Patritumab Deruxtecan Poised for Phase 2 Exploration in HER3+ Advanced CRC

Gilles Gallant, BPharm, PhD, FOPQ

The novel HER3-targeted antibody-drug conjugate (ADC) patritumab deruxtecan (U3-1402) is currently being investigated in a phase 2 trial as a potential treatment for patients with advanced or metastatic colorectal cancer (CRC) who are resistant, refractory, or intolerant to at least 2 previous lines of systemic therapy.¹

“The prognosis of patients with advanced or metastatic CRC remains poor, and there is a need to develop new treatment strategies, including targeting HER3,” said Gilles Gallant, BPharm, PhD, FOPQ, senior vice president and global head of Oncology Development, Oncology R&D, at Daiichi Sankyo.¹ “In this study, we are exploring whether the targeted delivery of cytotoxic chemotherapy with patritumab deruxtecan to cancer cells with varying levels of HER3 expression may be a potential treatment option for previously treated advanced or metastatic CRC.”

Increased levels of HER3 expression have been observed across several cancer types and have been linked with tumor development and poor clinical prognosis. Additionally, the upregulation of HER3 has been associated with resistance to other anticancer treatments, including HER2-targeted agents, endocrine therapies, and EGFR inhibitors.^2-4

In the multicenter, open-label, 2-cohort phase 2 trial (NCT04479436) investigators are examining the efficacy of the ADC in patients with advanced or metastatic CRC who are resistant, refractory, or intolerant to at least 2 previously approved systemic treatments. Prior therapies must comprise chemotherapy, an EGFR-targeted drug if clinically indicated, and a VEGF-targeted agent unless contraindicated. Patients with confirmed microsatellite instability–high (MSI-H) CRC are permitted but they must have had previous treatment with an immune checkpoint inhibitor, unless contraindicated.

The first portion of the study will examine patritumab deruxtecan in 2 cohorts of patients who have different levels of HER3 expression. The first cohort will enroll patients with high expression of immunohistochemistry (IHC) 3+ or 2+, while the second cohort will include those with low or negative expression of IHC 1+ or 0.

Additional participants may be enrolled to the second portion of the trial, depending on treatment response observed in both cohorts of patients. The second portion of the trial will further examine treatment with the agent in either just high HER3 expressors or both high and low expression.

The primary end point of the trial is objective response rate (ORR) with patritumab deruxtecan per blinded independent central review (BICR) assessment in accordance with RECIST v1.1 criteria. Secondary end points comprise duration of response, investigator-assessed ORR, disease control rate (DCR), time to response, progression-free survival, overall survival, safety and tolerability. Investigators will also assess levels of HER3 expression in the tissue and how that impacts efficacy, pharmacokinetics and immunogenicity. Secondary objectives will be evaluated by both BICR and investigator in accordance with RECIST v1.1 criteria.

In the trial, patients in both cohorts will receive patritumab deruxtecan at a dose of 5.6 mg/kg delivered via intravenous infusion on day 1 of each 21-day treatment cycle.⁵

The phase 2 trial is anticipated to enroll about 80 participants in the United States, Europe, and Japan and the first patient was dosed in September 2020.¹

The ADC has also been examined as a single agent in patients with HER3-overexpressing metastatic breast cancer in a phase 1/2 trial.⁶ Results from the trial showed that among 42 patients who received patritumab deruxtecan, the ORR was 46.3% (n = 19/41) with a DCR of 90.2% (n = 37/41).

As of June 1, 2018, 42 patients received the agent across dose-escalation (n = 34) and dose-finding (n = 8) phases of the trial. The median age of participants was 54.5 years and the majority, or 76.2%, had an ECOG performance status of 0 (n = 32/42). Moreover, 78.6% had received 5 or more previous anticancer regimens (n = 33/42).

In total, 12 participants discontinued treatment with patritumab deruxtecan because of disease progression, while 1 patient each discontinued due to clinical progression, grade 2 pneumonitis, and withdrawn consent.

With regard to safety, grade 3 or higher treatment-related adverse effects included were observed in more than half of patients (61.9%). All-grade and grade 3 or higher toxicities included nausea (83.3% and 4.8%, respectively), thrombocytopenia (71.4% and 33.3%), decreased appetite (64.3% and 7.1%), neutropenia (59.5% and 26.2%), and leukopenia (57.1% and 19.0%). The maximum-tolerated dose had not been reached. Dose-limiting toxicities comprised decreased platelet counts and increased aspartate aminotransferase and alanine aminotransferase.

Patritumab deruxtecan also showed early activity and manageable toxicity in a phase 1 trial in patients with metastatic EGFR-mutated, TKI-resistant non–small cell lung cancer (NSCLC). Results for 26 patients who received the ADC in 1 of 4 dose cohorts who underwent baseline and at least 1 post-baseline tumor assessment showed 6 confirmed partial responses with the ADC across 3 dose levels.⁷ Moreover, tumor shrinkage was observed in 22 participants across all doses examined; the median best percentage change was -25.7%. Notably, patients with a history of central nervous system metastases also responded to the treatment.

Daiichi Sankyo has also teamed up with AstraZeneca to evaluate patritumab deruxtecan in combination with osimertinib (Tagrisso) in patients with EGFR-mutated advanced or metastatic NSCLC.⁸

References

1. Daiichi Sankyo initiates phase 2 study of patritumab deruxtecan in patients with HER3 expressing advanced colorectal cancer. News release. Daiichi Sankyo Company, Limited. September 15, 2020. Accessed October 26, 2020. https://bit.ly/3mqyFFK.
2. Jacob W, James I, Hasmann M, Weisser M. Clinical development of HER3-targeting monoclonal antibodies: perils and progress. Cancer Treat Rev. 2018;68:111-123. doi:10.1016/j.ctrv.2018.06.011
3. Liu X, Liu S, Lyu H, Riker AI, Zhang Y, Liu B. Development of effective therapeutics targeting HER3 for cancer treatment. Biol Proced Online. 2019;21:5. doi:10.1186/s12575-019-0093-1
4. Mishra R, Patel H, Alanazi S, Yuan L, Garrett JT. HER3 signaling and targeted therapy in cancer. Oncol Rev. 2018;12(1):355. doi:10.4081/oncol.2018.355
5. A study to evaluate U3-1402 in subjects with advanced or metastatic colorectal cancer. ClinicalTrials.gov. Updated September 17, 2020. Accessed October 26, 2020. https://clinicaltrials.gov/ct2/show/NCT04479436.
6. Masuda N, Yonemori K, Takahashi S, et al. Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: updated results of a phase 1/2 trial. Cancer Res. 2019;79(suppl 4). doi:10.1158/1538-7445.SABCS18-PD1-03
7. Updated phase 1 data for Daiichi Sankyo’s U3-1402 in patients with EGFR mutated NSCLC presented at the 2019 World Conference on Lung Cancer. News release. Daiichi Sankyo Company, Limited. September 10, 2019. October 26, 2020. https://bit.ly/31LzfGb.
8. Daiichi Sankyo announces clinical trial collaboration with AstraZeneca to evaluate patritumab deruxtecan (U3-1402) in combination with Tagrisso in EGFR-mutated non-small cell lung cancer. News release. Daiichi Sankyo Company, Limited. August 7, 2020. Accessed October 26, 2020. https://bit.ly/34wMsoa.