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Amivantamab Patritumab deruxtecan Datopotamab deruxtecan

Amivantamab in the MARIPOSA and MARIPOSA II trials

 

Amivantamab, a first-in-class bispecific antibody, targets epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) by targeting both EGFR and mesenchymal-epithelial transition (MET) receptors, disrupting critical cancer cell signaling pathways. The Phase III MARIPOSA trial (NCT04487080) assessed amivantamab, with lazertinib, a third-generation tyrosine kinase inhibitor (TKI), in the first line setting.1 Addition of lazertinib with amivantamab is apt as lazertinib selectively targets the T790M and activating Ex19del and L858R EGFR mutations, sparing wild-type-EGFR.2

Patients were randomized to receive amivantamab with lazertinib, osimertinib, or lazertinib alone, and a progression-free survival (PFS) of 23.7 months was reported in the investigatory arm, compared to 16.6 months in the osimertinib arm (HR, 0.70; 95% CI, P<0.001). This outcome suggests that amivantamab is significantly to osimertinib alone in terms of PFS. The safety profile of the

 

combination was also consistent with known side effects, ensuring tolerability.

In addition to the MARIPOSA trial, the MARIPOSA-2 trial (NCT04988295) investigated amivantamab with chemotherapy with or without lazertinib versus chemotherapy alone. The trial met its dual primary endpoint, showing a significant improvement in PFS for the combination of amivantamab, lazertinib, and chemotherapy compared to chemotherapy alone. This underscores the potential of combining targeted therapies to enhance treatment outcomes.3

The MARIPOSA and MARIPOSA II trials represent a significant leap forward in EGFR-mutated NSCLC treatment. Amivantamab’s innovative bispecific targeting strategy, coupled with the inclusion of lazertinib, showcases the potential of combining multiple targeted therapies to overcome resistance, and cements the role of bispecific antibodies in the current armamentarium.

Patritumab deruxtecan in the HERTHENA-Lung01 trial

 

Antibody-drug conjugates (ADCs) have also emerged as a promising class of targeted therapies by combining the specificity of monoclonal antibodies with the potency of cytotoxic drugs, which enables targeted treatment delivered directly to cancer cells while minimizing damage to healthy tissue.4 In recent years, ADCs have shown considerable potential in improving outcomes for patients with various types of lung cancer, with traztuzumab deruxtecan being the first approved by the US FDA in August 2022 for human epidermal growth factor receptor 2 (HER2)-mutant NSCLC.5

HER3 has shown to be a promising target in EGFR-mutant lung cancer, where a vast majority express HER3. Among the latest contenders in this space is patritumab deruxtecan, a first-in-class anti-HER3 antibody attached to a topoisomerase I inhibitor payload, which was evaluated in the Phase II HERTHENA-Lung01 trial (NCT04619004).6 The trial aimed to assess the efficacy and safety of the HER3-directed ADC in patients with advanced or metastatic

 

EGFR-mutated NSCLC who had progressed on prior EGFR TKI therapy.

Patritumab deruxtecan was administered intravenously once every 3 weeks or in an up-titration regimen and confirmed objective response rate (ORR) was the primary endpoint. Clinically meaningful objective response rates and durable disease control were observed, where ORR was 29.8% (95% CI, 23.9 to 36.2) and median duration of response was 6.4 months. The safety profile of patritumab deruxtecan appeared manageable, with adverse events consistent with those expected for ADCs.

The findings from the HERTHENA-Lung-01 trial provide encouraging insights into the potential role of patritumab deruxtecan in EGFR-mutated NSCLC. As a novel ADC targeting HER3, patritumab deruxtecan offers a promising therapeutic option for patients who have progressed on EGFR TKIs, addressing an unmet need in this patient population.

Datopotamab deruxtecan evaluated in the TROPION-Lung01 trial

 

Another potential target that is found to be overexpressed in EGFR-mutant NSCLC is trophoblast cell surface antigen (Trop2), a cell surface glycoprotein.7 By targeting Trop2, researchers aim to disrupt cancer cell proliferation and survival pathways, potentially offering a new avenue for treating EGFR-mutant NSCLC. Datopotamab deruxtecan is one such Trop2-directed ADC that has been assessed in multiple clinical trials.

The Phase III TROPION-Lung01 trial (NCT04656652) compared datopotamab deruxtecan with docetaxel in patients with pretreated, locally advanced or metastatic non-squamous NSCLC. Patients were randomized to receive either the ADC or docetaxel, and dual primary endpoints were PFS and overall survival (OS), with ORR, duration of response (DOR), and safety being the secondary endpoints.8

The primary endpoint was met, where median PFS was 4.4 months (95% CI, 4.2-5.6) and 3.7 months (95% CI, 2.9-4.2) in

 

the datopotamab deruxtecan and docetaxel arms respectively. Interim data for the co-primary endpoint of OS were 12.4 months with datopotamab deruxtecan and 11.0 months for docetaxel (HR 0.90; 95% CI 0.72–1.13), suggesting that the ADC did not confer a statistically significant OS advantage. Fewer grade 3 or above adverse events, which led to dose reduction or discontinuation, were additionally reported in patients receiving datopotamab deruxtecan.

Whilst second and third generation TKIs such as osimertinib have made a demonstrable impact on the treatment landscape of EGFR-mutant lung cancer, especially in the front-line setting, treatment options are sorely needed for when TKI therapy has been exhausted. Immunotherapies such as bispecific antibodies and ADCs have shown very promising results in this setting, and ongoing studies evaluating the optimal sequencing and combination strategies will elucidate their role in the clinic.

References

  1. Cho BC, Felip E, Spira AI, Girard N, Js L, Sh L, et al. LBA14 Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Annals of Oncology. 2023 Oct 1;34:S1306–6
  2. Hayashi H, Nadal E, Gray JE, Ardizzoni A, Caria N, Puri T, et al. Overall Treatment Strategy for Patients With Metastatic NSCLC With Activating EGFR Mutations. Clinical Lung Cancer. 2021 Oct
  3. Passaro A, Wang J, Wang Y, Lee SH, Melosky B, Shih J, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Primary results from the phase 3 MARIPOSA-2 study. Annals of Oncology. 2023 Oct 1
  4. Coleman N, Yap TA, Heymach JV, Meric-Bernstam F, Le X. Antibody-drug conjugates in lung cancer: dawn of a new era? npj Precision Oncology. 2023 Jan 11;7(1)
  5. Research C for DE and. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA [Internet]. 2022 Aug 16; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung
  6. Yu HA, Goto Y, Hayashi H, Felip E, James Chih‐Hsin Yang, Reck M, 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. Journal of Clinical Oncology. 2023 Sep 10
  7. Parisi Claudia, Linda M, Anas G, Barlesi Fabrice. TROP-2 directed antibody-drug conjugates (ADCs): The revolution of smart drug delivery in advanced non-small cell lung cancer (NSCLC). Cancer Treatment Reviews. 2023 Jul 1;118:102572–2
  8. Ahn M-J, A.E. Lisberg, L. Paz-Ares, Cornelissen R, Girard N, E. Pons-Tostivint, et al. 509MO Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): Results of the randomized phase III study TROPION-Lung01. Annals of Oncology. 2023 Nov 1;34:S1665–6

Written by Simon Ng

The content of VJOncology is intended for healthcare professionals