Patritumab Deruxtecan Under Exploration in Phase 2 HERTHENA-Lung01 Trial for EGFR+ NSCLC

Pipeline Report | <b>Pipeline Report: February 2021</b>

The HER3-directed antibody-drug conjugate patritumab deruxtecan is under exploration in the treatment of patients with EGFR-mutated, metastatic or locally advanced non–small cell lung cancer who had previously received a TKI and platinum-based chemotherapy.

The HER3-directed antibody-drug conjugate (ADC) patritumab deruxtecan (U3-1402) is under exploration in the treatment of patients with EGFR-mutated, metastatic or locally advanced non–small cell lung cancer (NSCLC) who had previously received a TKI and platinum-based chemotherapy.1

In the global, multicenter, open-label phase 2 HERTHENA-Lung 01 trial (NCT04619004), investigators are examining the safety and efficacy of the agent in this patient population.

To be eligible for enrollment, patients needed to be aged 18 years or older, have histologically or cytologically confirmed locally advanced or metastatic NSCLC not amenable to curative surgery or radiation, have documented radiological disease progression while on/or after receiving their most recent therapy, and an EGFR-activating mutation.2 Moreover, they needed to have at least 1 measurable lesion, an ECOG performance status of 0 or 1, and acceptable bone marrow and organ function.

Participants will be randomized in a 1:1 fashion to receive the ADC at a fixed dose of 5.6 mg/kg every 3 weeks or an up-titration dose of patritumab deruxtecan in 3-week cycles. In the second arm, the ADC will be given at a dose of 3.2 mg/kg in the first treatment cycle, 4.8 mg/kg in the second cycle, and 6.4 mg/kg in the third and subsequent cycles.

The primary end point of the research is objective response rate (ORR), which will be examined per blinded independent central review (BICR). Key secondary end points will include duration of response (DOR), progression-free survival, disease control rate (DCR), and time to response (TTR); all of these end points will be evaluated per BICR and investigator assessment.

Additionally, ORR, overall survival, safety, and tolerability will also be evaluated per investigator assessment. Investigators also plan to examine HER3 protein expression levels in tumor tissue to determine who it might relate to efficacy of patritumab deruxtecan. Other areas of focus for exploration include pharmacokinetics and immunogenicity.

"Our focus is to rapidly and strategically advance the clinical development program of patritumab deruxtecan in cancers where HER3 is frequently overexpressed and is associated with poor prognosis,” Gilles Gallant, BPharm, PhD, FOPQ, senior vice president and global head of Oncology Development, Oncology R&D, at Daiichi Sankyo, stated in a press release. “This study will further inform whether targeting HER3 with an ADC may become a potential treatment strategy to overcome diverse mechanisms of EGFR TKI and chemotherapy resistance seen in patients with metastatic EGFR-mutated NSCLC.”

Results from the phase 1 trial (NCT03260491) examining the HER3-directed ADC showed that the agent had clinically meaningful antitumor activity with an acceptable toxicity profile when given at the recommended expansion dose of 5.6 mg/kg in pretreated patients with metastatic or unresectable EGFR-mutant NSCLC.3

As of April 30, 2020, a total of 57 patients with NSCLC harboring EGFR mutations from the dose-escalation and -expansion portions of the trial had received the ADC; 56 of these patients were determined to be evaluable for response.

Results indicated that the confirmed ORR per BICR was 25.0% (95% CI, 14.4%-38.4%); this comprised a 2% complete response rate (n = 1) and a 23% partial response rate (n = 13). Additionally, the stable disease rate with patritumab deruxtecan was 45.0% (n = 25).

In the dose-escalation portion of the phase 1 trial, patients with metastatic or unresectable EGFR-mutant NSCLC who had progressed on osimertinib (Tagrisso) or who were T790M negative following progression on erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif) were given patritumab deruxtecan at a dose of 5.6 mg/kg every 3 weeks.

In the dose-expansion cohort, patients with metastatic or unresectable EGFR-mutant NSCLC who had previously received at least 1 EGFR TKI and at least 1 platinum-based chemotherapy regimen were given the ADC at a dose of 5.6 mg/kg every 3 weeks.

For this trial, the primary end point was antitumor activity with patritumab deruxtecan, while secondary end points were safety and tolerability.

Study participants had previously received a median of 4 lines of treatment for either advanced or metastatic disease (range, 1-9); 86% of patients had prior osimertinib (n = 49), 5% had another EGFR-targeted therapy (n = 3), 90% had platinum-based chemotherapy (n = 51), and 40% had anti–PD-1/PD-L1 (n = 23). Forty-seven percent of patients had a history of central nervous system metastases (n = 27).

Additional results showed that patritumab deruxtecan resulted in a DCR of 70% (95% CI, 55.9%-81.2%; n = 39). The median TTR with the ADC was 2.0 months (range, 1.2-2.8) and the median DOR was 6.9 months (range, 3.0-7.0).

Regarding safety, the most frequently experienced treatment-emergent toxicities that were grade 3 or higher in severity included thrombocytopenia (n = 16; 28%) and neutropenia (n = 11; 19%). Nine percent of patients experienced treatment-emergent adverse effects (TEAEs) that resulted in discontinuation; 2 discontinued due to fatigue, 1 because of decreased appetite, 1 because of interstitial lung disease (ILD), 1 due to pneumonitis, and 1 because of upper respiratory tract infection. No patients who experienced thrombocytopenia or neutropenia discontinued because of their toxicities. Moreover, 5.3% of ILD effects were determined to be associated with treatment. No TEAEs resulted in death.

Data from an exploratory biomarker analysis indicated that almost all evaluable patients (n = 43) expressed membrane HER3 at baseline; out of 300, the median membrane H score was 180 (range, 2-280).

Investigators also detected heterogenous EGFR TKI resistance mechanisms in pretreatment tumor tissue and circulating tumor DNA (ctDNA). Patients with diverse TKI resistance mechanisms still experienced clinical responses with treatment; this included 53% of those with EGFR T790M, 8% with MET amplifications, 4% with ERBB2 (HER2) mutations, as well as in those with BRAF fusions, EGFR C797S mutations, and PIK3CA mutations.4

Additionally, all patient samples demonstrated a reduction in EGFR-activating mutations in the ctDNA after receiving the ADC. Notably, those who achieved a confirmed response to treatment were more likely to experience ctDNA clearance of EGFR-activating mutations at week 3 or week 6. A best overall response of disease progression was determined to be associated with failure to clear these mutations in the ctDNA.

Patritumab deruxtecan is also under investigation in another phase 2 trial (NCT04479436) in patients with advanced or metastatic colorectal cancer who are resistant, refractory, or intolerant to at least 2 prior lines of systemic treatment.5 Previous treatment must include chemotherapy, an EGFR-targeted drug if clinically indicated, and a VEGF-targeted therapy unless contraindicated.

References

  1. HERTHENA-Lung01 phase 2 study of Daiichi Sankyo’s patritumab deruxtecan initiated in patients with EGFR-mutated NSCLC. News release. Daiichi Sankyo Company, Limited. February 3, 2021. Accessed April 1, 2021. https://bit.ly/3ufqgZE
  2. HERTHENA-Lung01: patritumab deruxtecan in subjects with metastatic or locally advanced EGFR-mutated non-small cell lung cancer. ClinicalTrials.gov. Updated March 9, 2021. Accessed April 1, 2021. https://clinicaltrials.gov/ct2/show/NCT04619004
  3. Helena YA, Baik C, Gold K, et al. Efficacy and safety of the novel HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract OA03.04.
  4. Jänne PA, Baik C, Hayashi H, et al. Dynamics of molecular markers in EGFR-mutated NSCLC patients treated with patritumab deruxtecan (HER3-DXd; U3-1402). Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Poster P01.04
  5. 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 April 1, 2021. https://bit.ly/3mqyFFK