T-DXd Active in Many Solid Tumors; 'Shift in Thinking'

Neil Osterweil

June 06, 2023

CHICAGO —Trastuzumab deruxtecan (T-DXd) (Enhertu) already has proven efficacy against HER2-expressing metastatic breast, gastroesophageal, and lung cancers.

Now, preliminary data from an ongoing study indicate that T-DXd, which combines an antibody targeted to HER2 with a toxic payload, could be an effective therapy for a broader range of advanced solid tumors that express HER2, including malignancies of the cervix, endometrium, ovaries, bladder, and other sites.

The findings come from the ongoing DESTINY-PanTumor02 trial. Among 267 patients with solid tumors at various organ sites, the investigator-assessed objective response rate (ORR) among all patients was 37.1%, and ranged from as high as 57.5% for patients with endometrial cancers to as low as 4% for patients with pancreatic cancer, reported Funda Meric-Bernstam, MD, from the University of Texas MD Anderson Cancer Center in Houston.

For patients with tumors that had HER2 immunohistochemistry (IHC) scores of 3+, the highest level of HER2 expression, the overall response rate (ORR) was 61.3%..

The responses were also durable, with a median duration of 11.8 months among all patients and 22.1 months among patients with IHC 3+ scores.

"Our data to date showed that T-DXd had clinically meaningful activity across a variety of tumor types," she said in a briefing held prior to her presentation of the data at the American Society of Clinical Oncology (ASCO) annual meeting here.


"HER2 expression has been around a long time. We think about this all the time in breast cancer and drugs are approved there, but HER2 is expressed in other tumors as well, and that really represents an unmet need, because we have limited options in this situation" commented ASCO expert Bradley Alexander McGregor, MD, from the Dana-Farber Cancer Institute in Boston, an invited discussant at the briefing.

"Aside from pancreatic cancer we saw really, really encouraging results with no new safety signals, so while early I think this really exciting and represents a shift in how we think about cancer care," he added.

After the presentation, invited discussant Kohei Shitara, MD, of National Cancer Center Hospital East in Kashiwa, Japan, said that he agrees with authors that T-DXd is a potential new treatment option for patients with HER2-expressing solid tumors, and that the evidence suggests the potential for further tumor-agnostic development of the agent.

He cautioned, however, that there is a lack of concordance between local and central assessment of HER2 IHC, and that quality assurance will be required to ensure that the HER2 status of solid tumors is accurately characterized.

At a press briefing, Medscape Medical News asked Meric-Bernstam how she envisioned using T-DXd in therapy for various HER2-expressing tumors.

"I think the activity we've seen is quite compelling, and one hopes that eventually this will be a drug that's accessible for patients that are HER2-expressing across tumor types. Clearly, the activity is very compelling in some of the diseases to think about doing studies for earlier lines," she said.

"The data indicate that there is tumor-agnostic activity across the board," she said, but  noted that tumors with epithelial components such as ovarian and breast cancers appear to have the highest responses to T-DXd therapy.

Briefing moderator Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, asked McGregor whether, in the light of this new data, oncologists should test more patients for HER2 expression.

"We have some cancers where we know HER2 expression is there. I think the good thing about HER2 testing is that it's an IHC test, so this is something that can be easily done in local pathology [labs]," he said. As more evidence mounts of potential benefit of T-DXd in HER2 expressing tumors, clinicians will need to consider more routine HER2 testing, he added.

A Rendezvous with DESTINY

The DESTINY-PanTumor02 trial is a phase 2, open label, multicenter study looking at T-DXd in patients with advanced solid tumors who are not eligible for therapy with curative intent.

All patients had disease progression after at least two prior lines of therapy, and had tumors with HER2 expression of IHC 3+ or 2+ either by local or central testing. Patients were allowed to have previously received HER2-targeting therapy. Patients also had to have good performance status (ECOG/WHO performance status 0  or 1).

The investigators planned to enroll 40 patients in each cohort, including patients with cervical, endometrial, ovarian, biliary tract, pancreatic, or bladder cancers, as well those with other tumors expressing HER2 who were not included in the other cohorts.

Under the protocol, cohorts in which none of the first 15 patients had objective responses would be closed, as happened with the pancreatic cancer cohort.

At a median follow-up of 9.7 months, an objective response was seen in 99 patients out of the 267 in the entire study population (ORR, 37.1%). This ORR consisted of 15 complete responses (CR) and 84 partial responses (PR). An additional 123 patients had stable disease.

An analysis of ORR by HER2 expression showed that IHC 3+ expressing tumors had rates ranging from 84.6% in endometrial cancers, 75% in cervical cancer, 63.6% in ovarian cancers, and 56.3% in bladder cancers, down to zero in IHC 3+ expressing pancreatic cancer. 

The T-DXd safety profile was consistent with that seen in other clinical trials, with most common adverse events being nausea, fatigue, neutropenia, anemia, diarrhea and thrombocytopenia. There were 20 cases of interstitial lung disease, one of which was fatal.

The trial is ongoing, and investigators plan to report overall survival and progression-free survival results with additional follow-up.

DESTINY-PanTumor02 is funded by Daiichi-Sankyo. Meric-Bernstam disclosed a consulting/advisory role with multiple pharmaceutical companies, research funding to her institution from Daiichi-Sankyo and other, and travel expenses from ESMO and EORTC. McGregor disclosed a consulting/advisory role and institutional research funding with multiple companies, not including the study's funder. Gralow disclosed a consulting or advisory role with Genentech and Roche.

American Society of Clinical Oncology (ASCO) 2023: Abstract LBA3000. Presented June 5, 2023.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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