Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial☆

Abstract

Background: Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown potential activity in this subset of patients in small clinical series. Patients and methods: KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer with prior HER2-targeted therapy and chemotherapy. Patients received T-DM1 3.6 mg/kg every 3 weeks (intravenously) until unacceptable toxicity, withdrawal of consent, or disease progression. Tumor response and clinical outcomes in patients with baseline BM were evaluated in this post hoc, exploratory analysis. The main outcome measures were best overall response rate (complete response þ partial response) and clinical benefit rate (complete response þ partial response þ stable disease lasting !6 months) by RECIST v1.1 criteria, progression-free survival, overall survival, and safety. Results: Of 2002 treated patients, 398 had baseline BM. In 126 patients with measurable BM, the best overall response rate and clinical benefit rate were 21.4% [95% confidence interval (CI) 14.6e29.6] and 42.9% (95% CI 34.1e52.0), respectively. A reduction in the sum of the major diameters of BM !30% occurred in 42.9% (95% CI 34.1e52.0), including 49.3% (95% CI 36.9e61.8) of 67 patients without prior radiotherapy to BM. In the 398 patients with baseline BM, median progression-free survival and overall survival were 5.5 (95% CI 5.3e5.6) months and 18.9 (95% CI 17.1e21.3) months, respectively. The adverse event profile was broadly similar in patients with and without baseline BM, although nervous system adverse events were more common in patients with [208 (52.3%)] versus without [701 (43.7%)] baseline BM. Conclusion: This exploratory analysis of patients with HER2-positive metastatic breast cancer and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting. Trial registration: ClinicalTrials.gov identifier: NCT01702571.

Treatment strategies for breast cancer brain metastases

“…69 A subgroup analysis of 398 patients with BM included in the KAMILLA single-arm open-label, Phase 3b study published in 2020, confirms the efficacy and safety of T-DM1 in this situation, with a BM response rate of 21%, a median PFS of 6 months and a median OS of 19 months. 70 Pertuzumab-trastuzumab combination for patients with HER2 + BM. Pertuzumab is a recombinant humanised monoclonal antibody targeting the dimerisation domain II of HER2 that was approved for the first-line treatment of patients with HER2 + MBC following the randomised Phase 3 placebo-controlled CLEOPATRA trial.…”

Clinical implications of plasma ctDNA features and dynamics in gastric cancer treated with HER2‐targeted therapies

“…8 TDM1(Trastuzumab emtansine) has shown to be active in HER2-positive breast cancer patients with brain metasta-sis from the phase III KAMILLA trial. 13 Another HER2-ADC, RC48-ADC, has been carried out in phase II trials and demonstrated a clinically meaningful overall response rate (ORR) in pretreated HER2-positivie urothelial carcinoma patients. 15 Although these agents/combinations provide supporting evidence for further investigation in HER2-positivie GC, the response rate of HER2-positive patients received HER2-targeted therapy remain limited, and the frequently upcoming resistance is another reason that impaired therapeutic efficacy.…”

“…Due to its tight regulation to crucial downstream signaling nodes such as RAS/RAF/MYC and PI3K‐Akt, HER2 remains to be the prior choice of targeted drug development for patients with advanced GC 5 . To date, a variety of HER2‐targeted drugs has been developed and evaluated by clinical trials separately and combined, including HER2 antibody and its derivatives (Trastuzumab and Pertuzumab), tyrosine kinase inhibitor (Lapatinib, Neratinib, and Afatinib), and antibody‐drug conjugates (ADCs) (DS‐8201a, TDM1, and RC48) 6–13 . Monoclonal antibody Trastuzumab is the only HER2‐targeted agent currently approved for first‐line practice of GC 14 .…”

“…5 To date, a variety of HER2-targeted drugs has been developed and evaluated by clinical trials separately and combined, including HER2 antibody and its derivatives (Trastuzumab and Pertuzumab), tyrosine kinase inhibitor (Lapatinib, Neratinib, and Afatinib), and antibody-drug conjugates (ADCs) (DS-8201a, TDM1, and RC48). [6][7][8][9][10][11][12][13] Monoclonal antibody Trastuzumab is the only HER2-targeted agent currently approved for first-line practice of GC. 14 DS-8201a, also known as Trastuzumab deruxtecan, is an ADC conjugated with humanized anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload.…”

“…Both response rate and overall survival (OS) was significantly improved in DS‐8201‐treated patients compared to standard therapy 8 . TDM1(Trastuzumab emtansine) has shown to be active in HER2‐positive breast cancer patients with brain metastasis from the phase III KAMILLA trial 13 . Another HER2‐ADC, RC48‐ADC, has been carried out in phase II trials and demonstrated a clinically meaningful overall response rate (ORR) in pretreated HER2‐positivie urothelial carcinoma patients 15 .…”