Trastuzumab Deruxtecan Elicits Responses in Difficult-To-Treat HER2+ Solid Tumors

Funda Meric-Bernstam, MD

Fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated clinically meaningful activity across a wide range of HER2 expressing solid tumors, including hard-to-treat tumors, according to findings from the phase 2 DESTINY-PanTumor02 trial (NCT04482309) presented during the 2023 ASCO Annual Meeting.

Results from the study showed that at the November 16, 2022, data cutoff, patients with cervical (n = 40), endometrial (n = 40), ovarian (n = 40), biliary tract (n = 41) pancreatic (n = 25), bladder (n = 41), and other cancers (n = 40) experienced investigator-assessed overall response rates (ORRs) of 50.0%, 57.5%, 45.0%, 22.0%, 4.0%, 39.0%, and 30.0%, respectively. The complete response (CR) rates were 5.0%, 17.5%, 10.0%, 2.4%, 0%, 2.4%, and 0% respectively. The ORR in the total population (N = 267) was 37.1%, including a 5.6% CR rate.

Among all responders, the Kaplan-Meier estimate of duration of objective response at 12 months was 49.6%. Specifically in the cervical, endometrial, ovarian, biliary tract, pancreatic, bladder, and other cohorts, these rates were 47.6%, 72.3%, 45.8%, 41.7%, 0%, 23.2%, and 53.6%, respectively.

“Trastuzumab deruxtecan is a potent antibody-drug conjugate that has become a standard of care for HER2-low as well as HER2-positive breast cancer, HER2-positive gastric cancer, and HER2-mutant lung cancer,” Funda Meric-Bernstam, MD, said in a presentation of the data. Meric-Bernstam is chair of the Department of Investigational Cancer Therapeutics—the Phase I Program, medical director of the Institute for Personalized Cancer Therapy (IPCT), and the Nellie B. Connally Chair in Breast Cancer at MD Anderson Cancer Center in Houston, Texas. “However, HER2 is expressed across a variety of other tumor types, and for these patients there are no approved HER2-targeted treatments, and often the disease is refractive to standard-of-care therapies. In early-phase studies, trastuzumab deruxtecan demonstrated activity in several tumor types, including salivary gland, biliary [tract], and endometrial cancers.”

DESTINY-PanTumor02 was an open-label, multicenter study of patients with advanced solid tumors who were not eligible for curative therapy. Patients needed to be in their second line or later of therapy, have a HER2 expression by immunohistochemistry (IHC) of 3+ or 2+, and an ECOG performance status of 1 or 0. Prior HER2-directed therapy was permitted. Trastuzumab deruxtecan was administered at a dose of 5.4 mg/kg every 3 weeks in all cohorts.

In the overall population, the median age was 62 years (range, 23-85). Most patients were White (61.0%), had an ECOG performance status of 1 (52.1%), underwent local HER2 testing for eligibility (76.8%), and displayed a HER2-expression level of IHC 2+ (57.3%). Patients who received prior HER2-directed therapy were treated with a monoclonal antibody (12.7%) or a Tyrosine kinase inhibitor (0.4%).

The median number of prior lines of therapy was 2 (range, 0-13). Patients underwent 0 (1.1%), 1 (26.2%), 2 (31.5%), and at least 3 (40.1%) prior lines of treatment. There were also 3 patients who received an unknown number of prior lines of therapy.

The primary end point was confirmed ORR by investigator. Secondary end points included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

The safety profile of trastuzumab deruxtecan was found to be consistent with the known profile of the agent. In the overall population, common any-grade treatment-emergent adverse events (TEAEs) included nausea (54.3%), fatigue (37.8%), neutropenia (32.6%), anemia (25.8%), diarrhea (25.5%), vomiting (24.3%), decreased appetite (16.5%), thrombocytopenia (16.5%), alopecia (16.1%), and leukopenia (10.1%). These AEs occurred at a grade 3 or higher severity in 3.4%, 6.0%, 19.1%, 8.6%, 3.7%, 1.5%, 1.5%, 5.2%, 0.0%, and 2.6% of patients, respectively.

Regarding interstitial lung disease and pneumonitis related to treatment with trastuzumab deruxtecan, any-grade events were reported in 7.5% of patients. Most instances were grade 2 (4.5%), although grade 1 (2.2%), grade 3 (0.4%), and grade 5 (0.4%) events were also reported.

Any grade left ventricular dysfunction events were rare and consisted of decreased ejection fracation (2.6%) and cardiac failure (0.4%). Grade 1 (0.4%), grade 2 (1.5%), and grade 3 (0.4%) left ventricular dysfunction events occurred. The only instance of cardiac failure was grade 3 in severity.

Drug-related TEAEs that were associated with dose discontinuations occurred at a rate of 8.2% and 12.0% of patients experienced serious drug-related TEAEs. Drug-related TEAEs associated with dose interruptions, dose reductions, and deaths were reported in 18.4%, 18.7%, and 0.7% of patients, respectively.

Patients in the cervical, endometrial, ovarian, biliary tract, pancreatic, bladder, and other cohorts, were still on treatment at the data cutoff at rates of 25.0%, 65.0%, 15.0%, 7.3%, 4.0%, 12.2%, and 12.5%, respectively. The respective median follow-ups at data cutoff were 7.2 months (range, 0.9-23.0), 14.6 months (range, 0.8-24.2), 12.7 months (range, 0.7-23.7), 6.0 months (range, 0.7-20.0), 4.9 months (range, 1.1-19.8), 12.0 months (range, 0.4-21.2), and 12.0 months (range, 0.7-23.9). The median treatment durations at data cutoff were 5.5 months (range, 0.7-19.8), 9.0 months (range, 0.7-24.4) 5.9 months (range, 0.7-23.0), 3.5 months (range, 0.7-20.1), 2.1 months (range, 0.7-11.0), 6.2 months (range, 0.4-18.0), and 6.9 months (range, 0.7-19.9), respectively.

Overall, 83.5% of patients discontinued treatment. Reasons for discontinuation included disease progression (58.4%), AEs (11.2%), and other (13.9%).

Additional findings from the study revealed that the median DORs were 9.8 months (95% CI, 4.2-not evaluable [NE]), not reached (NR; 95% CI, 9.9-NE), 11.3 months (95% CI, 4.1-NE), 8.6 months (95% CI, 2.1-NE), not reached, 8.7 months (95% CI, 4.3-11.8), and not reached (95% CI, 4.1-NE) in the cervical, endometrial, ovarian, biliary tract, pancreatic, bladder, and other cohorts, respectively. The 12-week DCR rates were 67.5%, 80.0%, 70.0%, 65.9%, 36.0%, 70.7%, and 75.0%, respectively.

Notably, patients with a HER2 status of IHC 3+ generally experienced heightened response rates. The ORRs among patients with an IHC of 3+ were 75.0%, 84.6%, 63.6%, 56.3%, 0.0%, 56.3%, and 44.4%, in the cervical (n = 8), endometrial (n = 13), ovarian (n = 11), biliary tract (n = 16), pancreatic (n = 2), bladder (n = 16), and other (n = 9) cohorts, respectively. Comparatively, the ORRs for patients with a HER2 of IHC 2+ were 40.0%, 47.1%, 36.8%, 0.0%, 5.3%, 35.0%, and 18.8 % in the cervical (n =20), endometrial (n = 17), ovarian (n = 19), biliary tract (n = 14), pancreatic (n = 19), bladder (n = 20), and other (n = 16) cohorts, respectively.

The median DOR for all patients with an IHC of 3+ was 22.1 months (95% CI, 9.3-NE) and was 9.8 months (95% CI, 4.2-12.6) among those with an IHC of 2+. Overall, the median DOR was 11.8 months (95% CI, 9.8-NE).

“These were durable responses,” Meric-Bernstam said. “The trial is still ongoing, and we will be reporting OS and PFS [data] at a later date. However, data to date suggest that trastuzumab deruxtecan has broad activity and could represent a new therapy option in patients that are HER2-positive.”

Reference

Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41(suppl 17):LBA3000.