Clinical Trials Back T-DXd’s Star Power in Solid Tumors With HER2 Overexpression

What do a British prince, a reality TV star, and a gene have in common? Prince Harry, Khloé Kardashian, and HER2 (ERBB2) will all mark a 40-year milestone in 2024. While the overexposure of the first two may be a negative, the overexpression and/or amplification of HER2 has led to dramatic improvements in oncologic outcomes, particularly in breast, lung, and gastrointestinal (GI) cancers.

"The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug—the monoclonal antibody trastuzumab—almost 25 years ago," noted Sandra M. Swain, MD, of the Georgetown Lombardi Comprehensive Cancer Center/MedStar Health in Washington, and co-authors in a 2022 Nature Reviews Drug Discovery article.

T-DXd has three components—a humanized anti-HER2 IgG1 monoclonal antibody, a topoisomerase 1 inhibitor payload, and a tetrapeptide-based cleavable linker. "This ADC has several key attributes, but importantly, this is a payload that’s quite potent. It has a high drug-to-antibody ratio, and it also has a bystander antitumor effect," explained Funda Meric-Bernstam, MD, of the MD Anderson Cancer Center in Houston, during a presentation at the 2023 American Society of Clinical Oncology (ASCO) meeting.

HER2 overexpression has proved to be like the horse of many different colors, with the recognition it is also found in a variety of tumor types besides breast, GI, and lung. "HER2-targeted therapy has signal of activity in several tumor types...there is a rapidly growing number of new therapeutics targeting HER2," and that means "an increasing number of patients are likely to benefit from approved and emerging HER2-targeted therapies," said Meric-Bernstam and co-authors in a 2022 Clinical Cancer Research review.

Specifically, they pointed out that HER2 amplification can be seen in about 4% of bladder and gynecological cancers. Several trials are taking a deeper dive into the potential role of T-DXd in treating these solid tumors.

Bladder Cancer

In a 2022 Journal of Cellular and Molecular Medicine review, Nada Albarakati, PhD, of the King Abdullah International Medical Research Center in Jeddah, Saudi Arabia, and co-authors explained that a 2020 study sequenced >2,000 bladder tumors and revealed six distinct molecular subtypes, including HER2 and HER2-like. "Today, HER2 is considered one of the important prognostic biomarkers in bladder cancer," Albarakati’s group wrote. "Early data revealed that HER2- targeted therapy is beneficial for metastatic or advanced carcinoma patients with HER2 overexpression."

The 2018 phase IIa basket study had 251 patients with 35 different tumor types, including 13 with HER2-amplified bladder cancer and nine with advanced disease. Of the latter, 33% had responses to treatment with a number of HER2-targeting agents including trastuzumab. On responder had stable disease >120 days, reported John D. Hainsworth, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee, and co-authors in the Journal of Clinical Oncology.

Since then, multiple trials are underway evaluating the value of T-DXd in urothelial carcinoma such as the phase Ib DS8201-A-U105 reported at the 2022 (ASCO) Genitourinary Cancers Symposium. The combo of T-DXd and nivolumab in refractory disease offered an overall response rate (ORR) of about 38% (n=13/24 patients).

The ambitious phase II DESTINY-PanTumor02 trial is taking all-comers with HER2-overamplified solid tumors (endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other), testing T-DXd at a dose of 5.4 mg/kg once every 3 weeks. Patients have locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatment, explained Meric-Bernstam and co-authors in a 2023 Journal of Clinical Oncology study.

The primary analysis showed that among 267 patients, 41 had bladder cancer and, among those, the ORR was 39%. The researchers noted that, across all patients, the greatest benefit with T-DXd was observed for those with an IHC 3+ based on local or central testing.

Gynecologic

In a 2020 Current Opinion in Obstetrics & Gynecology review, Britt K. Erickson, MD, of the University of Minnesota in Minneapolis, pointed out ASCO/College of American Pathologists breast cancer algorithms are employed for the assessment of gynecologic cancers. "In the most recent 2018 algorithms, tumors are first evaluated for protein expression with an [IHC] assay," they wrote. "Results are given based on a percentage of tumor cells that are positive for HER2 as well as the completeness of membrane staining."

"Results are reported on a scale of 0 to 3, so that IHC 3+ would be considered positive. If the scoring is 2+ (defined as incomplete/weak staining in >10% of tumor cells or complete/intense staining in <10% of tumor cells), the tumor is then subject to in-situ hybridization," they added.

DESTINY-PanTumor02 turned in promising results among T-Dxd–treated patients with endometrial cancer (n=40), leading to an ORR 57.5% for all of them, an ORR 84.6% for IHC 3+, and 47.1% for IHC 2+. Patients with cervical cancer (n=40) and ovarian cancer (n=40) also saw good ORRs:

• Cervical cancer: 50% for all patients, 75% for IHC 3+, 40% for IHC 2+.
• Ovarian cancer: 45%, 63.6% for IHC 3+, 36.8% for IHC 2+, respectively.

AEs

Any promising treatment regimen is going to have adverse events (AEs) regardless of the tumor type. The question is, were they manageable?

Yes, Meric-Bernstam said in the ASCO 2023 presentation: "The safety we observed was consistent what is already known for T-DXd. For instance, among 267 treated patients with a median follow-up of 12.75 months, grade ≥3 drug-related AEs occurred in 40.8%, with the two top being neutropenia and anemia in around 11%. Drug-related AEs led to discontinuation in 8.6% and dose reduction in 20.2%, while drug-related AEs and non-drug-related AEs leading to death occurred in 1.5% and 7.1%, respectively.

T-DXd therapy has been associated with interstitial lung disease (ILD) and/or pneumonitis. However, in DESTINY-PanTumor02, adjudicated drug-related ILD/pneumonitis happened in about 10% of patients, but the majority of cases were low grade, according to Meric-Bernstam’s group, who added that "T-DXd-related ILD/pneumonitis can be safely managed with a multidisciplinary team [MDT]," and clinicians can find MDT guidance in a 2022 Cancer Treatment Reviews article.

In 2022 Drugs review, Misako Nagasaka, MD, of the University of California Irvine in Orange, and co-authors stated that the "underlying mechanism for anti-ERBB2[HER2]-induced lung damage is yet to be elucidated; however, it is likely to be associated with the cytotoxic agent (payload)."

ASCO expert Bradley Alexander McGregor, MD, of the Dana-Farber Cancer Institute in Boston, enthused in a 2023 statement that T-DXd "could provide a new treatment option for these patients," given that DESTINY-PanTumor02 offered "data for an unmet need for patients who have exhausted standard therapeutic options with tumors that overexpress HER2 for which no drug is yet approved. While additional follow-up is needed, there is robust activity across multiple HER2 expressing tumors with over 50% response rate in those with the highest levels of HER2 expression coupled with an encouraging safety profile."

DESTINY-PanTumor02 was supported by AstraZeneca and Daiichi Sankyo. Some co-authors are AstraZeneca employees.

Meric-Bernstam and co-authors reported relationships with, and/or support from, multiple entities including AstraZeneca and Daiichi Sankyo.

Meric-Bernstam F, et al "Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: Primary results from the DESTINY-PanTumor02 phase II trial" J Clin Oncol 2023; DOI: 10.1200/JCO.23.02005.