Trastuzumab Deruxtecan Showcases Clinical Efficacy in HER2+ Gynecological Cancers

“These data suggest that T-DXd is a potential treatment for patients with these gynecologic HER2-expressing tumors who have disease progression on prior therapy,” according to lead study author Jung-Yun Lee, MD.

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) demonstrated clinically meaningful benefit in patients with heavily pretreated endometrial, cervical, or ovarian cancer across varying HER2 immunohistochemistry (IHC) levels, according to findings from the phase 2 DESTINY-PanTumor02 trial (NCT04482309) that were presented during the 2023 Annual Global Meeting of the International Gynecological Cancer Society (IGCS).¹

Specifically in patients with endometrial cancer, the investigator-assessed objective response rate (ORR) was 57.5%, compared with 50.0% in those with cervical cancer and 45.0% in patients with ovarian cancer. The median duration of response (DOR) was not reached (NR; 95% CI, 9.9-not estimable [NE]) in the endometrial cancer cohort, 14.2 months (95% CI, 4.1-NE) in the cervical cancer group, and 11.3 months (95% CI, 4.1-22.1) in the ovarian cancer cohort.

Response rates were also evaluated by HER2 status, and data showed that responses were highest in those with IHC 3+ tumors. For example, in the endometrial cancer cohort (n = 40), patients with IHC 3+ had an ORR of 84.6%, IHC 2+ was 47.1%, IHC 1+ was 25.0%, and IHC 0 was 60.0%; the median DOR was NR (95% CI, 9.6-NE), 18.2 months (95% CI, 3.0-NE), NR (95% CI, not available), and 9.9 months (95% CI, 2.8-NE), respectively.

In those with cervical cancer (n = 40), the ORRs were 75.0%, 40.0%, 50.0%, and 50.0%, in the IHC 3+, 2+, 1+, and 0 groups, respectively; the median DORs were NR (95% CI, 9.3-NE), 3.8 months (95% CI, 2.8-NE), 14.2 months (95% CI, 8.3-NE), and NR (95% CI, 6.8-NE), respectively.

Finally, in the ovarian cancer cohort (n = 40), the ORRs were 63.6%, 36.8%, 20.0%, and 60.0%, respectively. Here, the median DORs were 22.1 months (95% CI, 4.2-NE), 11.3 months (95% CI, 2.8-NE), 8.3 months (95% CI, not available), and 4.5 months (95% CI, 2.6-NE) in the IHC 3+, 2+, 1+, and 0, respectively.

“These data suggest that T-DXd is a potential treatment for patients with these gynecologic HER2-expressing tumors who have disease progression on prior therapy,” lead study author Jung-Yun Lee, MD, of the Department of Obstetrics and Gynecology at Yonsei University College of Medicine in Seoul, North Korea, said in an oral presentation during the conference.

Patients, primarily those in the refractory setting, who have a HER2-expressing gynecologic cancer are an unmet need, as no targeted therapies are available.

T-DXd has previously demonstrated improved survival in patients with HER2-positive breast, lung, and gastric cancers. Early data showed that T-DXd has clinical activity in patients with HER2-expressing malignancies, including those with gynecological cancers.^2,3

In the open-label, multicenter, phase 2 DESTINY-PanTumor02 trial, investigators evaluated T-DXd in patients with HER2-expressing tumors. Prior results demonstrated T-DXd yielded clinically meaningful progression-free and overall survival (OS) and response rates, including those with gynecologic cancers.⁴ During the Annual Global Meeting of the IGCS 2023, Lee presented additional findings from the trial’s endometrial, cervical, and ovarian cancer cohorts.

To be eligible for enrollment, patients had to have advanced solid tumors that were ineligible for curative intent treatment, an ECOG performance status of 0 or 1, were considered a second-line plus patient population, and harbored HER2 expression (IHC 3+ or 2+), which was detected via a local test or central assay by HercepTest if a local test is not feasible; the cervical cancer cohort was expanded to include 5 patients with IHC 1+. Previous HER2-targeted treatment was permitted.

There were 40 patients treated in each gynecologic cancer cohort. T-DXd was administered at 5.4 mg/kg every 3 weeks. The primary end point was investigator-assessed ORR; secondary end points were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. An exploratory analysis of subgroups by HER2 status was also conducted.

The data cutoff date for the primary analysis was June 8, 2023. In the endometrial, cervical, and ovarian cancer cohorts, T-DXd treatment was ongoing at the data cutoff in 25.0%, 17.5%, and 12.5% of patients, respectively. Discontinuations occurred because of objective disease progression (40.0% in the endometrial cancer cohort, 57.5% in the cervical cancer cohort, and 70.0% in the ovarian cancer cohort), adverse effects (AEs; 7.5%, 10.0%, and 7.5%, respectively), patient decision (7.5%, 5.0%, and 2.5%), investigator decision (0.0%, 2.5%, and 2.5%), patient lost to follow-up (2.5%, 0.0%, and 0.0%), and subjective disease progression (7.5%, 2.5%, and 5.0%).

The median number of treatment cycles were 13.0 (range, 1.0-43.0) in the endometrial cancer cohort compared with 8.5 (range, 1.0-39.0) and 7.5 (range, 1.0-39.0) in the cervical and ovarian cancer cohorts, respectively. The median follow-up was 19.94 months (range, 0.8-31.1), 12.60 months (range, 0.9-31.0), and 13.13 months (range, 0.7-30.6) in each cohort, respectively.

Across 3 cohorts, the median age was 57.2 years (range, 28-79), and most patients were White (61.2%). The median prior lines of therapy were 2.5; 60.0% of patients in the ovarian cancer cohort had at least 3 lines of prior therapy, and in the endometrial cancer cohort, 22.5% of patients had previously received HER2-targeted therapy. A total 59.2% of patients had an ECOG performance status of 1.

Lee also reported the agreement between local and central HER2 IHC 2+ testing (49.1%) and 3+ testing (62.9%). Central testing was chosen as the proper testing method.

Additional efficacy data showed that the median progression-free survival (PFS) by investigator assessment in patients with endometrial cancer was 11.1 months (95% CI, 7.1-NE) and 14.1 months (95% CI, 7.3-NE) by independent central review (ICR). When stratified by HER2 expression level, the median PFS via investigator assessment was NR (95% CI, 7.3-NE) in the IHC 3+ group, 8.5 months (95% CI, 4.6-15.1) in the IHC 2+ group, 1.2 months (95% CI, 0.8-NE) in the IHC 1+ group, and 9.1 months (95% CI, 2.6-NE) in those whose IHC was 0. Patients with unknown IHC status had a median PFS that was NR.

Median OS in the endometrial cohort was 26.0 months (95% CI, 12.8-NE). The median OS was 26.0 months (95% CI, 18.9-NE), 16.4 months (95% CI, 8.0-NE), 5.2 months (95% CI, 0.8-NE), and NR (95% CI, 4.2-NE) in the IHC 3+, 2+, 1+, and 0 groups, respectively. Those with unknown IHC status had a median OS of 21.7 months (95% CI, not available).

In the cervical cancer cohort, the overall median PFS was 7.0 months (95% CI, 4.2-11.1) via investigator assessment. When looking at those with IHC 3+, 2+, 1+, and 0 status, the median PFS was NR (95% CI, 3.9-NE), 4.8 months (95% CI, 2.7-5.7), 11.1 months (95% CI, 1.4-NE), and 5.4 months (95% CI, 1.3-NE), respectively.

The median OS in the cervical cancer group was 13.6 months (95% CI, 11.1-NE); it was NR (95% CI, 3.9-NE), 11.5 months (95% CI, 5.1-NE), NR (95% CI, 4.6-NE), and 9.5 months (95% CI, 2.6-NE), in the IHC 3+, 2+, 1+, and 0 groups, respectively.

Finally, in the ovarian cancer cohort, the investigator-assessed median PFS was 5.9 months (95% CI, 4.0-8.3). In the IHC 3+, 2+, 1+, and 0 groups, the median PFS by investigator assessment was 12.5 months (95% CI, 3.1-NE), 4.1 months (95% CI, 2.3-12.6), 6.9 months (95% CI, 0.7-NE), and 5.6 months (95% CI, 1.3-NE).

The median OS in these patients with ovarian cancer overall was 13.2 months (95% CI, 8.0-17.7); it was 20.0 months (95% CI, 3.8-NE) in the IHC 3+ group, 13.0 months (95% CI, 4.7-21.9) in the 2+ group, 7.7 months (95% CI, 0.7-NE) in those with IHC 1+ status, and 12.3 months (95% CI, 6.2-NE) in those with IHC 0 disease.

Across the 3 gynecological cancer cohorts, responses were highest in those with HER2 amplification either detected by tissue (endometrial, 84.6%; cervical, 60.0%; and ovarian, 60.0%) or plasma (endometrial, 90.9%; cervical, 75.0%; and ovarian, 100.0%). Lee noted that the response rates were similar in those with HER2 IHC 3+ and plasma HER2 amplification.

Regarding safety, 88.3% of patients across the 3 cohorts (n = 120) experienced any treatment-related treatment-emergent adverse events (TEAEs); 45.0% were grade 3 or higher. Serious treatment-related TEAEs occurred in 15.0% of patients. A total 5.8% of patients had these TEAEs linked with dose discontinuations, 20.0% with dose interruptions and 29.2% with dose reductions. Two patients died due to drug-related TEAEs.

The most common treatment-related TEAEs were nausea (any-grade, 64.2%; grade ≥3, 4.2%), fatigue (44.2% and 6.7%, respectively), diarrhea (32.5% and 5.0%), anemia (30.8% and 13.3%), neutropenia (28.3% and 19.2%), vomiting (27.5% and 0.8%), decreased appetite (19.2% and 3.3%), alopecia (any-grade, 18.3%), and thrombocytopenia (15.0% and 6.7%).

Interstitial lung disease/pneumonitis that was adjudicated as related to T-DXd occurred in 10.8% (n = 13) of patients; these occurred at grade 1 (3.3%), grade 2 (6.7%), and grade 5 (0.8%).

References

1. Lee J-Y, Makker V, Manso L, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: results from the cervical, endometrial, and ovarian cancer cohorts of the DESTINY-PanTumor02 study. Presented at: Annual Global Meeting of the International Gynecological Cancer Society 2023; November 5-7, 2023; Seoul, North Korea.
2. Yoshino T, Di Bartolomeo M, Raghav KPS, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2022;40(suppl 15):abstr 119. doi:10.1200/JCO.2022.40.4_suppl.119
3. Tsutani J, Iwata H, Krop I, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov. 2020;10(5):688-701. doi:10.1158/2159-8290.CD-19-1014
4. Meric-Benstam F, Makker V, Oaknin A, et al. Trastuzumab deruxtecan (T-DXd) for pretreated patients (pts) with HER2-expressing solid tumors: primary analysis from the DESTINY-PanTumor02 (DP-02) study. Ann Oncol. 2023;34(suppl 2):S1254-S1335. doi:10.1016/annonc/annonc1358