Patritumab deruxtecan is a DXd antibody-drug conjugate (ADC) targeting HER3, discovered by Daiichi Sankyo and co-developed by Daiichi Sankyo and MSD.

Results from the HERTHENA-Lung02 Phase 3 trial, including the previously reported statistically significant progression-free survival (PFS) and topline OS results, will be presented on Sunday, June 1, 2025, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.#ASCO25) Presented at the annual meeting as an oral report (#8506).

HERTHENA-Lung02 is evaluating patritumab deruxtecan monotherapy versus doublet chemotherapy (platinum plus pemetrexed induction chemotherapy, followed by pemetrexed maintenance chemotherapy) for the treatment of patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small cell lung cancer (NSCLC) whose disease has progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. According to the investigator's assessment, patients who achieve tumor response will continue to receive patritumab deruxtecan or chemotherapy until disease progression.

Ken Takeshita, MD, Global Head of R&D at Daiichi Sankyo Company Limited, said: "EGFR-mutated non-small cell lung cancer has proven difficult to treat in second-line metastatic therapy and beyond. While we are disappointed with the overall survival results from HERTHENA-Lung02, we are conducting further biomarker analyses to better identify patients who may benefit from patritumab deruxtecan, guiding our continued development efforts in lung cancer. We remain confident in the broad development program for this HER3-targeted antibody-drug conjugate, which currently encompasses multiple clinical trials across 15 types of cancer."

Eliav Barr, M.D., Senior Vice President of Merck & Co., Inc., Research Laboratories, Head of Global Clinical Development and Chief Medical Officer, stated: "Lung cancer is one of the leading causes of cancer-related deaths worldwide, and these results underscore just how challenging it is to treat patients with EGFR-mutated non-small cell lung cancer in the second-line and beyond. We sincerely thank the patients, their families, and the investigators for participating in this study."

The safety of HERTHENA-Lung02 is consistent with the safety profile of patritumab deruxtecan observed in previous lung cancer clinical trials, with no new safety signals identified.

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Patritumab deruxtecan (HER3-DXd) in Patients with EGFR-Mutated (EGFRm) Advanced Non-Small Cell Lung Cancer (NSCLC) Resistant to Third-Generation EGFR TKI: HERTHENA-Lung02 Phase III Study

BackgroundIn EGFR-mutated advanced NSCLC patients with disease progression after receiving third-generation EGFR tyrosine kinase inhibitor (TKI) therapy, the efficacy of existing treatments is limited. HER3-DXd, an antibody-drug conjugate (ADC) composed of a humanized monoclonal antibody targeting HER3 linked to a topoisomerase I inhibitor via a stable tetrapeptide cleavable linker, demonstrated promising efficacy in the HERTHENA-Lung01 study.

MethodHERTHENA-Lung02 (NCT05338970) is a Phase III, randomized, open-label study comparing HER3-DXd with platinum-based chemotherapy (PBC) in patients with EGFR-mutated (Ex19del or L858R) NSCLC who have failed third-generation EGFR TKI treatment. The primary endpoint is progression-free survival (PFS) assessed by the independent imaging review committee (BICR), using a stratified log-rank test. A key secondary endpoint is overall survival (OS).

Results: A total of 586 patients were randomly assigned to the HER3-DXd or PBC group (median age 64 years, 61% female, 60% Asian). As of the primary analysis data cutoff date for PFS on May 31, 2024, the median follow-up time was 10.7 months (range 5.2-21.9 months), with treatment durations of 5.5 months (0.7-16.8) in the HER3-DXd group and 4.6 months (0.7-16.5) in the PBC group.

HER3-DXd showed a statistically significant improvement in PFS compared to PBC (HR=0.77; 95% CI: 0.63-0.94; P=0.011). The median PFS for the HER3-DXd group and the PBC group were 5.8 months (95% CI: 5.5-6.8) and 5.4 months (95% CI: 5.0-5.6), respectively.

PFS Rates of HER3-DXd vs PBC at Different Time Points: 6 Months: 50% vs 38%; 9 Months: 29% vs 19%; 12 Months: 18% vs 5%.

Objective Response Rate (ORR): HER3-DXd: 35.2% (95% CI: 29.7%-40.9%); PBC: 25.3% (95% CI: 20.4%-30.6%).

The median duration of response (DOR) was: HER3-DXd: 5.7 months (95% CI: 5.1-7.3); PBC: 5.4 months (95% CI: 4.1-5.6).

OS data are still immature.

In patients with baseline brain metastases (assessed by CNS BICR):

• In the HER3-DXd group (n=105), the median intracranial PFS was 5.4 months (95% CI: 4.0-5.9).

• PBC group (n=95) was 4.2 months (95% CI: 2.8-5.0) (HR=0.75; 95% CI: 0.53-1.06)

  
  

Safety Results：

• All patients (100%) in the HER3-DXd group and 99% in the PBC group experienced treatment-related adverse events (TEAE).

• The proportion of discontinuations due to TEAEs: 11% (33 cases) for HER3-DXd and 10% (27 cases) for PBC.

The most common adverse events included:

• Nausea: HER3-DXd 57.9% (168 cases), PBC 42.1% (118 cases)

• Thrombocytopenia: HER3-DXd 52.1% (151 cases), PBC 27.1% (76 cases)

• Fatigue: HER3-DXd 50.3% (146 cases), PBC 42.1% (118 cases)

Incidence of TEAE Grade 3 or higher: HER3-DXd: 73%, PBC: 57%.

Mainly due to the higher incidence of grade 3 or higher thrombocytopenia with HER3-DXd (30% vs 7.9%)

Each group had one case of grade 3 or higher bleeding event associated with grade 3 thrombocytopenia.

In the HER3-DXd group, 14 patients (5%) developed interstitial lung disease (ILD) assessed as drug-related, including: 11 cases of grade 1/2, 1 case of grade 3, and 2 cases of grade 5 (fatal).

Those who have worked on ADCs probably have a general understanding that HER3 is not an exceptionally highly expressed target. However, it must be acknowledged that the efficacy of ADCs relies to some extent on the level of antigen expression. As is well known, HER2 is highly expressed in HER2-positive breast cancer, and few targets can currently match it, which is why it performs so remarkably in clinical settings. The benefits of HER3-DXd on OS still await further data disclosure in the later stages.

On September 17, 2024, Daiichi Sankyo and MSD announced HER3-DXd ( patritumab deruxtecan ) HERTHENA-Lung02 Phase III Clinical Data.

Patritumab deruxtecan In patients with EGFR-mutated non-small cell lung cancer, a statistically significant improvement in progression-free survival was observed. These patients had received prior EGFR TKI treatment but their treatment needs remained unmet.

HERTHENA-Lung02 Phase III Clinical Trial EvaluatedPatritumab deruxtecanEfficacy in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who have received EGFR TKI treatment.The trial met the primary endpoint of progression-free survival (PFS), showing a statistically significant improvement compared to platinum plus pemetrexed induction chemotherapy and pemetrexed maintenance chemotherapy.Overall Survival (OS) data are not yet mature, and the trial will continue to further evaluate the secondary endpoint OS.

Non-small cell lung cancer accounts for approximately 85% of all lung cancer cases globally, with up to 70% of cases diagnosed at an advanced stage. EGFR-activating mutations occur in 14% to 38% of non-small cell lung cancer tumors worldwide. After initial treatment for metastatic NSCLC with EGFR mutations, many patients experience disease progression, and currently available second-line treatments are very limited.

The safety profile in the HERTHENA-Lung02 trial was consistent with what was previously observed in lung cancer clinical trials.Patritumab deruxtecanConsistent, no new safety signals were identified. Most interstitial lung disease (ILD) events were low-grade (Grade 1 and Grade 2). Two Grade 5 ILD events were observed.

HERTHENA-Lung02 is a global, multi-center, open-label Phase 3 trial evaluating the efficacy and safety of patritumab deruxtecan (5.6 mg/kg every three weeks) in combination with four cycles of pemetrexed and platinum-based chemotherapy in patients with metastatic or locally advanced NSCLC harboring EGFR-activating mutations (exon 19 deletions or L858R). These patients were enrolled after failing third-generation EGFR TKI treatments such as osimertinib, lazertinib, etc.

ADCs show a relatively significant PFS benefit, but whether they provide an OS benefit is gradually becoming an unresolved question. The perspective on ADCs is also maturing, as单纯的 ORR and PFS are no longer sufficient to prove OS benefits. Perhaps in the future, further verification will be needed to determine whether combining ADCs with PD-1 inhibitors as first-line treatment can surpass the effects of PD-1 inhibitors combined with chemotherapy. If the benefits are minimal, it may still impact the market promotion of ADCs. Currently, single-agent ADCs remain primarily used for later-line treatments, and moving towards front-line treatment will require combination therapy.

Nowadays, Daiichi Sankyo and MSD have only released preliminary PFS benefits, and the OS benefits are not yet mature, meaning that there is still a way to go before HER3-DXd can be fully accepted and recognized.

However, based on the Phase II HERTHENA-Lung01 study data, on December 22, 2023, Daiichi Sankyo and MSD jointly announced that the Biologics License Application (BLA) for HER3-DXd (patritumab deruxtecan) had been accepted by the FDA for priority review. The indication is for locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations that has previously received at least two systemic therapies.

But unfortunately, in July 2024, the marketing application for HER3-DXd (patritumab deruxtecan), an antibody-drug conjugate (ADC) targeting HER3 developed by Daiichi Sankyo/MSD,Delayed Approval by FDA, Its indications are for the treatment of patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) who have previously received at least two systemic therapies. It is reported that,The reason for the delay was mainly due to the inspection findings related to third-party manufacturing facilities., and there is no problem with its efficacy and safety data.

The failure of TROP2 DXD in non-small cell lung cancer OS has cast uncertainty over the ADC track. Of course, to a certain extent, the target point remains the dominant factor.

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But if Innovent's 363 comes out again, or a more optimized drug emerges, the current deal might once again become a joke—no one can guarantee it.