Datopotamab Deruxtecan/Pembrolizumab With or Without Chemotherapy Elicits Responses in Advanced NSCLC

The combination of the antibody-drug conjugate (ADC) datopotamab deruxtecan (DS-1062a) and pembrolizumab (Keytruda), with or without platinum-based chemotherapy, displayed promising efficacy and a manageable safety profile in patients with advanced/metastatic non–small cell lung cancer (NSCLC) without actionable genomic alterations, according to initial results from the phase 1b TROPION-Lung02 trial (NCT04526691).¹

The data, presented at the 2022 World Conference on Lung Cancer, showed that patients who received the combination of datopotamab deruxtecan, pembrolizumab, and chemotherapy (the triplet) as a first-line therapy (n = 20) achieved an overall response rate (ORR) of 50%, including a confirmed partial response (PR) rate of 35% and a pending PR rate of 15%. Additionally, 40% of patients had stable disease, and the disease-control rate (DCR) was 90%.

Patients administered datopotamab deruxtecan plus pembrolizumab without chemotherapy (the doublet) as a first-line therapy (n = 13) experienced an ORR of 62%, with all 8 responders achieving a confirmed PR. Furthermore, 39% of patients had stable disease, and the DCR was 100%.

As a second-line therapy, the doublet and triplet produced ORRs of 24% and 29%, respectively. In all patients who received the doublet, the ORR was 37%, and all patients given the triplet had an ORR of 41%. The overall DCR for both regimens was 84%.

Lead study author Benjamin Levy, MD, a thoracic medical oncologist and the clinical director of Medical Oncology for the Johns Hopkins Sidney Kimmel Cancer Center, noted that responses were observed irrespective of PD-L1 status.

“Not surprisingly, we saw ORRs for the doublet and triplet that were a little bit less [in the second line]. That’s still meaningful,” Levy said in an interview with OncLive^®. “Second-line docetaxel elicits a response anywhere from 15%-20%, so [datopotamab deruxtecan–based combinations] may be a viable option in the second line, too.”

Datopotamab deruxtecan consists of a TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload by a tetrapeptide-based cleavable linker. The ADC is being evaluated in the TROPION-Lung02 trial at 2 different dose levels in the doublet and the triplet regimens.

The trial is enrolling patients with advanced/metastatic NSCLC. In the dose-confirmation portion of the study, patients were required to have received no more than 2 lines of prior therapy. For the dose-expansion portion, no more than 1 prior line of therapy was permitted in cohorts 1 and 2, and cohorts 3-6 consisted of previously untreated patients.

Patients in cohorts 1 and 2 received doublet therapy. Cohort 1 (n = 20) were givenreceived 4 mg/kg of intravenous (IV) datopotamab deruxtecan plus 200 mg of IV pembrolizumab every 3 weeks. Cohort 2 (n = 20) received 6 mg/kg of IV datopotamab deruxtecan plus the same dose of pembrolizumab every 3 weeks.

Patients in cohorts 3-6 all received triplet therapy. Cohort 3 (n = 17) received 4 mg/kg of IV datopotamab deruxtecan, 200 mg of IV pembrolizumab, and IV carboplatin at an area under the curve of 5 (AUC 5) every 3 weeks, and cohort 4 (n = 20) was given 6 mg/kg of IV datopotamab deruxtecan, 200 mg of IV pembrolizumab, and IV carboplatin at AUC 5 every 3 weeks. Cohort 5 (n = 7) was administered 4 mg/kg of IV datopotamab deruxtecan, 200 mg of IV pembrolizumab, and 75 mg/m2 of IV cisplatin every 3 weeks, and cohort 6 (n = 4) received 6 mg/kg of IV datopotamab deruxtecan, 200 mg of IV pembrolizumab, and 75 mg/m2 of IV cisplatin every 3 weeks.

The primary end point of the study is safety and tolerability. Secondary end points consist of efficacy, pharmacokinetics, and anti-drug antibodies.

Among all patients treated with the doublet (n = 40), the median age was 68 years (range, 44-77), 70% were male, 70% had nonsquamous NSCLC, and 20% had a history of brain metastases. PD-L1 status was well balanced at less than 1% (33%), 1%-49% (33%), and at least 50% (30%). The median prior number of prior lines of therapy for advanced/metastatic disease was 1, and prior systemic therapies included immunotherapy (30%) and platinum-based chemotherapy (60%). Notably, 680% of patients received the doublet in the second line or later.

In all patients given the triplet (n = 48), the median age was 64 years (range, 33-84), 69% were male, 85% had nonsquamous NSCLC, and 21% had a history of brain metastases. PD-L1 status included less than 1% (44%), 1%-49% (29%), and at least 50% (23%). The median number of prior lines of therapy was 0, although 38% and 35% of patients had received prior immunotherapy and platinum-based chemotherapy, respectively. Sixty-three percent of patients received the triplet as first-line therapy.

At the time of data cutoff, treatment was ongoing for 53% and 77% of patients receiving the doublet and triplet regimens, respectively. The median treatment durations were 4.1 months and 3.0 months, respectively, and the median follow-up was 6.5 months and 4.4 months, respectively.

Regarding safety, treatment-emergent adverse effects (TEAEs) occurred in 93% of patients given the doublet (83% deemed treatment related) and 98% in patients administered the triplet (96% deemed treatment related). Grade 3 or higher TEAEs were reported in 40% and 60% of patients for who received the doublet and triplet regiments, respectively, and the rates of study treatment–related TEAEs were 35% and 54%, respectively. Serious TEAEs occurred in 23% and 27% of patients in the doublet and triplet arms, respectively, including study treatment–related serious TEAEs in 10% and 15%, respectively.

The most common any-grade TEAEs included nausea (41% and 48% in the doublet and triplet arms, respectively), stomatitis (56% and 29%), decreased appetite (28% and 38%), fatigue (25% and 37%), anemia (16% and 37%), constipation (23% and 21%), alopecia (23% and 19%), vomiting (15% and 25%), rash (23% and 13%), decreased platelet count (3% and 30%), decreased neutrophil count (3% and 28%), and diarrhea (18% and 15%).

The most common grade 3 or higher TEAEs in patients who received the doublet were stomatitis (8%) and fatigue (5%). The most common grade 3 or higher TEAEs for patients given the triplet were decreased platelet count (13%) and decreased neutrophil count (13%).

Instances of grade 1/2 interstitial lung disease (ILD) were reported in 5% of patients given the doublet and 0 who received the triplet. Grade 3 ILD was reported in 1 patient each who was administered the doublet and triplet.

TEAEs associated with death occurred in 2 patients who received the doublet and 1 patient given the triplet. Additionally, treatment discontinuation due to any drug occurred in 22% and 19% in the doublet and triplet arms, respectively. Treatment discontinuation due to datopotamab deruxtecan was reported in 15% and 10% of patients, respectively.

The TROPION-Lung02 trial is ongoing, and additional analyses with more patients are planned. Datopotamab deruxtecan will also be investigated in the phase 3 TROPION-Lung08 trial (NCT05215340), where the doublet will be compared with pembrolizumab alone as a first-line therapy for patients with advanced/metastatic NSCLC who have a PD-L1 expression of more than 50%.

“We know that in lung cancer, the further along [in treatment settings] that you explore a therapy, the less response you’re going to elicit. This may have to do with patient tolerability by the time they’ve received multiple lines of therapy. It may have to do with tumor heterogeneity,” Levy said. “It’s still meaningful to see these types of objective responses in the second and third line. We know this drug is active, and, yes, it’s more active in the first line, and there will be a lot of efforts looking at this drug either in combination with platinum-[based chemotherapy] or immunotherapy in the first line.”

Reference

1. Levy B, Paz-Ares L, Rixe O, et al. TROPION-Lung02: iInitial results from datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy in advanced NSCLC. Presented at: 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract MA13.07