Trastuzumab Deruxtecan Shows Efficacy in HER2+ Breast Cancer Brain Mets

Fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated continued benefit in patients with HER2-positive breast cancer who had stable, treated brain metastases at baseline, according to results from a subgroup analysis of the DESTINY-Breast01 (NCT03248492). The analysis of the central nervous system (CNS) subgroup also demonstrated a consistent safety profile when compared with the overall population.

Of the 24 patients with CNS metastases at baseline, 58.3% had a confirmed objective response rate (ORR; 95% CI, 36.6%-77.9%) with 4.2% achieving a complete response (CR), 54.2% experiencing a partial response (PR), and 33.3% having stable disease. These data are comparable with the analysis of all patients (n = 184), of which 60.9% had a confirmed ORR (95% CI, 53.4%-68.0%) with 6.0%, 54.9%, and 36.4% achieving a CR, PR, SD, respectively.^1,2 Of the 4 patients who experienced progressive disease, 1 was in the CNS subgroup.

These subgroup analysis data were presented by Guy Jerusalem, MD, a professor of Oncology at the Liege University, Belgium, and head of Medical Oncology at the University Hospital of Lieg, as part of the 2020 ESMO Breast Cancer Virtual Meeting.

Jerusalem noted that although similar results were observed in the CNS subgroup as in the overall population, it is important to note the wide confidence intervals in the CNS group.

Investigators enrolled 184 patients with unresectable or metastatic HER2-positive breast cancer who were heavily pretreated, including with ado-trastuzumab emtansine (T-DM1; Kadcyla) and other HER2-targeted treatments. All patients included in the intent-to-treat analysis received the recommended dose of trastuzumab deruxtecan, at 5.4 mg/kg every 3 weeks. The primary end point of the trial was confirmed ORR by independent central review per RECIST v1.1.

The baseline characteristics of the overall population and the CNS subgroup were well matched with each population having received a median of 6 prior treatments, with 100% of patients having received prior T-DM1 and trastuzumab (Herceptin), and 62.5% and 65.8% having received prior pertuzumab (Perjeta), respectively.^1,2

The disease control rate in the CNS subgroup was 91.7% compared with 97.3% in the overall population. Furthermore, those patients with CNS metastases experienced a longer median duration of response, at 16.9 months (95% CI, 5.7-16.9) versus 14.8 months (95% CI, 13.8-16.9) in the overall population. The median time to response was 2.8 months (95% CI, 1.3-4.1) for the CNS subgroup versus 1.6 months (95% CI, 1.4-2.6) for all patients.

At median follow-up of 11.0 months, the median progression-free survival in the CNS subgroup was 18.1 months (95% CI, 6.7-18.1) versus 16.4 months (95% CI, 12.7-not evaluable) at 11.1 months follow-up in the overall population.

The sites of progression were similar among all patients and the CNS subgroup. Of the 48 patients who experienced progression while on the study, only 4 (2.2%) were in the CNS. The CNS site progression occurred at days 78 and 85 in the CNS subgroup and at days 323 and 498 in those patients without a history of CNS metastases (n = 160). Other sites of metastases in the CNS subgroup and the non-CNS patients were lung (12.5% vs 10.6%, respectively), liver (8.3% vs 7.5%), and the bone (4.2% vs 1.3%).

At the time of data cutoff, 45.8% of patients with CNS metastases were ongoing and 54.2% of patients discontinued primarily for progressive disease (6/24; 25.0%).

The safety analysis demonstrated consistent treatment-emergent adverse events (TEAEs) between the CNS subgroup and the overall patient population. The predominant TEAEs were gastrointestinal or hematologic in nature. Two patients in the CNS subgroup discontinued due to TEAEs other than pneumonitis or interstitial lung disease (ILD). In the overall population, adverse events that led to discontinuation in at least 2 patients included pneumonitis (n = 11) and ILD (n = 5).

Prior reported analyses, simultaneously published in the New England Journal of Medicine, demonstrated the safety and efficacy of trastuzumab deruxtecan in the overall population. These results led to the approval of the novel antibody-drug conjugate for the treatment of unresectable or metastatic HER2-positive breast cancer after treatment with at least 2 prior anti—HER2-based regimens in the United States, or after prior chemotherapy in Japan.^3,4

Demonstrated Activity: A Case Study

In a case report presented by Jerusalem, a 48-year-old woman with HER2-positive (IHC 3+)/hormone receptor—negative metastatic breast cancer demonstrated a 55% regression of a metastatic brain lesion while receiving trastuzumab deruxtecan.

The patient had received 17 prior lines of treatment, including prior T-DM1, pertuzumab, trastuzumab, and lapatinib (Tykerb). Prior treatment for CNS metastases included whole brain radiotherapy and stereotactic radiosurgery 3 years prior to enrollment. Target lesions at baseline included brain, lymph nodes, and retroperitoneum. Nontarget lesions were present in the lung, pancreas, bone, and axillary lymph node.

At 6-week evaluation, scans showed that the brain lesion reduced by 36% from baseline with partial response (PR) in all target lesions. At 12 weeks, the lesion was reduced by 55% with continued PR in all target lesions. Despite this progress, “New lesions were observed in the chest wall and unfortunately, the response was progressive disease and we had to stop treatment,” explained Jerusalem.

Next Steps for Trastuzumab Deruxtecan

Jerusalem concluded by describing 3 important international large phase 3 studies that are ongoing in patients with HER2-expressing breast cancer. First, the DESTINY-Breast02 trial (NCT03523585) is evaluating trastuzumab deruxtecan versus standard of care after T-DM1 in HER2-positive disease. A head-to-head examination of T-DM1 versus trastuzumab deruxtecan in patients previously treated with trastuzumab and taxane in the advanced/metastatic setting is being explored in the DESTINY-Breast03 trial (NCT03529110). Finally, the DESTINY-Breast04 trial (NCT03734029) is investigating trastuzumab deruxtecan versus chemotherapy in patients with HER2-low expressing breast cancer that has spread or cannot be surgically removed.

All trials are currently recruiting.

References

1. Jerusalem G, Park YH, Yamashita T, et al. CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 138O.
2. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510
3. Enhertu. Package insert. Daiichi Sankyo, Inc; 2019. Accessed May 23, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf
4. Enhertu approved in Japan for treatment of patients with HER2 positive unresectable or metastatic breast cancer. New release. March 25, 2020. Accessed May 23, 2020. bit.ly/2Zxr2VJ

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