and received upfront THP (docetaxel, trastuzumab, and pertuzumab), how would you decide what drug to give in the second line, and what criteria would you use to select tucatinib with capecitabine plus trastuzumab or T‑DXd?

Joyce O’Shaughnessy, MD:
Thankfully, we now have a few agents. In addition to the tucatinib triplet discussed above, the DESTINY‑Breast03 trial in the second line showed that the T‑DXd was substantially more effective than T‑DM1 for PFS with an HR of approximately 0.28, the most impressive we have seen in breast cancer. There was also a very strong trend for OS.

In the case you mention, I would favor the tucatinib triplet, particularly when I fear that the brain is going to be the site of the life‑limiting metastases. Again, the OS benefit seen in HER2CLIMB is very impressive. Conversely, if someone has substantial metastatic disease with stable, treated brain metastases that are not active, and I am more worried about their systemic disease, I will use T-DXd in the second line. It depends on what I’m most worried about, but I’m putting a lot of emphasis on the survival data here with the tucatinib triplet in patients with brain metastases.

TBCRC049: Tucatinib Plus Trastuzumab/Capecitabine in HER2+ MBC With Leptomeningeal Metastases

Joyce O’Shaughnessy, MD:
TBCRC049 is an investigator-initiated, nonrandomized, open-label phase II trial for patients with HER2-positive MBC with leptomeningeal metastases.²¹ This type of metastasis is very difficult to treat, and heretofore we have had few options for these patients. In addition, there is scant prospective clinical trial data to guide treatment decisions.

For HER2-positive patients who have early leptomeningeal disease (LMD), before they have suffered substantial neurologic decline, I consider intrathecal trastuzumab. However, it requires frequent treatments and is difficult for patients, and there are very little prospective data to confirm efficacy, although there are trials ongoing. So, the data from this small but informative trial on tucatinib plus trastuzumab/capecitabine for patients with LMD are very welcome.

Sara Tolaney, MD, MPH:
Although this study only enrolled 17 patients, it also looked at metabolites in cerebrospinal fluid (CSF) and compared it with plasma levels. This suggests that metabolites were really the same and that the drug could penetrate the CSF, which is important to see for these patients with LMD.

TBCRC049: Tucatinib Plus Trastuzumab/Capecitabine Survival and Disease Progression

Joyce O’Shaughnessy, MD:
This study showed the first prospective evidence of OS benefit for HER2-positive LMD, reporting a clinically meaningful median OS of 10 months and a median time to CNS progression of approximately 7 months. Generally speaking, patients with LMD have a median survival of approximately 6 months.

TBCRC049: Safety

Joyce O’Shaughnessy, MD:
The most common adverse events were grade 1/2 diarrhea and fatigue. Grade 3 AEs included nausea/vomiting, hand–foot syndrome, and elevated liver enzymes.

TBCRC049: Conclusions

Joyce O’Shaughnessy, MD:
This prospective TBCRC049 trial, despite the small sample size, supports the tucatinib triplet as an option for patients on the wide spectrum of LMD.

This combination showed a median OS of 10 months with a satisfactory safety profile and evidence of CSF penetration. It is important to note that the tail on the survival curve showed that approximately 30% of patients approached the 2‑year mark. I think we can use this combination for patients who have LMD, and I think it is a new option now for patients.

Sara Tolaney, MD, MPH:

I agree. I typically use systemic therapy for our patients with LMD, and I think these data indicate that the tucatinib triplet does provide a benefit. Seeing a median OS of 10 months is remarkable in LMD, and the evidence of CSF penetration is encouraging. It is good to see that tucatinib benefit is not restricted to patients with parenchymal metastases. This suggests a signal in these LMD patients too.