Patritumab Deruxtecan Demonstrates Durable Efficacy in Heavily-Pretreated EGFR+ NSCLC Subset

Pasi A. Jänne, MD, PhD

In a phase 1 study (NCT03260491), treatment with patritumab deruxtecan (U3-1402) induced clinically meaningful, durable efficacy in heavily pretreated patients with EGFR-mutated non–small cell lung cancer (NSCLC) who were resistant to EGFR tyrosine kinase inhibitors (TKIs), according to data presented during the 2021 ASCO Annual Meeting.

The HER3-directed antibody-drug conjugate (ADC), when delivered at a dose of 5.6 mg/kg, elicited a confirmed objective response rate (ORR) of 39% (95% CI, 26%-52%) in 57 patients who previously received a TKI and platinum-based chemotherapy (PBC). The agent also induced a disease control rate (DCR) of 72% (59%-83%) and resulted in a median progression-free survival (PFS) of 8.2 months (95% CI, 4.4-8.3).

Notably, in 44 patients who had previously received osimertinib (Tagrisso) and PBC, the benefit derived from the ADC proved to be similar, 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]).

“[Patritumab deruxtecan] addresses an unmet need in EGFR TKI–resistant, EGFR-mutated NSCLC. Efficacy [with the agent] is clinically meaningful and durable,” Pasi A. Jänne, MD, PhD, lead study author and professor of medicine at Dana-Farber Cancer Institute, said during a presentation on the data. “Efficacy is also observed across EGFR TKI resistance mechanisms in this population of patients who are often difficult to treat and in those without resistance mechanisms. Antitumor activity was [also] observed across a wide range of baseline HER3 expression.”

EGFR TKIs represent the standard of care for patients with NSCLC whose tumors harbor EGFR mutations, but the efficacy of these drugs has been limited by the development of acquired resistance mechanisms. The resistance mechanisms are diverse, according to Jänne, and can include on-target mechanisms as well as bypass alterations.

“Importantly, in many patients, especially those treated with first-line osimertinib, no identifiable resistance mechanism is found,” Jänne noted.

Additionally, the use of PBC following progression on EGFR TKIs has been shown to have limited efficacy, with an ORR ranging between 25% and 44% and a median PFS ranging from 2.7 months to 6.4 months. The use of salvage therapies following progression on EGFR TKIs and PBC, has also proven to produce limited benefit, with a median PFS ranging from 2.8 months to 3.2 months.

Patritumab deruxtecan is an ADC that is comprised of 3 components: a fully human anti-HER3 IgG1 monoclonal antibody, patritumab, which is covalently linked to a topoisomerase I inhibitor payload, which is an exatecan derivative, through a tetrapeptide-based cleavable linker. The agent is currently under investigation in NSCLC, metastatic breast cancer, and colorectal cancer.

The phase 1 dose-escalation and -expansion U31402-A-U102 trial enrolled patients with locally advanced or metastatic NSCLC whose tumors harbored EGFR mutations and who had progressed on previous treatment with an EGFR TKI.

In the dose-escalation phase of the trial, patients with EGFR TKI–resistant, EGFR-mutated NSCLC received patritumab deruxtecan at the following doses: 6.4 mg/kg (n = 5), 5.6 mg/kg (n = 12), 4.8 mg/kg (n = 15), and 3.2 mg/kg (n = 4). “The 5.6-mg/kg dose was identified as the dose to use in the dose expansion,” Jänne noted.

A total of 45 patients received treatment in cohort 1 of the dose-expansion phase of the trial; these patients had adenocarcinoma NSCLC with EGFR mutations and had received previous EGFR TKI therapy and platinum-based chemotherapy.

The efficacy evaluation includes a total of 57 patients: 45 from the dose-expansion phase of the trial, and 12 from the dose-escalation portion of the trial, according to Jänne. 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 dose-escalation and -expansion cohort 1.

The median age of patients at the 5.6-mg/kg dose was 65 years (range, 40-80), 63% were female, and 60% had an ECOG performance status of 1. The median sum of diameters at baseline was 54 mm (range, 13-195) in these patients, and 47% had a history of central nervous system (CNS) metastases. The median prior lines of treatment received was 4 (range, 1-9), with 100% having received prior EGFR TKI treatment (100%), 91% having received previous PBC, and 40% having received prior immunotherapy. Notably, 86% of patients had received prior osimertinib.

Additional data revealed that of those who had received a prior TKI and PBC (n = 57) and responded to patritumab deruxtecan, 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 (TTR) to the ADC was 2.6 months (range, 1.2-5.4) and the median duration of response (DOR) was 6.9 months (95% CI, 3.1–NE).

Jänne noted that the subgroup of patients who were treated with prior osimertinib and PBC demonstrated similar efficacy to the overall efficacy population.

When looking at the resistance mechanisms that developed during the course of previous EGFR TKI therapy, investigators found a diverse range of mechanisms, which included secondary mutations like T790M and C797S; amplifications like ERBB2 and MET; and rearrangements like BRAF, Jänne said.

“[We saw that] there is not 1 category of individuals that are having a response or not having a response,” Jänne said. “Responses are observed in patients with identifiable resistance mechanisms and in those who do not have identifiable resistance mechanisms but have progressed on prior EGFR TKI therapy.”

Investigators also examined responses to the ADC in patients with and without a history of CNS metastases. Among the 25 patients who had 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). The efficacy with the agent proved to be similar in the 27 patients who did not have a history, with a confirmed ORR was 41% (95% CI, 22%-61%) and a median PFS of 8.3 months (95% CI, 3.0-NE).

“Although a significant number of the patients have early responses [to treatment], there are patients who achieve their first response even after 3 months of therapy,” Jänne noted. At the time of data cutoff, 32% of patients (n = 18/57) were still receiving treatment with the drug.

Biomarkers of efficacy were also evaluated as part of the phase 1 study, and HER3 expression was queried in all patients, when feasible, in a pre-treatment biopsy. HER3 expression was evaluable in 43 of 57 patients and all were found to express it.

“We also looked at whether there was a correlation between the time [since last] prior EGFR TKI [was received] and HER3 expression…and there is no clear correlation,” Jänne said. “Patients have high levels of HER3 expression, whether the biopsy was obtained the same day or greater than 100 days since the last EGFR TKI therapy [was received].”

Moreover, responses to the ADC were observed in patients with a wide range of baseline HER3 membrane H-scores, which shows that responses could be achieved patients with both high and low levels of HER3 expression.

Cell-free DNA (cfDNA) was examined in patients before treatment was started and during the course of therapy; this was noted to be evaluable in 40 of 57 patients. Investigators examined whether patients who had detectable cfDNA at baseline had clearance of cfDNA at week 3 or 6 of treatment.

“We found that patients who achieved clearance were more likely to have a response than those who had persistent cfDNA at 3 and 6 weeks.” The response rates in these 2 groups were 68% and 19%, respectively. Similarly, those who had cfDNA clearance at week 3 or 6 also experienced prolonged PFS vs those who retained cfDNA after treatment.

Regarding safety, all patients who received the 5.6-mg/kg dose experienced any-grade treatment-emergent adverse effects (TEAEs) with patritumab deruxtecan; 11% had TEAEs linked 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 TEAEs that resulted in death: these included disease progression (n = 2), respiratory failure (n = 2), and shock (n = 1). Seventy-four percent of patients experienced TEAEs that were grade 3 or higher.

Additionally, treatment-related AEs (TRAEs) were reported in 96% of patients and 54% of these effects were grade 3 or higher. The rate of adjudicated treatment-related interstitial lung disease (ILD) was 5% and none 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 associated with death.

Grade 3 or higher TEAEs that were experienced by 5% or more 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.

Additional studies examining the agent are underway, Jänne concluded. In the phase 2 HERTHENA-Lung01 trial (NCT04619004), patritumab deruxtecan is being examined in patients with metastatic or locally advanced EGFR-mutated NSCLC who progressed on TKIs and PBC. In another phase 1 study (NCT04676477), the agent is being combined with osimertinib in patients with locally advanced or metastatic EGFR-mutated NSCLC who have progressed following treatment with osimertinib and PBC.

_Reference

_{Jänne PA, Baik CS, Su W-C, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):9007. doi:10.1200/JCO.2021.39.15_suppl.9007}