FDA Grants Breakthrough Therapy Designation to Patritumab Deruxtecan for EGFR+ NSCLC

The FDA has 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.¹

The designation is based on findings from the dose-escalation portion and 2 expansion cohorts of the 3-cohort phase 1 U31402-A-U102 study (NCT03260491) that evaluated the first-in-class HER3-directed antibody-drug conjugate (ADC) in patients with EGFR-mutated NSCLC with resistance to EGFR TKIs.

Extended follow-up data from the dose-escalation portion and cohort 1 of the dose-expansion portion of the study were presented at the 2021 ASCO Annual Meeting and published in Cancer Discovery.² The results showed that, when given at a dose of 5.6 mg/kg, patritumab deruxtecan led to a confirmed objective response rate (ORR) of 39% (95% CI, 26%-52%) in 57 patients with prior exposure to a TKI and platinum-based chemotherapy. The agent also elicited a disease control rate (DCR) of 72% (59%-83%) and induced a median progression-free survival (PFS) of 8.2 months (95% CI, 4.4-8.3).

The agent also demonstrated comparable efficacy benefit in 44 patients who had received prior osimertinib (Tagrisso) and platinum-based chemotherapy, with a confirmed ORR of 39% (95% CI, 24%-55%), a DCR of 68% (95% CI, 52%-81%), and a median PFS of 8.2 months (95% CI, 4.0–not evaluable [NE]).

“The breakthrough therapy designation for patritumab deruxtecan acknowledges the need for new treatment approaches to overcome resistance and improve survival in patients with metastatic TKI-resistant, EGFR-mutated [NSCLC],” Ken Takeshita, MD, Global Head of R&D at Daiichi Sankyo, said in a news release.¹ “We are proud that the FDA has once again recognized our innovative science and technology and we look forward to bringing this potential first-in-class HER3 directed [ADC] to patients with this specific type of lung cancer as quickly as possible.”

The global, multicenter, open-label, two-part phase 1 study is evaluating patritumab deruxtecan in pretreated patients with metastatic or unresectable NSCLC.

The dose-escalation portion of the study evaluated patients with EGFR-mutated disease following progression on osimertinib or patients without a T790M mutation following progression on erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif).

The primary end point of this portion of the study was the safety and tolerability of patritumab deruxtecan and the recommended dose for expansion.

The dose-expansion portion of the study is evaluating patritumab deruxtecan at the recommended dose for expansion of 5.6 mg/kg every 3 weeks in 3 cohorts.

Cohort 1 includes patients with locally advanced or metastatic EGFR-mutated NSCLC with disease progression following at least 1 EGFR TKI and platinum-based chemotherapy regimen. Cohort 2 includes patients with squamous or nonsquamous NSCLC without EGFR-activating mutations following platinum-based chemotherapy and a PD-1/PD-L1–based regimen. Cohort 3 includes patients with NSCLC with EGFR-activating mutations including any histology other than combined small cell lung cancer and NSCLC; patients in cohort 3 will be randomized 1:1 to receive 5.6 mg/kg of patritumab deruxtecan (cohort 3a) or an escalated regimen of patritumab deruxtecan (cohort 3b).

The primary end point of the dose-expansion portion of the study is the efficacy of patritumab deruxtecan, which will be defined by confirmed ORR per blinded independent central review. Secondary end points include investigator-assessed ORR, safety, and pharmacokinetics.

The efficacy population includes 57 patients: 45 from the dose-expansion portion of the trial and 12 from the dose-escalation portion of the trial. The evaluation was done in pooled patients with EGFR-mutated disease, and the median follow-up was 10.2 months (range, 5.2-19.9). The safety evaluation included all 81 patients in the dose-escalation portion and dose-expansion cohort 1.

Additional data demonstrated that among responders who had prior treatment with a TKI and platinum-based chemotherapy (n = 57), 2% experienced a complete response, 37% had a partial response, 33% achieved stable disease, and 16% experienced disease progression; 12% of patients were not evaluable. In this subgroup, the median time to response was 2.6 months (range, 1.2-5.4), and the median duration of response was 6.9 months (95% CI, 3.1-NE).

Among the 25 patients with a history of brain metastases, the confirmed ORR with patritumab deruxtecan was 32% (95% CI, 15%-54%), with a median PFS of 8.2 months (95% CI, 4.0-NE). Comparable activity was seen in the 27 patients who did not have a history of brain metastases, with a confirmed ORR of 41% (95% CI, 22%-61%) and a median PFS of 8.3 months (95% CI, 3.0-NE).

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in all patients who received the 5.6-mg/kg dose of patritumab deruxtecan; 11% had TEAEs that were associated with treatment discontinuation, 21% had effects that led to dose reduction, and 37% had effects that led to dose interruption.

Seven percent of patients (n = 4) experienced fatal TEAEs: these included disease progression (n = 2), respiratory failure (n = 2), and shock (n = 1). Seventy-four percent of patients experienced grade 3 or higher TEAEs.

Additionally, treatment-related AEs (TRAEs) occurred in 96% of patients; 54% of these effects were grade 3 or higher. The rate of adjudicated treatment-related interstitial lung disease (ILD) was 5%, none of which were grade 4 or 5. The median time to adjudicated onset of treatment-related ILD was 53 days (range, 13-130). Notably, no TRAEs were fatal.

Grade 3 or higher TEAEs that occurred in at least 5% of patients included decreased platelet count, decreased neutrophil count, fatigue, anemia, dyspnea, febrile neutropenia, hypoxia, decreased white blood cell count, hypokalemia, and decreased lymphocyte count.

Patritumab deruxtecan is also under investigation in the pivotal phase 2 HERTHENA-Lung01 trial (NCT04619004) in patients with locally advanced or metastatic EGFR-mutated NSCLC previously treated with a TKI and platinum-based chemotherapy; a phase 1/2 study (NCT02980341) in HER3-expressing metastatic breast cancer; a phase 1 study (NCT04676477) in combination with osimertinib in locally advanced or metastatic EGFR-mutated NSCLC; and a phase 1 study (NCT03260491) in previously treated patients with metastatic or unresectable NSCLC.

References

1. 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 December 23, 2021. https://bit.ly/3mvZgUi
2. 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