Pertuzumab Plus Trastuzumab Demonstrates Clinical Activity in ERBB2/ERBB3+ Uterine Cancer

Eugene R. Ahn, MD

In patients with ERBB2/ERBB3-expressed, mutated, or -amplified uterine cancer, the combination of pertuzumab (Perjeta) and trastuzumab (Herceptin) led to a 37% (95% CI, 21%-50%) disease control rate (DCR), according to results from the Targeted Agent Profiling and Utilization Registry (TAPUR) study that were presented during the 2021 ASCO Annual Meeting.¹

Data showed that the objective response rate was 7% (95% CI, 1%-24%). Two patients had partial responses and 8 patients achieved stable disease (SD) at 16+ weeks, which translated to 10 patients meeting the prespecified criteria as responders to the combination.

“Pertuzumab and trastuzumab demonstrated antitumor activity in heavily pretreated patients with uterine cancer with HER2 amplification and/or specific mutations,” Eugene R. Ahn, MD, an investigator on the study and deputy medical director of clinical research at Cancer Treatment Centers of America, said in a presentation on the findings. “Additional study is warranted to confirm the efficacy of pertuzumab and trastuzumab in this patient population, and…to identify biomarkers for patients likely to respond to trastuzumab/pertuzumab; [this] will be an important step to advancing the benefits of precision medicine in this population.”

The TAPUR trial, which is conducted by ASCO, is a nonrandomized, phase 2 basket trial testing 18 commercially available treatments in more than 85 molecular targets across advanced solid tumors with specific genomic alterations. All cohorts follow a Simon’s optimal two-stage design.

The clinical significance of ERBB2 expression or ERBB2 amplification in endometrial cancer as a predictive marker for response to HER2-directed therapies has been controversial, Ahn said. Prior data have showed that the percentage of patients with high-grade endometrial cancer and ERBB2 gene amplification ranges from 17% to 30%, and up to 80% of this patient population has ERBB2 protein expression.²

Uterine serous carcinoma is the most likely subtype to have ERBB2 positivity; however, previous research has shown that 45% of patients with ERBB2-positive primary tumors had metastatic lesions that were also ERBB2 positive via immunohistochemistry or chromogenic in situ hybridization.³ Additionally, trastuzumab monotherapy has showed limited efficacy in ERBB2-positive endometrial cancer, Ahn noted.

In this arm of the TAPUR trial, investigators evaluated the combination of pertuzumab and trastuzumab in 28 patients with ERBB2/ERBB3-positive uterine cancer. To be eligible for enrollment on this cohort, patients needed to have advanced uterine cancer with an ECOG performance status of 0 to 2, adequate organ function, measurable disease, and have their genomic test performed in a CLIA-certified, CAP-accredited laboratory. Patients’ tumors must have harbored ERBB2 or ERBB3 amplification or overexpression, or any of the 13 prespecified ERBB2 mutations.

Pertuzumab was given intravenously at an initial dose of 850 mg over 1 hour, followed by 420 mg IV over 30 minutes to 1 hour, every 3 weeks. Trastuzumab was given IV at an initial dose of 8 mg/kg over 90 minutes, followed by 6 mg/kg every 30 minutes to 1 hour, every 3 weeks.

The primary end point of the trial is DCR, defined as objective response or SD at 16+ weeks via RECIST v1.1 criteria. Additional end points include progression-free survival (PFS), overall survival (OS), and potentially serious or treatment-related adverse events that are grades 3 to 5 in severity.

Of the 28 patients enrolled between August 2017 and November 2019, the median age was 69 years (range, 44-90+). Moreover, 21 patients were White, 2 were Black, 1 was Asian, 1 was more than 1 race, 2 were recorded as other, and 1 patient preferred not to answer. Eighty-nine percent (n = 25) of patients were non-Hispanic or non-Latino. More than half (n = 16) of patients had an ECOG performance status of 1, followed by 9 patients with a status of 0 and 11 with a status of 2. Twelve patients had received 1 to 2 prior lines of treatment, while 16 received 3 or more prior lines.

In the breakdown of genomic alterations, patients had either ERBB2 amplification (n = 21), ERBB2 overexpression (n = 1), ERBB2 mutations (n = 4), ERBB3 amplification (n = 1), or ERBB2 amplification and mutation (n = 1).

Additional findings showed that the median PFS was 28.1 weeks and the median OS was 60.9 weeks.

Regarding safety, 1 grade 3/4 adverse event (AE) was reported, which was grade 3 muscle weakness, and was considered to potentially be related to pertuzumab/trastuzumab. No other serious AEs or treatment-related toxicities were reported.

Ahn discussed additional clinical trials of HER2-directed treatments in ERBBB2-amplified uterine cancer. For example, results from the phase 2 GOG181Btrial of trastuzumab in women with stage III/IV HER2-positive endometrial cancer showed no objective responses in the 33 patients enrolled.⁴

Secondly, a phase 2 study (NCT01367002) randomized 58 patients with ERBB2-overexpressing uterine serous carcinomas to receive carboplatin/paclitaxel alone or with trastuzumab. Results showed that the median PFS was 12.9 months with the addition of trastuzumab compared with 8.0 months for chemotherapy alone (HR, 0.44; 90% CI, 0.26-0.76; P = .005).5 The median OS was 24.4 months and 19.6 months, respectively (HR, 0.58; 90% CI, 0.34-0.99; P = .046).

_References

_{1. Ali-Ahmad HM, Roth M, Mangat PK, et al. Pertuzumab plus trastuzumab (P+T) in patients (Pts) with uterine cancer (UC) with ERBB2 or ERBB3 amplification, overexpression or mutation: results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. J Clin Oncol. 2021;39(suppl 15):5508. doi:10.1200/JCO.2021.39.15_suppl.5508}

_{2. Konecny GE, Santos L, Winterhoff B, et al. HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer. Br J Cancer. 2009;100(1):89-95. doi:10.1038/sj.bjc.6604814}

_{3. Halle MK, Tangen IL, Berg HF, et al. HER2 expression patterns in paired primary and metastatic endometrial cancer lesions.Br J Cancer. 2018;118(3):378-387. doi:10.1038/bjc.2017.422}

_{4. Fleming GF, Sill MW, Darcy KM, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116(1):15-20. doi:10.1016/j.ygyno.2009.09.025}

_{5. Fader AN, Roque DM, Siegel E, et al. Randomized phase ii trial of carboplatin-paclitaxel compared with carboplatin-paclitaxel-trastuzumab in advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress Her2/Neu (NCT01367002): updated overall survival analysis. Clin Cancer Res. 2020;26(15):3928-3935. doi:10.1158/1078-0432.CCR-20-0953}