Patritumab Deruxtecan Shows Early Potential in Second-Line EGFR Inhibitor–Resistant, EGFR+ NSCLC

Tony SK Mok, MD

The newer generation antibody-drug conjugate (ADC) patritumab deruxtecan (U3-1402) has elicited encouraging responses with acceptable safety in patients with EGFR TKI–resistant, EGFR-mutated non–small cell lung cancer (NSCLC)—a difficult-to-treat population with an unmet medical need, according to Tony Mok, MD. He added that if data continue to be positive, this agent may be able to replace cytotoxic chemotherapy in these patients.

Data from the phase 1 U31402-A-U102 trial (NCT03260491) showed that the ADC, when administered at a dose of 5.6 mg/kg, produced a confirmed objective response rate (ORR) of 39% (95% CI, 26%-52%) in those who previously received a TKI with or without platinum-based chemotherapy (PBC; n = 57).1 In those who previously received osimertinib (Tagrisso) and PBC (n = 44), the ORR achieved with patritumab deruxtecan was also 39% (95% CI, 24%-55%).

The disease control rates in these 2 groups were 72% (95% CI, 79%-83%) and 68% (95% CI, 52%-81%), respectively, and the median duration of response was 6.9 months (95% CI, 3.1–not evaluable [NE]) and 7.0 months (95% CI, 3.1-NE), respectively. The median PFS was 8.2 months in both groups.

“[This] population was already previously treated, [with] a median of 4 [lines of prior systemic therapies received],” Mok noted. “[These patients] already [received a] TKI, chemotherapy, and 40% [had received] immunotherapy, and then they still achieved a reasonable and remarkable outcome [with patritumab deruxtecan]. As such, [this agent] is quite promising.”

In an interview with OncLive^®, Mok, chairman of the Department of Clinical Oncology, Li Shu Fan Professor of Clinical Oncology, fellow of ASCO (FASCO), member and ASCO Board of Director, and member of The Hong Kong Academy of Sciences, discussed what is known thus far about the safety and efficacy of patritumab deruxtecan in patients with EGFR inhibitor–resistant, EGFR-mutated NSCLC and outlined the next steps for research with the agent.

OncLive^®: Could you explain how HER3 has emerged as a biomarker of interest in lung cancer?

Mok: HER3 is part of the HER family, [which consists of] HER1, HER2, HER3, and HER4. HER1 is EGFR, and then there are the HER2 and HER4 [receptors]. The key [thing to remember with] HER3 is [that it is] part of the dimerization process, and there is no intrinsic cytoplasmic pathway from [this marker].

HER3 is not the most prominent among the HER family; it is like the little brother that just collaborates with the [rest] of the family. As such, the HER3 mutations have never caught much attention, and [HER3], as a target, has not [been explored too] much—except in the process of dimerization, [experts] thought that pan-HER inhibition might contribute to the EGFR pathway.

Despite the advances made in recent years, what are the remaining challenges faced in the treatment of patients with EGFR-mutated lung cancer? What is the current unmet need?

We have had decent success over the past decade and a half, with the development of 3 generations of EGFR TKIs, but it is the resistance to [these] TKIs that we need to manage. With osimertinib having the advantage of central nervous system penetration and [resulting in] longer PFS, we tend to use that [agent] as our first-line therapy. But then, [the question becomes], what next? We must [gain a better understanding of] resistance mechanisms and find a solution, apart from cytotoxic chemotherapy, that can [help us] prolong the disease control and [improve] survival in these patients.

Could you provide some background on the HER3-directed ADC patritumab deruxtecan?

Patritumab deruxtecan [fits into our] so-called new generation of ADCs. [We know that ADCs], meaning an antibody conjugate with a cytotoxic toxic drug going inside a cell that is targeted, have been around. However, the problem [with these agents is] the fact that the linker technology may not be that sophisticated, and each monoclonal antibody may only attach [to] 1, or [at most] 2, of the cytotoxic [molecules].

However, with novel technology, they can [now] carry up to about 7 or 8 cytotoxic molecules. In other words, [this technology has served to] increase the potency [of these newer generation agents], just like the warhead in a rocket. Now, you have a rocket that attacks a specific [target], but you have a more potent warhead in the rocket.

The phase 1 U31402-A-U102 trial explored the use of patritumab deruxtecan in patients with EGFR inhibitor–resistant, EGFR-mutated NSCLC. Could you explain the rationale for this research?

This study was published by Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute, and colleagues, in Cancer Discovery. This was a dose-escalation study, starting from a low dose of 3.2 mg/kg, then increased [to 4.8 mg/kg, to 5.6 mg/kg, up to 6.4 mg/kg]. The whole objective was to identify the maximum tolerated dose, which turned out to be [5.6] mg/kg.

Under that umbrella, they were able to report a significant [overall] response rate of 39% and a median PFS of 8.2 months. This was a typical phase 1, dose-escalation study. [They] were able to identify the dose, which was [5.6] mg/kg, and then we were able to establish a certain degree of efficacy, which is also important.

What was found with regard to safety?

One toxicity of concern is interstitial lung disease [ILD]. Approximately 5% to 6% of patients may end up with ILD, so that must be watched [for] carefully when we administer this drug to our patients.

The phase 2 HERTHENA-Lung01 trial (NCT04619004) is exploring fixed dose and up-titration dosing of patritumab deruxtecan. Could you elaborate on the rationale for that strategy?

HERTHENA-[Lung01] is an interesting trial; it is a randomized study [with] over 400 patients. It has 2 arms; both arms are being given [patritumab deruxtecan], but 1 arm is receiving the dose of [5.6]mg/kg, and the other arm is receiving intrapatient dose escalation. Once randomized to the [latter] arm, [the patient] starts with [a dose of] 3.2 mg/kg [in the first treatment cycle], then 4.8 mg/kg [in the second cycle], and then they go to 6.4 mg/kg [for the third cycle]. If they tolerate [the treatment], they continue [to receive the agent] at 6.4 mg/kg [in subsequent cycles].

This is an interesting design [that will allow them to determine] the best approach in terms of the dosing: [will the] fixed dose or intrapatient dose escalation [provide us with] higher efficacy? Why do they want to do that? In the phase 1 study, [which evaluated the agent] at [a dose of] 6.4 mg/kg, they observed several [incidences] of thrombocytopenia. Therefore, they [decided that the] recommended phase 2 dose [would be] 5.6 mg/kg. However, there was an observation that a patient may [experience better] efficacy if they go 1 notch higher [in terms of] the dose. [With this trial, investigators likely want] to see whether there is a better way to safely guide a patient to [receive a] higher dose [to attain better efficacy with the agent].

What should be the next steps for this agent?

We need to have a phase 3 trial because we see this efficacy [from the phase 1 trial] of a 39% ORR [with the agent, and a] median PFS of 8.2 months; this is probably better than standard chemotherapy. Therefore, the most rational approach is [to take] patients in whom TKIs, especially osimertinib, or other first- or second-generation drugs [have failed], and randomize them to receive either the ADC or standard chemotherapy. [If positive, this] will help us to have 1 newer generation of drug, [one that] hopefully, can replace cytotoxic [therapies].

Reference

1. 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

Funding from Daiichi Sanyko. Content Developed Independently by OncLive.