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New Insights in Breast Cancer: Independent Conference Coverage of SABCS 2020

Sara Hurvitz, MD, FACP
Joyce O'Shaughnessy, MD
Released: February 19, 2021

Updates and Advances in HER2+ and HER2-Mutant MBC

NALA: Neratinib/Cape vs Lapatinib/Cape in HER2+ MBC With ≥ 2 Previous Lines of HER2-Targeted Therapy

Sara Hurvitz, MD, FACP:
In the open-label phase III NALA trial, pretreated patients with HER2‑positive MBC (N = 621) were randomized to the combination of neratinib plus capecitabine or the standard‑of‑care regimen of lapatinib plus capecitabine.[37,38]

Previous results from NALA led to the FDA approval of neratinib in combination with capecitabine because it showed an approximately 2‑month improvement in mean PFS vs the comparator regimen.[39,40]

NALA: Analysis of Patients With Baseline CNS Disease

Sara Hurvitz, MD, FACP:
The NALA trial allowed enrollment of patients with stable, treated CNS metastases, and at SABCS 2020, data were presented on this subgroup of patients. Of the 621 randomized patients, 101 had asymptomatic CNS metastases at baseline and these patients were well balanced across the 2 treatment arms.

NALA: Efficacy in Patients With Baseline CNS Disease

Sara Hurvitz, MD, FACP:
In this subset of patients with stable brain metastases, we see a similar absolute improvement in the mean PFS of just over 2 months (7.8 months with neratinib plus capecitabine vs 5.5 months with lapatinib plus capecitabine). The HR is similar to that reported for the overall population (HR: 0.66; P = .074). Also, the time to intervention for CNS disease was improved in patients treated with neratinib, with the 12‑month cumulative incidence of CNS disease at 25.5% with neratinib compared with 36% in the lapatinib arm, and the median CNS PFS appeared to be prolonged in the neratinib arm.

The neratinib combination had some activity in the very small number of patients with known leptomeningeal disease. There were 2 patients in the neratinib arm who had progression of disease after 5.6 and 9.8 months, whereas 1 patient with leptomeningeal disease in the lapatinib arm had progression after 4.3 months. Certainly, this is not level 1 evidence, but it does support the CNS activity of neratinib.

NALA: Clinical Implications for CNS Disease

Joyce O’Shaughnessy, MD:
These results suggest that neratinib is a superior agent than lapatinib for the treatment of brain metastases. The superiority of neratinib held up even when looking at CNS progression, and there was no diminution in patients’ quality of life with neratinib compared to lapatinib. 

HER2CLIMB: Tucatinib or Placebo Plus Trastuzumab/Capecitabine in Previously Treated HER2+ MBC

Sara Hurvitz, MD, FACP:
We know from the ExteNET trial that neratinib appears to have more activity in patients with hormone receptor–positive/HER2‑positive breast cancer who are receiving concurrent ET.[16] In the metastatic setting, the NALA trial showed that patients with hormone receptor–negative disease may do better with neratinib when combined with chemotherapy and in the absence of ET.[37] Given these data associated with neratinib, an analysis from the HER2CLIMB trial was undertaken to explore the activity of another oral tyrosine kinase inhibitor, tucatinib, in patients whose tumors coexpressed hormone receptors or did not coexpress hormone receptors.[41]

In the randomized, double-blind phase II HER2CLIMB trial, 612 patients with previously treated HER2-positive MBC were randomized 2:1 to receive tucatinib 300 mg twice daily or placebo, plus trastuzumab 6 mg/kg every 3 weeks and capecitabine 1000 mg/m2 twice daily for the first 2 weeks of each cycle.[42] The presence of brain metastases was one of the stratification factors. In the primary analysis, tucatinib demonstrated improvement in PFS not only in the intention-to-treat population but also in the patients who had CNS metastases, as well as a significant benefit in terms of OS. These results led to the FDA approval of tucatinib in combination with trastuzumab and capecitabine in 2020.[43]

HER2CLIMB: Response by Hormone Receptor Status

Sara Hurvitz, MD, FACP:
The ORR was greater with tucatinib regardless of hormone receptor coexpression. In the hormone receptor–positive subgroup, the ORR was 37% with tucatinib vs 27% in the placebo arm (P = .07). In the hormone receptor–negative group, it was 45% for tucatinib vs 15.6% for the placebo arm (P = .00008). These data underscore the activity of tucatinib regardless of hormone receptor coexpression.

HER2CLIMB: Survival by Hormone Receptor Status

Sara Hurvitz, MD, FACP:
Similarly, PFS and OS for patients treated with tucatinib was better than placebo in the HER2CLIMB study regardless of hormone receptor coexpression. In the hormone receptor–positive subgroup, the median PFS was 2 months longer with tucatinib (HR: 0.58; P = .0008), whereas in the hormone receptor–negative subgroup, median PFS was 4 months longer with tucatinib (HR: 0.54; P = .008). Median OS was also improved with tucatinib regardless of hormone receptor coexpression in this analysis. The absolute delta does seem to show a greater impact of tucatinib in the hormone receptor–negative subgroup, but I would not use these data to select patients for the use of tucatinib.

HER2CLIMB: HRQoL in Patients With Brain Metastases

Sara Hurvitz, MD, FACP:
Health‑related quality of life was assessed in 164 patients with brain metastases in the HER2CLIMB trial.[44] This is an important outcome measure for our studies evaluating agents that are being used in MBC. Fortunately, tucatinib was associated with a significantly prolonged time to worsening of health‑related quality of life, based on the EQ‑5D‑5L Health Score, compared with the placebo arm and there was no evident change in the subscale responses from baseline through treatment. However, at 30‑day follow-up after discontinuing treatment, there was a worsening observed for mobility, usual activities, pain/discomfort, and self-care.

HER2CLIMB-02: Tucatinib or Placebo Plus T-DM1 in Previously Treated HER2+ Advanced BC

Sara Hurvitz, MD, FACP:
The HER2CLIMB‑02 trial, which is currently recruiting, is evaluating the utility of tucatinib in combination with T‑DM1 in less heavily pretreated patients with advanced HER2-positive disease. HER2CLIMB‑02 is a randomized, placebo‑controlled phase III trial in which patients with HER2‑positive MBC who have received trastuzumab and a taxane in any setting and have not received a tyrosine kinase inhibitor are randomly assigned to T‑DM1 in combination with tucatinib or placebo (planned N = 460).[45,46] Similar to HER2CLIMB, patients with progressing, active, or untreated CNS metastases or treated and stable metastases in the brain are allowed on this trial.

HER2CLIMB: Clinical Implications

Joyce O’Shaughnessy, MD:
In the HER2CLIMB trial, the PFS improvement with tucatinib was greater in patients with hormone receptor–negative disease. But I think the most important thing to all of us and our patients is survival, and I think we can use tucatinib equally effectively in hormone receptor–negative and hormone receptor–positive patients and expect them to receive an OS benefit. Indeed, tucatinib has become a standard of care for second-line and later treatment of patients with HER2-positive disease, especially those with brain metastases.

And now we have the ongoing HER2CLIMB‑02 trial evaluating tucatinib plus T‑DM1 in patients who received previous pertuzumab in the advanced disease setting. In addition, the phase III CompassHER2 RD trial is assessing T-DM1 with and without tucatinib in the high‑risk adjuvant setting for patients with residual disease after preoperative HER2‑based therapy.[47]

DESTINY Breast01

Sara Hurvitz, MD, FACP:
Another exciting update in HER2-positive disease was presented from the open-label phase II DESTINY-Breast01 trial, which evaluated trastuzumab deruxtecan at the standard dose of 5.4 mg/kg once every 3 weeks in patients with HER2-positive MBC whose disease had progressed after treatment with T-DM1.[48] Among 184 patients who had received a median of 6 previous lines of therapy, the updated median PFS was 19.4 months (median follow-up: 20.5 months). This was an increase from the previous report, where the median PFS was 16.4 months with 11.0 months of follow-up. Moreover, the median OS was 24.6 months in this heavily pretreated population. These data are very compelling and reinforce that trastuzumab deruxtecan is a very effective agent.

There were 3 additional cases of treatment-related interstitial lung disease, including 1 fatal case, that brought the rate of interstitial lung disease to 15% in this trial. Clearly, that is something we must be acutely aware of and have a low threshold for ordering a CT scan and holding the trastuzumab deruxtecan for any cough, fever, or dyspnea until we have ruled out interstitial lung disease.

Overall, it is encouraging to see that agents such as trastuzumab deruxtecan and tucatinib are being evaluated in earlier lines of therapy, especially in the curative setting.

SUMMIT: Neratinib Plus Trastuzumab Plus Fulvestrant in HER2-Mutant, Hormone Receptor+ MBC

Sara Hurvitz, MD, FACP:
A small subset of patients with breast cancer are found to have HER2 mutations and there is an ongoing study called SUMMIT, which is an international, multicohort phase II trial evaluating the use of a neratinib in patients with tumor HER2 mutations.[49] The current analysis presented at SABCS evaluated data associated with the combined use of neratinib with trastuzumab and fulvestrant in patients with HER2‑mutated, hormone receptor–positive MBC (N = 51).[50]

SUMMIT: Previous Therapy and Patient Disposition

Sara Hurvitz, MD, FACP:
It is interesting to note that in this study, which includes fulvestrant as part of a combination strategy, nearly three quarters of patients had previously received fulvestrant. It is also interesting that approximately 60% of patients had received a CDK4/6 inhibitor. In general, the patients were heavily pretreated.

SUMMIT: Efficacy Summary

Sara Hurvitz, MD, FACP:
The ORR associated with this triplet therapy was 46%, with a median duration of response of nearly 11 months and a clinical benefit rate of 54%. The median PFS was 8.3 months. These data are particularly encouraging for a targeted triplet therapy that does not involve the use of chemotherapy.

SUMMIT: Treatment-Emergent Adverse Events

Sara Hurvitz, MD, FACP:
It is important to note that 39% of patients experienced grade 3 diarrhea, which is very clinically significant diarrhea. This was likely due to the use of neratinib in combination with fulvestrant. These data warrant the use of upfront prophylactic strategies to mitigate this risk if this triplet regimen is brought forward into a larger population.

SUMMIT: Clinical Implications

Sara Hurvitz, MD, FACP:
Although these data are quite exciting for my patients with HER2 mutations, I believe it is important for us to enroll them on trials like SUMMIT rather than using tyrosine kinase inhibitors such as neratinib in the off‑trial setting. At this point, this drug and others are not approved for HER2‑mutated breast cancer.

Joyce O’Shaughnessy, MD:
The efficacy of this triplet regimen in this population is very good. Activating mutations in HER2 are not uncommon; up to 15% or more of patients with invasive lobular breast cancer in the metastatic setting may harbor these mutations, particularly as a mechanism of resistance to ET.[51] Likewise, 5% to 10% of patients with ductal cancer will have an activating HER2 mutation at some point along the course of their metastatic disease.[52] This triplet could give us a strategy to target these mutations and achieve durable responses with tolerable safety.

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