Patritumab Deruxtecan Induces Promising Efficacy in HER3-Expressing Metastatic Breast Cancers

Ian E. Krop, MD, PhD

Patritumab deruxtecan (HER3-DXd) produced encouraging responses in patients with HER3-expressing metastatic breast cancer (MBC) or metastatic triple negative breast cancer (TNBC), according to findings from the phase 1/2 U31402-A-J101 (NCT02980341) study presented at the 2022 ASCO Annual Meeting.^1,2

At a median follow-up of 31.9 months (range, 15-56), the objective response rate (ORR) was 30.1% (95% CI, 21.8%-39.4%) in patients with HER3-high or HER3-low, HR-positive/HER2-negative MBC. All responses were partial responses (PR).

The median duration of response (DOR) in this cohort was 7.2 months (95% CI, 5.3-not evaluable [NE]). The median progression-free survival (PFS) was 7.4 months (95% CI, 4.7-8.4) and the median overall survival (OS) was 14.6 months (95% CI, 11.3-19.5).

ORR was 22.6% (95% CI, 12.3%-36.2%) in patients with HER3-high metastatic TNBC. Again, all responders had PR. The median DOR was 5.9 months (95% CI, 3.0-8.4), with a median PFS of 5.5 months (95% CI, 3.9-6.8) and a median OS of 14.6 months (95% CI, 11.2-17.2).

In patients with HER3-high, HER2-positive MBC, the ORR was 42.9% (95% CI, 17.7%-71.1%). All responses were partial. The median DOR was 8.3 months (95% CI, 2.8-26.4), with a median PFS of 11.0 months (95% CI, 4.4-16.4) and median OS of 19.5 months (95% CI, 12.2-NE).

Daiichi Sankyo designed the novel, investigational antibody-drug conjugate (ADC). Patritumab deruxtecan includes a human anti-HER3 monoclonal antibody covalently bound to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker.

“Significant unmet need still remains for the treatment of patients with metastatic breast cancer and new treatment strategies need to be continuously explored," lead author Ian E. Krop, MD, PhD, chief clinical research officer and associate cancer center director for clinical research at Yale Cancer Center in New Haven, Connecticut, said in a news release. “Results from this trial show that patritumab deruxtecan produces clinically meaningful and durable antitumor activity in patients and further study is warranted to further evaluate the efficacy and safety of this HER3-directed ADC across patients with HR-positive/HER2-negative, HER2-positive, and TNBC.”

Investigators conducted a pooled analysis of patients with HER3-high or HER3-low, HR-positive/HER2-negative MBC (n = 113); HER3-high TNBC (n = 53); or HER3-high, HER2-positive MBC (n = 14). Patients were assigned to dose-escalation (3.2-8.0 mg/kg every 3 weeks) and dose-finding portions across molecular subtypes (n = 66). That was followed by dose expansion in these subtypes: HER3-high (4.8 mg/kg [n = 33] or 6.4 mg/kg [n = 31]); HER3-low (6.4 mg/kg [n = 21]) HR-positive/HER2-negative MBC or HER3-high TNBC (6.4 mg/kg [n = 31]).

Investigators defined HER3 high as 75% or greater membrane positivity and HER3 low as 25% to 74% membrane positivity. The primary study objective was to assess safety and efficacy. Secondary objectives included determining the relationship between efficacy and HER3 expression. Responses were assessed by blinded independent central review.

Patients with HR-positive/HER2-negative disease received a median of 6 (range, 2-13) prior lines of therapy in the advanced setting. Those with metastatic TNBC received a median of 2 (range, 1-13) prior therapies. Patients with HER2-positive MBC received a median of 5.5 (range, 2-11) prior therapies. The median treatment duration was 5.9 months (range, 0.7-30.6). Four patients remained on study treatment as of the August 16, 2021, data cutoff.

Investigators conducted a pooled safety analysis of all enrolled patients (N = 182). Treatment-emergent adverse events (TEAEs) led to treatment discontinuation in 9.9% of patients.

Treatment-related grade 3 or higher TEAEs occurred in 120 patients (65.9%). Events included neutrophil count decrease, platelet count decrease, white blood cell count decrease, anemia, alanine aminotransferase increase, aspartate aminotransferase increase, decreased appetite, nausea, fatigue, diarrhea, malaise, stomatitis, and vomiting.

An independent adjudication committee determined that 12 patients (6.6%) developed treatment-related interstitial lung disease (ILD) or pneumonitis. There were 3 (1.6%) incidents of grade 3 ILD and 1 (0.5%) grade 5 event, but most ILDs were mild.

“These data reinforce the potential emerging role of targeting HER3 with an ADC to overcome resistance to standard of care treatment in patients with HER3-expressing MBC…which we plan to continue to explore in additional trials,” Gilles Gallant, BPharm, PhD, senior vice president, global head, oncology development, oncology R&D, Daiichi Sankyo, said in a news release.

Efficacy in Lung Cancer

In December 2021, the FDA granted a breakthrough therapy designation to patritumab deruxtecan for the treatment of patients with metastatic or locally advanced EGFR-mutated non–small cell lung cancer (NSCLC) with disease progression on or after treatment with a third-generation TKI and platinum-based therapies.³ Investigators evaluated a dose of 5.6 mg/kg, patritumab deruxtecan in the dose-escalation portion and 2 expansion cohorts of the 3-cohort phase 1 U31402-A-U102 study (NCT03260491).⁴

The agent induced a confirmed ORR of 39% (95% CI, 26%-52%) in 57 patients with prior exposure to a TKI and platinum-based chemotherapy. The disease control rate (DCR) was 72% (59%-83%) and a median PFS of 8.2 months (95% CI, 4.4-8.3).

Among 44 patients in the study who received prior osimertinib (Tagrisso) and platinum-based chemotherapy, the confirmed ORR was 39% (95% CI, 24%-55%), with a DCR of 68% (95% CI, 52%-81%) and a median PFS of 8.2 months (95% CI, 4.0–NE).

References

1. Krop IE, Masuda N, Mukohara T, et al. Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC). J Clin Oncol. 40, 2022 (suppl 16):1002. doi: 10.1200/JCO.2022.40.16_suppl.1002
2. Patritumab Deruxtecan continues to show promising clinical activity in patients across subtypes of metastatic breast or lung cancer. News release. Daiichi Sankyo. June 3, 2022. Accessed June 4, 2022. https://bwnews.pr/3MkjAly
3. Patritumab deruxtecan granted U.S. FDA breakthrough therapy designation in patients with metastatic EGFR-mutated non-small cell lung cancer. News release. Daiichi Sankyo. December 23, 2021. Accessed June 4, 2022. https://bit.ly/3mvZgUi
4. Jänne PA, Baik C, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor–resistant, EGFR-mutated non–small cell lung cancer. Cancer Discov. Published online September 21, 2021. doi: 10.1158/2159-8290.CD-21-0715