Trastuzumab Deruxtecan Displays Antitumor Activity, Safety in HER2-Expressing Uterine Carcinosarcoma

The antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu) led to durable responses and a tolerable safety profile in patients with HER2-expressing uterine carcinosarcoma, according to findings from the phase 2 STATICE trial (UMIN000029506), previously presented at the 2021 ESMO Congress, that were published in the Journal of Clinical Oncology.^1,2

Considered a rare and aggressive high-grade endometrial cancer, uterine carcinosarcomas have increased in incidence and have few effective therapeutic options, especially in later lines of therapy.³ Therefore, investigators set out to evaluate the safety and efficacy of trastuzumab deruxtecan in patients with uterine carcinosarcoma with HER2 expression via immunohistochemistry (IHC) of at least 1+ who had previously received chemotherapy.¹

Thirty-two patients were included in the full analysis set, 22 of whom were classified has HER2 high (IHC 2+ or IHC 3+) and 10 were HER2 low (IHC 1+). IHC was assessed using criteria for gastric cancer.¹

The confirmed overall response rate (ORR) via central review was 54.5% (95% CI, 32.2%-75.6%) in the HER2-high cohort. One patient in the HER2-high cohort had a complete response with the remaining responders having partial responses and 10 (45.5%) patients having stable disease. The median duration of response (DOR) was 6.9 months (95% CI, 4.1-12.6).¹

ORR in the HER2-low cohort was an exploratory end point of the study; 70.0% (95% CI, 34.8%-93.3%) of patients had a response, all of which were partial responses. Three patients in this cohort had stable disease. The median DOR was 8.1 months (95% CI, 2.8-not reached [NR]).¹

No patients on study had progressive disease at data cutoff, translating to a 100% disease control rate.¹

“Trastuzumab deruxtecan demonstrated promising antitumor activity in patients with both HER2-high and HER2-low uterine carcinosarcoma,” Tadaaki Nishikawa, MD, PhD, and study authors wrote in the published findings.¹ “These efficacies exceeded those of other agents examined in clinical trials for recurrent [uterine carcinosarcoma]…. The results of this study suggest that [trastuzumab deruxtecan] is effective in patients with both HER2-high and HER2-low advanced or recurrent uterine carcinosarcoma who were previously treated with chemotherapy.”

The authors cited data systematic review of therapies for recurrent or treatment-refractory uterine carcinosarcomas in the second- or later-line settings, which showed response rates of only 5.5%, a median progression-free survival (PFS) and overall survival (OS) of 2 and up to 8 months with PI3K/mTOR inhibitors.^1,3

The median PFS among all treated patients in STATICE was 6.7 months (95% CI, 5.4-8.8) and the median OS was 15.8 months (95% CI, 10.5-NR).¹

In the HER2-high group the median PFS was 6.2 months (95% CI, 4.0-8.8). The 6- and 12-month PFS rates in this cohort were 54.4% (95% CI, 31.6%-72.2%) and 19.9% (95% CI, 5.5%-40.9%), respectively. The median OS was 13.3 months (95% CI, 8.8-NR). The 6- and 12-month OS rates were 81.8% (95% CI, 58.5%-92.8%) and 54.2% (95% CI, 29.8%-73.4%), respectively.¹

In the HER2-low group, the median PFS was 6.7 months (95% CI, 2.6-13.8). The median OS was NR (95% CI, 8.8-NR) in this cohort.¹

Patients were administered trastuzumab deruxtecan every 3 weeks until disease progression or unacceptable toxicity. Fourteen patients received trastuzumab deruxtecan at 6.4 mg/kg and following a safety analysis, the remaining 18 patients enrolled to the trial received the ADC at 5.4 mg/kg.^1,2

Seventeen patients received up to 7 doses of trastuzumab deruxtecan at either dosage; 5 patients were reported as having received 14 or more doses. Overall, the median cumulative number of doses was 40.8 (range, 13-194) for the 6.4-mg/kg dose and 37.8 (range, 11-113) for the 5.4-mg/kg dose. The median treatment duration was 143 days (range, 42-684) for the 6.4-mg/kg dose and 167 days (range, 42-462) for the 5.4-mg/kg dose.¹

Responses were also assessed via investigator review. In the HER2-high cohort, the ORR was 68.2% (95% CI, 45.1%-86.1%). In the HER2-low cohort the ORR was 60.0% (95% CI, 26.2%-87.8%).¹

The safety profile was consistent with what had been observed with the ADC is previous studies according to the investigators. Thirty-three patients were included in the safety analysis and 60.6% of patients had a grade 3 or 4 adverse effect (AE). The most common reported grade 3 or 4 events were anemia (24.2%), neutropenia (27.3%), fatigue (6.1%). Patients experienced grade 1, grade 2, and grade 3 pneumonitis at rates of 12.1%, 12.1%, and 3.0%. Overall, 33.3% of patients experienced an AE that led to permanent drug withdrawal.^1,2

The most common AEs associated with drug withdrawal were pneumonitis or interstitial lung disease (n = 6) and malaise (n = 2).

In the final efficacy set (n = 32), the median age was 64.5 years (range, 45-81). Most patients (75%) had an ECOG performance status of 0. When HER2 was assessed by florescence in situ hybridization 75% of patients were negative and 25% were positive. All patients had prior surgery for uterine carcinosarcoma. Over half (53.1%) of patients had 1 prior line of treatment, 28.1% had 2 prior lines of treatment, and 18.8% had 3 or more prior lines of treatment. Most patients received trastuzumab deruxtecan within 12 months of their prior treatment with 56.3% of patients having a treatment-free interval of fewer than 6 months and 28.1% of patients having a treatment-free interval of 6 to 12 months.¹

In terms of disease characteristics, 18.8% of patients had stage I disease, 34.4% had stage III, and 46.9% had stage IV. The carcinoma components of disease were primarily classified as mixed (31.3%). Others included endometroid (21.9%), serous (18.8%), and clear cell (3.1%), with 25% of patients having cases of high-grade endometrial carcinoma components with unclassifiable morphological characteristics. Sarcoma components were homologous in 34.4% of patients and heterologous in 65.6% of patients.¹

“The key limitations of the present study are the open-label design, enrollment of only Japanese patients, and mixture of results based on the 2 initial doses,” the authors wrote. “We evaluated a relatively small sample size; however, the predefined threshold of more than 4 responders among 22 treated patients was exceeded.”

References

1. Nishikawa T, Hasegawa K, Matsumoto K, et al. Trastuzumab deruxtecan for human epidermal growth factor receptor 2–expressing advanced or recurrent uterine carcinosarcoma (NCCH1615): the STATICE trial. J Clin Oncol. Published online March 28, 2023. doi:10.1200/JCO.22.02558
2. Hasegawa K, Nishikawa T, Hirakawa A, et al. Efficacy and safety of trastuzumab deruxtecan in HER2-expressing uterine carcinosarcoma (STATICE trial, NCCH1615): a multicenter, phase II clinical trial. Ann Oncol. 2021;32(suppl 5):767. doi:10.1016/j.annonc.2021.08.1255
3. Matsuzaki S, Klar M, Matsuzaki S, Roman LD, Sood AK, Matsuo K. Uterine carcinosarcoma: contemporary clinical summary, molecular updates, and future research opportunity. Gynecol Oncol. 2021;160(2):586-601. doi:10.1016/j.ygyno.2020.10.043