Patritumab Deruxtecan Elicits Durable Responses in Pretreated EGFR-Mutated NSCLC

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Article

Patrimumab deruxtecan garnered a 29.8% overall response rate in pretreated patients with EGFR-mutated non–small cell lung cancer.

Helena A. Yu, MD

Helena A. Yu, MD

Patritumab deruxtecan (HER3-DXd), a HER3-directed antibody-drug conjugate, led to clinically meaningful and durable efficacy among patients with advanced EGFR-mutated non–small cell lung cancer (NSCLC) whose disease had progressed on treatment with an EGFR-directed TKI and platinum-based chemotherapy, according to findings from the phase 2 HERTHENA-Lung01 trial (NCT04619004) presented during the 2023 World Conference on Lung Cancer and simultaneously published in the Journal of Clinical Oncology.1,2

The confirmed overall response rate (ORR) was 29.8% (95% CI, 23.9%-36.2%) among all patients who received a previous EGFR TKI and platinum-based chemotherapy (n = 225), including 1 patient who achieved a complete response (CR). The disease control rate (DCR) was 73.8% (95% CI, 67.5%-79.4%) and the median duration of response (DOR) was 6.4 months (95% CI, 4.9-7.8). The median progression-free survival (PFS) was 5.5 months (95% CI, 5.1-5.9) and the median overall survival (OS) was 11.9 (95% CI, 11.2-13.1).

“The results from HERTHENA-Lung01 provide compelling evidence of efficacy of patritumab deruxtecan in heavily pretreated patients with advanced EGFR-mutated NSCLC,” Helena A. Yu, MD, a thoracic oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York, said in a news release.3 “The clinically meaningful efficacy observed across a broad range of HER3 expression and diverse mechanisms of EGFR TKI resistance as well as the antitumor activity seen in patients with brain metastases, underscore the potential of patritumab deruxtecan to become an important treatment option for a population of patients with lung cancer who have limited treatment options.”

Patritumab deruxtecan previously received breakthrough therapy designation from the FDA in December 2021 for the treatment of patients with metastatic or locally advanced EGFR-mutated NSCLC who experienced disease progression on or after treatment with a third-generation TKI and platinum-based therapies. The regulatory decision was based on findings from the phase 1 U31402-A-U102 study (NCT03260491), which showed that the ORR was 39% (95% CI, 26%-52%) among patients who received the agent at a dose of 5.6 mg/kg (n = 57). Additionally, the median PFS was 8.2 months (95% CI, 4.4-8.3) and the DCR was 72% (95% CI, 59%-83%).4

The pivotal HERTHENA-Lung01 trial enrolled patients with advanced EGFR-mutated NSCLC who experienced disease progression on their most recent systemic therapy. Treatment with a prior EGFR TKI and platinum-based chemotherapy was required, as was pretreatment tumor tissue. Patients with inactive or previously treated asymptomatic brain metastases were allowed.1,2

Patients were initially randomly assigned 1:1 to receive patritumab deruxtecan at a fixed dose of 5.6 mg/kg (n = 225) or via an uptitration dosing schedule (n = 50). However, after a benefit-risk assessment of phase 1 data, the uptitration arm was closed. Only data from the 5.6-mg/kg arm were presented.

The primary end point was confirmed ORR by blinded independent central review (BICR). DOR as evaluated by BICR represented the key secondary end point.

Patients enrolled on 2 HERTHENA-Lung01 were heavily pretreated with a median of 3 prior lines of therapy (range, 1-11) and displayed adverse prognostic characteristics. The median age was 64 years (range, 37-82), and most patients were female (59%), had an ECOG performance status of 1 (66%), a history of central nervous system (CNS) metastasis (51%), had an Ex19del EGFR-activating mutation (63%). L858R mutations were reported in 36% of patients. The median time since initial diagnosis was 41.0 months (range, 9.1-224.7) and there were patients with brain metastasis (32%) as well as liver metastasis (33%) at baseline.

In terms of prior treatments, 26% of patients had 2 prior lines and 73% having received 2 or more. Most patients received a prior third-generation EGFR TKI (93%) and 40% had prior immunotherapy.

Additional findings from the study demonstrated that efficacy was observed across patient subgroups, including patients who were previously treated with a third-generation TKI and platinum-based chemotherapy (n = 209). In this subgroup, the confirmed ORR was 29.2% (95% CI, 23.1%-35.9%), including 1 CR. The DCR was 72.7% (95% CI, 66.2%-78.6%). Moreover, the median PFS was 5.5 months (95% CI, 5.1-6.4) and the median OS was 11.9 months (95% CI, 10.9-13.1).

Confirmed response was observed among a variety of mechanisms of EGFR TKI resistance. Patients with EGFR-dependent disease (n = 34), EGFR-independent disease (n =81), both EGFR-dependent and independent disease (n = 32), and those with no identified resistance mechanisms (n = 77) achieved confirmed ORRs of 32.4% (95% CI, 17.4%-50.5%), 27.2% (95% CI, 17.9%-38.2%), 37.5% (95% CI, 21.1%-56.3%), and 27.3% (95% CI, 17.7%-38.6%), respectively.

Notably, patients with brain metastasis at baseline who did not undergo prior radiotherapy (n = 30) experienced intracranial efficacy with patritumab deruxtecan. The confirmed intracranial ORR by CNS BICR per CNS RECIST criteria was 33.3% (95% CI, 17.3%-52.8%), with a CR rate of 30.0%. The DCR was 76.7% (95% CI, 57.7%-90.1%) and the median DOR was 8.4 months (95% CI, 5.8-9.2).

Patritumab deruxtecan displayed a manageable and tolerable profile; most patients experienced an any-grade treatment-emergent adverse effect (99.6%). TEAEs associated with treatment discontinuation (7.1%), dose reduction (21.3%), and dose interruption (40.4%) were all reported. Grade 3 or higher TEAEs occurred at a rate of 64.9%. Treatment-related TEAEs occurred in most patients (95.6%), including events associated with (1.8%), events of grade 3 or higher severity (45.3%), and serious TEAEs (15.1%).

Interstitial lung disease occurred sparingly (5.3%), and was reported at grade 1 (0.4%), grade 2 (3.6%), grade 3 (0.9%), and grade 5 (0.4%) severity. Other common grade 1 or 2 TEAEs included nausea (63%), thrombocytopenia (44%), decreased appetite (39%), and constipation (34%). Grade 3 or higher TEAEs included thrombocytopenia (21%), neutropenia (19%), anemia (14%), and leukopenia (10%).

Ongoing trials with patritumab deruxtecan include a phase 3 trial vs platinum-based chemotherapy in patients with EGFR-mutated NSCLC after progression on third-generation EGFR TKI therapy (HERTHENA-Lung02; NCT05338970) and a phase 1 trial in combination with osimertinib (Tagrisso) in patients with EGFR-mutated NSCLC after progression on firstline osimertinib or in previously untreated patients (NCT04676477).

References

  1. Yu HA, Goto Y, Hayashi H, et al. Patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC following EGFR TKI and platinum-based chemotherapy: HERTHENA-Lung01. Presented at: 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore.
  2. 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. Published online September 10, 2023. doi:10.1200/JCO.23.01476
  3. Patritumab deruxtecan demonstrated clinically meaningful and durable responses in patients with EGFR-mutated metastatic non-small cell lung cancer in HERTHENA-Lung01 phase 2 trial. News release. Daiichi Sankyo. September 10, 2023. Accessed September 10, 2023. https://daiichisankyo.us/press-releases/-/article/patritumab-deruxtecan-demonstrated-clinically-meaningful-and-durable-responses-in-patients-with-egfr-mutated-metastatic-non-small-cell-lung-cancer-in-
  4. 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 September 10, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202112/20211223_E1.pdf
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