Trastuzumab Deruxtecan Shows Promise Beyond Breast and Gastric Tumors

Bob T. Li, MD, MPH

Fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201), a HER2-directed antibody¬—drug conjugate (ADC), demonstrated significant clinical activity in multiple non-breast, non-gastric cancer solid tumor types, according to findings from a phase I study (NCT02564900) published in Cancer Discovery.^1,2

Trastuzumab deruxtecan elicited a confirmed objective response rate (ORR) of 28.3% with a median progression-free survival (PFS) of 7.2 months (95% CI, 4.8-11.1) for patients with pretreated HER2-overexpressing or HER2-mutated cancer. Overall survival was 23.4 months (95% CI, 15.6—NE).

Upon analysis, patients with HER2-mutated non—small cell lung cancer (NSCLC) had an ORR of 72.7% and a median duration of response (DOR) of 9.9 months. Nearly all patients with HER2-mutated cancer experienced disease control.

Of note, confirmed responses (CRs) were reported in 6 tumor types: HER2-expressing (NSCLC), colorectal cancer (CRC), salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant breast and NSCLC.

“HER2-targeted therapies have proven successful for patients with breast and gastric cancers. However, there are no approved HER2-targeted therapies available for patients with other HER2-overexpressing or HER2-mutated malignancies,” senior investigator Bob Li, MD of Memorial Sloan Kettering Cancer Center, said in a press release. “Conventional therapies for these other HER2-overexpressing cancers tend to have limited efficacy and considerable side effects. Additional treatment options are urgently needed for these patients.”

Of 60 patients treated with the ADC, 51 were evaluable for tumor shrinkage. Moreover, 80.4% of these patients showed tumor shrinkage from baseline after 6 weeks of therapy.

Importantly, patients with HER2-mutated NSCLC appeared to derive additional benefit from trastuzumab deruxtecan. These patients experienced more pronounced tumor shrinkage compared with historic findings of patients with non—HER2-mutated NSCLC. Additionally, a CR was reported in 55.6% of this patient subgroup with a 10.7-month and 1.4-month median DOR and time to response, respectively.

Patients with CRC did not derive as significant benefit as other patients in this study. Of these patients, 1 had a CR. However, a PFS rate of 85% for a median 4.0 months was noted and 100% of patients with HER2 IHC 3+ CRC experienced disease control with trastuzumab deruxtecan.

The study enrolled 60 patients with pretreated HER2-expressing (IHC ≥1+) solid tumors. Patients were evaluated in 3 subgroups of CRC (n = 20), NSCLC (n = 18), and “other” cancers, which included salivary gland (n = 8), esophageal (n = 2), endometrial (n = 2), biliary tract (n = 2), Paget’s disease (n = 2), pancreatic (n = 1), uterine cervix carcinoma (n = 1), extraskeletal myxoid chondrosarcoma (n = 1), and small-intestine adenocarcinoma (n = 1).

Additionally, 2 patients with HER2-mutated breast cancer were included in the “other” cancers subgroup. One of these patients had HER2 IHC 2+ and the other had HER2 missing per central laboratory assessment.

At baseline, all patients had visceral disease. A median time of 28.8 [IQR, 15.9-44.0] months between initial diagnosis and administration of the first dose of trastuzumab deruxtecan was observed. Patients had a median of 3.0 prior anticancer regimens with 33.3% of patients having received ≥5 therapies.

Of these, 56 patients had prior chemotherapy and 16 had prior immunotherapy. Additional prior anticancer regimens included HER2-targeted therapy (n = 17), hormonal therapy (n = 3), VEGF inhibitors (n = 28), EGFR inhibitor (n = 17), and ALK inhibitor (n = 1). Also, 66.7% of patients had previous cancer surgery and 51.7% had previous radiotherapy.

Regarding HER2-expression as assessed by a central laboratory, 36.7% of patients enrolled were HER2 IHC 3+, 15% were IHC 2+, 18.3% were IHC 1+, and 20% were IHC 0.

Patients were a median of 58.0 years old with an age range of 23 to 83 years and just over half (51.7%) the patients were female. The trial enrolled patients from Japan (n = 38) and the United States (n = 22).

In the trial, patients received a 6.4-mg/kg dose of trastuzumab deruxtecan intravenously once every 3 weeks. A previous phase I dose-escalation and expansion study established this regimen as the maximum-tolerated dose without dose-limiting toxicities among patients with HER2-positive breast and gastric cancer.

Regarding this study, trastuzumab deruxtecan was generally well tolerated among patients. The frequency of all-grade treatment-emergent adverse events (TEAEs) was similar across tumor types; gastrointestinal and hematologic TEAEs were the most common all-grade TEAEs experience.

“Therapies that target HER2 can be selectively directed to HER2-overexpressing or HER2-mutated cancer cells, which could improve efficacy and help reduce toxicities caused by off-target effects on normal cells,” lead author Junji Tsurutani, MD, PhD of Showa University in Tokyo, Japan, said in the press release.

Every patient had ≥1 TEAE with the most common being nausea (n = 26), vomiting (n = 24), and decreased appetite (n = 15).

Regardless of causality, 62.7% of patients had grade ≥3 TEAEs including anemia (n =15), decreased neutrophil count (n = 12), decreased platelet count (n = 9), decreased white blood cell count (n = 11), decreased appetite (n = 4), elevated aspartate aminotransferase (n = 3), febrile neutropenia (n = 3), and hyponatremia (n = 3).

Five patients discontinued treatment due to toxicity. Moreover, 2 of these events were due to pneumonitis and 1 was due to interstitial lung disease (ILD). ILD is a toxicity of concern reported in HER2-positive breast cancer, the indication for which trastuzumab deruxtecan received FDA accelerated approval in December 2019.

Additionally, 23.7% of patients required dose reduction and 37.3% required dose interruption as a result of TEAEs.

There were 5 TEAE-related patient deaths reported. One of these deaths was a result of respiratory failure brought on by ILD.

“The safety profile of trastuzumab deruxtecan is consistent with the previously reported breast and gastric cancer cohorts from this phase I study,” said Li. “ILD is an important identified TEAE that may be serious—even fatal—and thus requires monitoring and prompt intervention. Further research is required to minimize and manage this risk.”

A limitation of this study was the sample size and limited diversity of HER2 mutations included. As such, large clinical trials investigating trastuzumab deruxtecan in patients with non-breast/non-gastric solid tumors are ongoing.

“We are very excited by the results of this preliminary study,” Li concluded. “[Trastuzumab deruxtecan] shows early promise for transforming the standard of care for patients with HER2-overexpressing or HER2-mutated cancers and we look forward to continuing this important research in future clinical trials.”

References

1. HER2-targeted Therapy Trastuzumab Deruxtecan Shows Early Promise in Patients with Non-breast and Non-gastric Cancers. Published online March 25, 2020. https://bit.ly/3dGd7S4. Accessed March 30, 2020.
2. Tsurutani J, Iwata H, Krop I, et al. Targeted HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. [Published online ahead of print March 25,2020]. Cancer Discovery. 2020;10. doi: 10.1158/2159-8290.CD-19-1014