Dato-DXd Significantly Improves PFS in Select Subsets of Advanced/Metastatic NSCLC

The Trop-2 directed antibody drug conjugate datopotamab deruxtecan (Dato-DXd; DS-1062a) demonstrated a statistically significant improvement in progression-free survival (PFS) vs docetaxel in patients with advanced or metastatic non–small cell lung cancer (NSCLC); however those with squamous histology did not experience a benefit, according to data from the phase 3 TROPION-Lung01 study (NCT04656652) presented by Aaron Lisberg, MD, at the 2023 ESMO Congress.

Patients in the intention-to-treat (ITT) population who received Dato-DXd (n = 299) achieved a median PFS of 4.4 months (95% CI, 4.2-5.6) vs 3.7 months in the docetaxel arm (n = 305), demonstrating a statistically significant improvement in PFS (HR, 0.75; 95% CI, 0.62-0.91; P = .004). The objective response rate (ORR) was 26.4% (95% CI, 21.5%-31.8%) in the Dato-DXd arm vs 12.8% in the docetaxel arm (95% CI, 9.3%-17.1%), with median durations of response (DORs) of 7.1 months (95% CI, 5.6-10.9) vs 5.6 months (95% CI, 5.4-8.1), respectively.

Data from a forest plot revealed that among key subgroups a PFS benefit with Dato-DXd vs docetaxel was experienced by almost all patients except for those with squamous histology. The most pronounced benefits were among patients who had actionable genomic alterations (HR, 0.38), non-squamous histology (HR, 0.63), and brain metastases at baseline (HR, 0.64).

Patients with non-squamous histology experienced a median PFS of 5.6 months (95% CI, 4.4-7.0) in the Dato-DXd arm (n = 229) vs 3.7 months (95% CI, 2.9-4.2) in the docetaxel arm (n = 232; HR, 0.63; 95% CI, 0.51-0.78); the ORR was 31.2% vs 12.8% and the DOR was 7.7 months vs 5.6 months, respectively. However, those with squamous histology did not experience a benefit when treated with Dato-DXd vs docetaxel; patients experienced a median PFS of 2.8 months (95% CI, 1.9-4.0) in the Dato-DXd arm (n = 70) vs 3.9 months (95% CI, 2.8-4.5) in the docetaxel arm (n = 73; HR, 1.38; 95% CI, 0.94-2.02). The ORR was 9.2% vs 12.7%, respectively, and the DOR was 5.9 months in the Dato-DXd arm vs 8.1 months in the docetaxel arm.

“The question that arises is: is [this] non-squamous benefit we're seeing entirely driven by those patients with actual genomic alterations,” Lisberg, a thoracic medical oncologist at the University of California, Los Angeles (UCLA), said during the presentation. “All but 3 of those patients had non-squamous histology and a HR for PFS in favor of Dato-DXd of 0.38. The answer to that question is definitively no. Patients with non-squamous histology, both with and without actionable genomic alterations, are deriving a PFS benefit from Dato-DXd as the PFS HR for non-squamous patients without actionable genomic alterations is 0.71 [95% CI, 0.56-0.91].”

The interim overall survival (OS) analysis in the ITT population demonstrated that patients in the Dato-DXd arm experienced a median OS of 12.4 months (95% CI, 10.8-14.8) compared with 11.0 months (95% CI, 9.8-12.5) for patients in the docetaxel arm (HR, 0.90; 95% CI, 0.72-1.13). The HR for patients with non-squamous histology was 0.77 (95% CI, 0.59-1.01) and the HR for those with squamous histology was 1.32 (95% CI, 0.87-2.00). The information fraction at the interim analysis was 74% and the trial is continuing to the final OS analysis which Lisberg noted will be presented at a future meeting.

Baseline Patient Characteristics

The open-label, global study enrolled patients with stage IIIB, IIIC, or IV NSCLC who had not received prior therapy with docetaxel and had an ECOG performance status of 0 or 1. Those without actionable genomic alterations received 1 or 2 prior lines of therapy including platinum-based chemotherapy and an anti–PD-1/L1 monoclonal antibody. Patients with actionable genomic alternations were positive for EGFR, ALK, NTRK, BRAF, ROS1, MET exon 14 skipping, or RET alterations and had received 1 or 2 prior approved targeted therapies as well as platinum-based chemotherapy and up to 1 anti–PD-1/L1 monoclonal antibody.

Patients were randomly assigned 1:1 to receive Dato-DXd 6 mg/kg every 3 weeks or docetaxel 75 mg/m2every 3 weeks. Stratification occurred based on histology, presence of actionable genomic alternations, geography, and whether an anti–PD-1/L1 monoclonal antibody was included in the most recent prior therapy received. The primary end points of the trial were PFS by blinded independent central review and OS. Secondary end points included ORR, DOR, and safety.

Baseline characteristics were generally well balanced between the Dato-DXd and docetaxel arms. Patients were males (61% vs 69%); of Asian (40% vs 39%), White (41% vs 41%), Black (2% vs 1%), or other (17% vs 18%) race; and current or former smokers (80% vs 82%), respectively. In the Dato-DXd vs docetaxel arms patients had an ECOG performance status of 0 (30% vs 31%) or 1 (70% vs 69%), non-squamous histology (78% vs 77%), or brain metastases at baseline (17% vs 15%). Patients received 1 (56% vs 57%), 2 (36% vs 33%), or at least 3 (7% vs 9%) prior lines of therapy and previous systemic therapies included those that were platinum containing (99% vs 100%), anti–PD-1/L1 (88% vs 88%), and targeted (15% vs 16%), respectively.

Additionally, the median age was 63 years (range, 26-84) in the Dato-DXd arm and 64 years (range, 24-88) in the docetaxel arm. Actionable genomic alterations were present in 17% of patients in each arm—13% of patients in the Dato-DXd arm had EGFR mutations and 15% of patients in the docetaxel arm had EGFRmutations.

Length of Treatment with Dato-DXd vs Docetaxel

At the March 29, 2023, data cutoff, 18% of patients in the Dato-DXd arm remained on treatment compared with 6% of patients in the docetaxel arm. Reasons for discontinuation included adverse effects (AEs; 13% vs 16%), progressive disease (58% vs 62%), clinical progression (3% vs 4%), withdrawal or physician decision (4% vs 8%), death (3% vs 3%), or other reason (1% vs 1%).

“The number of patients ongoing on study treatment on the Dato-DXd arm is 3 times what we see on the docetaxel arm. More than half of patients treated with docetaxel were on therapy for 3 months or less. This is in contrast to the 20% of patients treated with Dato-DXd who were on therapy for 9 months or greater compared with less than 1 in 10 patients treated docetaxel on [therapy] for greater than 9 months,” Lisberg explained.

Patients received treatment for 0 to 3 months (40% vs 58%), at least 3 months to 6 months or less (25% vs 23%), at least 6 months to 9 months or less (16% vs 12%), or at least 9 months (20% vs 8%) in the Dato-DXd vs docetaxel arms, respectively.

No New Dato-DXd Safety Signals Observed

In the safety population, 87% of patients experienced any grade treatment-related AEs (TRAEs) in both the Dato-DXd (n = 297) and docetaxel (n = 290) arms with grade 3 or higher effects occuring in 25% of patients in the Dato-DXd arm and 41% of the docetaxel arm. In addition to fewer grade 3 TRAEs observed, patients in the the Dato-DXd arm also experienced fewer TRAEs leading to dose reductions or discontinuations compared with docetaxel. TRAEs were associated with dose reduction (20% vs 29%), dose delay (17% vs 11%), and discontinuation (8% vs 12%), respectively.

Additionally, 3 patients in the Dato-DXd arm and 2 patients in the docetaxel arm died due to TRAEs. Serious TRAEs occurred in 10% of the Dato-DXd arm and 12% of the docetaxel arm with grade 3 effects occuring in 8% and 11% of patients, respectively. The median treatment durations were 4.2 months and 2.8 months respectively.

No new safety signals were observed with Dato-DXd and the most common any grade TRAEs on the study were stomatitis (47% vs 16%), nausea (34% vs 17%), alopecia (32% vs 35%), neutropenia (4% vs 26%), decreased appetite (23% vs 16%), and anemia (15% vs 20%) in the Dato-DXd vs docetaxel arms, respectively. Hematologic TRAEs occurred more frequently with docetaxel with 23% of patients experienced grade 3 or higher neutropenia in the docetaxel arm. Grade 3 or higher TRAEs reported in the Dato-DXd arm included stomatitis (6%), anemia (4%), asthenia (3%), and nausea (2%) among others.

AEs of special interest in the Dato-DXd arm included dry eye occuring in 6.1% of patients primarily at grades 1 and 2 with increased lacrimation (5.4%) an ocular effect of interest as well; stomatitis which resulted in a low rate of discontinuation, 0.7%, was also of interest. Adjudicated drug-related interstitial lung disease (ILD) resulted in 7 deaths on the trial and 4 of the deaths were primarily attributed to disease progression by the investigator; the ILD AEs occurred in 4 patients with non- squamous disease and 3 patients with squamous.

Further, infusion-related reactions occurred in 8% of patients in each arm.

“Dato-DXd is the first antibody drug conjugate to demonstrate a statistically significant improvement in PFS over docetaxel in patients with previously treated locally advanced or metastatic NSCLC,” Lisberg concluded. “The data makes it very clear that the PFS benefit we have observed was primarily driven by patients with non-squamous histology both with and without actionable genomic alterations, and patients with squamous cell lung cancer did not derive the same benefit. Grade 3 or higher ILD was observed, which highlights the need for careful monitoring and adherence to ILD management guidelines.”

Reference

Ahn MJ, Lisberg A, Paz-Ares L, et al. Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase 3 study TROPION-Lung01. Ann Oncol. 2023;34(suppl 2):S1305-S1306. doi:10.1016/j.annonc.2023.10.061