In this JCO Article Insights episode, Ece Cali summarizes findings from the JCO article, "Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study."

TRANSCRIPT

Ece Cali: Hello and welcome to the JCO Article Insights. I'm your host Ece Cali and today we will be discussing the Journal of Clinical Oncology article the "Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study."

Despite significant advances in non-small cell lung cancer treatment over the past decades, second line treatment options for non-small cell lung cancer without actionable genomic alterations have remained largely unchanged since 2000. Many clinical trials failed to demonstrate improved overall survival compared to docetaxel based regimens. TROPION-Lung01 is a global open label randomized phase 3 trial comparing the efficacy and safety of Dato-DXd to docetaxel in patients with previously treated advanced or metastatic non-small cell lung cancer. Dato-DXd is an antibody drug conjugate targeting TROP2 and delivering deruxtecan, a DNA topoisomerase 1 inhibitor, as its payload. The trial is designed with dual primary endpoints of progression free survival, as assessed by blinded independent central review, and overall survival. The initial PFS results were presented at ESMO in 2023 and this article reports more detailed data and overall survival analysis of the trial.

In the TROPION-Lung01, 299 patients were randomly assigned to receive Dato-DXd and 305 patients to receive docetaxel. Patients were stratified by the presence of actionable genomic alterations, histology, treatment with PD-1/PD-L1 immunotherapy as the last line of therapy, and geographical region. The baseline characteristics of the patient population were overall balanced between the treatment arms. I'd like to highlight a couple of key points here. The median age was 63 years in the Dato-DXd and 64 years in the docetaxel arm. Similar to the many clinical trials in the thoracic oncology field, this is younger than the median age of lung cancer diagnosis in the US, which is around 70. African American and Hispanic patients were underrepresented in this trial with 41% of patients identifying themselves as white and 39% as Asian. The D\docetaxel arm had a slightly higher percentage of male patients, 69% versus 61%. The majority of the trial population, 73%, had adenocarcinoma. Patients with actionable genomic alterations were included in this trial if they received one or more targeted therapy and platinum based chemotherapy prior to the enrollment. 17% of the trial population had an actionable genomic alteration in this trial.

When it comes to the efficacy results in the full analysis set, the PFS improvement was statistically significant. The median PFS was reported as 4.4 months for the Dato-DXd, and 3.7 months for the docetaxel arm with the hazard ratio of 0.75 and a P value of 0.004. However, after a median follow up of 23 months, the trial did not meet its primary endpoint of overall survival. The median overall survival was 12.9 months for patients treated with Dato-DXd and 11.8 months for patients treated with docetaxel with the hazard ratio of 0.94 and a P value of 0.53. Objective response was a secondary endpoint and the confirmed objective response rate was 26% with Dato-DXd, and 13% with docetaxel.

Now let's take a closer look at some of the subgroup analyses. Exploratory analyses of key subgroups in TROPION-Lung01 demonstrated differences in efficacy based on histology. In the nonsquamous subgroup, Dato-DXd showed a longer progression free survival of 5.5 months compared to 3.6 months with docetaxel with a hazard ratio of 0.84. However, in the squamous subgroup, Dato-DXd performed worse with a progression free survival of 2.8 months compared to 3.9 months with docetaxel corresponding to a hazard ratio of 1.32. A similar trend was observed in the overall survival analyses, though confidence intervals crossed 1 in both histology subsets, in this case, the differences observed were not statistically significant. In the nonsquamous subset, the median overall survival was 14.6 months with Dato-DXd and 12.3 months with docetaxel with a hazard ratio of 0.84. In the squamous subset, both arms had shorter survival compared to the nonsquamous subset. The median overall survival with Dato-DXd was almost two months shorter, so 7.6 months, compared to 9.6 months with docetaxel corresponding to a hazard ratio of 1.32. While these analyses suggest the potential survival benefit for Dato-DXd in nonsquamous subset, this trial was not powered to test this hypothesis hence these analyses remain exploratory. Another subgroup analysis of note was the group with actionable genomic alterations. Patients with actionable genomic alterations achieved a median PFS of 5.7 months with Dato-DXD and 2.6 months with docetaxel corresponding to a hazard ratio of 0.35. Similarly, the median overall survival was longer in patients with actionable genomic alterations by almost six months, with a median overall survival of 15.6 months with Dato-DXd and 9.8 months with docetaxel corresponding to a hazard ratio of 0.65.

Now, let's talk about safety. Grade 3 or higher treatment related adverse events occurred in 26% of patients with Dato-DXd and 42% with docetaxel. The most common adverse event of any grade seen in the Dato-DXd arm were stomatitis seen in 47% of patients, nausea in 34%, and alopecia in 32%. Treatment related interstitial lung disease occurred in 8.8% of patients on Dato-DXd and 4.1% of patients on docetaxel. Of note, grade 5 drug related ILD was more frequent with Dato-DXd. Seven patients on Dato-DXd and one patient on docetaxel died secondary to drug related ILD in this trial.

In summary, TROPION-Lung01 aims to address an unmet need for patients with previously treated non-small cell lung cancer. For this population, the treatment options remain limited with poor survival outcomes. TROPION-Lung01 is a positive trial by design due to clinically modest improvement in PFS. However, the lack of overall survival improvement is disappointing. Exploratory subgroup analyses suggest Dato-DXd may offer survival advantage in specific subsets such as nonsquamous non-small cell lung cancer and patients with actionable genomic alterations. However, these findings require further validation in a prospective trial since TROPION-Lung01 was not designed to address these questions. The data from this trial alone is not sufficient to argue for a change in clinical practice. However, it informs how the future trials using this drug should be tailored. This highlights the importance of studying potential predictive biomarkers earlier in the drug development and incorporating these biomarkers prospectively into the clinical trial designs.

Due to the lack of overall survival benefit in this trial, the biologic license application for accelerated approval of Dato-DXd for patients with previously treated nonsquamous non-small cell lung cancer was voluntarily withdrawn. New BLA was submitted for Dato-DXd for patients with previously treated advanced EGFR positive non-small cell lung cancer. This BLA is based on data from TROPION-Lung05, TROPION-Lung01 and TROPION-PanTumor01. Of note, the results of TROPION-Lung05 trial have been just published in JCO.

This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

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