Datopotamab Deruxtecan Elicits Antitumor Activity in Pretreated NSCLC With Actionable Genomic Alterations

Luis Paz-Ares, MD, PhD

Datopotamab deruxtecan (Dato-DXd; DS-1062a) elicited encouraging responses in patients with heavily pretreated non–small cell lung cancer (NSCLC) harboring actionable genomic alterations, according to findings from the phase 2 TROPION-Lung05 trial (NCT04484142) presented at the 2023 ESMO Congress.¹

The Trop2-directed antibody-drug conjugate (ADC) elicited a confirmed objective response rate (cORR) of 35.8% (95% CI, 27.8%-44.4%) in all treated patients (n = 137), with 3% of patients achieving a complete response and 33% experiencing a partial response. The median duration of response (DOR) of 7.0 months (95% CI, 4.2-9.8). The confirmed disease control rate (DCR) was 78.8% (95% CI, 71.0%-85.3%), and the median progression-free survival (PFS) was 5.4 months (95% CI, 4.7-7.0).

In the subset of patients harboring EGFR mutations (n = 78), the cORR was slightly higher, at 43.6% (95% CI, 32.4%-55.3%). The median DOR in this group was also 7.0 months (95% CI, 4.2-10.2), and the confirmed DCR was 82.1% (95% CI, 71.7%-89.8%). The median PFS was also slightly higher, at 5.8 months (95% CI, 5.4-8.3). In those with a sensitizing or T790M mutation who had previously received osimertinib (Tagrisso; n = 68), the ORR with the ADC was 49.1%.

In the group of patients with ALK rearrangements (n = 34), the cORR was lower, at 23.5% (95% CI, 10.7%-41.2%). The median DOR was 7.0 months (95% CI, 2.8-8.4) and the confirmed DCR was 73.5% (95% CI, 55.6%-87.1%). The median PFS for this subset was 4.3 months (95% CI, 2.6-6.9). Notably, these patients were more heavily pretreated, with a median of 4 prior lines of therapy received, and they also had more liver metastases, Luis Paz-Ares, MD, PhD, of the Hospital Universitano 12 de Octubre in Madrid, Spain, said in a presentation of the data.

“[Overall,] Dato-DXd is an active ADC for heavily pretreated patients with NSCLC with genomic alterations, including EGFR mutations and ALK rearrangements,” Paz-Arez said. “The safety profile was consistent with what has previously been described, with no new signals [observed].”

Dato-DXd is comprised of a human anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload through a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. Previously, the ADC was found to have antitumor activity with a manageable toxicity profile in heavily pretreated patients with advanced NSCLC enrolled in the phase 1 TROPION-PanTumor01 trial (NCT03401385).² In the group of patients who received the ADC at 6 mg/kg every 3 weeks, the cORR was 26% (95% CI, 14.6%-40.3%), the median DOR was 10.5 months (95% CI, 5.6-26.5), the DCR rate was 70% (95% CI, 55.4%-82.1%), and the median PFS was 6.9 months (95% CI, 2.7-8.8).

The single-arm TROPION-Lung05 study enrolled patients with stage IIIB, IIIC, or IV NSCLC who had an ECOG performance status of 0 or 1 and at least 1 actionable genomic alteration, such as EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET.¹ Patients must have received at least 1 line of targeted therapy and 1 or 2 cytotoxic agent–containing regimens, including platinum-based therapy in the metastatic setting. They also needed to have experienced radiographic disease progression following targeted treatment.

Study participants were given Dato-DXd at a dose of 6 mg/kg every 3 weeks.

ORR by blinded independent central review (BICR) served as the trial’s primary end point. Secondary end points comprised DOR, DCR, clinical benefit rate, PFS, and time to response—all assessed by BICR and investigators. Other end points of interest included investigator-assessed ORR, overall survival, safety, pharmacokinetics, and immunogenicity.

In the total population (n = 137), the median patient age was 60 years (range, 29-79). More than half of patients were female (61%) and most had adenocarcinoma (95%). Fifty-one percent of patients had a history of brain metastases. The median number of prior lines of therapy received for advanced or metastatic disease was 3. All patients previously received treatment, with 72% having received at least 3 lines, 36% having received anti–PD-1/PD-L1 agents, and 60% having received at least 2 lines of targeted therapies for their indicated alteration. All patients had prior exposure to platinum-based chemotherapy.

Regarding genomic alterations, 57% had EGFR mutations, 25% had ALK rearrangements, 7% had ROS1 rearrangements, 6% had RET rearrangements, 4% had MET exon 14 skipping mutations, and 3% had BRAF mutations.

At the time of the data cutoff date of December 14, 2022, the median treatment duration with the ADC was 4 months (range, 1-21), 44% of patients were still on the study and 15% were still receiving treatment with Dato-DXd.

Treatment-emergent adverse effects (TEAEs; AEs) occurred in all patients, with 47% of AEs being grade 3 or higher. Treatment-related AEs (TRAEs) occurred in 94% of patients, with 29% experiencing TRAEs that are grade 3 or higher. Serious AEs were observed in 25% of patients with 5% being grade 3 or higher.

The most common TEAEs experienced by at least 15% of patients included nausea (grade 1, 35%; grade 2, 23%; grade ≥3, 2%), stomatitis (29%; 20%; 10%), alopecia (36%; 16%; 0%), constipation (23%; 9%; 0%), reduced appetite (12%; 12%; 4%), fatigue (12%; 10%; 4%), vomiting (14%; 8%; 1%), anemia (4%; 5%; 6%), asthenia (7%; 7%; 2%), COVID-19 (10%; 5%; 1%), rash (12%; 4%; 0%), and cough (10%; 4%; 0%).

TEAEs led to dose reduction, treatment withdrawal, or death for 22%, 10%, and 2% of patients, respectively.

AEs of special interest included oral mucositis (66%), ocular surface toxicity (26%), infusion-related reaction (16%), and adjudicated drug-related interstitial lung disease (4%).

In the ongoing phase 3 TROPION-Lung01 study (NCT04656652), investigators are evaluating the safety and efficacy of Dato-DXd compared with docetaxel in patients with pretreated advanced or metastatic NSCLC, including those harboring genomic alterations.³

Data from this trial were also presented at the 2023 ESMO Congress and showed that Dato-DXd resulted in a median PFS of 4.4 months vs 3.7 months with docetaxel (HR, 0.75; 95% CI, 0.62-0.91; P = .004). In the investigative and control arms, the ORRs were 26.4% (95% CI, 21.5%-31.8%) and 12.8% (95% CI, 9.3%-17.1%), respectively. The median DORs were 7.1 months (95% CI, 5.6-10.9) and 5.6 months (95% CI, 5.4-8.1), respectively.⁴

References

1. Paz-Ares L, Ahn M-J, Lisberg AE, et al. 1314MO TROPION-Lung05: datopotamab deruxtecan (Dato-DXd) in previously treated non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGAs). Ann Oncol. 2023;34(suppl 2):S755-S756. doi:10.1016/j.annonc.2023.09.2348
2. Shimizu T, Sands J, Yoh K, et al. First-in-human, phase I dose-escalation and dose-expansion study of Trophoblast cell-surface antigen 2-directed antibody-drug conjugate datopotamab deruxtecan in non-small-cell lung cancer: TROPION-Pantumor01. J Clin Oncol. 2023;41(29):4678-4687. doi:10.1200/JCO.23.00059
3. Study of DS-1062a versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer with or without actionable genomic alterations (TROPION-Lung01). ClinicalTrials.gov. Updated October 12, 2023. Accessed October 25, 2023. https://clinicaltrials.gov/study/NCT04656652
4. 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