Datopotamab Deruxtecan Plus Pembrolizumab Displays Efficacy in Advanced NSCLC With or Without Chemotherapy

Treatment with datopotamab deruxtecan (Dato-DXd; formerly DS-1062) plus pembrolizumab (Keytruda) with or without platinum-based chemotherapy demonstrated activity with a tolerable safety profile in patients with advanced non–small cell lung cancer (NSCLC) according to findings from the phase 1 TROPION-Lung02 trial (NCT04526691) presented during the 2023 ASCO Annual Meeting.

At the April 7, 2023, data cutoff, findings from the study showed that patients with advanced NSCLC who received datopotamab deruxtecan plus pembrolizumab (n = 61) experienced an overall response rate (ORR) of 38% (95% CI, 26%-51%) and had a disease control rate (DCR) of 84%. Additionally, patients who had platinum-based chemotherapy added to datopotamab deruxtecan and pembrolizumab (n = 71) achieved an ORR of 49% (95% CI, 37%-61%) and a DCR of 87%. The preliminary median progression-free survival for all patients who received the doublet was 8.3 months (95% CI, 6.8-11.8) and 7.8 months (95% CI, 5.6-11.1) among those who also received chemotherapy.

Specifically in the frontline setting, the ORR for patients who received the doublet (n = 34) was 50% (95% CI, 32%-68%) and the DCR was 91%. For patients who were treated with the combination plus chemotherapy in the first-line setting (n = 53), these figures were 57% (95% CI, 42%-70%) and 91%, respectively.

The median duration of response was not yet estimable for any subgroup.

“This is a very interesting study that is pursuing the standard of care outside of immunotherapy,” Yasushi Goto, MD, PhD, said in an interview with OncLive^®. “We have been treating patients with platinum pemetrexed and paclitaxel. I hope [this can be] another option in the future.”

Datopotamab deruxtecan is a TROP2-directed IgG1 monoclonal antibody that is linked to a potent topoisomerase I inhibitor cytotoxic payload by a tumor-selective cleavable linker. The agent has previously displayed activity as a monotherapy among patients with heavily pretreated advanced or metastatic NSCLC.

In terms of safety, most patients who received either the doublet or the combination and chemotherapy experienced a treatment-emergent adverse effect (TEAE), at 97% and 100%, respectively. Moreover, grade 3 or higher TEAEs were reported in 53% and 76% of patients, respectively. Patients in both arms experienced death (5% vs 7%), dose reduction of any agent (22% vs 19%), dose reduction of datopotamab deruxtecan (22% vs 15%), discontinuation of any drug (28% vs 38%), and discontinuation of datopotamab deruxtecan (23% vs 28%).

In an interview with OncLive, Goto, of the National Cancer Center Hospital in Tokyo, Japan, delved further into the details of TROPION-Lung02, which he coauthored and presented at the 2023 ASCO Annual Meeting.

OncLive: What was the rationale for initiating TROPION-Lung02?

Goto: This is a phase 1 study evaluating the safety of the combination [of datopotamab deruxtecan plus pembrolizumab with or without chemotherapy]. Datopotamab deruxtecan has already shown efficacy NSCLC as a single agent and a phase 3 study [TROPION-Lung01] is ongoing in the second-line setting comparing it with single-agent docetaxel.

[TROPION-Lung02] is going beyond that by [adding] pembrolizumab, which is an immune checkpoint inhibitor. There are some data [indicating] that the combination of datopotamab deruxtecan plus pembrolizumab has the potential for more efficacy.

Can you describe the mechanism of action of datopotamab deruxtecan?

Datopotamab deruxtecan is an antibody-drug conjugate [ADC] with a TROP2 antibody and topoisomerase I inhibitor as a payload. However, we are not enriching the patients with TROP2 expression and are [instead] studying an all-comer population. Single-agent therapy has some potential, but an ADC [is both] both targeting and [delivering a kind] of a chemotherapy. So, there is not only one mechanism for the efficacy in the treatment of cancer.

What were some of the key findings from TROPION-Lung02 that you highlighted during your ASCO presentation?

We evaluated safety for 2 doses of datopotamab deruxtecan: 4 mg/kg and 6 mg/kg. We first evaluated [the ADC] with the pembrolizumab as a doublet, and then we went into the triplet which added cisplatin or carboplatin. [The trial includes] 6 cohorts.

The data are immature to show the survival [results]. But the response rates were quite high, [at] approximately 60% and the DCR was more than 90% in some patients in the first-line setting. This is a phase 1 study with lots of cohorts and patients [of various] backgrounds, including a variety of PD-L1 expressions. We can’t make any conclusions right now; however, the preliminary results in terms of the response rate are quite exciting.

Are there any safety concerns when using datopotamab deruxtecan?

With datopotamab deruxtecan in combination with pembrolizumab and a platinum treatment, we can see the AEs, which we usually see with each agent. [For example], immune-related AEs from the pembrolizumab and hematologic toxicity from the cytotoxic chemotherapy.

[Specifically], mucositis is one of the characteristics of datopotamab deruxtecan. We also observed interstitial lung disease, which may be attributed to the datopotamab deruxtecan, but maybe not because we are adding pembrolizumab, too.

[Overall], there are no new safety signals. We managed AEs well. We learned during the study that mucositis should be [managed with] prophylaxis mainly, but in general we can manage the toxicity and then we can move on to the first-line setting.

What are the potential future implications of TROPION-Lung02?

[The combination] is now being evaluated in the second line vs docetaxel [alone]. Since this drug is still kind of a chemotherapy, we would like to replace the docetaxel in the second line at first, hopefully. Then we will try to go on to the first line.

It is very interesting that there are very few studies to try to show more efficacy compared with the standard of care outside of the immunotherapy recently. This is a new challenge we are now facing in the lung cancer. I hope we will come out with a new treatment in NSCLC, which is still has a lot of unmet needs.

Reference

Goto Y, Su WC, Levy BP, et al. TROPION-Lung02: datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) in advanced non-small cell lung cancer (aNSCLC). J Clin Oncol. 2023;41(suppl 16):9004. doi:10.1200/JCO.2023.41.16_suppl.9004