HER3-DXd May Lead to an Additional Treatment Option in EGFR+ NSCLC

Helena A. Yu, MD, and Sandip P. Patel, MD, reviewed the use of patritumab deruxtecan, which was assessed in the phase 2 HERTHENA-Lung01 trial.

In a recent Between the Lines, Helena A. Yu, MD, and Sandip P. Patel, MD, discussed the phase 2 HERTHENA-Lung01 trial (NCT04619004).¹ The trial evaluated patritumab deruxtecan (HER3-DXd) for patients with EGFR-mutated non–small cell lung cancer (NSCLC) after EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy.

Yu, associate attending physician at Memorial Sloan Kettering Cancer Center, and lead author of this study, and Patel, professor of medicine at the University of California at San Diego Health, reviewed this trial as well as current treatment options in the space. They also touched on adverse effect (AE) management and addressing unmet needs in the population.

Providing Context of EGFR Mutations in NSCLC

EGFR mutations are observed in about 14% to 38% of patients with NSCLC. Other mutations that are commonly found include exon 19, exon 21, exon 18, exon 20, and p.Thr790Met.^2,3 Most commonly, EGFR mutations are observed in nonsmokers, women, and those from East Asia.

Yu noted that she recommends testing for EGFR in all patients diagnosed with NSCLC. Patel agreed, echoing that molecular testing should be used, including either tissue-based or cell-free DNA.

“Your point about just saying a patient has an EGFR mutation is insufficient information. Now you have to name both the street and the address because we have different therapeutic strategies,” Patel said.

The use of an EGFR TKI is standard-of-care, first-line therapy for patients with EGFR-mutated NSCLC. However, those with EGFR mutations are sensitive to EGFR TKIs, with resistance occurring between 9 and 16 months.²

Patel mentioned 2 trials that focus on EGFR mutations: the phase 3 FLAURA2 trial (NCT04035486) assessing osimertinib (Tagrisso) with or without chemotherapy in the first-line setting and the phase 3 MARIPOSA-2 trial (NCT04988295) of amivantamab-vmjw (Rybrevant) plus chemotherapy with or without lazertinib after disease progression on osimertinib.^4,5 For Yu, although these 2 trials are pivotal, she still prefers first-line osimertinib monotherapy as a baseline treatment.

HER3 Relevance in NSCLC

Yu asked Patel why HER3 expressions were important for EGFR-mutated NSCLC. Patel cited the biology of HER3. “EGFR is HER1, right? It’s part of a family of kinases that’s upregulated. The way these kinases signal as they crosstalk, they dimerize. They lead to cancer cell growth. It makes biological sense as well as clinical sense why HER3-directed strategies may be particularly potent.”

Yu mentioned that the idea behind these therapies is to use them as targeted options; however, HER3 or TROP2 expression does not typically mediate or predict response. About 100% of patients overexpress HER3, which is a poor prognostic biomarker that includes shorter time to recurrence and shorter survival. “The thought is that upregulation of HER3 can lead to resistance to EGFR-directed therapies. Maybe by targeting HER3, we can mitigate or reverse resistance,” Yu said. HER3-DXd is an antibody-drug conjugate composed of 3 parts, including patritumab, a fully human HER3 IgG1 monoclonal antibody; DXd, a topoisomerase inhibitor payload; and a tetrapeptide-base cleavable linker that bonds the other 2 components covalently.⁶

HERTHENA-Lung01 Trial

The conversation then transitioned to the study results of HERTHENA-Lung01. Patients were randomly assigned 1:1 to a fixed-dose regimen of HER3-DXd at 5.6 mg/kg intravenously every 3 weeks and then continued to enrollment (n =225) or uptitration. During uptitration, patients received HER3-DXd on cycle 1 day 1 at 3.2 mg/kg, cycle 2 day 1 at 4.8 mg/kg, and cycle 3 day 1 following subsequent cycles at 6.4 mg/kg with 50 patients discontinuing.

The primary end point was confirmed objective response rate (ORR) and the secondary end point was duration of response (DOR) by blinded independent central review (BICR). The data cutoff was November 21, 2022, the median follow-up was 13.1 months; the median treatment duration was 5.5 months; and 28 patients remain on study treatment.

The median patient age was 64 years, 59% of patients were female, and 47% were Asian. The median time since NSCLC diagnosis was 41.0 months, and 66% of patients had an ECOG performance status of 0 or 1. Of note, patients had a history of central nervous system (CNS) metastases (51%), brain metastases at baseline (32%), and liver metastases at baseline (33%). Most patients had received prior third-generation EGFR TKI (93%).

At the time of the analysis, the confirmed ORR was 28.4% (95% CI, 22.6%-34.8%); however, after 6 months of additional follow-up it was 29.8% (95% CI, 23.9%-36.2%). A complete response (CR) was observed in 0.4% of patients, 28.0% had a partial response (PR), 45.3% had stable disease, 19.1% had progressive disease, and 7.1% were not evaluable (NE). The disease control rate was 73.8% (95% CI, 67.5%-79.4%), the median DOR was 6.0 months (95% CI, 4.4-7.2), the median progression-free survival was 5.5 months (95% CI, 5.1-5.9), and the median overall survival was 11.8 months (95% CI, 11.2-12.6).

Regarding intracranial response by CNS BICR, 30 patients were evaluated, with a confirmed ORR of 33.3% (95% CI, 17.3%-52.8%); the CR was 30.0%, PR was 3.3%, stable disease was 43.3%, progressive disease was 13.3%, and 10.0% was NE. The median DOR was 8.4 months (95% CI, 5.8-NE). In 1 of 7 patients, there was a complete CNS response.

Regarding safety, any grade treatment-emergent AEs (TEAEs) occurred in 99.6% of patients, with grade 3 or higher occurring in 64.9%. TEAEs associated with death were observed in 1.8% of patients, and serious TEAEs in 15.1%. Adjudicated interstitial lung disease was observed in 5.3% of patients.

The most common grade 3 or higher TEAEs included thrombocytopenia (21%), neutropenia (19%), anemia (14%), leukopenia (10%), and fatigue (6%). The investigators noted that any hematologic AEs were typically observed at the beginning of treatment, were transient, and were not associated with clinical sequelae.

“I was pleasantly surprised by monotherapy efficacy, especially in the brain. Historically, we thought these were big molecules. They don’t necessarily have robust CNS penetration,” Patel noted after the presentation. Yu agreed with this takeaway, commenting on the importance of intracranial efficacy in novel agents.

AE Management

Although the intracranial efficacy showed surprising results, the toxicities observed were a conversation point for both clinicians. TEAEs were the focus of toxicity for this trial. “When I think about TEAEs and how to understand if they’re meaningful, I think of the TEAEs that are associated with treatment discontinuation, which is a metric that I pay close attention to because these are patients [who] needed to come off study because they could not tolerate the drug,” Yu said.

Interstitial lung disease was observed; Patel described this AE as “vexing” and asked whether Yu had advice on how best to manage it. Yu found that although higher doses of HER3-DXd were tested, 5.6 mg/kg was the sweet spot in terms of efficacy and safety outcomes. She also highlighted being quick to dose reduce if toxicities are significant.

Patel noted that radiation could be needed for CNS metastases. Yu wanted to know how to process determining radiation use after treatment with an antibody-drug conjugate. As they are novel agents, real-world data are lacking in this space. He will hold treatment for 1 cycle as the patient undergoes treatment. He does think this should be a key area of study, and important questions surrounding this topic need to be addressed.

Future Treatment Options With HER3-DXd

The critical issue is how HER3-DXd will impact the standard of care if it is approved. Both clinicians noted it comes down to CNS metastases and the ability to sequence between other agents. Both agreed that shared decision-making would come into play.

“ADCs have their own class of toxicities. Some of the other drugs like amivantamab have clear EGFR and MET toxicities that are not ideal for certain patients. Having certain options to choose first or sequence if [a patient is] intolerable will be an important option,” Yu said.

When clinicians do not have a biomarker to determine what treatment might work best, they turn to the potential toxicities and see which may be least harmful to the patient. “Fundamentally, patients have way more options in 2024 than any other year. It’s exciting to see that we have these agents either in our therapeutic armamentarium or about to be there to help us maximize benefit,” Patel said.

Yu hopes to see amivantamab plus lazertinib, amivantamab plus chemotherapy, and HER3-DXd approved to add as options in the space. “In particular for EGFR-mutant lung cancer, finding ways to make immune-cold tumors responsive to immunotherapy [with the use of] cellular therapy could be the key there,” Yu concluded.

References

1. Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor–mutated non–small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. 2023;41(35):5363-5375. doi:10.1200/JCO.23.01476
2. Schoenfeld AJ, Yu HA. The evolving landscape of resistance to osimertinib. J Thorac Oncol. 2020;15(1):18-21. doi:10.1016/j.jtho.2019.11.005
3. Riely GJ, Marks J, Pao W. KRAS mutations in non–small cell lung cancer. Proc Am Thorac Soc. 2009;6(2):201-205. doi:10.1513/pats.200809-107LC
4. Planchard D, Jänne PA, Cheng Y, et al; FLAURA2 Investigators. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
5. Passaro A, Wang J, Wang Y, et al; MARIPOSA-2 Investigators. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90. doi:10.1016/j.annonc.2023.10.117
6. Hashimoto Y, Koyama K, Kamai Y, et al. A novel HER3-targeting antibody-drug conjugate, U3-1402, exhibits potent therapeutic efficacy through the delivery of cytotoxic payload by efficient internalization. Clin Cancer Res. 2019;25(23):7151-7161. doi:10.1158/1078-0432.CCR-19-1745